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What changed in PTC THERAPEUTICS, INC.'s 10-K — 2024 vs 2025

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Paragraph-level year-over-year comparison of PTC THERAPEUTICS, INC.'s 2024 and 2025 10-K annual filings, covering the Business, Risk Factors, Legal Proceedings, Cybersecurity, MD&A and Market Risk sections. Every new, removed and edited paragraph is highlighted side-by-side so you can see exactly what management changed in the 2025 report.

+866 added−1034 removedSource: 10-K (2026-02-19) vs 10-K (2025-02-27)

Top changes in PTC THERAPEUTICS, INC.'s 2025 10-K

866 paragraphs added · 1034 removed · 655 edited across 8 sections

Item 1. Business

Business — how the company describes what it does

270 edited+83 added−208 removed403 unchanged
Biggest changeIn addition to the upfront consideration paid to the Censa securityholders upon the closing of the Censa Merger, p ursuant to the Censa Merger Agreement, Censa securityholders will be entitled to receive contingent payments from us based on (i) the achievement of certain development and regulatory milestones up to an aggregate maximum amount of $217.5 million for sepiapterin’s two most advanced programs and receipt of a priority review voucher from the FDA as set forth in the Censa Merger Agreement, (ii) $109 million in development and regulatory milestones for each additional indication of sepiapterin, (iii) the achievement of certain net sales milestones up to an aggregate maximum amount of $160.0 million, (iv) a percentage of annual net sales during specified terms, ranging from single to low double digits of the applicable net sales threshold amount, and (v) any sublicense fees paid to us in consideration of any sublicense of Censa’s intellectual property to commercialize sepiapterin, on a country-by-country basis, which contingent payment will equal to a mid-double digit percentage of any such sublicense fees.
Biggest changeIn addition to the upfront consideration paid to the Censa securityholders upon the closing of the Censa Merger, p ursuant to the Censa Merger Agreement, Censa securityholders will be entitled to receive contingent payments from us based on (i) the achievement of certain development and regulatory milestones up to an aggregate maximum amount of $217.5 million for sepiapterin’s two most advanced programs and receipt of a priority review voucher from the FDA as set forth in the Censa Merger Agreement, (ii) $109 million in development and regulatory milestones for each additional indication of sepiapterin, (iii) the achievement of certain net sales milestones up to an aggregate maximum amount of $160.0 million, including payments of $30.0 million for the first occurrence of a four consecutive calendar quarter period in which aggregate Net Sales of Product (as defined below) exceed $250.0 million, $50.0 million for the first occurrence of a four consecutive calendar quarter period in which aggregate Net Sales of Product exceed $500.0 million, and $80.0 million for the first occurrence of a four consecutive calendar quarter period in which aggregate Net Sales of Product exceed $1.0 billion, (iv) a percentage of annual net sales during specified terms, equal to (a) 8% of annual Net Sales of Product for that portion of annual Net Sales of Product less than or equal to $250.0 million, (b) 10% of annual Net Sales of Product for that portion of annual Net Sales of Product greater than $250.0 million but less than $500.0 million and (c) 12% of annual Net Sales of Product for that portion of annual Net Sales of Product greater than $500.0 million, which we collectively refer to as the Net Sales Payments, and (v) any sublicense fees paid to us in consideration of any sublicense of Censa’s intellectual property to commercialize sepiapterin, on a country-by-country basis, which contingent payment will equal to a mid-double digit percentage of any such sublicense fees.
In October 2024, we announced that the pre-specified endpoint for two different FA long-term extension studies was met, with statistically significant evidence of durable treatment benefit on disease progression. In December 2024, we submitted an NDA to the FDA for vatiquinone for the treatment of children and adults living with FA.
In October 2024, we announced that the pre-specified endpoint for two different FA long-term extension studies was met, with statistically significant evidence of durable treatment benefit on disease progression. In December 2024, we submitted an NDA to the FDA for vatiquinone for the treatment of children and adults living with FA.
Manufacturing We do not currently own or operate functional manufacturing or distribution facilities for the production of clinical or commercial quantities of our products or product candidates or compounds that we are testing in our preclinical programs.
Manufacturing We do not currently own or operate functional manufacturing or distribution facilities for the production of clinical or commercial quantities of our products or product candidates or compounds that we are testing in our preclinical or clinical programs.
A violation of the federal Anti-Kickback Statute is a per se violation of civil False Claims Act. Potential liability under the federal civil False Claims Act includes treble damages and significant per claim penalties.
A violation of the federal Anti-Kickback Statute is a per se violation of the civil False Claims Act. Potential liability under the federal civil False Claims Act includes treble damages and significant per claim penalties.
Currently, no treatment options are available for the underlying cause of the disorder, and care is limited to palliative options with significant burden on caregivers. The prevalence of AADC deficiency has been estimated to be approximately 5,000 patients worldwide, with a live-birth incidence of up to 1 in 40,000 worldwide.
Currently, no other treatment options are available for the underlying cause of the disorder, and care is limited to palliative options with significant burden on caregivers. The prevalence of AADC deficiency has been estimated to be approximately 5,000 patients worldwide, with a live-birth incidence of up to 1 in 40,000 worldwide.
The last issued U.S. patent relating to composition of matter is currently scheduled to expire in September of 2038. Our patent rights include granted patents or pending counterpart patent applications in a number of other jurisdictions, including Canada, certain South American countries, Europe, certain Middle Eastern countries, certain African countries, certain Asian countries and certain Eurasian countries.
The last issued U.S. patent relating to composition of matter is currently scheduled to expire in September of 2038. Our patent rights include granted patents or pending counterpart patent applications in a number of other jurisdictions, including certain South American countries, Europe, certain Middle Eastern countries, certain African countries, certain Asian countries and certain Eurasian countries.
There are also other requirements for lawful processing, including transparency obligations, data minimization requirements, data transfer restrictions and compliance obligations with individuals’ stringent rights to access their personal data and to otherwise control the processing of their personal data. There are data breach notification obligations, to supervisory authorities and to individuals, where certain risk thresholds to them have occurred.
There are also other requirements for lawful processing, including transparency obligations, data minimization requirements, data transfer restrictions and compliance obligations with individuals’ stringent rights to access their personal data and to otherwise control the processing of their personal data. There are data breach notification obligations, to supervisory authorities and to individuals, where certain risk thresholds have occurred.
Regulation outside the United States In order to market any product outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of our products.
Regulation outside the United States In order to market any product outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization, manufacturing, commercial sales and distribution of our products.
Subject to any regulatory delays or issues, we are obligated to research, use and develop the Technology to manufacture Licensed Products by December 23, 2025. Additionally, we were obligated to obtain marketing approval of Upstaza for the treatment of AADC deficiency, either by the FDA or by the EMA, by December 31, 2024.
Subject to any regulatory delays or issues, we were obligated to research, use and develop the Technology to manufacture Licensed Products by December 23, 2025. Additionally, we were obligated to obtain marketing approval of Upstaza for the treatment of AADC deficiency, either by the FDA or by the EMA, by December 31, 2024.
In the EU, for a period of eight years from the grant of a marketing authorization of an innovative product (the “reference medicinal product”), competent authorities may not accept marketing authorization applications from applicants seeking to market “generic medicinal products” where such applications rely on the data in the marketing authorization dossier of the reference product.
In the EU, for a period of eight years from the notification of the grant of a marketing authorization of an innovative product (the “reference medicinal product”), competent authorities may not accept marketing authorization applications from applicants seeking to market “generic medicinal products” where such applications rely on the data in the marketing authorization dossier of the reference product.
The FDA has issued, and continues to issue, various guidance documents regarding the development and commercialization of gene therapies, which outline additional factors that the FDA will consider at each of the above stages of development and relate to, among other things: the proper preclinical and nonclinical assessment of gene therapies; the design and conduct of clinical trials, the CMC information that should be included in an IND application; the proper design of tests to measure product potency in support of an IND or BLA application; and long term patient and clinical study subject follow up and regulatory reporting.
The FDA has issued, and continues to issue, various guidance documents regarding the development and commercialization of gene therapies, which outline additional factors that the FDA will consider at each of the above stages of development and relate to, among other things: the proper preclinical and nonclinical assessment of gene therapies; the design and conduct of clinical trials, the CMC information that should be included in an IND application; the proper design of tests to measure product potency in support of an IND or BLA application; expedited programs; and long term patient and clinical study subject follow up and regulatory reporting.
Translarna and Emflaza can generally only be returned if agreed upon in writing by us and the product is not opened nor in receipt by the final user, except in the case of quality issues associated with the product.
Sephience, Translarna and Emflaza can generally only be returned if agreed upon in writing by us and the product is not opened nor in receipt by the final user, except in the case of quality issues associated with the product.
In addition, where the trial was intended to be used for obtaining a marketing authorization the applicant must submit the clinical study report 30 days after MA has been granted, refused or withdrawn.
In addition, where the trial was intended to be used for obtaining a marketing authorization the applicant must submit the clinical study report 30 days after marketing authorization has been granted, refused or withdrawn.
The rule also expanded the definition of products identified as “line extensions” and, in certain circumstances, required inclusion of patient copay assistance in Medicaid best price (effective January 1, 2023), thereby potentially increasing Medicaid rebates paid by manufacturers for such drugs. 340B program guidance regulations on civil monetary penalties for statutory violations, which had been finalized in early 2017 but deferred, also recently went into effect.
The rule also expanded the definition of products identified as “line extensions” and, in certain circumstances, required inclusion of patient copay assistance in Medicaid best price (effective January 1, 2023), thereby potentially increasing Medicaid rebates paid by manufacturers for such drugs. 340B program guidance regulations on civil monetary penalties for statutory violations, which had been finalized in early 2017 but deferred, also went into effect on January 1, 2019.
Akcea is also entitled to receive royalty payments in the mid-twenty percent range of net sales on a country-by-country and Product-by-Product basis, commencing on the earlier to occur of (1) 12 months after the first commercial sale of such Product in Brazil or (2) the date when we, our affiliates or sublicensees have recognized revenue of $10.0 million 25 Table of Contents or more in cumulative net sales for such Product in the PTC Territory.
Akcea is also entitled to receive royalty payments in the mid-twenty percent range of net sales on a country-by-country and Product-by-Product basis, commencing on the earlier to occur of (1) 12 months after the first commercial sale of such Product in Brazil or (2) the date when we, our affiliates or sublicensees have recognized revenue of $10.0 million 17 Table of Contents or more in cumulative net sales for such Product in the PTC Territory.
In the event that we were unable to procure the applicable supply from a validated manufacturer, we believe that there are a number of potential replacements for each of our outsourced services, however we likely would experience delays in our ability to supply Translarna, sepiapterin or vatiquinone to patients or in advancing our clinical trials while we identify and qualify replacement suppliers.
In the event that we were unable to procure the applicable supply from a validated manufacturer, we believe that there are a number of potential replacements for each of our outsourced services, however we likely would experience delays in our ability to supply Sephience, Translarna or vatiquinone to patients or in advancing our clinical trials while we identify and qualify replacement suppliers.
Certain gene therapy research must also be conducted in accordance with the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines; ● development of manufacturing processes to ensure the product candidate’s identity, strength, quality, purity, and potency; ● submission and FDA acceptance of an NDA or BLA, and satisfactory completion of an FDA Advisory Committee meeting, if applicable; ● satisfactory completion of an FDA inspection or remote regulatory assessment of the manufacturing facility or facilities at which the product is produced to assess compliance with cGMPs, which require that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity, as well as satisfactory completion of an FDA inspection or remote regulatory assessment of selected clinical sites and selected clinical investigators to determine GCP compliance; ● FDA review and approval of the NDA or BLA to permit commercial marketing for particular indications for use ; and ● compliance with any post approval requirements and commitments, including Risk Evaluation and Mitigation Strategies, or REMS, and post approval studies required by the FDA. ​ Nonclinical Studies and IND Submission Nonclinical tests include laboratory evaluations of product chemistry, pharmacology, stability, toxicity and product formulation, as well as animal or other nonclinical studies to assess potential safety and efficacy.
Certain gene therapy research must also be conducted in accordance with the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines; ● development of manufacturing processes to ensure the product candidate’s identity, strength, quality, purity, and potency; ● submission and FDA acceptance of an NDA or BLA, and satisfactory completion of an FDA Advisory Committee meeting, if applicable; ● satisfactory completion of an FDA inspection (remotely or in person) of the manufacturing facility or facilities at which the product is produced to assess compliance with cGMPs, which require that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity, as well as satisfactory completion of an FDA inspection (remotely or in person) of selected clinical sites and selected clinical investigators to determine GCP compliance; ● FDA review and approval of the NDA or BLA to permit commercial marketing for particular indications for use ; and ● compliance with any post approval requirements and commitments, including Risk Evaluation and Mitigation Strategies, or REMS, and post approval studies required by the FDA. ​ Nonclinical Studies and IND Submission Nonclinical tests include laboratory evaluations of product chemistry, pharmacology, stability, toxicity and product formulation, as well as animal or other nonclinical studies to assess potential safety and efficacy.
Termination. Unless terminated earlier, the SMA License Agreement will expire on the date when no royalty or other payment obligations are or will become due under the agreement.
Unless terminated earlier, the SMA License Agreement will expire on the date when no royalty or other payment obligations are or will become due under the agreement.
On November 13, 2024, the FDA granted accelerated approval of our gene therapy for the treatment of children and adults with AADC deficiency, which is marketed with the brand name Kebilidi in the United States. We are obligated to complete certain post-marketing requirements in connection with the FDA's approval, including clinical safety studies.
In November 2024, the FDA granted accelerated approval of our gene therapy for the treatment of children and adults with AADC deficiency, which is marketed with the brand name Kebilidi in the United States. We are obligated to complete certain post-marketing requirements in connection with the FDA's approval, including clinical safety studies.
In that event, we may become obligated to pay royalties to Roche on sales of any such product. 23 Table of Contents SMA Foundation Overview. In June 2006, we entered into a sponsored research agreement with the SMA Foundation under which we and the SMA Foundation have collaborated in the research and preclinical development of small molecule therapeutics for SMA.
In that event, we may become obligated to pay royalties to Roche on sales of any such product. 15 Table of Contents SMA Foundation Overview. In June 2006, we entered into a sponsored research agreement with the SMA Foundation under which we and the SMA Foundation have collaborated in the research and preclinical development of small molecule therapeutics for SMA.
Federal enforcement agencies have shown increased interest under the federal Anti-Kickback Stature and the federal civil False Claims Act in pharmaceutical companies’ product and patient assistance programs, including reimbursement and co-pay support services and donations to independent charitable patient assistance programs. A number of investigations into these programs have resulted in significant civil and criminal settlements.
Federal enforcement agencies have shown increased interest under the federal Anti-Kickback Statute and the federal civil False Claims Act in pharmaceutical companies’ product and patient assistance programs, including reimbursement and co-pay support services and donations to independent charitable patient assistance programs. A number of investigations into these programs have resulted in significant civil and criminal settlements.
A core element of this mission is our equality, diversity and inclusion, or ED&I, program which is managed by an ED&I professional, who routinely meets with our executive committee. Our ED&I program seeks to enable all employees to feel a sense of purpose and belonging through their connections with our internal 61 Table of Contents communities.
A core element of this mission is our equality, diversity and inclusion, or ED&I, program which is managed by an ED&I professional, who routinely meets with our executive committee. Our ED&I 53 Table of Contents program seeks to enable all employees to feel a sense of purpose and belonging through their connections with our internal communities.
Our Collaborations, License Agreements and Funding Arrangements We currently have ongoing collaborations with Roche and the SMA Foundation for SMA, a license agreement with National Taiwan University, or NTU, for Upstaza, a collaboration and license agreement with Akcea for Tegsedi and Waylivra, a license agreement with Shiratori Pharmaceutical Co., Ltd., or Shiratori, relating to the manufacturing processes and technology for sepiapterin, and a license and collaboration agreement with Novartis for our PTC518 HD program .
Our Collaborations, License Agreements and Funding Arrangements We currently have ongoing collaborations with Roche and the SMA Foundation for SMA, a license agreement with National Taiwan University, or NTU, for Upstaza, a collaboration and license agreement with Akcea for Tegsedi and Waylivra, a license agreement with Shiratori Pharmaceutical Co., Ltd., or Shiratori, relating to the manufacturing processes and technology for sepiapterin, and a license and collaboration agreement with Novartis for our votoplam HD program .
In addition to the upfront consideration paid to Marathon upon the closing of the Emflaza transaction, Marathon is entitled to receive contingent payments from us based on annual net sales of Emflaza, up to a specified aggregate maximum amount over the expected commercial life of the asset, subject to the terms and conditions of the Emflaza Asset Purchase Agreement.
In addition to the upfront consideration paid to Marathon upon the closing of the Emflaza transaction, Marathon was entitled to receive contingent payments from us based on annual net sales of Emflaza, up to a specified aggregate maximum amount over the expected commercial life of the asset, subject to the terms and conditions of the Emflaza Asset Purchase Agreement.
While the FDA’s guidance is not binding, it does provide the FDA’s current interpretation and approach. 37 Table of Contents The new drug and biologic approval process In the United States, an NDA is the vehicle through which the FDA approves a new pharmaceutical drug product for sale and marketing in the United States.
While the FDA’s guidance is not binding, it does provide the FDA’s current interpretation and approach. 29 Table of Contents The new drug and biologic approval process In the United States, an NDA is the vehicle through which the FDA approves a new pharmaceutical drug product for sale and marketing in the United States.
Sponsors can also request designation of a product candidate as a ‘‘breakthrough therapy.’’ A breakthrough therapy is defined as a product that is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
Sponsors can also request designation of a product candidate as a ‘‘breakthrough therapy.’’ A breakthrough therapy is defined as a product that is intended, alone or in combination with one or more other products, to treat a serious or life- 32 Table of Contents threatening disease or condition, and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
We announced the results from our Phase 1 study of PTC518 in healthy volunteers in September 2021 demonstrating dose-dependent lowering of huntingtin messenger ribonucleic acid and protein levels, that PTC518 efficiently crosses blood brain barrier at significant levels and that PTC518 was well tolerated.
We announced the results from our Phase 1 study of votoplam in healthy volunteers in September 2021 demonstrating dose-dependent lowering of huntingtin messenger ribonucleic acid and protein levels, that votoplam efficiently crosses blood brain barrier at significant levels and that votoplam was well tolerated.
Business-Our Collaborations, License Agreements and Funding Arrangements-National Taiwan University.” Additionally, we exclusively in-license or jointly own patent applications with claims directed to composition of matter, formulation and methods of use of other gene therapy products candidates currently in development.
Business-Our Collaborations, License Agreements and Funding Arrangements-National Taiwan University.” Additionally, we exclusively in-license or jointly own patent applications with claims directed to composition of matter, formulation and methods of use of other gene therapy product candidates currently in development.
Decisions regarding the extent of coverage and the amount of reimbursement to be provided for Emflaza are made on a plan-by-plan, and in some cases, on a patient-by-patient basis. Coverage and reimbursement decisions by third-party payors, including the processing and adjudication of prescriptions, may vary from weeks to several months.
Decisions regarding the extent of coverage and the amount of reimbursement to be provided are made on a plan-by-plan, and in some cases, on a patient-by-patient basis. Coverage and reimbursement decisions by third-party payors, including the processing and adjudication of prescriptions, may vary from weeks to several months.
As a result, our commercial launches of products in the EEA has been and is expected to continue to be on a country-by-country basis and we generally will not be able to commence commercial sales of our products pursuant to our marketing authorizations in the EEA in any particular member state of the EEA until we conclude the applicable pricing and reimbursement negotiations and comply with any licensing, employment or related regulatory requirements in that country.
As a result, our commercial launches of products in the EEA has been and is expected to continue to be on a 26 Table of Contents country-by-country basis and we generally will not be able to commence commercial sales of our products pursuant to our marketing authorizations in the EEA in any particular member state of the EEA until we conclude the applicable pricing and reimbursement negotiations and comply with any licensing, employment or related regulatory requirements in that country.
We have also delivered more than 130 coaching hours with internal coaches. Our executive team routinely reviews employee turnover throughout the organization to monitor employee satisfaction. Over the last four years, our voluntary turnover rate has been below 10%.
We have also delivered more than 242 coaching hours with internal coaches. Our executive team routinely reviews employee turnover throughout the organization to monitor employee satisfaction. Over the last four years, our voluntary turnover rate has been below 10%.
Vyndaqel (tafamids meglumine) and Vyndamax (tafamidis) are commercialized in the United States, EU and some countries in Latin America by Pfizer. Other companies are also pursuing product candidates for the treatment of ATTR Amyloidosis with polyneuropathy including BridgeBio Pharma (AG 10), Intellia Therapeutics (NTLA2001), Proclara Biosciences (NPT 189) and SOM Biotech (tolcapone). ● Evrysdi.
Vyndaqel (tafamids meglumine) and Vyndamax (tafamidis) are commercialized in the United States, EU and some countries in Latin America by Pfizer. Other companies are also pursuing product candidates for the treatment of ATTR Amyloidosis with polyneuropathy including BridgeBio Pharma (AG 10), Intellia Therapeutics (NTLA2001), Proclara Biosciences (NPT 189) and SOM Biotech (tolcapone). 28 Table of Contents ● Evrysdi.
Our patent rights relating to ataluren include granted patents or pending counterpart patent applications in a number of other jurisdictions, including Canada, certain South American countries, Europe, certain Middle Eastern countries, certain African countries, certain Asian countries and certain Eurasian countries.
Our patent rights relating to vatiquinone include granted patents or pending counterpart patent applications in a number of other jurisdictions, including Canada, certain South American countries, Europe, certain Middle Eastern countries, certain African countries, certain Asian countries and certain Eurasian countries.
We have received orphan drug designation from the FDA for Translarna for the treatment of nmDMD, Emflaza for the treatment of DMD, Kebilidi for the treatment of AADC deficiency, Evrysdi for the treatment of SMA, vatiquinone for the treatment of FA, sepiapterin for the treatment of hyperphenylalaninemia, including hyperphenylalaninemia caused by PKU, and PTC518 for the treatment of HD.
We have received orphan drug designation from the FDA for Translarna for the treatment of nmDMD, Emflaza for the treatment of DMD, Kebilidi for the treatment of AADC deficiency, Evrysdi for the treatment of SMA, vatiquinone for the treatment of FA, sepiapterin for the treatment of hyperphenylalaninemia, including hyperphenylalaninemia caused by PKU, and votoplam for the treatment of HD.
Separate from regulatory enforcement actions, individuals may bring private actions (including potentially group or representative actions) against us. There is no statutory cap in the GDPR on the amount of compensation or the damages which individuals may recover.
Separate from regulatory enforcement actions, individuals may bring private actions (including potentially group or representative actions) against us. There is no statutory cap set out in the GDPR on the amount of compensation or the damages which individuals may recover.
Payments and Contingent Payments. Pursuant to the SMA License Agreement, Roche paid us an upfront non-refundable payment of $30.0 million. During the research term, which was terminated effective December 31, 2014, Roche provided us with funding, based on an agreed-upon full-time equivalent rate, for an agreed-upon number of full-time equivalent employees that we contributed to the research program.
Pursuant to the SMA License Agreement, Roche paid us an upfront non-refundable payment of $30.0 million. During the research term, which was terminated effective December 31, 2014, Roche provided us with funding, based on an agreed-upon full-time equivalent rate, for an agreed-upon number of full-time equivalent employees that we contributed to the research program.
As discussed above, we have outlicensed rights to Roche pursuant to a license and collaboration agreement. We are not obligated to make such payments unless and until annual sales of a collaboration product exceed a designated threshold.
As discussed above, we have outlicensed rights to Roche pursuant to the SMA License Agreement. We are not obligated to make such payments unless and until annual sales of a collaboration product exceed a designated threshold.
However, uniQure (AMT-130), Roche and Ionis (tominersen), Skyhawk Therapeutics (SKY 0515), Vico Therapeutics (VO659) and Wave Life Sciences (WVE-003) are all developing product candidates for treatment of Huntington disease. ● Vatiquinone for FA. If approved, vatiquinone could face competition from Skyclarys (omaveloxolone) from Biogen, which is approved in the United States and the EU.
However, uniQure (AMT-130), Roche and Ionis (tominersen), Skyhawk Therapeutics (SKY 0515), Vico Therapeutics (VO659) and Wave Life Sciences (WVE-003) are all developing product candidates for treatment of HD. ● Vatiquinone for FA. If approved, vatiquinone could face competition from Skyclarys (omaveloxolone) from Biogen, which is approved in the United States and the EU.
In 2023, we implemented a program that offers financial support and access to high quality fertility care and family forming benefits to our employees. Total rewards offerings are established by employee positions, skill levels, experience, knowledge, and geographic location. We also provide flexible work arrangements for our employees, including remote work options when practicable.
We have implemented a program that offers financial support and access to high quality fertility care and family forming benefits to our employees. Total rewards offerings are established by employee positions, skill levels, experience, knowledge, and geographic location. We also provide flexible work arrangements for our employees, including remote work options when practicable.
Emflaza is approved in the United States for the treatment of DMD in patients two years and older. 6 Table of Contents o Upstaza TM (eladocagene exuparvovec) / Kebilidi TM (eladocagene exuparvovec-tneq) – Upstaza, a gene therapy for the treatment of Aromatic L-Amino Decarboxylase, or AADC, deficiency, a rare central nervous system, or CNS, disorder is approved for the treatment of AADC deficiency for patients 18 months and older within the EEA and the United Kingdom.
Emflaza is approved in the United States for the treatment of DMD in patients two years and older. o Upstaza TM (eladocagene exuparvovec) / Kebilidi TM (eladocagene exuparvovec-tneq) – Upstaza, a gene therapy for the treatment of Aromatic L-Amino Decarboxylase, or AADC, deficiency, a rare central nervous system, or CNS, disorder is approved for the treatment of AADC deficiency for patients 18 months and older within the EEA and the United Kingdom.
Our platforms focus on identifying small molecules that intervene in pathways required for RNA processing and energy production. Careful control and manipulation of these processes allow us to address a wide range of deficiencies. Splicing Post-transcriptional control processes are the events that occur in a cell following the transcription of DNA into RNA.
Our platforms focus on identifying small molecules that intervene in pathways required for RNA processing and energy production. Careful control and manipulation of these processes allow us to address a wide range of deficiencies. 13 Table of Contents Splicing Post-transcriptional control processes are the events that occur in a cell following the transcription of DNA into RNA.
PTC Therapeutics International Limited, our subsidiary, entered into a Collaboration and License Agreement, or the Tegsedi-Waylivra Agreement, dated August 1, 2018 by and between us and Akcea, for the commercialization by us of Tegsedi, Waylivra and products containing those compounds, which we refer to collectively as the Products, in countries in Latin America and the Caribbean, or the PTC Territory.
PTC Therapeutics International Limited, our subsidiary, entered into a Collaboration and License Agreement, or the Tegsedi-Waylivra Agreement, dated August 1, 2018 by and between us and Akcea, a subsidiary of Ionis Pharmaceuticals, Inc., for the commercialization by us of Tegsedi, Waylivra and products containing those compounds, which we refer to collectively as the Products, in countries in Latin America and the Caribbean, or the PTC Territory.
Listing patents in the Orange Book that do not qualify for listing can be considered to be anticompetitive conduct and, in 2023, the Federal Trade Commission sent letters to a number of companies with respect to certain patents that the agency asserted were improperly listed or inaccurate and improper listings have been the subject of recent court cases.
Listing patents in the Orange Book that do not qualify for listing can be considered to be anticompetitive conduct. The Federal Trade Commission has sent letters to a number of companies with respect to certain patents that the agency asserted were improperly listed or inaccurate and improper listings have been the subject of court cases.
Thus, approval of an ANDA or 505(b)(2) NDA could be delayed for a significant period of time depending on the patent certification the applicant makes and the reference drug sponsor’s decision to initiate patent litigation. 47 Table of Contents Exclusivity provisions under the FDCA can delay the submission or the approval of certain applications for competing products.
Thus, approval of an ANDA or 505(b)(2) NDA could be delayed for a significant period of time depending on the patent certification the applicant makes and the reference drug sponsor’s decision to initiate patent litigation. Exclusivity provisions under the FDCA can delay the submission or the approval of certain applications for competing products.
Early access programs Many jurisdictions allow the supply of unauthorized medicinal products in the context of strictly regulated and exceptional EAP programs, and some countries may provide reimbursement for drugs provided in the context of such programs.
Early access programs Many jurisdictions allow the supply of unauthorized medicinal products in the context of strictly regulated and exceptional EAP programs or schemes, and some countries may provide reimbursement for drugs provided in the context of such programs.
These introns 21 Table of Contents are removed from the final mRNA product by a process called splicing that also joins the exons together such that only the exons are retained in the mature mRNA. Approximately 94% of all human genes encode pre-mRNAs that undergo splicing, as such the majority of the human genome is targetable with splicing modulation.
These introns are removed from the final mRNA product by a process called splicing that also joins the exons together such that only the exons are retained in the mature mRNA. Approximately 94% of all human genes encode pre-mRNAs that undergo splicing, as such the majority of the human genome is targetable with splicing modulation.
Other biopharmaceutical companies are developing treatments addressing the underlying cause of disease for different mutations in the DMD gene, including Dyne Therapeutics (DYNE-251), Wave Life Sciences (WVE-N53), Daiichi Sankyo (DS-5141)), Nippon Shinyaku (Viltolarsen (NS-065/NCNP-01) and NS-089/NCNP-02)), and Astellas (AT-702).
Other biopharmaceutical companies are developing treatments addressing the underlying cause of disease for different mutations in the DMD gene, including Dyne Therapeutics (DYNE-251), Wave Life Sciences (WVE-N53), Daiichi Sankyo (DS-5141), and Nippon Shinyaku (Viltolarsen (NS-065/NCNP-01) and NS-089/NCNP-02)).
Clinical Trials Clinical trials involve the administration of an investigational product to human subjects under the supervision of qualified investigators. Clinical trials are conducted in accordance with protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety, the effectiveness criteria to be evaluated, and a statistical analysis plan.
Clinical Trials Clinical trials involve the administration of an investigational product to human subjects under the supervision of qualified investigators. Clinical trials are conducted in accordance with protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety, the effectiveness criteria to be evaluated, and a statistical analysis 30 Table of Contents plan.
As of December 31, 2024, there are no remaining development and regulatory event milestones that we can receive. The remaining potential sales milestones as of December 31, 2024 are $150.0 million upon achievement of certain sales events.
As of December 31, 2025, there are no remaining development and regulatory event milestones that we can receive. The remaining potential sales milestones as of December 31, 2025 are $150.0 million upon achievement of certain sales events.
We currently obtain our supplies of Translarna, sepiapterin and most of our other products and product candidates from our third-party manufacturers pursuant to agreements that include specific supply timelines and volume expectations.
We currently obtain our supplies of Sephience, Translarna, and most of our other products and product candidates from our third-party manufacturers pursuant to agreements that include specific supply timelines and volume expectations.
Other than in connection with our transition to a new third-party distributor, we have never had a request for a return of a material amount of product for either Translarna or Emflaza.
Other than in connection with our transition to a new third-party distributor, we have never had a request for a return of a material amount of product for Sephience, Translarna or Emflaza.
It has also received marketing authorization in the United States and EU for the same indication. hATTR amyloidosis is a progressive, systemic and fatal inherited disease caused by the abnormal formation of the TTR protein and aggregation of TTR amyloid deposits in various tissues and organs throughout the body, including in peripheral nerves, heart, intestinal tract, eyes, kidneys, central nervous system, thyroid and bone marrow.
It has also received marketing authorization in the United States and the EU for the same indication. hATTR amyloidosis is a progressive, systemic and fatal inherited disease caused by the abnormal formation of the TTR protein and aggregation of TTR amyloid deposits in various tissues and organs throughout the body, including in peripheral nerves, heart, intestinal tract, eyes, kidneys, CNS, thyroid and bone marrow.
Emflaza’s orphan drug exclusivity related to the treatment of DMD in patients two years of age to less than five expires in June 2026. See “Item 1. Business-Government Regulation” for further discussion with respect to marketing protection we rely on.
Emflaza’s orphan drug exclusivity related to the 9 Table of Contents treatment of DMD in patients two years of age to less than five expires in June 2026. See “Item 1. Business-Government Regulation” for further discussion with respect to marketing protection we rely on.
Business – Our Collaborations, License Agreements and Funding Arrangements – Novartis Pharmaceuticals Corporation.” Inflammation and Ferroptosis Platform Our inflammation and ferroptosis platform consists of small molecule compounds that target oxidoreductase enzymes that regulate oxidative stress and inflammatory pathways central to the pathology of a number of CNS diseases.
Business – Our Collaborations, License Agreements and Funding Arrangements – Novartis Pharmaceuticals Corporation.” Inflammation and Ferroptosis Platform Our inflammation and ferroptosis platform consists of small molecule compounds that target enzymes and pathways known to regulate oxidative stress and inflammatory pathways central to the pathology of a number of CNS and non-CNS diseases.
The patent rights relating to sepiapterin owned by us include five issued U.S. patents relating to composition of matter and methods of use, and one issued U.S. patent, co-owned by us and Shiratori, relating to methods of manufacture, as well as pending U.S. patent applications. We do not license any material patent rights relating to sepiapterin to unaffiliated parties.
The patent rights relating to sepiapterin owned by us include five issued U.S. patents relating to composition of matter and methods of use, and one issued U.S. patent, exclusively licensed to us by Shiratori, relating to methods of manufacture, as well as pending U.S. patent applications. We do not license any material patent rights relating to sepiapterin to unaffiliated parties.
In addition, there can be considerable pressure by governments and other stakeholders on prices 54 Table of Contents and reimbursement levels, including as part of cost containment measures. In some countries, governments can set conditions that must be satisfied for prices to be set at a certain value.
In addition, there can be considerable pressure by governments and other stakeholders on prices and reimbursement levels, including as part of cost containment measures. In some countries, governments can set conditions that must be satisfied for prices to be set at a certain value.
The results of Phase 4 studies can confirm or refute the effectiveness of a product candidate, and can provide important safety information. Additional kinds of data may also help support a BLA or NDA, such as patient experience data and real world evidence.
The results of Phase 4 studies can confirm or refute the effectiveness of a product candidate, and can provide important safety information. 31 Table of Contents Additional kinds of data may also help support a BLA or NDA, such as patient experience data and real world evidence.
The FDA has issued a number of guidance documents outlining an approach to review and approval of biosimilars, including guidance documents on the demonstration of interchangeability and the licensure of biosimilar and interchangeable products for fewer than all of the reference product’s licensed conditions of use.
The FDA has issued a number of guidance documents outlining an approach to review and approval of biosimilars, including guidance 39 Table of Contents documents on the demonstration of interchangeability and the licensure of biosimilar and interchangeable products for fewer than all of the reference product’s licensed conditions of use.
Based on the outcome of negotiations surrounding the exchanged information, the reference product sponsor may bring a patent infringement suit and injunction proceedings 48 Table of Contents against the biosimilar product sponsor. The biosimilar applicant may also be able to bring an action for declaratory judgment concerning the patent.
Based on the outcome of negotiations surrounding the exchanged information, the reference product sponsor may bring a patent infringement suit and injunction proceedings against the biosimilar product sponsor. The biosimilar applicant may also be able to bring an action for declaratory judgment concerning the patent.
Several different types of mutation in the dystrophin gene can result in DMD, including deletion, duplication and nonsense mutations. A test known as multiplex ligation-dependent probe amplification (MLPA) can detect large deletions and duplications, which account for approximately 75% of all mutations. However, gene sequencing is required to identify small mutations such as nonsense mutations.
Several different 8 Table of Contents types of mutation in the dystrophin gene can result in DMD, including deletion, duplication and nonsense mutations. A test known as multiplex ligation-dependent probe amplification can detect large deletions and duplications, which account for approximately 75% of all mutations. However, gene sequencing is required to identify small mutations such as nonsense mutations.
This gene therapy is marketed with the brand name Kebilidi in the United States. o Tegsedi® (inotersen) and Waylivra ® (volanesorsen) – We hold the rights for the commercialization of Tegsedi and Waylivra for the treatment of rare diseases in countries in Latin America and the Caribbean pursuant to our Collaboration and License Agreement with a subsidiary of Ionis Pharmaceuticals, Inc., or Ionis.
This gene therapy is approved and marketed with the brand name Kebilidi in the United States. o Tegsedi® (inotersen) and Waylivra ® (volanesorsen) – We hold the rights for the commercialization of Tegsedi and Waylivra for the treatment of rare diseases in countries in Latin America and the Caribbean 6 Table of Contents pursuant to our Collaboration and License Agreement with a subsidiary of Ionis Pharmaceuticals, Inc., or Ionis.
We followed the FDA’s recommendation and collected, using newer technologies via procedures and methods that we designed, such dystrophin data in a new study, Study 045, and announced the results of Study 045 in February 2021. Study 045 did not meet its pre-specified primary endpoint.
We followed the FDA’s recommendation and collected, using newer technologies via procedures and methods that we designed in a new study, Study 045, and announced the results of Study 045 in February 2021. Study 045 did not meet its pre-specified primary endpoint.
The patent rights relating to vatiquinone owned by us include seven issued U.S. patents relating to methods of use, formulations, dosing regimens and methods of manufacture and multiple pending U.S. patent applications relating to methods of use, formulation, and dosing regimens. We do not license any material patent rights relating to vatiquinone to unaffiliated parties.
The patent rights relating to vatiquinone owned by us include 13 issued U.S. patents relating to methods of use, formulations, dosing regimens and methods of manufacture and multiple pending U.S. patent applications relating to methods of use and methods of manufacture. We do not license any material patent rights relating to vatiquinone to unaffiliated parties.
Observations classified as major may include a pattern of deviations or numerous minor observations. 53 Table of Contents ● Minor: Conditions, practices or processes that would not be expected to adversely affect the rights, safety or wellbeing of the subjects or the quality and integrity of data.
Observations classified as major may include a pattern of deviations or numerous minor observations. ● Minor: Conditions, practices or processes that would not be expected to adversely affect the rights, safety or wellbeing of the subjects or the quality and integrity of data.
In addition, other federal and state laws, such as the California Consumer Privacy Act, or CCPA, may regulate the privacy and security of personal information that we maintain, many of which may differ from each other in significant ways.
In addition, other federal laws, including federal health information privacy laws and consumer protection laws, and state laws, such as the California Consumer Privacy Act, or CCPA, may regulate the privacy and security of personal information that we maintain, many of which may differ from each other in significant ways.
As a condition of approval of an NDA or BLA, the FDA may require the applicant to conduct additional clinical trials or other post market testing and surveillance to further monitor and assess the product’s safety and efficacy.
As a condition of approval of an NDA or 35 Table of Contents BLA, the FDA may require the applicant to conduct additional clinical trials or other post market testing and surveillance to further monitor and assess the product’s safety and efficacy.
We are also obligated to pay Shiratori certain regulatory and development milestones. Termination. Unless earlier terminated, the Shiratori License Agreement will continue in full force and effect on a country-by-country and product-by-product basis until the obligation to pay royalties with respect to the sale of such Sepiapterin Product in such country expires.
We are also obligated to pay Shiratori certain regulatory and development milestones that are of an immaterial amount. Termination. Unless earlier terminated, the Shiratori License Agreement will continue in full force and effect on a country-by-country and product-by-product basis until the obligation to pay royalties with respect to the sale of such Sepiapterin Product in such country expires.
Although these Medicare providers, suppliers and plans have faced federal False Claims Act liability since 2010 for failures to comply with the Overpayment Statute, these final rules interpreting the Overpayment Statute provide guidance regarding how to comply with applicable obligations, and guidance to government regulators and enforcement authorities regarding 58 Table of Contents monitoring and prosecuting suspected violations.
Although these Medicare providers, suppliers and plans have faced federal False Claims Act liability since 2010 for failures to comply with the Overpayment Statute, these final rules interpreting the Overpayment Statute provide guidance regarding how to comply with applicable obligations, and guidance to government regulators and enforcement authorities regarding monitoring and prosecuting suspected violations.
We also rely on trade 28 Table of Contents secrets, know-how, continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position. As of January 31, 2025, our patent portfolio included a total of 106 active U.S. patents and 53 pending U.S. non-provisional patent applications, including continuations and divisional applications, that are owned, co-owned, or exclusively in-licensed.
We also rely on trade secrets, know-how, continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position. As of January 31, 2026, our patent portfolio included a total of 106 active U.S. patents and 53 pending U.S. non-provisional patent applications, including continuations and divisional applications, that are owned, co-owned, or exclusively in-licensed.
Under the centralized procedure, the EMA’s Committee for Human Medicinal Products, or CHMP, is required to adopt an opinion on a valid 50 Table of Contents application within 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions.
Under the centralized procedure, the EMA’s Committee for Human Medicinal Products, or CHMP, is required to adopt an opinion on a valid application within 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions.
After 5 years, the authorization is renewed under exceptional circumstances for an unlimited period, unless the EMA decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal. A marketing authorization under exceptional circumstances will not be granted when a conditional marketing authorization is more appropriate.
After 5 years, the authorization is renewed under exceptional circumstances for an unlimited period, unless the EMA decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year 43 Table of Contents renewal. A marketing authorization under exceptional circumstances will not be granted when a conditional marketing authorization is more appropriate.
Subject to our limited ability to review and redact a narrow sub-set of confidential commercial information, these new EU policies will result in the EMA’s public disclosure of certain of our clinical study reports, clinical trial data summaries and clinical overviews for recently completed and future MAA submissions.
Subject to our limited ability to review and redact a narrow sub-set of confidential commercial information, these new EU policies will result in the EMA’s public disclosure of certain of our clinical study reports, clinical trial data summaries and clinical overviews for recently completed and future marketing authorization application submissions.
Congressional inquiries and proposed bills designed to, among other 55 Table of Contents things, bring more transparency to drug pricing, penalize companies that do not agree to cap prices paid for certain drugs, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.
Congressional inquiries and proposed bills designed to, among other things, bring more transparency to drug pricing, penalize companies that do not agree to cap prices paid for certain drugs, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.
Failure to conduct the required Phase 4 confirmatory studies or to conduct such studies with due diligence, as well as failure to submit the required update reports can subject a sponsor to 40 Table of Contents penalties. Promotional materials for a drug or biologic approved under the accelerated approval pathway are subject to the FDA prior review.
Failure to conduct the required Phase 4 confirmatory studies or to conduct such studies with due diligence, as well as failure to submit the required update reports can subject a sponsor to penalties. Promotional materials for a drug or biologic approved under the accelerated approval pathway are subject to the FDA prior review.
However, Roche may not exercise its final decision-making authority with respect to certain specified matters, including any decision that would increase our or the SMA Foundation’s obligations, reduce our or the SMA Foundation’s rights, expand Roche’s rights, or reduce Roche’s obligations under the license and collaboration agreement. Commercialization.
However, Roche may not exercise its final decision-making authority with respect to certain specified matters, including any decision that would increase our or the SMA Foundation’s obligations, reduce our or the SMA Foundation’s rights, expand Roche’s rights, or reduce Roche’s obligations under the license and collaboration agreement. 14 Table of Contents Commercialization.
In seeking approval for a drug through an NDA, applicants are required to list with the FDA each patent with claims that cover the applicant’s drug or a method of using the drug.
In seeking approval for a drug through an NDA, applicants are required 38 Table of Contents to list with the FDA each patent with claims that cover the applicant’s drug or a method of using the drug.
We initiated a Phase 2 study of PTC518 for the treatment of HD in the first quarter of 2022, which consists of an initial 12-week placebo-controlled phase focused on safety, pharmacology and pharmacodynamic effects followed by a nine-month placebo-controlled phase focused on PTC518 biomarker effect.
We initiated a Phase 2 study of votoplam for the treatment of HD in the first quarter of 2022, which consisted of an initial 12-week placebo-controlled phase focused on safety, pharmacology and pharmacodynamic effects followed by a nine-month placebo-controlled phase focused on votoplam biomarker effect.
We initiated a Phase 2 study of PTC518 for the treatment of HD in the first quarter of 2022, which consists of an initial 12-week placebo-controlled phase focused on safety, pharmacology and pharmacodynamic effects followed by a nine-month placebo-controlled phase focused on PTC518 biomarker effect.
We initiated a Phase 2 study of votoplam for the treatment of HD in the first quarter of 2022, which consisted of an initial 12-week placebo-controlled phase focused on safety, pharmacology and pharmacodynamic effects followed by a nine-month placebo-controlled phase focused on votoplam biomarker effect.
Subject to the terms and conditions of the BioElectron Asset Purchase Agreement, BioElectron may also become entitled to receive contingent payments based on a percentage of net sales of certain products.
Subject to the terms and conditions of the BioElectron Asset Purchase Agreement, BioElectron may also become entitled to receive contingent payments based on a percentage of net sales of certain products. Censa Pharmaceuticals, Inc.
The key competitive factors affecting the success of our products and product candidates are likely to be its efficacy, safety, convenience, price and the availability of coverage and reimbursement from government and other third-party payors. The competition for our products and product candidates includes the following: ● Translarna for nmDMD.
The key competitive factors affecting the success of our products and product candidates are likely to be its efficacy, safety, convenience, price and the availability of coverage and reimbursement from government and other third-party payors. The competition for our products and product candidates includes the following: ● Sephience for PKU.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeOur future capital requirements will depend on many factors, including: ● our ability to maintain our marketing authorization for Translarna for the treatment of nmDMD in the EEA following the CHMP’s negative opinion on the conditional marketing authorization following a re-examination procedure and the EC’s potential adoption of the negative opinion, or to identify other potential mechanisms in which we may provide Translarna to nmDMD patients in the EEA; ● our ability to maintain the marketing authorization for Translarna and our other products in territories outside of the EEA; ● our ability to commercialize and market our products and product candidates that may receive marketing authorization; ● our ability to negotiate, secure and maintain adequate pricing, coverage and reimbursement terms, on a timely basis, with third-party payors for our products and products candidates; ● the amount of generic drug competition that we face for Emflaza following its loss of orphan drug exclusivity related to the treatment of DMD in patients five years and older; ● our ability to obtain marketing authorization for sepiapterin for the treatment of PKU in the United States and EEA; ● our ability to obtain marketing authorization for Translarna for the treatment of nmDMD in the United States; ● our ability to obtain marketing authorization for vatiquinone for the treatment of FA in the United States; ● unexpected decreases in revenue or increase in expenses resulting from potential widespread outbreaks of contagious disease; ● our ability to successfully complete all post-marketing requirements imposed by regulatory agencies with respect to our products; ● the progress and results of activities for sepiapterin and our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications; ● the scope, costs and timing of our commercialization activities, including product sales, marketing, legal, regulatory, distribution and manufacturing, for any of our products and for any of our other product candidates that may receive marketing authorization or any additional territories in which we receive authorization to market Translarna; ● the costs, timing and outcome of regulatory review of sepiapterin and our splicing and inflammation and ferroptosis programs and Translarna and Upstaza in other territories; ● our ability to satisfy our obligations under the indenture governing the 2026 Convertible Notes; ● the timing and scope of any potential future growth in our employee base; ● the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our other product candidates, including those in our splicing and inflammation and ferroptosis programs; ● revenue received from commercial sales of our products or any of our product candidates; ● our ability to obtain additional and maintain existing reimbursed named patient and cohort EAP programs for Translarna for the treatment of nmDMD on adequate terms, or at all; 83 Table of Contents ● the ability and willingness of patients and healthcare professionals to access Translarna through alternative means if pricing and reimbursement negotiations in the applicable territory do not have a positive outcome; ● the costs of preparing, filing and prosecuting patent applications, maintaining, and protecting our intellectual property rights and defending against intellectual property-related claims; ● the extent to which we acquire or invest in other businesses, products, product candidates, and technologies, including the success of any acquisition, in-licensing or other strategic transaction we may pursue, and the costs of subsequent development requirements and commercialization efforts, including with respect to our acquisitions of Emflaza, Agilis, our inflammation and ferroptosis platform and Censa and our licensing of Tegsedi and Waylivra; and ● our ability to establish and maintain collaborations, including our collaborations with Roche, the SMA Foundation and our collaboration with Novartis, and our ability to obtain research funding and achieve milestones under these agreements.
Biggest changeOur future capital requirements will depend on many factors, including: ● our ability to commercialize and market our products and product candidates that may receive marketing authorization; ● our ability to commercialize Sephience for the treatment of PKU in the jurisdictions in which it is approved; ● the ability and willingness of individual countries within the EU to leverage Articles 117(3) and 5(1) of the EU Directive 2001/83 to allow continued commercial use of Translarna. ● our plans for vatiquinone, including with respect to the expected timing of clinical trials and studies, availability of data, regulatory submissions and responses, meetings with regulatory agencies, and other matters; ● our ability to negotiate, secure and maintain adequate pricing, coverage and reimbursement terms, on a timely basis, with third-party payors for our products and product candidates; ● unexpected decreases in revenue or increase in expenses resulting from potential widespread outbreaks of contagious disease; ● our ability to successfully complete all post-marketing requirements imposed by regulatory agencies with respect to our products; ● the progress and results of activities for our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications; ● the scope, costs and timing of our commercialization activities, including product sales, marketing, legal, regulatory, distribution and manufacturing, for any of our products and for any of our other product candidates that may receive marketing authorization; ● the costs, timing and outcome of regulatory review of our splicing and inflammation and ferroptosis programs and Sephience, Translarna and Upstaza in other territories; ● our ability to satisfy our obligations under the indenture governing the 2026 Convertible Notes; 73 Table of Contents ● the timing and scope of any potential future growth in our employee base; ● the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our other product candidates, including those in our splicing and inflammation and ferroptosis programs; ● revenue received from commercial sales of our products or any of our product candidates; ● our ability to obtain additional and maintain existing reimbursed named patient and cohort EAP programs for Translarna for the treatment of nmDMD on adequate terms, or at all; ● the ability and willingness of patients and healthcare professionals to access Translarna through alternative means if pricing and reimbursement negotiations in the applicable territory do not have a positive outcome; ● the costs of preparing, filing and prosecuting patent applications, maintaining, and protecting our intellectual property rights and defending against intellectual property-related claims; ● the extent to which we acquire or invest in other businesses, products, product candidates, and technologies, including the success of any acquisition, in-licensing or other strategic transaction we may pursue, and the costs of subsequent development requirements and commercialization efforts, including with respect to our acquisitions of Emflaza, Agilis, our inflammation and ferroptosis platform and Censa and our licensing of Tegsedi and Waylivra; and ● our ability to establish and maintain collaborations, including our collaborations with Roche and the SMA Foundation and our collaboration with Novartis, and our ability to obtain research funding and achieve milestones under these agreements.
Future changes in legal and regulatory requirements may introduce new risks into our operations and future prospects, which we are not able to currently anticipate.
Changes in legal and regulatory requirements may introduce new risks into our operations and future prospects, which we are not able to currently anticipate.
The respective orphan designation and exclusivity frameworks in the United States and in the EU are subject to change, and any such changes may affect our ability to obtain, or the impact of obtaining, EU or United States orphan designations in the future.
The respective orphan designation and exclusivity frameworks in the United States and in the EU are subject to change, and any such changes may affect our ability to obtain, or the impact of obtaining, United States or EU orphan designations in the future.
We, our products and product candidates, our operations, our facilities, our suppliers and our contract manufacturers, distributors, contract research organizations, clinical trial sites and contract testing laboratories are subject to extensive regulation by governmental authorities in the EEA, the United States, and other territories, with regulations differing from country to country.
We, our products and product candidates, our operations, our facilities, our suppliers and our contract manufacturers, distributors, contract research organizations, clinical trial sites and contract testing laboratories are subject to extensive regulation by governmental authorities in the United States, the EEA, and other territories, with regulations differing from country to country.
We are not permitted to market our product candidates in the EEA, the United States, or other territories until we have received requisite regulatory approvals.
We are not permitted to market our product candidates in the United States, the EEA, or other territories until we have received requisite regulatory approvals.
Thus, we do not know with certainty whether any of our products or product candidates, or our commercialization thereof, would or would not infringe any third party’s intellectual property. We may become party to, or threatened with, future adversarial proceedings or litigation regarding intellectual property rights or other proprietary with respect to our products and technology.
Thus, we do not know with certainty whether any of our products or product candidates, or our commercialization thereof, would or would not infringe any third party’s intellectual property. We may become party to, or threatened with, future adversarial proceedings or litigation regarding intellectual property rights or other proprietary rights with respect to our products and technology.
In addition, later discovery of previously unknown adverse events or other problems with our products, manufacturers or manufacturing processes, or failure to comply with regulatory requirements, both before and after product approval, may yield various results which could negatively affect our business, including: ● restrictions on such products, manufacturers or manufacturing processes; ● changes to or restrictions on the labeling or marketing of a product; ● modifications to promotional pieces; ● issuance of corrective information; ● clinical holds or termination of clinical trials; ● changes in the way a product is administered; ● liability for harm caused to patients or subjects; ● adverse publicity, reputational harm, or the product becoming less competitive; ● regulatory authority issuance of safety alerts, Dear Healthcare Provider letters, press releases, or other communications containing warnings or other safety information about the product; ● restrictions on product distribution or use; ● requirements to implement a REMS; 89 Table of Contents ● requirements to conduct post-marketing studies or clinical trials; ● warning, cyber or untitled letters; ● withdrawal of the products from the market or marketing suspensions; ● refusal to approve pending applications or supplements to approved applications that we submit; ● recall of products; ● fines, restitution or disgorgement of profits or revenues; ● suspension or withdrawal of marketing authorizations; ● refusal to permit the import or export of our products; ● product seizure or detention; ● injunctions; ● the imposition of civil or criminal penalties; or ● FDA debarment, suspension and debarment from government contracts, and refusal of orders under existing government contracts, exclusion from federal healthcare programs, consent decrees, or corporate integrity agreements.
In addition, later discovery of previously unknown adverse events or other problems with our products, manufacturers or manufacturing processes, or failure to comply with regulatory requirements, both before and after product approval, may yield various results which could negatively affect our business, including: ● restrictions on such products, manufacturers or manufacturing processes; ● changes to or restrictions on the labeling or marketing of a product; ● modifications to promotional pieces; ● issuance of corrective information; ● clinical holds or termination of clinical trials; ● changes in the way a product is administered; ● liability for harm caused to patients or subjects; ● adverse publicity, reputational harm, or the product becoming less competitive; ● regulatory authority issuance of safety alerts, Dear Healthcare Provider letters, press releases, or other communications containing warnings or other safety information about the product; ● restrictions on product distribution or use; 79 Table of Contents ● requirements to implement a REMS; ● requirements to conduct post-marketing studies or clinical trials; ● warning, cyber or untitled letters; ● withdrawal of the products from the market or marketing suspensions; ● refusal to approve pending applications or supplements to approved applications that we submit; ● recall of products; ● fines, restitution or disgorgement of profits or revenues; ● suspension or withdrawal of marketing authorizations; ● refusal to permit the import or export of our products; ● product seizure or detention; ● injunctions; ● the imposition of civil or criminal penalties; or ● FDA debarment, suspension and debarment from government contracts, and refusal of orders under existing government contracts, exclusion from federal healthcare programs, consent decrees, or corporate integrity agreements.
The exact impact of any contagious disease outbreak may not be fully known until the applicable trials are complete or are submitted to the applicable regulatory authorities; ● we may be unable to enroll a sufficient number of patients in our clinical trials, the number of patients required for clinical trials may be larger than we anticipate, enrollment in these clinical trials may be slower than we 66 Table of Contents anticipate or participants may drop out of these clinical trials, not comply with trial procedures, misrepresent their eligibility, or be lost to follow-up at a higher rate than we anticipate; ● we may enroll patients in foreign countries in which clinical sites may have less experience with studies or the disease at issue, or may use a different standard of care; ● regulatory authorities may not accept the data generated at foreign sites or may find that such data is not sufficiently representative of the population of the approving country; ● our third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at all, or we may be required to engage in additional clinical trial site monitoring; ● regulators, institutional review boards, institutional biosafety committees, or independent ethics committees may not authorize us or our investigators to commence or continue a clinical trial, may require additional data or studies, or may require changes to our studies, including applications and protocols; ● we may be unable to engage trial sites and contract research organizations or they may withdraw from our studies; ● we, regulators, institutional review boards, institutional biosafety committees, or independent ethics committees may require the suspension or termination of studies for various reasons, including noncompliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks; ● the cost of clinical trials of our products or our product candidates may be greater than we anticipate or we may have insufficient funds for a clinical trial or to pay the substantial user fees required by the FDA upon the filing of a marketing application; ● the supply or quality of our products or our product candidates or other materials necessary to conduct clinical trials of our products or our product candidates may be insufficient or inadequate; ● regulators may require us to perform additional or unanticipated studies, develop additional manufacturing information, or make changes to our manufacturing process to obtain approval; ● there may be changes in the applicable regulatory authorities’ approval requirements, which may render our data insufficient to obtain marketing approval; ● the FDA or comparable regulatory authorities may disagree with our intended indications; ● regulators may fail to approve or subsequently find fault with the manufacturing processes or facilities for clinical and future commercial supplies; ● the FDA or comparable regulatory authorities may take longer than we anticipate to make a decision on our product candidates; or ● we may decide to abandon the development of a product candidate or development program. ​ These risks may be increased for product candidates intended for the treatment of diseases for which there is little clinical experience, where we are using new endpoints or methodologies, or where the product candidates are new or novel.
The exact impact of any contagious disease outbreak may not be fully known until the applicable trials are complete or are submitted to the applicable regulatory authorities; ● we may be unable to enroll a sufficient number of patients in our clinical trials, the number of patients required for clinical trials may be larger than we anticipate, enrollment in these clinical trials may be slower than we anticipate or participants may drop out of these clinical trials, not comply with trial procedures, misrepresent their eligibility, or be lost to follow-up at a higher rate than we anticipate; ● we may enroll patients in foreign countries in which clinical sites may have less experience with studies or the disease at issue, or may use a different standard of care; ● regulatory authorities may not accept the data generated at foreign sites or may find that such data is not sufficiently representative of the population of the approving country; ● our third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at all, or we may be required to engage in additional clinical trial site monitoring; ● regulators, institutional review boards, institutional biosafety committees, or independent ethics committees may not authorize us or our investigators to commence or continue a clinical trial, may require additional data or studies, or may require changes to our studies, including applications and protocols; ● we may be unable to engage trial sites and contract research organizations or they may withdraw from our studies; ● we, regulators, institutional review boards, institutional biosafety committees, or independent ethics committees may require the suspension or termination of studies for various reasons, including noncompliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks; ● the cost of clinical trials of our products or our product candidates may be greater than we anticipate or we may have insufficient funds for a clinical trial or to pay the substantial user fees required by the FDA upon the filing of a marketing application; ● the supply or quality of our products or our product candidates or other materials necessary to conduct clinical trials of our products or our product candidates may be insufficient or inadequate; ● regulators may require us to perform additional or unanticipated studies, develop additional manufacturing information, or make changes to our manufacturing process to obtain approval; ● there may be changes in the applicable regulatory authorities’ approval requirements, which may render our data insufficient to obtain marketing approval; ● the FDA or comparable regulatory authorities may disagree with our intended indications; ● regulators may fail to approve or subsequently find fault with the manufacturing processes or facilities for clinical and future commercial supplies; ● the FDA or comparable regulatory authorities may take longer than we anticipate to make a decision on our product candidates; or ● we may decide to abandon the development of a product candidate or development program. ​ These risks may be increased for product candidates intended for the treatment of diseases for which there is little clinical experience, where we are using new endpoints or methodologies, or where the product candidates are new or novel.
Our current and anticipated future dependence upon others for the manufacture and distribution of Translarna, Emflaza, Upstaza, Kebilidi, Tegsedi, Waylivra and our product candidates may adversely affect our business, financial condition, results of operations and limit our ability to grow including our ability to develop product candidates and commercialize our products that receive regulatory approval on a timely and competitive basis.
Our current and anticipated future dependence upon others for the manufacture and distribution of Sephience, Translarna, Emflaza, Upstaza, Kebilidi, Tegsedi, Waylivra and our product candidates may adversely affect our business, financial condition, results of operations and limit our ability to grow including our ability to develop product candidates and commercialize our products that receive regulatory approval on a timely and competitive basis.
By example, changes taking place in the United States associated with a new federal administration, as well as changes in legal standards, including the reduced level of judicial deference due to administrative agencies following a 2024 Supreme Court decision, may introduce uncertainties with respect to our current and future operations and our future likelihood of success.
By example, changes taking place in the United States associated with the current federal administration, as well as changes in legal standards, including the reduced level of judicial deference due to administrative agencies following a 2024 Supreme Court decision, may introduce uncertainties with respect to our current and future operations and our future likelihood of success.
Similarly, sales of Emflaza or our other products in the United States could also be reduced if they, or products similar to them, are imported into the United States from lower-priced markets, whether legally or illegally. For example, in the United States, prices for pharmaceuticals are generally higher than in the bordering nations of Mexico and Canada.
Similarly, sales of Sephience, Emflaza or our other products in the United States could also be reduced if they, or products similar to them, are imported into the United States from lower-priced markets, whether legally or illegally. For example, in the United States, prices for pharmaceuticals are generally higher than in the bordering nations of Mexico and Canada.
We may not be able to conclude pricing and reimbursement negotiations or comply with additional regulatory requirements in the countries in which we seek to commercialize Translarna or Upstaza on a timely basis, or at all. The pricing and reimbursement process varies from country to country and can take a substantial amount of time from initiation to completion.
We may not be able to conclude pricing and reimbursement negotiations or comply with additional regulatory requirements in the countries in which we seek to commercialize Sephience, Translarna, or Upstaza on a timely basis, or at all. The pricing and reimbursement process varies from country to country and can take a substantial amount of time from initiation to completion.
Additionally, within Europe, each country has its own reimbursement regime employing various health technology assessment approaches to assess the cost-effectiveness of the product (for example, in the United Kingdom a HTA assessment is conducted by NICE) which may significantly affect the effective access to the market.
Additionally, within Europe, each country has its own reimbursement regime employing various health technology assessment, or HTA, approaches to assess the cost-effectiveness of the product (for example, in the United Kingdom a HTA assessment is conducted by NICE) which may significantly affect the effective access to the market.
In addition to the foregoing, we expect to continue to incur significant costs in connection with ongoing, planned and potential future clinical trials and studies for sepiapterin and our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications.
In addition to the foregoing, we expect to continue to incur significant costs in connection with ongoing, planned and potential future clinical trials and studies for our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications.
International operations inherently subject us to a number of risks and uncertainties, including: ● political, regulatory, compliance and economic developments that could restrict our ability to manufacture, market and sell our products, including the Russia-Ukraine conflict and related sanctions that have been imposed by various countries in response thereto; ● financial risks such as longer payment cycles, difficulty collecting accounts receivable, potentially high inflation rates, sustained high interest rates and exposure to fluctuations in foreign currency exchange rates; ● difficulty in staffing and managing international operations; ● potentially negative consequences from changes in or interpretations of tax laws; ● changes in international medical reimbursement policies and programs; ● unexpected changes in healthcare policies of ex-U.S. jurisdictions; ● trade protection measures, including import or export licensing requirements and tariffs; ● our ability to develop relationships with qualified local distributors and trading companies; ● political and economic instability in particular ex-U.S. economies and markets, in particular in emerging markets, for example in Brazil; ● diminished protection of intellectual property in some countries outside of the United States; ● differing labor regulations and business practices; ● regulatory and compliance risks that relate to maintaining accurate information and control over sales and distributors’ and service providers’ activities that may fall within the purview of the Foreign Corrupt Practices Act, UK Bribery Act or similar local regulation; and ● various effects and responsive measures relating to outbreaks of contagious disease.
International operations inherently subject us to a number of risks and uncertainties, including: ● political, regulatory, compliance and economic developments that could restrict our ability to manufacture, market and sell our products, including the Russia-Ukraine conflict and related sanctions that have been imposed by various countries in response thereto; ● financial risks such as longer payment cycles, difficulty collecting accounts receivable, potentially high inflation rates, sustained high interest rates and exposure to fluctuations in foreign currency exchange rates; ● difficulty in staffing and managing international operations; ● potentially negative consequences from changes in or interpretations of tax laws; ● changes in international medical reimbursement policies and programs; ● unexpected changes in healthcare policies of ex-U.S. jurisdictions; ● trade protection measures, including import or export licensing requirements and tariffs; ● our ability to develop relationships with qualified local distributors and trading companies; ● political and economic instability in particular ex-U.S. economies and markets, in particular in emerging markets, for example in Brazil; ● diminished protection of intellectual property in some countries outside of the United States; ● differing labor regulations and business practices; ● regulatory and compliance risks that relate to maintaining accurate information and control over sales and distributors’ and service providers’ activities that may fall within the purview of the U.S., UK or similar local anti-bribery regulations; and ● various effects and responsive measures relating to outbreaks of contagious disease.
Factors that may materially affect our efforts to commercialize our products include: ● our ability to recruit, train and retain adequate numbers of effective sales and marketing personnel; ● our ability to monitor the legal and regulatory compliance of sales and marketing personnel; ● an inability to secure adequate coverage and reimbursement by government and private health plans; ● reduced realization on government sales from mandatory discounts, rebates and fees, and from price concessions to private health plans and pharmacy benefit managers necessitated by competition for access to managed formularies; ● the clinical indications for which the products are approved and the claims that we may make for the products; 72 Table of Contents ● limitations or warnings, including distribution or use restrictions, contained in the products’ approved labeling; ● any distribution and use restrictions imposed by the FDA or to which we agree as part of a mandatory REMS or voluntary risk management plan; ● liability for sales or marketing personnel who fail to comply with the applicable legal and regulatory requirements; ● our ability to implement third-party marketing and distribution relationships on favorable terms, or at all, in territories where we do not pursue direct commercialization; ● the ability of our commercial team to obtain access to or persuade adequate numbers of physicians to prescribe our current or any future products; ● the lack of complementary products to be offered by our commercial team, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and ● unforeseen costs and expenses associated with creating an independent commercial organization.
Factors that may materially affect our efforts to commercialize our products include: ● our ability to recruit, train and retain adequate numbers of effective sales and marketing personnel; ● our ability to monitor the legal and regulatory compliance of sales and marketing personnel; ● an inability to secure adequate coverage and reimbursement by government and private health plans; ● reduced realization on government sales from mandatory discounts, rebates and fees, and from price concessions to private health plans and pharmacy benefit managers necessitated by competition for access to managed formularies; ● the clinical indications for which the products are approved and the claims that we may make for the products; ● limitations or warnings, including distribution or use restrictions, contained in the products’ approved labeling; ● any distribution and use restrictions imposed by the FDA or other regulatory agencies or to which we agree as part of a mandatory REMS or voluntary risk management plan; ● liability for sales or marketing personnel who fail to comply with the applicable legal and regulatory requirements; ● our ability to implement third-party marketing and distribution relationships on favorable terms, or at all, in territories where we do not pursue direct commercialization; ● the ability of our commercial team to obtain access to or persuade adequate numbers of physicians to prescribe our current or any future products; 63 Table of Contents ● the lack of complementary products to be offered by our commercial team, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and ● unforeseen costs and expenses associated with creating an independent commercial organization.
For example, given the nature of biologics manufacturing, there is a risk of contamination. Any contamination could materially adversely affect our ability to produce our gene therapy product candidates on schedule and could, therefore, harm our results of operations and cause reputational damage.
For example, given the nature of biologics manufacturing, there is a risk of contamination. Any contamination could materially adversely affect our ability to produce our gene therapy product on schedule and could, therefore, harm our results of operations and cause reputational damage.
We cannot guarantee that we, our employees, our consultants, our third-party contractors, or the healthcare professionals or entities with whom we expect to do business, are or will be in compliance with all federal, state and ex-U.S. regulations and codes.
We cannot guarantee that we, our employees, our consultants, our third-party contractors, or the healthcare professionals or entities with whom we expect to do business, are or will be in compliance with all federal, state, local, and ex-U.S. regulations and codes.
Changes in FDA laws, regulations, and policies may also make it more difficult to obtain and maintain marketing authorizations. In the EU, similar political, economic and regulatory developments may affect our ability to profitably commercialize Translarna, Upstaza and our product candidates.
Changes in FDA laws, regulations, and policies may also make it more difficult to obtain and maintain marketing authorizations. In the EU, similar political, economic and regulatory developments may affect our ability to profitably commercialize Sephience, Translarna, Upstaza and our product candidates.
We or our collaborators may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing authorization or commercialize our products or our product candidates, including: ● clinical trials may produce negative or inconclusive results, regulators may disagree with our interpretation of results, our studies may fail to reach the necessary level of statistical significance, or we may not be able to demonstrate that our product candidates are safe, effective, or provide an advantage over current standard of care or other therapies; ● our clinical trials may not meet their primary endpoints.
We or our collaborators may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing authorization or commercialize our products or our product candidates, including: ● clinical trials may produce negative or inconclusive results, regulators may disagree with our interpretation of results, our studies may fail to reach the necessary level of statistical significance, or we may not be able to demonstrate that our product candidates are safe, effective, or provide an advantage over current standard of care or other therapies; ● our cli nical trials may not meet their primary endpoints.
Our failure, or the failure of our third-party manufacturers or distributors, over whom we have no direct control, to comply with applicable regulations could result in sanctions being imposed on us, including fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, clinical holds or termination of clinical studies, warning or untitled letters, regulatory communications warning the public about safety issues with a product, import or export refusals, 96 Table of Contents license revocation, seizures, detentions, or recalls of product candidates or products, operating restrictions, criminal prosecutions or debarment, suits under the civil False Claims act, corporate integrity agreements, or consent decrees, any of which could significantly and adversely affect our reputation and supplies of our products or product candidates and our business, results of operations and financial condition could be materially adversely affected.
Our failure, or the failure of our third-party manufacturers or distributors, over whom we have no direct control, to comply with applicable regulations could result in sanctions being imposed on us, including fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, clinical holds or termination of clinical studies, warning or untitled letters, regulatory communications warning the public about safety issues with a product, import or export refusals, license revocation, seizures, detentions, or recalls of product candidates or products, operating restrictions, criminal prosecutions or debarment, suits under the civil False Claims act, corporate integrity agreements, or consent decrees, any of which could significantly and adversely affect our reputation and supplies of our products or product candidates and our business, results of operations and financial condition could be materially adversely affected.
Our ability to make scheduled payments of the principal of, to pay interest on or to refinance the 2026 Convertible Notes depends on our future performance, which is subject to economic, financial, competitive and other factors beyond our control.
Our ability to make scheduled payments of the principal of, to pay interest on or to refinance the 2026 Convertible Notes depends on our future performance and financial position, which is subject to economic, financial, competitive and other factors beyond our control.
In addition, to the extent that any contract manufactures that we engage develop proprietary manufacturing processes or procedures, should we need to change manufacturers, we may not be able to transfer know-how to a new manufacturer.
In addition, to the extent that any contract manufacturers that we engage develop proprietary manufacturing processes or procedures, should we need to change manufacturers, we may not be able to transfer know-how to a new manufacturer.
Regardless of merit or eventual outcome, liability claims may result in: ● reduced resources of our management to pursue our business strategy; ● decreased demand for our products or any product candidates that we may develop; 101 Table of Contents ● injury to our reputation and significant negative media attention; ● the inability to continue current clinical trials or begin planned clinical trials; ● withdrawal or reduced enrollment of clinical trial participants; ● significant costs to defend the related claims/litigation; ● increased insurance costs, or an inability to maintain appropriate insurance coverage; ● substantial monetary awards to trial participants, patients and/or their families; ● loss of revenue; ● the inability to commercialize or to continue commercializing any products or product candidates; ● initiation of investigations and enforcement actions by regulators; and ● the withdrawal of products from the market, product recalls, or the cessation of development or regulatory disapproval of product candidates or withdrawal of approvals, as well as labeling, marketing, or promotional restrictions.
Regardless of merit or eventual outcome, liability claims may result in: ● reduced resources of our management to pursue our business strategy; ● decreased demand for our products or any product candidates that we may develop; ● injury to our reputation and significant negative media attention; ● the inability to continue current clinical trials or begin planned clinical trials; ● withdrawal or reduced enrollment of clinical trial participants; ● significant costs to defend the related claims/litigation; ● increased insurance costs, or an inability to maintain appropriate insurance coverage; ● substantial monetary awards to trial participants, patients and/or their families; ● loss of revenue; ● the inability to commercialize or to continue commercializing any products or product candidates; ● initiation of investigations and enforcement actions by regulators; and ● the withdrawal of products from the market, product recalls, or the cessation of development or regulatory disapproval of product candidates or withdrawal of approvals, as well as labeling, marketing, or promotional restrictions.
The rule also expanded the definition of products identified as “line extensions” and, in certain circumstances, required inclusion of patient copay assistance in Medicaid best price (effective January 1, 2023), thereby potentially increasing Medicaid rebates paid by manufacturers for such drugs. 340B program guidance regulations on civil monetary penalties for statutory violations, which had been finalized in early 2017 but deferred, recently also went into effect.
The rule also expanded the definition of products identified as “line extensions” and, in certain circumstances, required inclusion of patient copay assistance in Medicaid best price (effective January 1, 2023), thereby potentially increasing Medicaid rebates paid by manufacturers for such drugs. 340B program guidance regulations on civil monetary penalties for statutory violations, which had been finalized in early 2017 but deferred, also went into effect on January 1, 2019.
However, our insurance program may not adequately cover the risks that we face for a variety of reasons, including: ● certain risks and related losses, such as delays to our clinical and development programs, are too speculative or unquantifiable for us to adequately insure against; ● if we were to face multiple claims, renewing or replacing our insurance may become more expensive, the terms (including deductibles and limits) we receive may worsen, and we may even have difficulty securing any coverage at all; ● our insurance limits may not be adequate to cover all liabilities and defense costs that we may incur; and ● we may need to further increase our insurance coverage if we commercialize our current products in additional jurisdictions, our sales increase, or we commercialize new products. ​ The cost of insurance coverage is highly variable, based on a wide range of factors.
However, our insurance program may not adequately cover the risks that we face for a variety of reasons, including: ● certain risks and related losses, such as delays to our clinical and development programs, are too speculative or unquantifiable for us to adequately insure against; 92 Table of Contents ● if we were to face multiple claims, renewing or replacing our insurance may become more expensive, the terms (including deductibles and limits) we receive may worsen, and we may even have difficulty securing any coverage at all; ● our insurance limits may not be adequate to cover all liabilities and defense costs that we may incur; and ● we may need to further increase our insurance coverage if we commercialize our current products in additional jurisdictions, our sales increase, or we commercialize new products. ​ The cost of insurance coverage is highly variable, based on a wide range of factors.
Commercialization of Translarna and Upstaza has been in, and is expected to continue to take place in, countries that tend to impose strict price controls, which may adversely affect our revenues.
Commercialization of Sephience, Translarna and Upstaza has been in, and is expected to continue to take place in, countries that tend to impose strict price controls, which may adversely affect our revenues.
We outsource most of the manufacturing, packaging, labeling and distribution of our products and certain of our product candidates to third parties, including our commercial supply of Translarna, Emflaza, and Upstaza/Kebilidi.
We outsource most of the manufacturing, packaging, labeling and distribution of our products and certain of our product candidates to third parties, including our commercial supply of Sephience, Translarna, Emflaza and Upstaza/Kebilidi.
We generally will not be able to commence commercial sales of Translarna for the treatment of nmDMD or Upstaza for the treatment of AADC deficiency pursuant to the marketing authorization granted by the EC in any particular member state of the EEA until we conclude the applicable pricing and reimbursement negotiations and comply with any licensing, employment or related regulatory requirements in that country.
We generally will not be able to commence commercial sales of Sephience for the treatment of PKU, Translarna for the treatment of nmDMD, or Upstaza for the treatment of AADC deficiency pursuant to the marketing authorization granted by the EC in any particular member state of the EEA until we conclude the applicable pricing and reimbursement negotiations and comply with any licensing, employment or related regulatory requirements in that country.
Sales of substantial amounts of shares of our common stock or other securities by our stockholders or by us, including sales made under our At the Market Offering Sales Agreement with Cantor Fitzgerald and RBC Capital Markets, LLC, pursuant to which we may offer and sell shares of our common stock having an aggregate offering price of up to $125 million from time to time, through the Sales Agent by any method that is deemed to be an “at the market” offering as defined in Rule 415(a)(4) promulgated under the Securities Act, or the issuance of shares of our common stock upon conversion of our outstanding 2026 Convertible Notes or any future securities convertible or exchangeable into our common stock or in connection with a strategic transaction or otherwise, could dilute our stockholders, lower the market price of our common stock and impair our ability to raise capital through the sale of equity securities. ​ Item 1B.
Sales of substantial amounts of shares of our common stock or other securities by our stockholders or by us, including sales made under our At the Market Offering Sales Agreement with Cantor Fitzgerald and RBC Capital Markets, LLC, pursuant to which we may offer and sell shares of our common stock having an aggregate offering price of up to $125 million from time to time, through the Sales Agent by any method that is deemed to be an “at the market” offering as defined in Rule 415(a)(4) promulgated under the Securities Act, or the issuance of shares of our common stock upon conversion or maturity of our outstanding 2026 Convertible Notes or any future securities convertible or exchangeable 102 Table of Contents into our common stock or in connection with a strategic transaction or otherwise, could dilute our stockholders, lower the market price of our common stock and impair our ability to raise capital through the sale of equity securities. ​ Item 1B.
If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct our preclinical studies or clinical trials in accordance with regulatory requirements or our stated protocols, if they need to be replaced or if the quality or accuracy of the data they obtain is compromised due to the failure to adhere to our protocols, regulatory requirements or for other reasons, our trials may be repeated, extended, delayed, or terminated, we may not be able to obtain, or may be delayed in obtaining, marketing approvals for our product candidates, we may not be able to, or may be delayed in our efforts to, successfully commercialize our product candidates, or we or they may be subject to regulatory enforcement actions.
If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct our preclinical studies or clinical trials in accordance with regulatory requirements or our stated protocols, if they need to be replaced or if the quality or accuracy of the data they obtain is compromised due to the failure to adhere to our protocols, 88 Table of Contents regulatory requirements or for other reasons, our trials may be repeated, extended, delayed, or terminated, we may not be able to obtain, or may be delayed in obtaining, marketing approvals for our product candidates, we may not be able to, or may be delayed in our efforts to, successfully commercialize our product candidates, or we or they may be subject to regulatory enforcement actions.
These cost containment measures may include: ● controls on government funded reimbursement for drugs; ● caps or mandatory discounts under certain government sponsored programs; 94 Table of Contents ● controls on healthcare providers; ● challenges to the pricing of drugs or limits on reimbursement of specific products through other means; ● reform of drug importation laws and policies; ● expansion of use of managed care systems in which the healthcare providers contract to provide comprehensive healthcare for a fixed cost per person; and ● requirements or restrictions related to direct-to-consumer advertising or drug marketing practices.
These cost containment measures may include: ● controls on government funded reimbursement for drugs; ● caps or mandatory discounts under certain government sponsored programs; ● controls on healthcare providers; ● challenges to the pricing of drugs or limits on reimbursement of specific products through other means; ● reform of drug importation laws and policies; ● expansion of use of managed care systems in which the healthcare providers contract to provide comprehensive healthcare for a fixed cost per person; and ● requirements or restrictions related to direct-to-consumer advertising or drug marketing practices.
Laws and regulations governing export restrictions and economic sanctions may preclude us from developing and selling certain products, generating revenue from such products, and manufacturing certain materials outside of the United States. Many countries, including the United States, restrict the export or import of products to or from certain countries through, for example, bans, sanction programs, and boycotts.
Laws and regulations governing export restrictions and economic sanctions may preclude us from developing and selling certain products, generating revenue from such products, and manufacturing certain materials outside of the United States. Many countries, including the United States, restrict the export or import of products to or from certain countries through, for example, bans, sanction programs, and embargoes.
Failure to comply with the applicable regulatory requirements, including with respect to clinical trials conducted outside the EU and United States, can also lead regulatory authorities to refuse to accept into account clinical trial data submitted as part of a marketing application, as well as other regulatory consequences, as further described above.
Failure to comply with the applicable regulatory requirements, including with respect to clinical trials conducted outside the EU and United States, can also lead regulatory authorities to refuse to accept clinical trial data submitted as part of a marketing application, as well as other regulatory consequences, as further described above.
Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.
Further, on November 30, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.
We have entered into arrangements with certain third parties to market or distribute Translarna for the treatment of nmDMD in certain countries and, as we continue to implement our commercialization plans for Translarna, we anticipate that we will engage additional third parties to perform these functions for us in other countries.
We have entered into arrangements with certain third parties to market or distribute Sephience for the treatment of PKU and Translarna for the treatment of nmDMD in certain countries and, as we continue to implement our commercialization plans for Sephience and Translarna, we anticipate that we will engage additional third parties to perform these functions for us in other countries.
While we have submitted pricing and reimbursement dossiers with respect to Translarna for the treatment of nmDMD and Upstaza for the treatment of AADC deficiency in many EEA countries, we have only received both pricing and reimbursement approval on terms that are acceptable to us in a limited number of countries.
While we have submitted pricing and reimbursement dossiers with respect to Sephience for the treatment of PKU, Translarna for the treatment of nmDMD, and Upstaza for the treatment of AADC deficiency in many EEA countries, we have only received both pricing and reimbursement approval on terms that are acceptable to us in a limited number of countries.
As a result, a purchaser in one EU member state may seek to import Translarna from another EU member state where Translarna is sold at a lower price. This could have a negative impact on our business, financial condition, results of operations and growth.
As a result, a purchaser in one EU member state may seek to import Sephience from another EU member state where Sephience is sold at a lower price. This could have a negative impact on our business, financial condition, results of operations and growth.
If we or our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the EU member state regulatory authorities, FDA, or other ex-U.S. regulatory agencies, we and they will not be able to secure and/or maintain regulatory approval for the manufacturing facilities, and we would not be able to secure and/or maintain, or may be delayed in securing regulatory approval of marketing applications or supplements for the applicable products or product candidates.
If we or our 86 Table of Contents contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the EU member state regulatory authorities, FDA, or other ex-U.S. regulatory agencies, we and they will not be able to secure and/or maintain regulatory approval for the manufacturing facilities, and we would not be able to secure and/or maintain, or may be delayed in securing regulatory approval of marketing applications or supplements for the applicable products or product candidates.
For example, our marketing authorization for Translarna for the treatment of nmDMD in the EEA is subject to annual review and renewal by the EC following reassessment by the EMA of the benefit-risk balance of the authorization, as well as the specific obligation to conduct and report the results of Study 041.
For example, our marketing authorization for Translarna for the treatment of nmDMD in the EEA was subject to annual review and renewal by the EC following reassessment by the EMA of the benefit-risk balance of the authorization, as well as the specific obligation to conduct and report the results of Study 041.
In the EU, reference pricing systems and other measures may lead to cost containment and reduced prices with respect to Translarna for the treatment of nmDMD, Upstaza for the treatment of AADC deficiency and other product candidates that might receive marketing authorization in the future.
In the EU, reference pricing systems and other measures may lead to cost containment and reduced prices with respect to Sephience for the treatment of PKU, Translarna for the treatment of nmDMD, Upstaza for the treatment of AADC deficiency and other product candidates that might receive marketing authorization in the future.
Recent legislation further delayed implementation of the new safe harbors and the revision to the discount safe harbor until January 1, 2032. There may be future changes in legal and regulatory requirements that may materially impact our results of operation.
Recent legislation further delayed implementation of the new safe harbors and the revision to the discount safe harbor until January 1, 2032. There may be future and have been changes in legal and regulatory requirements that may materially impact our results of operation.
If we do not successfully maintain our marketing authorizations for our products and obtain new marketing authorizations for our product candidates and new uses of our approved products, our ability to generate additional revenue will be 62 Table of Contents jeopardized and, consequently, our business will be materially harmed.
If we do not successfully maintain our marketing authorizations for our products and obtain new marketing authorizations for our product candidates and new uses of our approved products, our ability to generate additional revenue will be 54 Table of Contents jeopardized and, consequently, our business will be materially harmed.
As a result, we might obtain marketing authorization for a product in a particular country, but then be subject to price regulations, in some countries at national as well as regional levels, that delay our commercial launch of the product, possibly for lengthy time periods, and negatively impact the 76 Table of Contents revenues we are able to generate from the sale of the product in that country.
As a result, we might obtain marketing authorization for a product in a particular country, but then be subject to price regulations, in some countries at national as well as regional levels, that delay our commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the product in that country.
These sales also might make it difficult for us to sell equity securities in the future at a time and at a price that we deem appropriate. 111 Table of Contents Certain of our employees, executive officers and directors have entered or may enter into Rule 10b5-1 plans providing for sales of shares of our common stock from time to time.
These sales also might make it difficult for us to sell equity securities in the future at a time and at a price that we deem appropriate. Certain of our employees, executive officers and directors have entered or may enter into Rule 10b5-1 plans providing for sales of shares of our common stock from time to time.
For example, there are no marketed therapies approved to treat the underlying cause of nmDMD and there is limited clinical trial experience with respect to drugs to treat nmDMD and other diseases that we are studying or have studied.
For example, there are no marketed therapies approved to treat the underlying cause of HD and there is limited clinical trial experience with respect to drugs to treat HD and other diseases that we are studying or have studied.
Enforcing a claim that a third party illegally obtained and is using any of our inventions or trade secrets is expensive and time-consuming, and the outcome is unpredictable. In addition, courts outside of the United States are sometimes less willing to protect trade secrets. Moreover, our competitors may independently develop equivalent knowledge, methods and know-how.
Enforcing a claim that a third party illegally obtained and is using any of our inventions or trade secrets is expensive and time-consuming, and the outcome is unpredictable. In addition, courts outside of the United States are 97 Table of Contents sometimes less willing to protect trade secrets. Moreover, our competitors may independently develop equivalent knowledge, methods and know-how.
Our current gene therapy license agreements, including our agreement with NTU pursuant to which we have in-licensed certain intellectual property rights and know-how relevant to Upstaza/Kebilidi for the treatment of AADC deficiency, impose various obligations, including certain payment obligations, including contingent payments to be made upon reaching certain development and regulatory milestones.
Our current gene therapy license agreements, including our agreement with NTU pursuant to which we have in-licensed certain intellectual property rights and know-how relevant to Upstaza/Kebilidi for the treatment of AADC deficiency, impose various obligations, including certain payment obligations, including contingent payments to be made 98 Table of Contents upon reaching certain development and regulatory milestones.
The FDA must specify the conditions for the required post approval studies, including enrollment targets, the study protocol, milestones, and target completion dates, by the time of approval and the FDA may require that the post-approval studies be commenced before the date of approval.
The FDA must specify the conditions for the required post approval studies, including enrollment targets, the study protocol, milestones, and target completion dates, by the time of approval and the FDA may, and frequently does, require that the post-approval studies be commenced before the date of approval.
We have obtained orphan drug designations from the EMA and from the FDA for Translarna for the treatment of nmDMD, Upstaza/Kebilidi for the treatment of AADC, Evrysdi for the treatment of SMA, sepiapterin for the treatment of patients with hyperphenylalaninemia, including hyperphenylalaninemia caused by PKU and vatiquinone for the treatment of FA.
We have obtained orphan drug designations from the FDA and the EMA for Sephience for the treatment of patients with hyperphenylalaninemia, including hyperphenylalaninemia caused by PKU, Translarna for the treatment of nmDMD, Upstaza/Kebilidi for the treatment of AADC, Evrysdi for the treatment of SMA, and vatiquinone for the treatment of FA.
For example, certain changes and supplements to an approved BLA, and certain subsequent applications filed by the same sponsor, manufacturer, licensor, predecessor in interest, or other related entity do not qualify for the 12-year exclusivity 90 Table of Contents period. Moreover, there have been legislative efforts to decrease this period of exclusivity to a shorter timeframe.
For example, certain changes and supplements to an approved BLA, and certain subsequent applications filed by the same sponsor, manufacturer, licensor, predecessor in interest, or other related entity do not qualify for the 12-year exclusivity period. Moreover, there have been legislative efforts to decrease this period of exclusivity to a shorter timeframe.
The degree of market acceptance of our products or product candidates, if approved for commercial sale, will depend on a number of factors, including: ● the efficacy and potential advantages, as well as cost effectiveness compared to alternative treatments; ● the prevalence and severity of any side effects, as well as perceived safety; ● limitations or warnings contained in, as well as permitted claims based on the product’s FDA-approved labeling; ● whether patients may be ineligible to receive a particular product or whether a particular product, especially in the case of gene therapies, may preclude future treatments; ● distribution and use restrictions imposed by the FDA or which we voluntarily implement; ● the ability to offer our products or product candidates for sale at competitive prices; ● the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies.
The degree of market acceptance of our products or product candidates, if approved for commercial sale, will depend on a number of factors, including: ● the efficacy and potential advantages, as well as cost effectiveness compared to alternative treatments; ● the prevalence and severity of any side effects, as well as perceived safety; ● limitations or warnings contained in, as well as permitted claims based on the product’s approved labeling; ● whether patients may be ineligible to receive a particular product or whether a particular product, especially in the case of gene therapies, may preclude future treatments; ● distribution and use restrictions imposed by the FDA or other regulatory agencies, or which we voluntarily implement; 61 Table of Contents ● the ability to offer our products or product candidates for sale at competitive prices; ● the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies.
Cost reduction initiatives and other provisions of this legislation could decrease the coverage and reimbursement that we receive for any approved products. While the Medicare Modernization Act applies only to drug benefits for Medicare beneficiaries, private payors often follow Medicare coverage policy and payment limitations in setting their own policies.
Cost reduction initiatives and other provisions of this 83 Table of Contents legislation could decrease the coverage and reimbursement that we receive for any approved products. While the Medicare Modernization Act applies only to drug benefits for Medicare beneficiaries, private payors often follow Medicare coverage policy and payment limitations in setting their own policies.
Government authorities, including the United States government and state legislatures, and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. Prices at which our products are reimbursed can be subject to challenge, reduction or denial by the government and other payers.
Government authorities, including the United States government and state legislatures, and other third-party payors have 67 Table of Contents attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. Prices at which our products are reimbursed can be subject to challenge, reduction or denial by the government and other payers.
Certain of our products and product candidates may be difficult to produce, presenting manufacturing challenges that may delay product development and regulatory approval. Manufacturers of pharmaceutical products must comply with strictly enforced manufacturing and quality requirements, including cGMP requirements, state and federal regulations, as well as ex-U.S. requirements when applicable.
Certain of our products and product candidates may be difficult to produce, presenting manufacturing challenges that may delay product development and regulatory approval. 60 Table of Contents Manufacturers of pharmaceutical products must comply with strictly enforced manufacturing and quality requirements, including cGMP requirements, state and federal regulations, as well as ex-U.S. requirements when applicable.
Other biopharmaceutical companies are developing treatments addressing the underlying cause of disease for different mutations in the DMD gene, including, Dyne Therapeutics (DYNE-251), Wave Life Sciences (WVE-N53), Daiichi Sankyo (DS 5141)), Nippon Shinyaku (Viltolarsen (NS 065/NCNP 01) and NS 089/NCNP 02)), and Astellas (AT 702).
Other biopharmaceutical companies are developing treatments addressing the underlying cause of disease for different mutations in the DMD gene, including, Dyne Therapeutics (DYNE-251), Wave Life Sciences (WVE-N53), Daiichi Sankyo (DS 5141)), and Nippon Shinyaku (Viltolarsen (NS 065/NCNP 01) and NS 089/NCNP 02)).
Further, any of these third parties may terminate their engagements with us at any time. If we need to enter into alternative arrangements, it will delay our product development activities. 98 Table of Contents Our reliance on these third parties for clinical development activities reduces our control over these activities but does not relieve us of our responsibilities.
Further, any of these third parties may terminate their engagements with us at any time. If we need to enter into alternative arrangements, it will delay our product development activities. Our reliance on these third parties for clinical development activities reduces our control over these activities but does not relieve us of our responsibilities.
We have previously relied on an orphan exclusivity period to commercialize Emflaza in the United States. Emflaza’s seven-year period of orphan drug exclusivity related to the treatment of DMD in patients five years and older expired in February 2024. We expect the expiration of this orphan drug exclusivity to have a significant negative impact on Emflaza net product revenue.
We have previously relied on an orphan exclusivity period to commercialize Emflaza in the United States. Emflaza’s seven-year period of orphan drug exclusivity related to the treatment of DMD in patients five years and older expired in February 2024. We expect the expiration of this orphan drug exclusivity will continue to have a negative impact on Emflaza net product revenue.
If we fail to successfully secure and maintain pricing and reimbursement coverage for Translarna or Upstaza or are significantly delayed in doing so or if burdensome conditions are imposed by private payers, government authorities or other third-party payors on such reimbursement, planned launches in the affected countries will be delayed and our business, results of operations and financial condition could be adversely affected.
If we fail to successfully secure and maintain pricing and reimbursement coverage for Sephience, Translarna or Upstaza or are significantly delayed in doing so or if burdensome conditions are imposed by private payers, government authorities 82 Table of Contents or other third-party payors on such reimbursement, planned launches in the affected countries will be delayed and our business, results of operations and financial condition could be adversely affected.
Failure to maintain a comprehensive and effective compliance program, and to 92 Table of Contents integrate the operations of any acquired businesses into a combined comprehensive and effective compliance program on a timely basis, could result in business practices and operations that expose us to a range of regulatory actions that could adversely affect our ability to commercialize our products and could harm or prevent sales of the affected products, or could substantially increase the costs and expenses of commercializing and marketing our products.
Failure to maintain a comprehensive and effective compliance program, and to integrate the operations of any acquired businesses into a combined comprehensive and effective compliance program on a timely basis, could result in business practices and operations that expose us to a range of regulatory and enforcement actions that could adversely affect our ability to commercialize our products and could harm or prevent sales of the affected products, or could substantially increase the costs and expenses of commercializing and marketing our products.
If these third-party service 100 Table of Contents providers fail to comply with applicable laws and regulations, fail to meet expected deadlines, or otherwise do not carry out their contractual duties to us, or encounter physical or natural damage at their facilities, our ability to deliver product to meet commercial demand would be significantly impaired and we may be subject to regulatory enforcement action.
If these third-party service providers fail to comply with applicable laws and regulations, fail to meet expected deadlines, or otherwise do not carry out their contractual duties to us, or encounter physical or natural damage at their facilities, our ability to deliver product to meet commercial demand would be significantly impaired and we may be subject to regulatory enforcement action.
During this time, the FDA may not make the licensure of a biosimilar product effective. Biosimilar applications can, however, be submitted for FDA review beginning four years after the date of the reference product’s first licensure. This exclusivity period, however, is subject to certain limitations.
During this time, the FDA may not make the licensure of a biosimilar product effective. Biosimilar applications can, however, be submitted for FDA review beginning four years 80 Table of Contents after the date of the reference product’s first licensure. This exclusivity period, however, is subject to certain limitations.
Additionally, outside parties may attempt to fraudulently induce employees, collaborators, or other third-party vendors to disclose sensitive information or take other actions, including making fraudulent payments or downloading malware, by using “spoofing” and “phishing” emails or other types of attacks.
Additionally, outside parties may attempt to fraudulently induce employees, collaborators, or other third-party vendors to disclose sensitive information or take other actions, including making fraudulent payments or downloading malware, by using “spoofing” and “phishing” emails or 91 Table of Contents other types of attacks.
In addition, future strategic transactions may entail numerous operational, financial and legal risks, including: ● incurrence of substantial debt, dilutive issuances of securities or depletion of cash to pay for acquisitions; ● exposure to known and unknown liabilities, including possible intellectual property infringement claims, violations of laws, tax liabilities and commercial disputes; ● higher than expected acquisition and integration costs; ● difficulty in integrating operations and personnel of any acquired business; 84 Table of Contents ● increased amortization expenses or, in the event that we write-down the value of acquired assets, impairment losses; ● impairment of relationships with key suppliers or customers of any acquired business due to changes in management and ownership; ● inability to retain personnel, customers, distributors, vendors and other business partners integral to an in-licensed or acquired product, product candidate or technology; ● potential failure of the due diligence processes to identify significant problems, liabilities or other shortcomings or challenges; ● entry into indications or markets in which we have no or limited direct prior development or commercial experience and where competitors in such markets have stronger market positions; and ● other challenges associated with managing an increasingly diversified business.
Any of the foregoing could have a detrimental effect on our business, results of operations and financial condition. 74 Table of Contents In addition, future strategic transactions may entail numerous operational, financial and legal risks, including: ● incurrence of substantial debt, dilutive issuances of securities or depletion of cash to pay for acquisitions; ● exposure to known and unknown liabilities, including possible intellectual property infringement claims, violations of laws, tax liabilities and commercial disputes; ● higher than expected acquisition and integration costs; ● difficulty in integrating operations and personnel of any acquired business; ● increased amortization expenses or, in the event that we write-down the value of acquired assets, impairment losses; ● impairment of relationships with key suppliers or customers of any acquired business due to changes in management and ownership; ● inability to retain personnel, customers, distributors, vendors and other business partners integral to an in-licensed or acquired product, product candidate or technology; ● potential failure of the due diligence processes to identify significant problems, liabilities or other shortcomings or challenges; ● entry into indications or markets in which we have no or limited direct prior development or commercial experience and where competitors in such markets have stronger market positions; and ● other challenges associated with managing an increasingly diversified business.
These new laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidates is prescribed or used.
These laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidates are prescribed or used.
We expect to continue to generate operating losses through 2025 and, while we anticipate that operating losses generated in future periods should decline versus prior periods, we may never generate profits from operations or maintain profitability. The net losses we incur may fluctuate significantly from period to period.
We may continue to generate operating losses through 2026 and, while we anticipate that operating losses generated in future periods should decline versus prior periods, we may never generate profits from operations or maintain profitability. The net losses we incur may fluctuate significantly from period to period.
For instance, orphan drug designations may be revoked if the FDA finds that the request for designation contained an untrue statement of material fact or omitted material information, or if the FDA finds that the product candidate was not eligible for designation at the time of the submission of the request.
For instance, orphan drug designations may be revoked if the FDA finds that the request for designation contained an untrue statement of material fact or omitted 77 Table of Contents material information, or if the FDA finds that the product candidate was not eligible for designation at the time of the submission of the request.
Furthermore, the successful development of another product candidate from our spinal 99 Table of Contents muscular atrophy program will depend on the success of our collaborations with the SMA Foundation and Roche, including whether Roche pursues clinical development of any other compounds identified under the collaborations.
Furthermore, the successful development of another product candidate from our spinal muscular atrophy program will depend on the success of our collaborations with the SMA Foundation and Roche, including whether Roche pursues clinical development of any other compounds identified under the collaborations.
More recently, Congress amended the Medicaid statute, effective October 1, 2019, to exclude prices paid by secondary manufacturers for an authorized generic drug (but 93 Table of Contents not a product approved under the BLA process) from the NDA holder’s AMP for the brand, thereby increasing the rebate amount and the 340B price for the brand.
More recently, Congress amended the Medicaid statute, effective October 1, 2019, to exclude prices paid by secondary manufacturers for an authorized generic drug (but not a product approved under the BLA process) from the NDA holder’s AMP for the brand, thereby increasing the rebate amount and the 340B price for the brand.
In addition, because our board of directors is responsible for appointing our management team, these provisions may frustrate or prevent any 109 Table of Contents attempts by our stockholders to replace or remove our current management by making it more difficult for stockholders to replace members of our board of directors.
In addition, because our board of directors is responsible for appointing our management team, these provisions may frustrate or prevent any attempts by our stockholders to replace or remove our current management by making it more difficult for stockholders to replace members of our board of directors.
A substantial portion of our commercial sales currently occurs in territories outside of the United States which subjects us to additional business risks that could adversely affect our revenue and results of operations. We commercialize Translarna, Upstaza, Tegsedi and Waylivra outside of the United States. We have operations in multiple European countries, Latin America and other territories.
A significant portion of our commercial sales currently occurs in territories outside of the United States which subjects us to additional business risks that could adversely affect our revenue and results of operations. We commercialize Sephience, Translarna, Upstaza, Tegsedi and Waylivra outside of the United States. We have operations in multiple European countries, Latin America, Japan and other territories.
In some countries we may be required to conduct additional clinical trials or other studies of our product, including trials that compare the cost-effectiveness of our product to other available therapies in 91 Table of Contents order to obtain reimbursement or pricing approval.
In some countries we may be required to conduct additional clinical trials or other studies of our product, including trials that compare the cost-effectiveness of our product to other available therapies in order to obtain reimbursement or pricing approval.
We must further ensure that our preclinical trials are conducted in accordance with good laboratory practices, or GLPs, as appropriate. Regulatory authorities enforce these requirements through periodic inspections or remote regulatory assessments of trial sponsors, clinical and preclinical investigators, and trial sites. Similar GCP and transparency requirements apply in the EU.
We must further ensure that our preclinical trials are conducted in accordance with good laboratory practices, or GLPs, as appropriate. Regulatory authorities enforce these requirements through periodic inspections (remotely or in person) of trial sponsors, clinical and preclinical investigators, and trial sites. Similar GCP and transparency requirements apply in the EU.
We believe that we have in the past experienced ownership changes within the meaning of Sections 382 and 383 that have resulted in limitations under Sections 382 and 383 (and similar state provisions) on the use of our NOLs and other tax attributes.
We believe that we 75 Table of Contents have in the past experienced ownership changes within the meaning of Sections 382 and 383 that have resulted in limitations under Sections 382 and 383 (and similar state provisions) on the use of our NOLs and other tax attributes.
There is significant risk that we will be unable to obtain approval for our product candidates on a timely basis or at all, and we may be required to perform additional clinical trials, non-clinical studies or CMC assessments, work, or analyses at significant cost.
There is significant risk that we will be unable to obtain approval for our product candidates on a timely basis or at all, and we may be required to perform additional clinical trials, non-clinical studies or CMC assessments, work, or analyses at 55 Table of Contents significant cost.
In some instances, reimbursement may be subject to challenge, reduction or denial by the government and other payors. For example, in France, EAP and commercial sales of a product can begin while pricing and reimbursement rates are under discussion with the applicable government health programs.
In some instances, reimbursement may be subject to challenge, reduction or denial by the government and other payors. In some countries, EAP and commercial sales of a product can begin while pricing and reimbursement rates are under discussion with the applicable government health programs.
We may rely on third parties to perform many essential services for any products that we commercialize, including services related to warehousing and inventory control, distribution, government price reporting, customer service, accounts receivable management, cash collection, and pharmacovigilance and adverse event reporting.
We may rely on third parties to perform many essential services for any products that we commercialize, including services related to warehousing and inventory control, distribution, government price reporting, customer service, 90 Table of Contents accounts receivable management, cash collection, and pharmacovigilance and adverse event reporting.
Our business may not generate cash flow from operations in the future sufficient to service our debt, including the 2026 Convertible Notes.
Our business may not generate cash flow from operations sufficient to service our debt, including the 2026 Convertible Notes.
Accordingly, we and others with whom we work must continue to expend time, money, and effort in all areas of regulatory compliance, including manufacturing and distribution. Regulatory authorities conduct ongoing reviews and inspections or remote regulatory assessments of marketed products, as well as sponsors and manufacturing facilities.
Accordingly, we and others with whom we work must continue to expend time, money, and effort in all areas of regulatory compliance, including manufacturing and distribution. Regulatory authorities conduct ongoing reviews and inspections (remotely or in person) of marketed products, as well as sponsors and manufacturing facilities.
In addition, U.S. government-funded inventions must be reported to the government and U.S. government 108 Table of Contents funding must be disclosed in any resulting patent applications. Furthermore, our rights in such inventions are subject to government license rights and certain restrictions on manufacturing products outside the United States.
In addition, U.S. government-funded inventions must be reported to the government and U.S. government funding must be disclosed in any resulting patent applications. Furthermore, our rights in such inventions are subject to government license rights and certain restrictions on manufacturing products outside the United States.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeOur CIO reports directly to our Chief Legal Officer, both of whom are members of our executive committee leadership team. Cybersecurity incident status updates are provided as necessary to the executive committee as set forth in our GIRM. In the event of a cybersecurity incident, our IT team is trained to follow our GIRM.
Biggest changeCybersecurity incident status updates are provided as necessary to the executive committee as set forth in our GIRM.
Item 1C. Cybersecurity Cybersecurity Risk Management and Strategy As is the case for most companies, we are regularly subject to cyber-attacks and other cyber incidents and, therefore, cybersecurity is an important element of our overall enterprise risk management program.
Item 1C. Cybersecurity Cybersecurity Risk Management and Strategy As is the case for most companies, we are regularly subject to cyber-attacks and other cyber incidents, therefore, cybersecurity is an important element of our overall enterprise risk management program.
As part of our overall risk management strategy, we also maintain cyber insurance coverage; however, such insurance may not be sufficient in type or amount to cover us against claims related to security breaches, cyber-attacks and other related breaches.
As part of our overall risk management strategy, we also maintain cyber insurance coverage, however, such insurance may not be sufficient in type or amount to cover us against all claims related to security breaches, cyber-attacks and other related breaches.
Risk Factors, “Our business and operations would suffer in the event of computer system failures, cyber-attacks or a deficiency in our, or our collaborators’ or third-party vendors’, cyber-security.”
Risk Factors, “ Our business and operations would suffer in the event of computer system failures, cyber-attacks or a deficiency in our, or our collaborators’ or third-party vendors’, cyber-security. ”
See “ Our business and operations would suffer in the event of computer system failures, cyber-attacks or a deficiency in our, or our collaborators’ or third-party vendors’, cyber-security” in Part I, Item 1A. “Risk Factors” for additional information.
See “ Our business and operations would suffer in the event of computer system failures, cyber-attacks or a deficiency in our, or our collaborators’ or third-party vendors’, cyber-security ” in Part I, Item 1A. “Risk Factors” for additional information.
As regulatory disclosure requirements regarding cybersecurity incidents and data privacy matters have 112 Table of Contents become more prevalent, we have developed an incident workflow designed to monitor and evaluate if such disclosure requirements are triggered by an incident through the inclusion of members of our legal, data privacy and executive teams in the incident response process.
As regulatory disclosure requirements regarding cybersecurity incidents and data privacy matters have become more prevalent, we have developed an incident workflow designed to monitor and evaluate if such disclosure requirements are triggered by an incident through the inclusion of members of our legal, data privacy and executive teams in the incident response process.
The Board of Directors receives regular reports from the Audit Committee. Our CIO also presents directly to our Board of Directors on an annual basis on these matters. Our IT team is responsible for maintaining daily operations and ensuring the confidentiality, integrity and availability of data.
The Board of Directors receives regular reports from the Audit Committee. Our CIO also presents directly to our Board of Directors on an annual basis on these matters. Our CIO oversees a cybersecurity and IT team that is responsible for maintaining daily operations and ensuring the confidentiality, integrity, and availability of data.
Cybersecurity Governance and Oversight Our Board of Directors administers its cybersecurity risk oversight function primarily through the Audit Committee of the Board of Directors.
Cybersecurity Governance and Oversight 103 Table of Contents Our Board of Directors administers its cybersecurity risk oversight function primarily through the Audit Committee of the Board of Directors.
We also conduct security assessments of all third-party providers before engagement and maintain ongoing monitoring to ensure compliance with our cybersecurity standards.
In relation to third party risk management, we conduct security assessments of third-party providers and software before engagement and maintain ongoing monitoring to ensure compliance with our cybersecurity standards.
We have a multilayered approach for assessing, identifying and managing cybersecurity risks, that is designed to help protect such information from internal and external cyber threats by understanding and seeking to mitigate risk while ensuring business resiliency.
We have a multilayered approach for assessing, identifying and managing cybersecurity risks, that is designed to help protect such information from internal and external cyber threats by understanding and seeking to mitigate risk while ensuring business resiliency. Our cybersecurity program aligns with the industry standard National Institute of Standards and Technology Cybersecurity Framework.
This process involves third-party providers responding to cybersecurity questionnaires and information technology, or IT, security team meetings to review and assess the third-party providers security posture to confirm that the provider is ensuring the security, integrity, and availability of processed data. We have also established a global incident response management standard operating procedure, or GIRM.
This process involves third-party providers responding to cybersecurity and information technology questionnaires and attending review meetings to assess the third-party providers security posture to confirm that the provider is ensuring the security, integrity, and availability of processed data.
Our GIRM provides step-by-step instructions for managing any global incident which is disruptive of or interferes with the delivery and operation of our IT services and systems that are in use. Specifically, our GIRM provides direction as to how information with respect to a cybersecurity incident is communicated internally, including with our executive committee leadership team.
Our GIRM Standard Operating Procedure provides step-by-step instructions for managing any global incident which is disruptive of or interferes with the delivery and operation of our IT services and systems that are in use. The GIRM process involves IT groups, the Cybersecurity team, IT Leadership, and the Executive Leadership where appropriate.
We engage third parties, including independent privacy assessors, computer security firms and risk management and governance experts to enhance our cybersecurity oversight. For example, on an annual basis we run a penetration test of our systems, performed by a different external third party each year. We also regularly consult with these third parties on emerging industry trends.
We regularly engage third parties, including independent privacy assessors, computer security firms and risk management and governance experts to enhance our cybersecurity oversight and consult with these third parties on emerging industry trends.
Our CIO oversees a cybersecurity team that has over 15 years’ experience in cybersecurity along with advanced and undergrad degrees in cybersecurity, and industry recognized security certifications such as CISSP (Certified Information Systems Security Professional) and CISM (Certified Information Security Manager).
The cybersecurity team has over 15 years’ experience in cybersecurity along with advanced and undergraduate degrees in cybersecurity, and industry recognized security certifications such as CISSP (Certified Information Systems Security Professional) and CISM (Certified Information Security Manager). Our CIO reports directly to our Chief Legal Officer, both of whom are members of our executive committee leadership team.
Our cybersecurity prevention methods include implementing the National Institute of Standards and Technology cybersecurity framework, instituting a training and compliance program on cybersecurity for all employees, completing a yearly external audit and penetration test, conducting vulnerability scans and remediations and monitoring threat intelligence feeds.
Our program is comprehensive and provides for the identification, prevention, and mitigation of cybersecurity threats and risks. We have monthly and annual cybersecurity training, a compliance program on cybersecurity for employees and contractors, an annual external audit, independent penetration tests, ongoing vulnerability scans and remediations.
Added
We also utilize a Managed Detection and Response vendor to support our cybersecurity program and monitor our network internally and externally for threat identification and mitigation. In addition, we have established a global incident response management, or GIRM, process.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeAdditionally, we lease approximately 5,000 square feet of office space in Sao Paulo, Brazil, that we occupy under a lease that expires in 2028. We also lease 113 Table of Contents additional laboratory and office space in the U.S. and other countries to support our operations as a global organization, but these leases are not material to us.
Biggest changeAdditionally, we lease approximately 5,000 square feet of office space in Sao Paulo, Brazil, that we occupy under a lease that expires in 2028. We also lease additional laboratory and office space in the U.S. and other countries to support our operations as a global organization, but these leases are not material to us.

Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

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Biggest changeMine Safety Disclosures None. ​ 114 Table of Contents PART II
Biggest changeMine Safety Disclosures None. ​ 104 Table of Contents PART II

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeHolders As of February 25, 2025, there were 78 holders of record of our common stock. This number does not include beneficial owners whose shares are held in street name.
Biggest changeHolders As of February 18, 2026, there were 73 holders of record of our common stock. This number does not include beneficial owners whose shares are held in street name.

Item 7. Management's Discussion & Analysis

Management's Discussion & Analysis (MD&A) — revenue / margin commentary

137 edited+71 added−89 removed101 unchanged
Biggest changeOur future capital requirements will depend on many factors, including: ● our ability to maintain our marketing authorization for Translarna for the treatment of nmDMD in the EEA following the CHMP’s negative opinion on the conditional marketing authorization procedure, and the EC’s potential adoption of the negative opinion, or identify other potential mechanisms in which we may provide Translarna to nmDMD patients in the EEA; ● our ability to maintain the marketing authorization for Translarna and our other products in territories outside of the EEA; ● our ability to commercialize and market our products and product candidates that may receive marketing authorization; ● our ability to negotiate, secure and maintain adequate pricing, coverage and reimbursement terms, on a timely basis, with third-party payors for our products and products candidates; ● the amount of generic drug competition that we face for Emflaza for the treatment of DMD in patients five years and older; ​ ● our ability to obtain marketing authorization for sepiapterin for the treatment of PKU in the United States and EEA; ● our ability to obtain marketing authorization for Translarna for the treatment of nmDMD in the United States; ● our ability to obtain marketing authorization for vatiquinone for the treatment of FA in the United States; ● our ability to successfully complete all post-marketing requirements imposed by regulatory agencies with respect to our products; ● the progress and results of activities for sepiapterin and our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications; ● the scope, costs and timing of our commercialization activities, including product sales, marketing, legal, regulatory, distribution and manufacturing, for any of our products and for any of our other product candidates that may receive marketing authorization or any additional territories in which we receive authorization to market Translarna; ● the costs, timing and outcome of regulatory review of sepiapterin and our splicing and inflammation and ferroptosis programs and Translarna and Upstaza/Kebilidi in other territories; ● our ability to satisfy our obligations under the indenture governing the 2026 Convertible Notes; ● the timing and scope of any potential future growth in our employee base; 136 Table of Contents ● the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our other product candidates, including those in our splicing and inflammation and ferroptosis programs; ● revenue received from commercial sales of our products or any of our product candidates; ● our ability to obtain additional and maintain existing reimbursed named patient and cohort EAP programs for Translarna for the treatment of nmDMD on adequate terms, or at all; ● the ability and willingness of patients and healthcare professionals to access Translarna through alternative means if pricing and reimbursement negotiations in the applicable territory do not have a positive outcome; ● the costs of preparing, filing and prosecuting patent applications, maintaining, and protecting our intellectual property rights and defending against intellectual property-related claims; ● the extent to which we acquire or invest in other businesses, products, product candidates, and technologies, including the success of any acquisition, in-licensing or other strategic transaction we may pursue, and the costs of subsequent development requirements and commercialization efforts, including with respect to our acquisitions of Emflaza, Agilis, our inflammation and ferroptosis platform and Censa and our licensing of Tegsedi and Waylivra; and ● our ability to establish and maintain collaborations, including our collaborations with Roche and the SMA Foundation, and our ability to obtain research funding and achieve milestones under these agreements. ● the progress and results of activities for our PTC518 program, including our right to receive any development, regulatory and sales milestones, profit sharing and royalty payments from Novartis; and ● unexpected decreases in revenue or increase in expenses resulting from potential widespread outbreaks of contagious disease.
Biggest changeOur future capital requirements will depend on many factors, including: ● our ability to commercialize and market our products and product candidates that may receive marketing authorization; 125 Table of Contents ● our ability to negotiate, secure and maintain adequate pricing, coverage and reimbursement terms, on a timely basis, with third-party payors for our products and product candidates; ● our plans for vatiquinone including with respect to the expected timing of clinical trials and studies, availability of data, regulatory submissions and responses, meetings with regulatory agencies, and other matters; ● our ability to successfully complete all post-marketing requirements imposed by regulatory agencies with respect to our products; ● the progress and results of activities for our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications; ● the scope, costs and timing of our commercialization activities, including product sales, marketing, legal, regulatory, distribution and manufacturing, for any of our products and for any of our other product candidates that may receive marketing authorization; ● the costs, timing and outcome of regulatory review of our splicing and inflammation and ferroptosis programs and Sephience, Translarna and Upstaza/Kebilidi in other territories; ● our ability to satisfy our obligations under the indenture governing the 2026 Convertible Notes; ● the timing and scope of any potential future growth in our employee base; ● the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our other product candidates, including those in our splicing and inflammation and ferroptosis programs; ● revenue received from commercial sales of our products or any of our product candidates; ● our ability to obtain additional and maintain existing reimbursed named patient and cohort EAP programs for Translarna for the treatment of nmDMD on adequate terms, or at all; ● the ability and willingness of patients and healthcare professionals to access Translarna through alternative means if pricing and reimbursement negotiations in the applicable territory do not have a positive outcome; ● the costs of preparing, filing and prosecuting patent applications, maintaining, and protecting our intellectual property rights and defending against intellectual property-related claims; ● the extent to which we acquire or invest in other businesses, products, product candidates, and technologies, including the success of any acquisition, in-licensing or other strategic transaction we may pursue, and the costs of subsequent development requirements and commercialization efforts, including with respect to our acquisitions of Emflaza, Agilis, our inflammation and ferroptosis platform and Censa and our licensing of Tegsedi and Waylivra; ● our ability to establish and maintain collaborations, including our collaborations with Roche and the SMA Foundation, and our ability to obtain research funding and achieve milestones under these agreements. ● the progress and results of activities for our votoplam program, including our right to receive any development, regulatory and sales milestones, profit sharing and royalty payments from Novartis; and ● unexpected decreases in revenue or increase in expenses resulting from potential widespread outbreaks of contagious disease. 126 Table of Contents With respect to our outstanding 2026 Convertible Notes, cash interest payments are payable on a semi-annual basis in arrears, which will require total funding of $4.3 million annually.
Research and development expense also included a total of $65.0 million regulatory success-based milestones paid to the former Censa securityholders for the year ended December 31, 2024, as compared to a $30.0 million success-based development milestone paid to the former Censa securityholders for the year ended December 31, 2023. ​ Selling, general and administrative expense.
Research and development expense also included a total of $65.0 million of regulatory success-based milestones paid to the former Censa securityholders for the year ended December 31, 2024, as compared to a $30.0 million success-based development milestone paid to the former Censa securityholders for the year ended December 31, 2023. Selling, general and administrative expense.
Loss on extinguishment of debt was $0.0 million for the year ended December 31, 2024, a decrease of $137.6 million, or 100%, from loss on extinguishment of debt of $137.6 million for the year ended December 31, 2023.
Loss on extinguishment of debt. Loss on extinguishment of debt was $0.0 million for the year ended December 31, 2024, a decrease of $137.6 million, or 100%, from loss on extinguishment of debt of $137.6 million for the year ended December 31, 2023.
Under the Novartis Agreement, and upon the closing of the transaction contemplated by the Novartis Agreement in January 2025, we received an upfront payment of $1.0 billion on the effective date and can receive up to $1.9 billion in development, regulatory and sales milestones, a 40% share of U.S. profits and losses, and tiered double-digit royalties on ex-U.S. sales.
Under the Novartis Agreement, and upon the closing of the transaction contemplated by the Novartis Agreement in January 2025, we received an upfront payment of $1.0 billion on the effective date and can receive up to $1.9 billion in development, regulatory and sales milestones, a 40% share of U.S. profits and losses, and tiered double-digit royalties on ex-U.S. sales.
The remaining potential sales milestones as of December 31, 2024 are $150.0 million upon achievement of certain sales events. In June 2024, we entered into an amendment to the A&R Royalty Purchase Agreement, and we exercised our first put option in exchange for $241.8 million in cash consideration.
The remaining potential sales milestones as of December 31, 2025 are $150.0 million upon achievement of certain sales events. In June 2024, we entered into an amendment to the A&R Royalty Purchase Agreement, and we exercised our first put option in exchange for $241.8 million in cash consideration.
In addition to the foregoing, we expect to continue to incur significant costs in connection with ongoing, planned and potential future clinical trials and studies for sepiapterin and our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications.
In addition to the foregoing, we expect to continue to incur significant costs in connection with ongoing, planned and potential future clinical trials and studies for our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications.
In addition to the foregoing, we expect to continue to incur significant costs in connection with ongoing, planned and potential future clinical trials and studies for sepiapterin and our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications.
In addition to the foregoing, we expect to continue to incur significant costs in connection with ongoing, planned and potential future clinical trials and studies for our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications.
Upstaza is a gene therapy for the treatment of Aromatic L Amino Decarboxylase, or AADC, deficiency, a rare central nervous system, or CNS, disorder arising from reductions in the enzyme AADC that results from mutations in the dopa decarboxylase gene.
Upstaza/Kebilidi is a gene therapy for the treatment of Aromatic L Amino Decarboxylase, or AADC, deficiency, a rare central nervous system, or CNS, disorder arising from reductions in the enzyme AADC that results from mutations in the dopa decarboxylase gene.
The decrease relates to sales milestone of $100.0 million that was recognized for the achievement of $1.5 billion in worldwide annual net sales from Evrysdi in the year ended December 31, 2023. Royalty revenue.
The decrease relates to a sales milestone of $100.0 million that was recognized for the achievement of $1.5 billion in worldwide annual net sales from Evrysdi in the year ended December 31, 2023. Royalty revenue.
We may redeem for cash all or any portion of the 2026 Convertible Notes, at our option, if the last reported sale price of our common stock has been at least 130% of the conversion price then in effect on the last trading day of, and for at least 19 other trading days (whether or not consecutive) during, any 30 consecutive trading day period ending on, and including, the trading day immediately preceding the date on which we provide notice of redemption, at a redemption price equal to 100% of the principal amount 132 Table of Contents of the 2026 Convertible Notes to be redeemed, plus accrued and unpaid interest to, but excluding, the redemption date.
We may redeem for cash all or any portion of the 2026 Convertible Notes, at our option, if the last reported sale price of our common stock has been at least 130% of the conversion price then in effect on the last trading day of, and for at least 19 other trading days (whether or not consecutive) during, any 30 consecutive trading day period ending on, and including, the trading day immediately preceding the date on which we provide notice of redemption, at a redemption price equal to 100% of the principal amount of the 2026 Convertible Notes to be redeemed, plus accrued and unpaid interest to, but excluding, the redemption date.
Pursuant to the A&R Royalty Purchase Agreement, Royalty Pharma has paid to us aggregate cash consideration of $1.9 billion (less Royalty payments received by us with respect to the Assigned Royalty Rights) in exchange for 90.49% of the Royalty, which will be reduced to 83.33% of the Royalty after Royalty Pharma receives $1.3 billion in aggregate payments from the Royalty assigned at the closing of the Original Purchase Agreement.
Pursuant to the A&R Royalty Purchase Agreement, Royalty Pharma has paid to us aggregate cash consideration of $1.9 billion (less Royalty payments received by us with respect to the Assigned Royalty Rights) in exchange for 90.49% of the Royalty, which was to be reduced to 83.33% of the Royalty after Royalty Pharma receives $1.3 billion in aggregate payments from the Royalty assigned at the closing of the Original Purchase Agreement.
Facilities and other. Consists of indirect costs incurred for the benefit of multiple programs, including information technology, and other facility-based expenses, such as rent expense.
Consists of indirect costs incurred for the benefit of multiple programs, including information technology, and other facility-based expenses, such as rent expense.
Tegsedi has received marketing authorization in the United States, European Union, or EU, and Brazil for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis, or hATTR amyloidosis. In August 2021, ANVISA, the Brazilian health regulatory authority, approved Waylivra as the first treatment for familial chylomicronemia syndrome, or FCS, in Brazil.
Tegsedi has received marketing authorization in the United States, EU, and Brazil for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis, or hATTR amyloidosis. In August 2021, ANVISA, the Brazilian health regulatory authority, approved Waylivra as the first treatment for familial chylomicronemia syndrome, or FCS, in Brazil.
We did not issue or sell any shares of common stock pursuant to the Sales Agreement during the years ended December 31, 2024, 2023 and 2022. The remaining shares of our common stock available to be issued and sold, under the Sales Agreement, have an aggregate offering price of up to $93.0 million as of December 31, 2024.
We did not issue or sell any shares of common stock pursuant to the Sales Agreement during the years ended December 31, 2025, 2024 and 2023. The remaining shares of our common stock available to be issued and sold, under the Sales Agreement, have an aggregate offering price of up to $93.0 million as of December 31, 2025.
In order to commence commercial sale of product pursuant to our Translarna marketing authorization in any particular country in the EEA, we must finalize pricing and reimbursement negotiations with the applicable government body in such country. As a result, our commercial launch will continue to be on a country-by-country basis.
In order to commence commercial sale of product pursuant to our Sephience marketing authorization in any particular country in the EEA, we must finalize pricing and reimbursement negotiations with the applicable government body in such country. As a result, our commercial launch will continue to be on a country-by-country basis.
We announced the results from our Phase 1 study of PTC518 in healthy volunteers in September 2021 demonstrating dose-dependent lowering of huntingtin messenger ribonucleic acid and protein levels, that PTC518 efficiently crosses blood brain barrier at significant levels and that PTC518 was well tolerated.
We announced the results from our Phase 1 study of votoplam in healthy volunteers in September 2021 demonstrating dose-dependent lowering of huntingtin messenger ribonucleic acid and protein levels, that votoplam efficiently crosses blood brain barrier at significant levels and that votoplam was well tolerated.
We are not obligated to make such payments unless and until annual sales of a collaboration product exceed a designated threshold. Since inception, the SMA Foundation has earned $52.5 million, all of which was paid as of December 31, 2024.
We are not obligated to make such payments unless and until annual sales of a collaboration product exceed a designated threshold. Since inception, the SMA Foundation has earned $52.5 million, all of which was paid as of December 31, 2025.
Our research and development expenses consist of: ● external research and development expenses incurred under agreements with third-party contract research organizations and investigative sites, third-party manufacturing organizations and consultants; ● employee-related expenses, which include salaries and benefits, including share-based compensation, for the personnel involved in our drug discovery and development activities; and ● facilities, depreciation and other allocated expenses, which include direct and allocated expenses for rent and maintenance of facilities, IT, human resources, and other support functions, depreciation of leasehold improvements and equipment, and laboratory and other supplies.
Our research and development expenses consist of: ● external research and development expenses incurred under agreements with third-party contract research organizations and investigative sites, third-party manufacturing organizations and consultants; ● employee-related expenses, which include salaries and benefits, including share-based compensation, for the personnel involved in our drug discovery and development activities; and 111 Table of Contents ● facilities, depreciation and other allocated expenses, which include direct and allocated expenses for rent and maintenance of facilities, IT, human resources, and other support functions, depreciation of leasehold improvements and equipment, and laboratory and other supplies.
In October 2022, we entered into the Credit Agreement, dated October 27, 2022, by and among us and certain of our subsidiaries from time to time party thereto, as guarantors, or, collectively with us, the Loan Parties, funds and other affiliated entities advised or managed by Blackstone Life Sciences and Blackstone Credit, or collectively, Blackstone, as lenders, together with their permitted assignees, the Lenders, and Wilmington Trust, National Association, as the administrative agent for the Lenders, or the Blackstone Credit Agreement.
In October 2022, we entered into the Credit Agreement, dated October 27, 2022, by and among us and certain of our subsidiaries from time to time party thereto, as guarantors, or, collectively with us, the Loan Parties, funds and other affiliated entities advised or managed by Blackstone Life Sciences and Blackstone Credit, or collectively, Blackstone, as lenders, together with their permitted assignees, the Lenders, and Wilmington Trust, National Association, as the administrative agent for the Lenders, or the Blackstone Credit Agreement, which we terminated in October 2023.
During the year ended December 31, 2023, as a result of our strategic portfolio prioritization in 2023 and decision to discontinue our preclinical and early research programs in our gene therapy platform, which included programs for FA and Angelman syndrome, we fully impaired the FA and Angelman syndrome intangible assets and recorded impairment expense of $217.8 million. ​ Tangible asset impairment and losses (gains) on transactions, net.
During the year ended December 31, 2023, as a result of our strategic portfolio prioritization in 2023 and decision to discontinue our preclinical and early research programs in our gene therapy platform, which included programs for FA and Angelman syndrome, we fully impaired the FA and Angelman syndrome intangible assets and recorded impairment expense of $217.8 million. 120 Table of Contents Tangible asset impairment and losses (gains) on transactions, net.
The cash used in investing activities for the year ended December 31, 2023 is primarily attributable to the purchases of marketable securities – available for sale, purchases of marketable securities – equity investments, purchases of fixed assets, and the acquisition of product rights, offset by the sale and redemption of marketable securities – available for sale, sale and redemption of marketable securities – equity investments, and the sale and redemption of ClearPoint Equity Investments.
The cash used in investing activities for the year ended December 31, 2023 is primarily attributable to the purchases of marketable securities, purchases of fixed assets, and the acquisition of product rights, offset by the sale of marketable securities and the sale of ClearPoint equity investments.
Under the Novartis Agreement, and upon the closing of the transaction contemplated by the Novartis Agreement in January 2025, we received an upfront payment of $1.0 billion on the effective date and can receive up to $1.9 billion in development, regulatory and sales milestones, a 40% share of U.S. profits and losses, and tiered double-digit royalties on ex-U.S. sales See “Item 7.
Under the Novartis Agreement, and upon the closing of the transaction contemplated by the Novartis Agreement in January 2025, we received an upfront payment of $1.0 billion on the effective date and can receive up to $1.9 billion in development, regulatory and sales milestones, a 40% share of U.S. profits and losses, and tiered double-digit royalties on ex-U.S. sales.
We have reached our obligation to make such payments to the SMA Foundation of an aggregate of $52.5 million as of December 31, 2024. Refer to “Ongoing Acquisition- Related Obligations” in Item 1. Business.
We have reached our obligation to make such payments to the SMA Foundation of an aggregate of $52.5 million as of December 31, 2025. Refer to “Ongoing Acquisition- Related Obligations” in Item 1. Business.
The loss on extinguishment of debt consisted of $82.0 million in prepayment premiums, exit fees, and creditor expenses and debt issuance costs of $10.7 million. All liens and security interests securing the loans made pursuant to the Blackstone Credit Agreement were released upon termination.
The loss on 123 Table of Contents extinguishment of debt consisted of $82.0 million in prepayment premiums, exit fees, and creditor expenses and debt issuance costs of $10.7 million. All liens and security interests securing the loans made pursuant to the Blackstone Credit Agreement were released upon termination.
For the year ended December 31, 2024, compared to the years ended December 31, 2023 and 2022, the change in facilities and other expenses primarily related to decreases in facility-based expenses at our facility in Hopewell Township, New Jersey as a result of an amendment and restatement of our lease for such facility.
For the year ended December 31, 2025, compared to the years ended December 31, 2024 and 2023, the change in facilities and other expenses primarily related to decreases in facility-based expenses at our facility in Hopewell Township, New Jersey as a result of an amendment and restatement of our lease for such facility and at our facility in Warren, New Jersey as a result of an amendment to our lease for such facility in the year ended December 31, 2024.
Our ongoing ability to generate revenue from sales of Translarna for the treatment of nmDMD is dependent upon our ability to maintain our marketing authorizations in Brazil, Russia and in the EEA and secure market access through commercial programs following the conclusion of pricing and reimbursement terms at sustainable levels in the member states of the EEA or through EAP programs or similar styled programs in the EEA and other territories.
Additionally, for Translarna, our ongoing ability to generate revenue from sales of Translarna for the treatment of nmDMD is dependent upon our ability to maintain our marketing authorizations in other geographies and secure market access through commercial programs following the conclusion of pricing and reimbursement terms at sustainable levels in the member states of the EEA or through EAP programs or similar styled programs in the EEA and other territories.
In addition to our SMA program, our splicing platform also includes PTC518, which is being developed for the treatment of Huntington’s disease, or HD.
In addition to our SMA program, our splicing platform also includes votoplam, which is being developed for the treatment of Huntington’s disease, or HD.
The most advanced molecule in our inflammation and ferroptosis platform is vatiquinone. We announced topline results from a registration-directed Phase 3 trial of vatiquinone in children and young adults with FA, called MOVE-FA, in May 2023.
The most advanced molecule in our inflammation and ferroptosis platform is vatiquinone. We announced topline results from a registration-directed Phase 3 trial of vatiquinone in children and young adults with Friedreich’s ataxia, or FA, called MOVE-FA, in May 2023.
If we are unable to raise additional funds through equity, debt or other financings when needed or on attractive terms, we may be required to delay, limit, reduce or terminate our product development or commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves. 138 Table of Contents
If we are unable to raise additional funds through equity, debt or other financings when needed or on attractive terms, we may be required to delay, limit, reduce or terminate our product development or commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.
In October 2023, we terminated the Blackstone Credit Agreement. In connection with the termination of the Blackstone Credit Agreement, we repaid outstanding principal of $300.0 million, accrued interest of $2.1 million, an additional $82.0 million in prepayment premiums, exit fees, and creditor expenses, and $0.2 million in legal fees.
In connection with the termination of the Blackstone Credit Agreement, we repaid outstanding principal of $300.0 million, accrued interest of $2.1 million, an additional $82.0 million in prepayment premiums, exit fees, and creditor expenses, and $0.2 million in legal fees.
We have previously relied on Emflaza’s seven-year marketing exclusivity period in the United States for its approved indications under the provisions of the Orphan Drug Act of 1983, or the Orphan Drug Act, when commercializing Emflaza. Emflaza’s seven-year period of orphan drug exclusivity related to the treatment of DMD in patients five years and older expired in February 2024.
With respect to Emflaza, we have previously relied on Emflaza’s seven-year marketing exclusivity period in the United States for its approved indications under the provisions of the Orphan Drug Act of 1983, or the Orphan Drug Act, when commercializing Emflaza for the treatment of DMD in patients five years and older, which expired in February 2024.
The 124 Table of Contents preparation of these financial statements requires us to make estimates and assumptions that affect the reported amounts of assets and liabilities and the disclosure of contingent assets and liabilities at the date of the financial statements, as well as the reported revenues and expenses during the reporting periods.
The preparation of these financial statements requires us to make estimates and assumptions that affect the reported amounts of assets and liabilities and the disclosure of contingent assets and liabilities at the date of the financial statements, as well as the reported revenues and expenses during the reporting periods.
Cost of product sales, excluding amortization of acquired intangible asset. Cost of product sales, excluding amortization of acquired intangible asset, was $57.4 million for the year ended December 31, 2024, a decrease of $8.1 126 Table of Contents million, or 12%, from $65.5 million for the year ended December 31, 2023.
Cost of product sales, excluding amortization of acquired intangible asset, was $57.4 million for the year ended December 31, 2024, a decrease of $8.1 million, or 12%, from $65.5 million for the year ended December 31, 2023.
The cash provided by investing activities for the year ended December 31, 2024 was primarily attributable to the sale and redemption of marketable securities – available for sale, sale and redemption of marketable securities – equity investments, proceeds from sales of fixed assets, proceeds from the sale of the PRV, and proceeds from settlement of the ClearPoint convertible debt security, offset by the acquisition of product rights, purchases of marketable securities – available for sale, purchases of fixed assets, and purchases of marketable securities –equity investments.
The cash provided by investing activities for the year ended December 31, 2024 was primarily attributable to the sale of marketable securities, proceeds from sales of fixed assets, proceeds from the sale of the PRV, and proceeds from settlement of the ClearPoint convertible debt security, offset by the acquisition of product rights, purchases of marketable securities, and purchases of fixed assets.
We initiated a Phase 2 study of PTC518 for the treatment of HD in the first quarter of 2022, which consists of an initial 12-week placebo-controlled phase focused on safety, pharmacology and pharmacodynamic effects followed by a nine-month placebo-controlled phase focused on PTC518 biomarker effect.
We initiated a Phase 2 study of votoplam for the treatment of HD in the first quarter of 2022, which consisted of an initial 12-week placebo-controlled phase focused on safety, pharmacology and pharmacodynamic effects followed by a nine-month placebo-controlled phase focused on votoplam biomarker effect.
We anticipate that we will continue to incur significant expenses in connection with our commercialization efforts in the United States, the EEA, Latin America and other territories, including expenses related to our commercial infrastructure and corresponding sales and marketing, legal and regulatory, and distribution and manufacturing undertakings as well as 120 Table of Contents administrative and employee-based expenses.
We anticipate that we will continue to incur significant expenses in connection with our commercialization efforts in the United States, the EEA, Latin America, Japan and other territories, including expenses related to our commercial infrastructure and corresponding sales and marketing, legal and regulatory, and distribution and manufacturing undertakings as well as administrative and employee-based expenses.
We expect our research and development expenses to fluctuate in connection with our ongoing activities, particularly in connection with our activities for sepiapterin and our splicing and inflammation and ferroptosis programs and 122 Table of Contents performance of any post-marketing requirements imposed by regulatory agencies with respect to our products.
We expect our research and development expenses to fluctuate in connection with our ongoing activities, particularly in connection with our activities for our splicing and inflammation and ferroptosis programs and performance of any post-marketing requirements imposed by regulatory agencies with respect to our products.
As of December 31, 2024, we had recognized a total of $310.0 million in milestone payments and $545.6 million royalties on net sales pursuant to the SMA License Agreement. As of December 31, 2024, there are no remaining research and development event milestones that we can receive.
As of December 31, 2025, we had recognized a total of $310.0 million in milestone payments and $789.8 million in royalties on net sales pursuant to the SMA License Agreement. As of December 31, 2025, there are no remaining research and development event milestones that we can receive.
During 2024, our revenues were primarily generated from sales of Translarna for the treatment of nmDMD in countries where we were able to obtain acceptable commercial pricing and reimbursement terms and in select countries where we are permitted to distribute Translarna under our EAP programs or through similar styled programs, and from sales of Emflaza for the treatment of DMD in the United States.
During 2025, our revenues were primarily generated from sales of Sephience for the treatment of PKU in the U.S. and EEA, Translarna for the treatment of nmDMD in countries where we were able to obtain acceptable commercial pricing and reimbursement terms and in select countries where we are permitted to distribute Translarna under our EAP programs or through similar styled programs, and from sales of Emflaza for the treatment of DMD in the United States.
We have financed our operations to date primarily through the private offerings of convertible senior notes, public and “at the market offerings” of common stock, proceeds from royalty purchase agreements, net proceeds from our borrowings under our credit agreement with Blackstone, private placements of our convertible preferred stock and common stock, collaborations, bank and institutional lender debt, other convertible debt, grant funding and clinical trial support from governmental and philanthropic organizations and patient advocacy groups in the disease area addressed by our product candidates.
We have financed our operations to date primarily through private offerings of convertible senior notes, public and “at the market offerings” of common stock, proceeds from royalty purchase agreements, private placements of our convertible preferred stock and common stock, collaborations, bank and institutional lender debt, other convertible debt, grant funding and clinical trial support from governmental and philanthropic organizations and patient advocacy groups in the disease areas addressed by our product candidates.
For the year ended December 31, 2024, compared to the years ended December 31, 2023 and 2022, the change in payroll, benefits, and share-based stock compensation expenses primarily relates to our reduction in workforce in 123 Table of Contents connection with our strategic pipeline prioritization in 2023 and discontinuation of our preclinical and early research programs in our gene therapy platform.
For the year ended December 31, 2025, compared to the years ended December 31, 2024 and 2023, the change in payroll, benefits, and share-based stock compensation expenses primarily relates to our reduction in workforce in connection with our strategic pipeline prioritization in 2023 and discontinuation of our preclinical and early research programs in our gene therapy platform. Facilities and other.
Interest expense, net Interest expense, net consists of interest expense from the liability for the sale of future royalties related to the Original Royalty Purchase Agreement, the A&R Royalty Purchase Agreement, the 2026 Convertible Notes outstanding, the Blackstone Credit Agreement that we repaid and terminated in October 2023, the 3.00% convertible senior notes due 2022, or the 2022 Convertible Notes, that we repaid in August 2022, offset by interest income earned on investments.
Interest expense, net Interest expense, net consists of interest expense from the liability for the sale of future royalties related to the Original Royalty Purchase Agreement, the A&R Royalty Purchase Agreement, the 2026 Convertible Notes outstanding and the Blackstone Credit Agreement that we repaid and terminated in October 2023, offset by interest income earned on investments.
Management’s Discussion and Analysis of Financial Condition and Results of Operations—Liquidity and capital resources—Sources of Liquidity” for additional information.
See “Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations—Liquidity and capital resources—Sources of liquidity” for additional information.
Holders may convert their 2026 Convertible Notes at their option at any time prior to the close of business on the business day immediately preceding March 15, 2026 only under the following circumstances: (1) during any calendar quarter commencing on or after December 31, 2019 (and only during such calendar quarter), if the last reported sale price of our common stock for at least 20 trading days (whether or not consecutive) during a period of 30 consecutive trading days ending on the last trading day of the immediately preceding calendar quarter is greater than or equal to 130% of the conversion price on each applicable trading day; (2) during the five business day period after any five consecutive trading day period, or the measurement period, in which the trading price (as defined in the 2026 Convertible Notes Indenture) per $1,000 principal amount of 2026 Convertible Notes for each trading day of the measurement period was less than 98% of the product of the last reported sale price of our common stock and the conversion rate on each such trading day; (3) during any period after we have issued notice of redemption until the close of business on the scheduled trading day immediately preceding the relevant redemption date; or (4) upon the occurrence of specified corporate events.
We received net proceeds of $279.3 million after deducting the initial purchasers’ discounts and commissions and the offering expenses payable by us. 122 Table of Contents Holders may convert their 2026 Convertible Notes at their option at any time prior to the close of business on the business day immediately preceding March 15, 2026 only under the following circumstances: (1) during any calendar quarter commencing on or after December 31, 2019 (and only during such calendar quarter), if the last reported sale price of our common stock for at least 20 trading days (whether or not consecutive) during a period of 30 consecutive trading days ending on the last trading day of the immediately preceding calendar quarter is greater than or equal to 130% of the conversion price on each applicable trading day; (2) during the five business day period after any five consecutive trading day period, or the measurement period, in which the trading price (as defined in the 2026 Convertible Notes Indenture) per $1,000 principal amount of 2026 Convertible Notes for each trading day of the measurement period was less than 98% of the product of the last reported sale price of our common stock and the conversion rate on each such trading day; (3) during any period after we have issued notice of redemption until the close of business on the scheduled trading day immediately preceding the relevant redemption date; or (4) upon the occurrence of specified corporate events.
Our process for recognizing revenue is described below under “Critical accounting policies and significant judgments and estimates—Revenue recognition”. 121 Table of Contents Roche and the SMA Foundation Collaboration.
Our process for recognizing revenue is described below under “Critical accounting policies and significant judgments and estimates—Revenue recognition”. Roche and the SMA Foundation Collaboration.
In connection with our FDA approval of Kebilidi, we received a Priority Review Voucher, or PRV, and sold the PRV for aggregate net proceeds of $148.0 million.
In connection with our FDA approval of Kebilidi, we received a PRV and sold the PRV for aggregate net proceeds of $148.0 million.
The cash provided by financing activities for the year ended December 31, 2024 was primarily attributable to the proceeds received from the A&R Royalty Purchase Agreement, exercise of options, issuance of stock under our Employee Stock Purchase Plan, or ESPP, offset by payments on contingent consideration obligation, and payments on our finance lease principal.
The cash provided by financing activities for the years ended December 31, 2025 and 2024 were primarily attributable to the proceeds received from the A&R Royalty Purchase 124 Table of Contents Agreement, exercise of options, issuance of stock under our Employee Stock Purchase Plan, or ESPP, offset by payments on contingent consideration obligation, and payments on our finance lease principal.
In addition, our expenses will increase if and as we: ● seek to satisfy contractual and regulatory obligations that we assumed through our acquisitions and collaborations; ● execute our commercialization strategy for our products, including initial commercialization launches of our products, label extensions or entering new markets; ● are required to complete any additional clinical trials, non-clinical studies or Chemistry, Manufacturing and Controls, or CMC, assessments or analyses in order to advance our products or product candidates in the United States or elsewhere; ● are required to take other steps to maintain our current marketing authorization in the EEA, Brazil and Russia for Translarna for the treatment of nmDMD or to obtain further marketing authorizations for Translarna for the treatment of nmDMD or other indications; ● initiate or continue the research and development of sepiapterin and our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications; ● seek to discover and develop additional product candidates; ● seek to expand and diversify our product pipeline through strategic transactions; ● maintain, expand and protect our intellectual property portfolio; and 135 Table of Contents ● add operational, financial and management information systems and personnel, including personnel to support our product development and commercialization efforts.
In addition, our expenses will increase if and as we: ● seek to satisfy contractual and regulatory obligations that we assumed through our acquisitions and collaborations; ● execute our commercialization strategy for our products, including initial commercialization launches of our products, label extensions or entering new markets; ● are required to complete any additional clinical trials, non-clinical studies or Chemistry, Manufacturing and Controls, or CMC, assessments or analyses in order to advance our products or product candidates in the United States or elsewhere; ● initiate or continue the research and development of our splicing and inflammation and ferroptosis programs as well as studies in our products for maintaining authorizations, label extensions and additional indications; ● seek to discover and develop additional product candidates; ● seek to expand and diversify our product pipeline through strategic transactions; ● maintain, expand and protect our intellectual property portfolio; and ● add operational, financial and management information systems and personnel, including personnel to support our product development and commercialization efforts.
Our performance obligations are to provide products based on customer orders from distributors, hospitals, specialty pharmacies or retail pharmacies. The performance obligations are satisfied at a point in time when our customer obtains control of the product, which is typically upon delivery.
We recognize revenue when performance obligations with customers have been satisfied. Our performance obligations are to provide products based on customer orders from distributors, hospitals, specialty pharmacies or retail pharmacies. The performance obligations are satisfied at a point in time when our customer obtains control of the product, which is typically upon delivery.
The net cash used in operating activities primarily related to supporting clinical development and commercial activities for the years ended December 31, 2024, 2023, and 2022. Net cash provided by investing activities was $44.2 million for the year ended December 31, 2024. Net cash used in investing activities was $176.7 million for the year ended December 31, 2023.
The net cash used in operating activities primarily related to supporting clinical development and commercial activities for the years ended December 31, 2024, and 2023. Net cash used in investing activities was $862.0 million for the year ended December 31, 2025. Net cash provided by investing activities was $44.2 million for the year ended December 31, 2024.
We also generated revenue from sales of Upstaza for the treatment of AADC deficiency in the EEA and have recognized revenue associated with milestone and royalty payments from Roche pursuant to a License and Collaboration Agreement, or the SMA License Agreement, by and among us, Roche and, for the limited purposes set forth therein, the SMA Foundation, under our SMA program.
We also generated revenue from sales of Upstaza/Kebilidi for the treatment of AADC deficiency in the EEA and in the U.S., and have recognized revenue associated with milestone and royalty payments from Roche pursuant to a License and Collaboration Agreement, or the SMA License Agreement, by and among us, Roche and, for the limited purposes set forth therein, the SMA Foundation, under our SMA program and we have recognized license revenues related to performance obligations completed pursuant to the Novartis Agreement .
We have financed our operations to date primarily through private offerings of convertible senior notes, public and “at the market offerings” of common stock, proceeds from royalty purchase agreements, net proceeds from our borrowings under our credit agreement with Blackstone, private placements of our convertible preferred stock and common stock, collaborations, bank and institutional lender debt, other convertible debt, grant funding and clinical trial support from governmental and philanthropic organizations and patient advocacy groups in the disease area addressed by our product candidates.
We have financed our operations to date primarily through the private offerings of convertible senior notes, public and “at the market offerings” of common stock, proceeds from royalty purchase agreements, private placements of our 109 Table of Contents convertible preferred stock and common stock, collaborations, bank and institutional lender debt, other convertible debt, grant funding and clinical trial support from governmental and philanthropic organizations and patient advocacy groups in the disease areas addressed by our product candidates.
Translarna net product revenues were $339.9 million for the year ended December 31, 2024, a decrease of $15.9 million, or 4%, compared to $355.8 million for the year ended December 31, 2023. These results were due to the timing of bulk patient orders, as well as the residual impact from the CHMP negative opinion in September 2023.
Translarna net product revenues were $321.1 million for the year ended December 31, 2024, a decrease of $11.7 million, or 4%, compared to $332.8 million for the year ended December 31, 2023. These results were due to the timing of bulk patient orders, as well as the residual impact from the CHMP negative opinion in September 2023.
We have a total of $24.0 million in obligations that stem from a commercial manufacturing services agreement entered into with MassBio on June 19, 2020, for a term of 12.5 years. Pursuant to the terms of the agreement, MassBio agreed to provide us with four dedicated rooms for our Upstaza/Kebilidi program.
We have a total of $156.9 million in obligations that stem from our operating leases. We have a total of $6.0 million in obligations that stem from a commercial manufacturing services agreement entered into with MassBio on June 19, 2020. Pursuant to the terms of the agreement, MassBio agreed to provide us with four dedicated rooms for our Upstaza/Kebilidi program.
Net cash provided by financing activities was $255.9 million, $646.4 million, and $168.0 million for the years ended December 31, 2024, 2023 and 2022, respectively.
Net cash provided by financing activities was $331.1 million, $255.9 million, and $646.4 million for the years ended December 31, 2025, 2024 and 2023, respectively.
Our ability to negotiate, secure and maintain reimbursement for product under commercial and EAP programs can be subject to challenge in any particular country and can also be affected by political, economic and regulatory developments in such country.
Our ability to negotiate, secure and maintain reimbursement for product under commercial and EAP programs can be subject to challenge in any particular country and can also be affected by political, economic and regulatory developments in such country. Translarna is an investigational new drug in the United States.
We had previously recorded an indefinite lived intangible asset for the PRV of $48.1 million in connection with the acquisition of Agilis in 2018, which was included as part of the book balance of our PTC-AADC indefinite lived intangible asset balance.
We had previously recorded an indefinite lived intangible asset for the PRV of $48.1 million in connection with the acquisition of Agilis in 2018, which was included as part of the book balance of our PTC-AADC indefinite lived intangible asset balance. Accordingly, we derecognized the book value of the PRV and recorded a gain of $99.9 million upon the sale.
For a description of our significant accounting policies, see note 2 to our consolidated financial statements. 125 Table of Contents Year ended December 31, 2024 compared to year ended December 31, 2023 The following table summarizes revenues and selected expense and other income data for the year ended December 31, 2024 and 2023: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year ended ​ ​ ​ ​ ​ December 31, ​ Change (in thousands) 2024 2023 2024 vs. 2023 Net product revenue ​ $ 600,951 ​ $ 661,249 ​ $ (60,298) Collaboration revenue ​ 304 ​ 100,030 ​ $ (99,726) Royalty revenue ​ ​ 203,864 ​ ​ 168,856 ​ $ 35,008 Manufacturing revenue ​ ​ 1,661 ​ ​ 7,687 ​ $ (6,026) Cost of product sales, excluding amortization of acquired intangible assets ​ 57,398 ​ 65,486 ​ $ (8,088) Amortization of acquired intangible assets ​ 60,738 ​ 222,635 ​ $ (161,897) Research and development expense ​ 534,480 ​ 666,563 ​ $ (132,083) Selling, general and administrative expense ​ 300,911 ​ 332,540 ​ $ (31,629) Change in the fair value of contingent consideration ​ (4,475) ​ (127,700) ​ $ 123,225 Intangible asset impairment ​ ​ 159,548 ​ ​ 217,800 ​ $ (58,252) Tangible asset impairment and losses (gains) on transactions, net ​ ​ 750 ​ ​ — ​ $ 750 Interest expense, net ​ (166,993) ​ (129,180) ​ $ (37,813) Other income, net ​ 6,544 ​ 10,130 ​ $ (3,586) Gain on sale of priority review voucher ​ ​ 99,900 ​ ​ — ​ $ 99,900 Loss on extinguishment of debt ​ ​ — ​ ​ (137,558) ​ $ 137,558 Income tax (expense) benefit ​ (176) ​ 69,506 ​ $ (69,682) ​ Net product revenue.
Additionally, we incur income tax expenses in various foreign jurisdictions, and our foreign tax liabilities are largely dependent upon the distribution of pre-tax earnings among these different jurisdictions. 118 Table of Contents Year ended December 31, 2024 compared to year ended December 31, 2023 The following table summarizes revenues and selected expense and other income data for the years ended December 31, 2024 and 2023: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year ended ​ ​ ​ ​ ​ December 31, ​ Change (in thousands) ​ ​ 2024 ​ ​ ​ 2023 ​ ​ ​ 2024 vs. 2023 Net product revenue ​ $ 582,145 ​ $ 638,177 ​ $ (56,032) Collaboration revenue ​ 304 ​ 100,030 ​ $ (99,726) Royalty revenue ​ 203,864 ​ 168,856 ​ $ 35,008 Translarna France ​ ​ 18,806 ​ ​ 23,072 ​ $ (4,266) Manufacturing revenue ​ ​ 1,661 ​ ​ 7,687 ​ $ (6,026) Cost of product sales, excluding amortization of acquired intangible assets ​ 57,398 ​ 65,486 ​ $ (8,088) Amortization of acquired intangible assets ​ ​ 60,738 ​ ​ 222,635 ​ $ (161,897) Research and development expense ​ ​ 534,480 ​ ​ 666,563 ​ $ (132,083) Selling, general and administrative expense ​ 300,911 ​ 332,540 ​ $ (31,629) Change in the fair value of contingent consideration ​ (4,475) ​ (127,700) ​ $ 123,225 Intangible asset impairment ​ 159,548 ​ 217,800 ​ $ (58,252) Tangible asset impairment and losses on transactions, net ​ ​ 750 ​ ​ — ​ $ 750 Interest expense, net ​ (166,993) ​ (129,180) ​ $ (37,813) Other income, net ​ 6,544 ​ 10,130 ​ $ (3,586) Gain on sale of priority review voucher ​ ​ 99,900 ​ ​ — ​ $ 99,900 Loss on extinguishment of debt ​ ​ — ​ ​ (137,558) ​ $ 137,558 Income tax (expense) benefit ​ (176) ​ 69,506 ​ $ (69,682) ​ Net product revenue.
For the year ended December 31, 2024, compared to the years ended December 31, 2023 and 2022, the increase in milestone expenses primarily related to the achievement of a $15.0 million success-based regulatory milestone for the validation and acceptance of an MMA for sepiapterin for PKU in May 2024, the achievement of a $25.0 million regulatory milestone for the decision to submit an NDA to the FDA for sepiapterin for PKU in July 2024, and the achievement of a $25.0 million regulatory milestone for the acceptance of an NDA to the FDA for sepiapterin for PKU in September 2024, as compared to the achievement of a $30.0 million success-based development milestone for the completion of enrollment of a Phase 3 clinical trial for sepiapterin for PKU in February 2023, and no milestones achieved in the year ended December 31, 2022.
Consists of development and regulatory milestone expenses incurred in connection with our collaborative arrangements. 112 Table of Contents For the year ended December 31, 2025, compared to the years ended December 31, 2024 and 2023, the changes in milestone expenses primarily related to no milestones expensed in year the ended December 31, 2025, as compared to the achievement of a $15.0 million success-based regulatory milestone for the validation and acceptance of an MMA for Sephience for PKU in May 2024, the achievement of a $25.0 million regulatory milestone for the decision to submit an NDA to the FDA for Sephience for PKU in July 2024, and the achievement of a $25.0 million regulatory milestone for the acceptance of an NDA by the FDA for Sephience for PKU in September 2024, as compared to the achievement of a $30.0 million success-based development milestone for the completion of enrollment of a Phase 3 clinical trial for Sephience for PKU in February 2023.
Net product revenue was $601.0 million for the year ended December 31, 2024, a decrease of $60.3 million, or 9%, from net product revenue of $661.2 million for the year ended December 31, 2023.
Net product revenue was $582.1 million for the year ended December 31, 2024, a decrease of $56.0 million, or 9%, from net product revenue of $638.2 million for the year ended December 31, 2023.
To date, our product revenue has primarily consisted of sales of Translarna for the treatment of nmDMD in territories outside of the United States and from Emflaza for the treatment of DMD in the United States.
To date, our product revenue has primarily consisted of sales of Translarna for the treatment of nmDMD in territories outside of the United States and from Emflaza for the treatment of DMD in the United States. Beginning in the second half of 2025, our net product revenues also includes sales of Sephience for the treatment of PKU.
The following table provides information regarding our cash flows and our capital expenditures for the periods indicated. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years ended ​ ​ December 31, (in thousands) ​ 2024 2023 2022 Cash (used in) provided by: ​ ​ ​ ​ Operating activities ​ $ (107,688) ​ $ (158,418) ​ $ (356,654) Investing activities ​ $ 44,182 ​ $ (176,737) ​ $ 290,181 Financing activities ​ $ 255,866 ​ $ 646,400 ​ $ 167,952 ​ Net cash used in operating activities was $107.7 million, $158.4 million, and $356.7 million for the years ended December 31, 2024, 2023, and 2022, respectively.
The following table provides information regarding our cash flows and our capital expenditures for the periods indicated. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Years ended ​ ​ December 31, (in thousands) ​ 2025 ​ ​ ​ 2024 ​ ​ ​ 2023 Cash provided (used in) by: ​ ​ ​ ​ ​ ​ ​ Operating activities ​ $ 711,196 ​ $ (107,688) ​ $ (158,418) Investing activities ​ $ (861,984) ​ $ 44,182 ​ $ (176,737) Financing activities ​ $ 331,094 ​ $ 255,866 ​ $ 646,400 ​ Net cash provided by operating activities was $711.2 million for the year ended December 31, 2025.
Cash flows As of December 31, 2024, we had cash and cash equivalents and marketable securities of $1,139.7 million.
Cash flows As of December 31, 2025, we had cash and cash equivalents and marketable securities of $1,945.4 million.
With respect to our outstanding 2026 Convertible Notes, cash interest payments are payable on a semi-annual basis in arrears, which will require total funding of $4.3 million annually.
With respect to our outstanding 2026 Convertible Notes, cash interest payments are payable on a semi-annual basis in arrears, which will require total funding of $4.3 million annually. These notes are currently convertible and will mature and become due and payable on September 15, 2026 unless earlier redeemed or converted.
These estimates for variable consideration are adjusted to reflect known changes in factors and may impact such estimates in the quarter those changes are known. Revenue recognized does not include amounts of variable consideration that are constrained.
These estimates for variable consideration are adjusted to reflect known changes in factors and may impact such estimates in the quarter those changes are known.
Consists of costs incurred for product candidates before initiation of a clinical trial. For the year ended December 31, 2024, compared to the years ended December 31, 2023 and 2022, the decrease in research expenses was primarily related to our strategic pipeline prioritization in 2023 where we discontinued several preclinical and early research programs. Milestones.
For the year ended December 31, 2025, compared to the years ended December 31, 2024 and 2023, the decrease in research expenses was primarily related to our strategic pipeline prioritization in 2023 where we discontinued several preclinical and early research programs.
We have never been profitable and we will need to generate significant revenues to achieve and sustain profitability, and we may never do so. Accordingly, we may need to obtain substantial additional funding in connection with our continuing operations. Adequate additional financing may not be available to us on acceptable terms, or at all.
Accordingly, we may need to obtain substantial additional funding in connection with our continuing operations. Adequate additional financing may not be available to us on acceptable terms, or at all.
The increase in interest expense, net was primarily due to interest expense recorded from the liability for the sale of future royalties related to the A&R Royalty Purchase Agreement and the Original Royalty Purchase Agreement. ​ 130 Table of Contents Other income (expense), net .
The decrease in interest expense, net was primarily due to an increase in interest income from marketable securities-available for sale, offset by an increase in interest expense related to the liability for the sale of future royalties related to the A&R Royalty Purchase Agreement. Other (expense) income, net .
As a result of the acceptance, we paid a $20.0 million milestone payment to former equity holders of Agilis, during the year ended December 31, 2024. On November 13, 2024, our BLA for our gene therapy treatment of AADC deficiency was approved by the FDA. In connection with the approval, we were granted a rare disease PRV.
On November 13, 2024, our BLA for Kebilidi for the treatment of AADC deficiency was approved by the FDA. In connection with the approval, we were granted a rare disease PRV. The FDA approval of the BLA and the PRV triggered $11.0 million regulatory milestone, which was paid during the year ended December 31, 2025.
Failure to obtain and maintain acceptable pricing and reimbursement terms for Translarna for the treatment of nmDMD or Upstaza for the treatment of AADC deficiency in the EEA and other countries where Translarna is available would delay or prevent us from marketing our product in such regions, which would adversely affect our business, results of operations, and financial condition. ” In August 2019, we entered into an At the Market Offering Sales Agreement, or the Sales Agreement, with Cantor Fitzgerald and RBC Capital Markets, LLC, or together, the Sales Agents, pursuant to which, we may offer and sell shares of our common stock, having an aggregate offering price of up to $125.0 million from time to time through the Sales Agents by any method that is deemed to be an “at the market offering” as defined in Rule 415(a)(4) promulgated under the Securities Act of 1933, as amended, or the Securities Act.
In August 2019, we entered into an At the Market Offering Sales Agreement, or the Sales Agreement, with Cantor Fitzgerald and RBC Capital Markets, LLC, or together, the Sales Agents, pursuant to which, we may offer and sell shares of our common stock, having an aggregate offering price of up to $125.0 million from time to time through the Sales Agents by any method that is deemed to be an “at the market offering” as defined in Rule 415(a)(4) promulgated under the Securities Act of 1933, as amended, or the Securities Act.
In November 2024, the FDA granted accelerated approval of our gene therapy for the treatment of children and adults with AADC deficiency, which is marketed with the brand name Kebilidi in the United States.
In November 2024, the FDA granted accelerated approval of our gene therapy for the treatment of children and adults with AADC deficiency, which is marketed with the brand name Kebilidi in the United States. We are obligated to complete certain post-marketing requirements in connection with the FDA's approval, including clinical safety studies.
In October 2017, the Office of Drug Evaluation I of the FDA issued a Complete Response Letter, or CRL, for the NDA, stating that it was unable to approve the application in its current form. In response, we filed a formal dispute resolution request with the Office of New Drugs of the FDA.
During the first quarter of 2017, we filed an NDA for Translarna for the treatment of nmDMD over protest with the FDA. In October 2017, the Office of Drug Evaluation I of the FDA issued a complete response letter for the NDA, stating that it was unable to approve the application in its current form.
Interest expense, net was $167.0 million for the year ended December 31, 2024, an increase of $37.8 million, or 29%, from interest expense, net of $129.2 million for the year ended December 31, 2023.
These amounts were partially offset by a gain of $2.2 million on lease terminations, and a gain of $5.5 million on lease modifications. Interest expense, net. Interest expense, net was $167.0 million for the year ended December 31, 2024, an increase of $37.8 million, or 29%, from interest expense, net of $129.2 million for the year ended December 31, 2023.
Additionally, Emflaza’s seven-year period of orphan drug exclusivity related to the treatment of DMD in patients five years and older expired in February 2024. We have previously relied on this exclusivity period to commercialize Emflaza in the United States. We expect the expiration of this orphan drug exclusivity to have a significant negative impact on Emflaza net product revenue.
Additionally, for Emflaza, its seven-year period of orphan drug exclusivity related to the treatment of DMD in patients five years and older expired in February 2024. With the expiration of this orphan drug exclusivity, we have seen an increase in competition from generics, which has, and we expect will continue to have, a negative impact on Emflaza net product revenue.
We had a net loss of $363.3 million, $626.6 million, and $559.0 million for the fiscal years ended December 31, 2024, 2023 and 2022, respectively.
As of December 31, 2025, we had an accumulated deficit of $2,964.2 million. We had a net income of $682.6 million for the year ended December 31, 2025, and a net loss of $363.3 million and a net loss of $626.6 million for the fiscal years ended December 31, 2024 and 2023, respectively.
The cash provided by investing activities for the years ended December 31, 2022 was primarily related to net sales and redemptions of marketable securities – available for sale and net sales and redemptions of marketable securities – equity investments, partially offset by purchases of marketable securities – available for sale, purchases of marketable securities – equity investments, purchases of fixed assets, and the acquisition of product rights.
The cash used in investing activities for the year ended December 31, 2025, was primarily attributable to acquisition of product rights, purchases of marketable securities, and purchases of fixed assets, offset by the sale of marketable securities, sale of ClearPoint equity investments, and proceeds from sales of fixed assets.
Pursuant to the Original Royalty Purchase Agreement, we sold to RPI 42.933%, or the Original Assigned Royalty Rights, of the Royalty (as defined below) for $650.0 million. At that time, we retained a 57.067% interest in the Royalty and all economic rights to receive the remaining potential regulatory and sales milestone payments under the SMA License Agreement.
At that time, we retained a 57.067% interest in the Royalty and all economic rights to receive the remaining potential regulatory and sales milestone payments under the SMA License Agreement.
As a growing commercial-stage biopharmaceutical company, we are engaging in significant commercialization efforts for our products while also devoting a substantial portion of our efforts on research and development related to our products, product candidates and other programs.
Liquidity and capital resources Sources of liquidity While we have generated net income in the year ended December 31, 2025, we have historically incurred significant operating losses. 121 Table of Contents As a growing commercial-stage biopharmaceutical company, we are engaging in significant commercialization efforts for our products while also devoting a substantial portion of our efforts on research and development related to our products, product candidates and other programs.
Other income, net was $10.1 million for the year ended December 31, 2023, a change of $59.3 million, or over 100%, from other expense, net of $49.2 million for the year ended December 31, 2022.
Other expense, net was $18.1 million for the year ended December 31, 2025, a change of $24.6 million, or over 100%, from other income, net of $6.5 million for the year ended December 31, 2024.
On or after March 15, 2026, until the close of business on the business day immediately preceding the maturity date, holders may convert their 2026 Convertible Notes at any time, regardless of the foregoing circumstances. Upon conversion, we will pay or deliver, as the case may be, cash, shares of our common stock or any combination thereof at our election.
The 2026 Convertible Notes are currently convertible. On or after March 15, 2026, until the close of business on the business day immediately preceding the maturity date, holders may convert their 2026 Convertible Notes at any time, regardless of the foregoing circumstances.

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Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

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Biggest changeWe will evaluate the use of derivative financial instruments to hedge our exposure as the needs and risks should arise. In September 2019, we issued $287.5 million of 1.50% convertible senior notes due September 15, 2026, or the 2026 Convertible Notes.
Biggest changeWe will evaluate the use of derivative financial instruments to hedge our exposure as the needs and risks should arise. 129 Table of Contents In September 2019, we issued $287.5 million of 1.50% convertible senior notes due September 15, 2026, or the 2026 Convertible Notes.
Our available for sale securities are subject to interest rate risk and will fall in value if market interest rates increase. At any time, sharp changes in interest rates can affect the fair value of the investment portfolio and its interest earnings. There were no investments classified as long-term at December 31, 2024.
Our available for sale securities are subject to interest rate risk and will fall in value if market interest rates increase. At any time, sharp changes in interest rates can affect the fair value of the investment portfolio and its interest earnings. There were no investments classified as long-term at December 31, 2025.
A hypothetical ten percent increase or decrease in the exchange rate between the U.S. dollar and the British Pound, Euro, Brazilian Real, or Swiss Franc from the December 31, 2024 rate would not have a significant impact on our cash flows. We are not currently engaged in any foreign currency hedging activities.
A hypothetical ten percent increase or decrease in the exchange rate between the U.S. dollar and the British Pound, Euro, Brazilian Real, or Swiss Franc from the December 31, 2025 rate would not have a significant impact on our cash flows. We are not currently engaged in any foreign currency hedging activities.
At December 31, 2024, we held $1,139.7 million in cash and cash equivalents and marketable securities. After a review of our marketable investment securities, we believe that in the event of a hypothetical ten percent increase in interest rates, the resulting decrease in fair value of our marketable investment securities would be insignificant to the consolidated financial statements.
At December 31, 2025, we held $1,945.4 million in cash and cash equivalents and marketable securities. After a review of our marketable investment securities, we believe that in the event of a hypothetical ten percent increase in interest rates, the resulting decrease in fair value of our marketable investment securities would be insignificant to the consolidated financial statements.
For the year ended December 31, 2024, we recognized realized foreign currency transaction losses, net, of $6.8 million, which is recorded within other income, net on the Statement of Operations.
For the year ended December 31, 2025, we recognized realized foreign currency transaction losses, net, of $11.3 million, which is recorded within other income, net on the Statement of Operations.
The 2026 Convertible Notes are also affected by the price and volatility of our common stock and will generally increase or decrease as the market price of our common stock changes. The estimated fair value of the 2026 Convertible Notes was approximately $321.3 million as of December 31, 2024. ​ 139 Table of Contents
The 2026 Convertible Notes are also affected by the price and volatility of our common stock and will generally increase or decrease as the market price of our common stock changes. The estimated fair value of the 2026 Convertible Notes was approximately $424.5 million as of December 31, 2025. ​ 130 Table of Contents

Other PTCT 10-K year-over-year comparisons