10q10k10q10k.net

What changed in Protagonist Therapeutics, Inc's 10-K — 2024 vs 2025

vs

Paragraph-level year-over-year comparison of Protagonist 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.

+490 added−522 removedSource: 10-K (2026-02-25) vs 10-K (2025-02-21)

Top changes in Protagonist Therapeutics, Inc's 2025 10-K

490 paragraphs added · 522 removed · 289 edited across 10 sections

Item 1. Business

Business — how the company describes what it does

100 edited+112 added−168 removed121 unchanged
Biggest changeFailure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending NDAs, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties. 23 Table of Contents The process required by the FDA before a drug may be marketed in the United States generally involves the following: ● completion of pre-clinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practices (“GLP”) regulations; ● submission to the FDA of an IND application, which must become effective before human clinical trials may begin; ● approval by an independent institutional review board (“IRB”) at each clinical site before each trial may be initiated; ● performance of adequate and well-controlled human clinical trials in accordance with good clinical practice (“GCP”) requirements to establish the safety and efficacy of the proposed drug product for each indication; ● submission to the FDA of an NDA (or Biologics License Application (“BLA”) for a biologic product); ● satisfactory completion of an FDA advisory committee review, if applicable; ● satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with current good manufacturing practices (“cGMP”) requirements and to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity; ● satisfactory completion of an FDA inspection of one or more clinical trial sites to assure compliance with GCP requirements and the clinical protocol; and ● FDA review and approval of the NDA.
Biggest changeThe process required by the FDA before a drug may be marketed in the United States generally involves the following: ● completion of pre-clinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practices (“GLP”) regulations; ● submission to the FDA of an IND application, which must become effective before human clinical trials may begin; ● approval by an independent institutional review board (“IRB”) at each clinical site before each trial may be initiated; ● performance of adequate and well-controlled human clinical trials in accordance with good clinical practice (“GCP”) requirements to establish the safety and efficacy of the proposed drug product for each indication; ● submission to the FDA of an NDA (or Biologics License Application (“BLA”) for a biologic product); ● satisfactory completion of an FDA advisory committee review, if applicable; ● satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with current good manufacturing practices (“cGMP”) 19 Table of Contents requirements and to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity; ● satisfactory completion of an FDA inspection of one or more clinical trial sites to assure compliance with GCP requirements and the clinical protocol; and ● FDA review and approval of the NDA.
Government Regulation In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act and its implementing regulations. The process of obtaining regulatory approvals and the compliance with applicable federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.
Government Regulation In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act and its implementing regulations. The process of obtaining regulatory approvals and compliance with applicable federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.
One national regulatory authority (the reporting EU Member State proposed by the applicant) will take the lead in validating and evaluating the application consult and coordinate with the other concerned Member States. If an application is rejected, it may be amended and resubmitted through the EU clinical trials portal.
One national regulatory authority (the reporting EU Member State proposed by the applicant) will take the lead in validating and evaluating the application and consult and coordinate with the other concerned Member States. If an application is rejected, it may be amended and resubmitted through the EU clinical trials portal.
The laws that may affect our ability to operate include the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic health care transactions and protects the security and privacy of protected health information; the criminal health care fraud statutes under HIPAA also prohibit persons and entities from knowingly and willfully executing a scheme to defraud any health care benefit program, including private payors, or knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for health care benefits, items or services; the Anti-Kickback Statute, which prohibits persons from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made under federal health care programs such as the Medicare and Medicaid programs; federal false claims laws and civil monetary penalties laws that prohibit any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to the federal government, or knowingly making, or causing to be made, a false statement to have a false claim paid; and the Physician Payments Sunshine Act, which requires certain manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to the CMS information related to payments and other transfers of value made to various healthcare professionals including physicians, physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, certified nurse-midwives and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members.
The laws that may affect our ability to operate include the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic health care transactions and protects the security and privacy of protected health information; the criminal health care fraud statutes under HIPAA also prohibit persons and entities from knowingly and willfully executing a scheme to defraud any health care benefit program, including private payors, or knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for health care benefits, items or services; the Anti-Kickback Statute, which prohibits persons from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made under federal health care programs such as the Medicare and Medicaid programs; federal false claims laws and civil monetary penalties laws that prohibit any person or entity from knowingly 25 Table of Contents presenting, or causing to be presented, a false claim for payment to the federal government, or knowingly making, or causing to be made, a false statement to have a false claim paid; and the Physician Payments Sunshine Act, which requires certain manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to the CMS information related to payments and other transfers of value made to various healthcare professionals including physicians, physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, certified nurse-midwives and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members.
Rapid expansion into other IL-17 mediated diseases, including PsA, HS and axSpA, is expected to be based on results observed in psoriasis studies. We believe an IL-17 antagonist peptide like PN-881, with best-in-class potential as an oral targeted therapy, may offer an attractive therapeutic option for patients with broad opportunity for multiple indications in addition to psoriasis.
Rapid expansion into other IL-17 mediated diseases, including PsA, HS and axSpA, is expected to be based on results observed in the psoriasis studies. We believe an IL-17 antagonist peptide like PN-881, with best-in-class potential as an oral targeted therapy, may offer an attractive therapeutic option for patients with broad opportunity for multiple indications in addition to psoriasis.
For more information, please see Item 1A, “Risk Factors—Risks Related to Our Intellectual Property.” Manufacturing We contract with third parties for the manufacturing of our product candidates for pre-clinical studies and clinical trials and eventually for commercial supplies and intend to continue to do so in the future.
For more information, see Item 1A, “Risk Factors—Risks Related to Our Intellectual Property.” ​ Manufacturing ​ We contract with third parties for the manufacturing of our product candidates for pre-clinical studies and clinical trials and eventually for commercial supplies and intend to continue to do so in the future.
OUR PEPTIDE TECHNOLOGY PLATFORM Our proprietary technology platform is purposefully built to exploit the advantages of constrained peptides, which are much smaller than antibody-based drugs and may be delivered orally but are big enough to bind and block the difficult targets that antibodies bind and modulate.
OUR PROPRIETARY TECHNOLOGY PLATFORM Our proprietary technology platform is purposefully built to exploit the advantages of constrained peptides, which are much smaller than antibody-based drugs and may be delivered orally but are big enough to bind and block the difficult targets that antibodies bind and modulate.
Our human capital is fundamental to our ability to innovate and develop life-changing peptide drug therapies. We invest in our employees by seeking to foster a supportive and inclusive workplace. We offer competitive compensation and benefits and provide opportunities for professional growth and development.
Our human capital is fundamental to our ability to innovate and develop life-changing drug therapies. We invest in our employees by seeking to foster a supportive and inclusive workplace. We offer competitive compensation and benefits and provide opportunities for professional growth and development.
Since January 31, 2023, submission of initial clinical trial applications via CTIS is mandatory, and by January 31, 2025, all ongoing trials approved under the former Clinical Trials Directive will need to comply with the CTR and have to be transitioned to CTIS.
Since January 31, 2023, submission of initial clinical trial applications via CTIS is mandatory, and by January 31, 2025, all ongoing trials approved under the former Clinical Trials Directive need to comply with the CTR and have to be transitioned to CTIS.
For more information, please see Item 1A, “Risk Factors—Risks Related to Our Intellectual Property.” We own or co-own 30 issued U.S. patents, over 68 granted ex-U.S. patents, and numerous U.S. and ex-U.S. patent applications related to our clinical assets. We possess substantial know-how and trade secrets relating to the discovery, development and commercialization of peptide based therapeutic products.
For more information, please see Item 1A, “Risk Factors—Risks Related to Our Intellectual Property.” ​ We own or co-own over 30 issued U.S. patents, over 80 granted ex-U.S. patents, and numerous U.S. and ex-U.S. patent applications related to our clinical assets. We possess substantial know-how and trade secrets relating to the discovery, development and commercialization of peptide-based therapeutic products.
The centralized procedure is compulsory for specific medicinal products, including for medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, advanced therapy medicinal products (gene therapy, somatic cell therapy or tissue engineered medicines), and medicinal products with a new active substance indicated for the treatment of certain diseases (HIV/AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune and viral diseases).
The centralized procedure is compulsory for specific medicinal products, including for medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, advanced therapy medicinal products (gene therapy, somatic cell therapy or tissue engineered medicines), and medicinal products with a new active substance indicated for the treatment of certain diseases (HIV/AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other dysfunctions, and viral diseases).
Research Collaboration and License Agreement with Zealand Pharma A/S In June 2012, we entered into a Research Collaboration and License Agreement (the “Zealand Agreement”) with Zealand Pharma A/S (“Zealand”) to identify, optimize and develop novel disulfide-rich peptides to discover a hepcidin mimetic. We amended this agreement on February 28, 2014, at which point we assumed responsibility for the development program.
Research Collaboration and License Agreement with Zealand Pharma A/S In June 2012, we entered into a Research Collaboration and License Agreement (the “Zealand Agreement”) with Zealand Pharma A/S (“Zealand”) to identify, optimize and develop novel disulfide-rich peptides to discover a hepcidin mimetic. We amended this agreement in February 2014, at which point we assumed responsibility for the development program.
We make available, free of charge on our corporate website, copies of our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, Proxy Statements, and all amendments to these reports, as soon as reasonably practicable after such material is electronically filed with or furnished to the SEC pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended (“Exchange Act”). 34 Table of Contents
We make available, free of charge on our corporate website, copies of our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, Proxy Statements, and all amendments to these reports, as soon as reasonably practicable after such material is electronically filed with or furnished to the SEC pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended (“Exchange Act”).
Regarding transfers to the US, the EU commission issued an adequacy decision for transfers to companies that are certified under the new EU-US Data Privacy Framework, which entered into force on June 10, 2023.
Regarding transfers to the United States, the EU commission issued an adequacy decision for transfers to companies that are certified under the new EU-US Data Privacy Framework, which entered into force on June 10, 2023.
An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by 25 Table of Contents the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance. 27 Table of Contents Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.
Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance. Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.
Moreover, a patent can only be extended 22 Table of Contents once, and thus, if a single patent is applicable to multiple products, it can only be extended based on one product. Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug.
Moreover, a patent can only be extended once, and thus, if a single patent is applicable to multiple products, it can only be extended based on one product. Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug.
In addition to financial support of continuing 33 Table of Contents education, we are active sponsors, mentors, and hosts for students seeking to broaden their understanding of life sciences in the interest of advancing human health. Human Capital We recognize that our success is driven by the knowledge, skills and dedication of our employees.
In addition to financial support of continuing education, we are active sponsors, mentors, and hosts for students seeking to broaden their understanding of life sciences in the interest of advancing human health. Human Capital We recognize that our success is driven by the knowledge, skills and dedication of our employees.
There have been executive, judicial and Congressional challenges to certain aspects of the ACA. For example, President Trump signed several Executive Orders and other directives designed to delay the implementation of certain ACA requirements or otherwise circumvent some of the health insurance mandates. Concurrently, Congress considered legislation to repeal or repeal and replace all or part of the ACA.
There have been executive, judicial and Congressional challenges to certain aspects of the ACA. For example, there have been several Executive Orders and other directives designed to delay the implementation of certain ACA requirements or otherwise circumvent some of the health insurance mandates. Concurrently, Congress considered legislation to repeal or repeal and replace all or part of the ACA.
Orphan designation must be requested before submitting an NDA or BLA. After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Drugs or 26 Table of Contents biologics with orphan designation are not subject to a PDUFA fee upon the submission of an NDA.
Orphan designation must be requested before submitting an NDA or BLA. After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Drugs or biologics with orphan designation are not subject to a PDUFA fee upon the submission of an NDA.
The Inflation Reduction Act (“IRA”), enacted August 16, 2022, aims to control prescription drug prices in the upcoming years. The IRA will allow the Centers for Medicare & Medicaid Services (“CMS”) to cap out-of-pocket costs in 2025 and to negotiate prescription drug prices in 2026 for the first time.
The Inflation 24 Table of Contents Reduction Act (“IRA”), enacted August 16, 2022, aims to control prescription drug prices in the upcoming years. The IRA will allow the Centers for Medicare & Medicaid Services (“CMS”) to cap out-of-pocket costs in 2025 and to negotiate prescription drug prices in 2026 for the first time.
In addition, the FDA may mandate testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS. This can materially affect the potential market and profitability of the product.
In addition, the 21 Table of Contents FDA may mandate testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS. This can materially affect the potential market and profitability of the product.
We also rely on trade secrets relating to our proprietary technology platform and on know-how, and continuing technological innovation to develop, strengthen, and maintain our 21 Table of Contents proprietary position in the field of peptide-based therapeutics that may be important for the development of our business.
We also rely on trade secrets relating to our proprietary technology platform and on know-how, and continuing technological innovation to develop, strengthen, and maintain our proprietary position in the field of peptide-based therapeutics that may be important for the development of our business.
Additionally, the IRA provides a new “inflation rebate” covering Medicare patients beginning in 2023 to prevent rapid and arbitrary price increases in prescription drugs. These and any other legislation or healthcare reform measures of the Biden administration may impact the ACA and our business.
Additionally, the IRA provides a new “inflation rebate” covering Medicare patients beginning in 2023 to prevent rapid and arbitrary price increases in prescription drugs. These and any other legislation or healthcare reform measures may impact the ACA and our business.
Historically, exclusivity was specific to the orphan indication for which the drug or biologic was approved. As a result, the scope of exclusivity was interpreted as preventing approval of a competing product. However, in 2021, the federal court in Catalyst Pharmaceuticals, Inc. v.
Historically, exclusivity was specific to the orphan indication for which the drug or biologic was approved. As a result, the scope of exclusivity was interpreted as preventing approval of a competing product. However, in 2021, the federal 22 Table of Contents court in Catalyst Pharmaceuticals, Inc. v.
The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, collectively referred to as the ACA, enacted in March 2010, has had and is expected to continue to have a 28 Table of Contents significant impact on the health care industry.
The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, collectively referred to as the ACA, enacted in March 2010, has had and is expected to continue to have a significant impact on the health care industry.
In the future we may tackle other I&I, metabolic and blood disorders and expand our technology platform to provide potential opportunities to pursue a wider variety of diseases that may include oral, topical and systemic approaches.
In the future we may tackle 14 Table of Contents other I&I, blood and metabolic disorders and expand our technology platform to provide potential opportunities to pursue a wider variety of diseases that may include oral, topical and systemic approaches.
Adoption of price controls and other cost-containment measures, and adoption of more 29 Table of Contents restrictive policies in jurisdictions with existing controls and measures reforms may prevent or limit our ability to generate revenue, attain profitability or commercialize our product candidates.
Adoption of price controls and other cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures reforms may prevent or limit our ability to generate revenue, attain profitability or commercialize our product candidates.
We have established a global supply chain for raw material, active pharmaceutical ingredients (“API”), drug product manufacturing and distribution. We work with contract manufacturers in the United States, Europe and Asia. Although we rely on contract manufacturers, our personnel and consultants have extensive manufacturing and quality control experience overseeing CMOs.
We have established a global supply chain for raw material, active pharmaceutical ingredients (“API”), drug product manufacturing and distribution. We work with contract manufacturers in the United States, Europe and Asia. Although we rely on contract manufacturers, our 18 Table of Contents personnel and consultants have extensive manufacturing and quality control experience overseeing CMOs.
When relying on SCCs, data exporters are also required to conduct a transfer risk assessment to verify if anything in the law and/or practices of the third country may impinge on the effectiveness of the SCCs in the context of the transfer at stake and, if so, to identify and adopt supplementary measures that are necessary to bring the level of protection of the data transferred to the EU standard of essential equivalence.
When relying on the appropriate safeguards, data exporters, with the assistance of the data importers, are also required to conduct a transfer risk assessment to verify if anything in the law and/or practices of the third country may impinge on the effectiveness of the safeguards in the context of the transfer at stake and, if so, to identify and adopt supplementary measures that are necessary to bring the level of protection of the data transferred to the EU standard of essential equivalence.
If an approval is issued, the sponsor may start the clinical trial in all concerned Member States. However, a concerned EU Member State may in limited circumstances declare an “opt-out” from an approval and prevent the clinical trial from being conducted in such Member State.
If an approval is issued, the sponsor may start the clinical trial in all concerned Member States. However, a concerned EU 26 Table of Contents Member State may in limited circumstances declare an “opt-out” from an approval and prevent the clinical trial from being conducted in such Member State.
The GDPR imposes strict requirements on the processing of personal data, including the legal basis for the processing, the information that has to be provided to individuals before their data is processed, 32 Table of Contents personal data breaches which may have to be notified to national data protection authorities and data subjects, the measures to be taken when engaging processors, and the technical and organization measures to ensure the security and confidentiality of the personal data.
The GDPR and UK GDPR impose strict requirements on the processing of personal data, including the legal basis for the processing, the information that has to be provided to individuals before their data is processed, personal data breaches which may have to be notified to national data protection authorities and data subjects, the measures to be taken when engaging processors, and the technical and organization measures to ensure the security and confidentiality of the personal data.
Under the centralized procedure, the timeframe for the evaluation of an MAA by the CHMP is, in principle, 210 days 31 Table of Contents from receipt of a valid MAA.
Under the centralized procedure, the timeframe for the evaluation of an MAA by the CHMP is, in principle, 210 days from receipt of a valid MAA.
EU Member States may also have additional requirements for health, genetic, and biometric data through their national legislation. The GDPR also imposes restrictions on the transfer of personal data to countries outside of the EU that do not provide an adequate level of data protection.
EEA countries may also have additional requirements for the processing of health, genetic, and biometric data through their national legislation. The GDPR also imposes restrictions on the transfer of personal data to countries outside of the EEA that do not provide an adequate level of data protection.
Among the over 8 million patients in the United States with psoriasis in 2024, it is estimated that approximately 1 million patients have PsA. Many patients with active PsA may have mild psoriasis and many patients with severe psoriasis may have only mild PsA symptoms. PsA is associated with several chronic conditions.
Among the over 8 million patients in the United States with psoriasis in 2024, it is estimated that approximately 1.7 million patients have PsA. Many patients with active PsA may have mild psoriasis and many patients with severe psoriasis may have only mild PsA symptoms.
Information about certain clinical trials must be submitted within specific time frames to the National Institutes of Health for public dissemination on www.clinicaltrials.gov. 24 Table of Contents Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined: ● Phase 1: The drug is initially introduced into healthy human subjects or patients with the target disease or condition and is tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness. ● Phase 2: The drug is administered to a limited patient population to identify possible adverse effects and safety risks, and to preliminarily evaluate the efficacy of the investigational drug product for specific targeted diseases and to determine dosage tolerance and optimal dosage. ● Phase 3: The drug is administered to an expanded patient population to establish the overall risk-benefit profile of the product, and to provide adequate labeling information (labeling) for the safe and efficacious administration for the labeling of the product.
Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined: ● Phase 1: The drug is initially introduced into healthy human subjects or patients with the target disease or condition and is tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness. ● Phase 2: The drug is administered to a limited patient population to identify possible adverse effects and safety risks, and to preliminarily evaluate the efficacy of the investigational drug product for specific targeted diseases and to determine dosage tolerance and optimal dosage. ● Phase 3: The drug is administered to an expanded patient population to establish the overall risk-benefit profile of the product, and to provide adequate labeling information (labeling) for the safe and efficacious administration for the labeling of the product.
We also intend to progress our platform to achieve systemic bioavailability and activity with oral peptides, macrocycles and peptidomimetics, thereby enabling us to address systemic diseases. Examples of this approach are the discovery and development of icotrokinra, our IL-23R antagonist in collaboration with JNJ, and PN-881, our recently announced IL-17 peptide antagonist product candidate, as described above.
We also intend to progress our platform to achieve systemic bioavailability and activity with oral peptides, macrocycles and peptidomimetics, thereby enabling us to address systemic diseases. Examples of this approach are the discovery and development of Icotyde, our IL-23R antagonist in collaboration with JNJ, and PN-881, our wholly-owned Phase 1 IL-17 oral peptide antagonist, as described above.
The length of the patent term extension is related to the length of time the drug is under regulatory review. A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended.
A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended.
Other potential consequences include: ● restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls; ● fines, warning letters or holds on post-approval clinical trials; ● refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product approvals; ● product seizure or detention, or refusal to permit the import or export of products; or ● injunctions or the imposition of civil or criminal penalties.
Other potential consequences include: ● restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls; ● fines, warning letters or holds on post-approval clinical trials; ● refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product approvals; ● product seizure or detention, or refusal to permit the import or export of products; or ● injunctions or the imposition of civil or criminal penalties. 23 Table of Contents The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market.
PN-881 In the fourth quarter of 2024, we announced the selection of PN-881, a potential best-in-class oral peptide IL-17 antagonist, as a development candidate for the treatment of immune-mediated skin diseases. PN-881 targets three IL-17 dimers (IL-17 AA, AF and FF), which may offer potential treatment options for h idradenitis suppurativa (“HS”), spondyloarthritis, plaque psoriasis and psoriatic arthritis (“PsA”).
We are developing PN-881, a potential best-in-class oral peptide IL-17 antagonist, for the treatment of immune-mediated skin diseases. PN-881 targets three IL-17 dimers (IL-17 AA, AF and FF), and may offer potential treatment options for plaque psoriasis, psoriatic arthritis (“PsA”), h idradenitis suppurativa (“HS”), and spondyloarthritis.
If we are found to be in violation of any of the laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including significant administrative, civil and criminal penalties, damages, fines, imprisonment, disgorgement, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, exclusion of products from reimbursement under U.S. federal or state health care programs, and the curtailment or restructuring of our operations. 30 Table of Contents Government Regulation Outside of the United States In addition to regulations in the United States, we will be subject to a variety of regulations in other jurisdictions governing clinical studies and any commercial sales and distribution of our products.
If we are found to be in violation of any of the laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including significant administrative, civil and criminal penalties, damages, fines, imprisonment, disgorgement, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, exclusion of products from reimbursement under U.S. federal or state health care programs, and the curtailment or restructuring of our operations.
Medicines that fall outside the mandatory scope of the centralized procedure have three routes to authorization: (i) they can be authorized under the centralized procedure if they concern a significant therapeutic, scientific or technical innovation, or if their authorization would be in the interest of public health; (ii) they can be authorized under a decentralized procedure where an applicant applies for simultaneous authorization in more than one EU Member State; or (iii) they can be authorized in an EU Member State in accordance with that state’s national procedures and then be authorized in other EU countries by a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization (mutual recognition procedure).
Medicines that fall outside the mandatory scope of the centralized procedure have three routes to authorization: (i) they can be authorized under the centralized procedure if they concern a significant therapeutic, scientific or technical innovation, or if their authorization would be in the interest of public health; (ii) they can be authorized under a decentralized procedure where an applicant applies for simultaneous authorization in more than one EU Member State; or (iii) they can be authorized in an EU Member State in accordance with that state’s national procedures and then be authorized in other EU countries by a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization (mutual recognition procedure). 27 Table of Contents The decentralized procedure permits companies to file identical MA applications for a medicinal product to the competent authorities in various EU Member States simultaneously if such medicinal product has not received marketing approval in any EU Member State before.
Our commercial success may depend in part on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business; defend and enforce our patents; preserve the confidentiality of our trade secrets; and operate without infringing the valid enforceable patents and proprietary rights of third parties.
We will also take advantage of regulatory protection afforded through data exclusivity, market exclusivity and patent term extensions where available. ​ Our commercial success may depend in part on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business; defend and enforce our patents; preserve the confidentiality of our trade secrets; and operate without infringing the valid enforceable patents and proprietary rights of third parties.
We believe that our focus and expertise will help us develop products based on our proprietary intellectual property. The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the date of filing the non-provisional application.
We believe that our focus and expertise will help us develop products based on our proprietary intellectual property. ​ The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained.
Planned clinical studies include a Phase 1 single ascending dose (“SAD”) and multiple ascending dose (“MAD”) study expected to begin in the fourth quarter of 2025. Results of the Phase 1 trial are expected to inform the design and dosing in a subsequent dose-ranging psoriasis trial.
We initiated a Phase 1 PN-881 first-in-human study in the fourth quarter of 2025. Results of the Phase 1 single ascending dose (“SAD”) and multiple ascending dose (“MAD”) study are expected to inform the design and dosing in a subsequent dose-ranging psoriasis trial.
The FDA and other agencies enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.
Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved prescribing information. The FDA and other agencies enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.
None of our employees are represented by a labor union or covered by a collective bargaining agreement. We consider our relationship with our employees to be good. Attracting, developing and retaining talented employees to support the growth of our business is an integral part of our human capital strategy and critical to our long-term success.
We consider our relationship with our employees to be good. Attracting, developing and retaining talented employees to support the growth of our business is an integral part of our human capital strategy and critical to our long-term success.
For example, this peptide technology platform has been used to develop product candidates for diverse target classes including G-protein-coupled receptors, ion channels, transporters, cytokines and their receptors for a variety of therapeutic areas.
Discovery and Pre-clinical Activities We believe we have built a versatile, well-validated and unique discovery platform. For example, this technology platform has been used to develop product candidates for diverse target classes including G-protein-coupled receptors, ion channels, transporters, cytokines and their receptors for a variety of therapeutic areas.
PsA may present even before skin symptoms in 10% to 15% of patients. Cardiovascular comorbidities have a higher prevalence in PsA than psoriasis and can impact lifespan and quality of life. Several new targeted therapies have been approved for use in PsA, with additional therapies in development.
PsA is associated with several chronic conditions and may present even before skin symptoms in 10% to 15% of patients. Cardiovascular comorbidities have a higher prevalence in PsA than psoriasis and can impact both lifespan and quality of life.
We earned the $165.0 million milestone payment described above during the fourth quarter of 2024. We have earned a total of $337.5 million in nonrefundable payments from JNJ from 2017 through December 31, 2024.
We have earned a total of $337.5 million in milestone payments from JNJ under the agreement, including a $165.0 million milestone payment earned in the fourth quarter of 2024.
Rusfertide Ruxolitinib, marketed as Jakafi®, was approved in 2014 for the treatment of adults with PV who have inadequate response to or are intolerant to hydroxyurea. Approximately 5,300 PV patients are treated with Jakafi® each year. Besremi®, a ropeginterferon alfa-2b product indicated for the treatment of adults with PV, was approved with a black box warning in November 2021.
Ruxolitinib, marketed as Jakafi® (Incyte), was approved in 2014 for adults with PV who are intolerant of or have an inadequate response to hydroxyurea. Besremi® (ropeginterferon alfa-2b-nicotinamide, PharmaEssentia/AOP), indicated for adults with PV, was approved in November 2021 and carries a black box warning.
The competent authority of a single EU Member State, known as the reference EU Member State, is appointed to review the application and provide an assessment report.
This procedure is available for pharmaceutical products not falling within the mandatory scope of the centralized procedure. The competent authority of a single EU Member State, known as the reference EU Member State, is appointed to review the application and provide an assessment report.
We currently engage CMOs on a “fee for services” basis for our current development and clinical supplies. Government Regulation The FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial requirements upon companies involved in the clinical development, manufacture, marketing and distribution of drugs, such as those we are developing.
Takeda is responsible for the manufacturing of rusfertide pursuant to the Takeda Collaboration Agreement. ​ Government Regulation ​ The FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial requirements upon companies involved in the clinical development, manufacture, marketing and distribution of drugs, such as those we are developing.
European Data Protection Laws The collection and use of personal health data and other personal data in the EU is governed by the provisions of the European General Data Protection Regulation (EU) 2016/679 (“GDPR”) and related data protection laws in individual EU Member States.
European Data Protection Laws The processing of personal data, including health-related personal data in the European Economic Area (“EEA”) is mainly governed by the provisions of the European General Data Protection Regulation (EU) 2016/679 (“GDPR”) and related data protection laws in individual EEA countries.
At JNJ’s Enterprise Business Review in December 2023, JNJ highlighted icotrokinra as a potential first- and best-in-class targeted oral IL-23 peptide antagonist with potential across multiple indications, including plaque psoriasis, PsA and inflammatory bowel disease, with potential peak year sales projected at greater than $5.0 billion.
At JNJ’s Enterprise Business Review in December 2023, JNJ highlighted Icotyde as a potential first- and best-in-class drug with potential across multiple indications, including plaque psoriasis, PsA and inflammatory bowel disease, with potential peak year sales projected at greater than $5.0 billion. ​ PN-881: An Oral IL-17 Receptor Antagonist PN-881, a wholly owned oral peptide antagonist of the IL-17 pathway, was selected in the fourth quarter of 2024 as a potential best-in-class oral therapy for the treatment of immune-mediated skin diseases.
To support our employees personally and professionally, we have Employee Assistance Programs to address employee challenges and needs. We value feedback from our employees and use it to improve our workplace policies and practices. Corporate and Other Information Our website address is www.protagonist-inc.com.
We also allow for flexible working arrangements for certain of our employees. We value feedback from our employees and use it to improve our workplace policies and practices. Corporate and Other Information Our website address is www.protagonist-inc.com.
We expect our patents and patent applications, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire from October 2033 to December 2044 (excluding possible patent term extensions).
Applications are currently pending in the United States and other major jurisdictions, including Australia, Canada, China, Japan, and Europe. We 17 Table of Contents expect our patents and patent applications, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire from October 2033 to September 2045 (excluding possible patent term extensions).
We are also eligible to receive tiered royalties from 10% to 17% on ex-U.S. net sales of rusfertide and other specified second-generation injectable hepcidin memetic compounds (the “Licensed Products”). We and Takeda will also share equally in profits and losses (50% to us and 50% to Takeda) of the Licensed Products in the United States, if approved.
Under the Takeda Collaboration Agreement, we and Takeda share equally in profits and losses (50% to us and 50% to Takeda) associated with rusfertide in the United States. We also will receive tiered royalties ranging from 10% to 17% on ex-U.S. net sales of rusfertide.
Stelara® is a monoclonal antibody targeting IL-12 and IL-23 through their common p40 subunit is approved in psoriasis, PsA, CD and UC. Stelara® generated $10.4 billion in sales in 2024. Tremfya® is a specific IL-23 monoclonal antibody. It is approved in psoriasis and PsA and has completed successful Phase 3 trials in UC and CD.
JNJ is an experienced innovator in therapeutics targeting the IL-23 pathway. Stelara®, a monoclonal antibody targeting IL-12 and IL-23 through their common p40 subunit, is approved in psoriasis, PsA, CD and UC. Stelara® generated $10.4 billion in global sales in 2024 and $6.1 billion in global sales in 2025.
Marketing Approval Following successful completion of the required clinical testing and the results of the pre-clinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other information, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications.
Similarly, an IRB or ethics committee can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients. 20 Table of Contents Marketing Approval Following successful completion of the required clinical testing and the results of the pre-clinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other information, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications.
See Part II, Item 7, “Management’s Discussion and Analysis – Overview” and Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information. JNJ License and Collaboration Agreement In July 2017, we entered into the JNJ License and Collaboration Agreement. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
Specific patents and patent applications are directed to compositions of α 4 β7 integrin peptides, IL-23R antagonist peptides, IL-17 antagonist peptides and hepcidin mimetics peptides, as well as methods of synthesizing and using these peptides to treat disorders. Applications are currently pending in the United States and other major jurisdictions, including Australia, Canada, China, Japan, and Europe.
Specific patents and patent applications are directed to compositions of α 4 β7 integrin peptides, IL-23R antagonist peptides, IL-17 antagonist peptides, hepcidin mimetics peptides and small molecules, and glucagon superfamily receptor agonists, as well as methods of synthesizing and using these compounds to treat disorders.
The term of a patent that covers an FDA-approved drug may also be eligible for patent term extension, which permits patent term restoration of a U.S. patent as compensation for the patent term lost during the FDA regulatory review process. The Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration of the patent.
Patent and Trademark Office in granting a patent or may be shortened if a patent is terminally disclaimed over an earlier-filed patent. ​ The term of a patent that covers an FDA-approved drug may also be eligible for patent term extension, which permits patent term restoration of a U.S. patent as compensation for the patent term lost during the FDA regulatory review process.
Pre-clinical Studies Pre-clinical studies include laboratory evaluation of product chemistry, toxicity and formulation, as well as animal studies to assess potential safety and efficacy. These pre-clinical studies must comply with GLP.
Pre-clinical Studies Pre-clinical studies include laboratory evaluation of product chemistry, toxicity and formulation, as well as animal studies to assess potential safety and efficacy. These pre-clinical studies must comply with GLP. In April 2025, the FDA published a roadmap to reduce animal testing in preclinical safety studies, including those required in INDs, with scientifically validated new approach methodologies.
See Note 3 to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for further details related to the agreement, including our right to opt-out of the 50:50 U.S. profit and loss sharing arrangement.
In addition, we will receive tiered royalties ranging from 10% to 17% on ex-U.S. net sales of rusfertide. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report for further details related to the agreement, including our opt-out rights.
For injectable products, stability in blood is determined using in vitro assay techniques to identify chemical and biological sites of degradation, which are then optimized while still maintaining potency and selectivity. Conjugation strategies are used to optimize the exposure of the injected peptide.
For injectable products, stability in blood is determined using in vitro assay techniques to identify chemical and biological sites of degradation, which are then optimized while still maintaining potency and selectivity. For Icotyde, phage display is tightly coupled to medicinal chemistry, structural biology and oral stability techniques to develop potent, selective and orally delivered molecules.
Following icotrokinra’s joint discovery by us and JNJ scientists pursuant to our IL-23R collaboration, we were primarily responsible for the development of icotrokinra through Phase 1, with JNJ assuming responsibility for development in Phase 2 and beyond.
Following Icotyde’s joint discovery by Protagonist and JNJ scientists, pursuant to the license and collaboration agreement, we were primarily responsible for the development of Icotyde through Phase 1, with JNJ assuming responsibility for development in Phase 2 and beyond. In July 2025 and September 2025, respectively, JNJ submitted a New Drug Application (“NDA”) to the U.S.
In multiple preclinical studies with oral dosing, PN-881 showed effective blockade in vivo of IL-17 in serum and skin and achieved pre-clinical proof-of-concept in a skin inflammation rodent disease model. 18 Table of Contents IND-enabling, or foreign equivalent, studies of PN-881 are ongoing or planned, including 7-day and 3-month toxicology studies.
PN-881 was evaluated in extensive preclinical studies, including for oral stability, potency, tissue distribution, and pharmacokinetics measurements, and was evaluated in immunologic pharmacodynamics and preclinical efficacy models. In multiple preclinical studies with oral dosing, PN-881 showed effective blockade in vivo of IL-17 in serum and skin and achieved pre-clinical proof-of-concept in a skin inflammation rodent disease model.
Safeguarding the health and safety of our employees is a top priority. We are committed to providing a safe working environment for all of our employees. Our cross-functional safety committee meets regularly to discuss policies and protocols, strategic planning, business continuity and other matters. We invest in initiatives aimed at promoting employee well-being.
Our cross-functional safety committee meets regularly to discuss policies and protocols, strategic planning, business continuity and other matters. We invest in initiatives aimed at promoting employee mental and physical well-being, including providing meals and access to fitness facility onsite. To support our employees personally and professionally, we have Employee Assistance Programs to address employee challenges and needs.
As of December 31, 2024, our total global workforce consisted of 126 full-time equivalent employees, 98 of whom were in research and development. The remaining 28 employees worked in finance, legal, business development, human resources, information technology (“IT”) and administrative support. 117 of our full-time equivalent employees are located in the United States and 9 are located in Australia.
The remaining 29 employees worked in finance, legal, business development, 29 Table of Contents human resources, information technology (“IT”) and administrative support. 123 of our full-time equivalent employees are located in the United States and 9 are located in Australia. None of our employees are represented by a labor union or covered by a collective bargaining agreement.
Rusfertide, an injectable mimetic of the natural hormone hepcidin, is currently in Phase 3 development for treatment of the rare blood disorder polycythemia vera (“PV”). Rusfertide is being co-developed and will be co-commercialized with Takeda Pharmaceuticals, Inc. (“Takeda”) and the Company remains primarily responsible for development through NDA filing.
Rusfertide Rusfertide is a first-in-class investigational injectable mimetic of the natural hormone hepcidin in development for the treatment of the rare blood disorder polycythemia vera (“PV”). We discovered rusfertide, advanced it into Phase 3 development, and in early 2024 entered into a co-development and co-commercialization arrangement with Takeda Pharmaceuticals, Inc.
See Part II, Item 7, “Management’s Discussion and Analysis – Overview” and Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
Our weighted average royalty rate on the first $4.0 billion in annual net sales is 7.25%, and the rate on net sales over $4.0 billion is 10%. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report for additional information.
ICOTROKINRA: AN ORAL IL-23 RECEPTOR ANTAGONIST JNJ License and Collaboration Agreement We have a worldwide license and collaboration agreement with JNJ to research, develop and co-detail IL-23R antagonist compounds for all indications, including IBD. See Part II, Item 7.
IL-23, a member of the IL-12 family of pro-inflammatory cytokines, is a protein that regulates inflammatory and immune function and plays a key role in the development of IBD. We have a worldwide license and collaboration agreement with JNJ to research, develop and co-detail IL-23R antagonist compounds for all indications, including IBD.
For the year ended December 31, 2024, our employee turnover rate was approximately 11%. We have a performance development review process in which managers provide regular feedback to assist with the development of our employees, including the use of individual plans to assist with career development.
We have a performance development review process in which managers provide regular feedback to assist with the development of our employees, including the use of individual plans to assist with career development. We also invest in the growth and development of our employees through various training and development programs that help build and strengthen our employees’ leadership and professional skills.
Tremfya® generated $3.7 billion in sales in 2024. We believe that in both psoriasis and IBD, there is an urgent need for safe and effective oral therapies. It is notable that Stelara® lost patent exclusivity in 2023 with biosimilar competition expected.
It is notable that Stelara® lost patent exclusivity in 2023, with expected biosimilar competition. Tremfya®, a specific IL-23 monoclonal antibody, is approved in psoriasis, PsA, UC and CD. Tremfya® generated $3.7 billion in sales in 2024 and $5.2 billion in 2025.
Bimekizumab (anti-IL-17A and F, UCB) has completed a positive Phase 3 program in psoriasis. Otezla® (Amgen) was the first oral agent approved in both psoriasis and PsA. The oral JAK inhibitors Xeljanz® (Pfizer) and Rinvoq® are approved in PsA. Several oral small molecules that inhibit the Janus kinase TYK2 are advancing in development.
Otezla® (Amgen) was the first oral agent approved in both psoriasis and PsA. The oral JAK inhibitors Xeljanz® (Pfizer) and Rinvoq® (AbbVie) are approved in PsA. Several oral TYK2 inhibitors are advancing in development. Bristol Myers Squibb’s Sotyktu® was approved for psoriasis in 2022.
The injectable mAbs Cosentyx and Taltz targeting IL-17 AA and AF are approved in psoriasis, PsA, and SpA. Cosentyx was also recently the first IL-17 inhibitor approved in HS. Siliq, a mAb to the IL-17 receptor, is approved in psoriasis only and carries a black box warning for suicidal ideations.
Injectable monoclonal antibodies targeting the IL-17 pathway are well established across multiple inflammatory indications. Cosentyx® and Taltz®, monoclonal antibodies targeting IL-17A, are approved in psoriasis, PsA, and spondyloarthritis, and Cosentyx is also approved in HS. Siliq®, a monoclonal antibody targeting the IL-17 receptor, is approved in psoriasis only and carries a boxed warning for suicidal ideation and behavior.
In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S. Patent and Trademark Office in granting a patent or may be shortened if a patent is terminally disclaimed over an earlier-filed patent.
In most countries in which we file, the patent term is 20 years from the date of filing the non-provisional application. In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S.
We have a pre-clinical stage program to identify an orally administered hepcidin mimetic/ferroportin blocker, which we believe to be complementary to the injectable rusfertide for offering the best treatment options for PV and other potential erythropoietic and iron imbalance disorders, and we expect to nominate a development candidate in the fourth quarter of 2025.
In December 2025, we nominated development candidate PN-8047, an orally administered hepcidin functional mimetic small molecule, which we believe may be complementary to the injectable rusfertide for offering the best treatment options for PV.
We also invest in the growth and development of our employees through various training and development programs that help build and strengthen our employees’ leadership and professional skills. This reflects the quality and readiness of our people to take on new roles, as well as our intentional focus on growing and developing careers, as well as promoting from within.
This reflects the quality and readiness of our people to take on new roles, as well as our intentional focus on growing and developing careers and promoting from within. Safeguarding the health and safety of our employees is a top priority. We are committed to providing a safe working environment for all of our employees.

… 300 more changes not shown on this page.

Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

102 edited+55 added−18 removed221 unchanged
Biggest changeUnder the terms of the Takeda Collaboration Agreement, Takeda may terminate the agreement for convenience in its entirety or as to a major region by providing advance written notice following the earliest of (i) the receipt of Phase 3 data with respect to the VERIFY clinical trial, (ii) the third anniversary of the effective date of the agreement or (iii) the occurrence of certain specified adverse events related to the clinical development of rusfertide.
Biggest changeJNJ’s decisions with respect to such development and commercialization will affect the timing and availability of potential future payments under the agreement, if any. Under the terms of the Takeda Collaboration Agreement, Takeda may terminate the agreement for convenience in its entirety or as to a major region by providing advance written notice to us.
Other than our collaboration with JNJ License and Collaboration Agreement and our collaboration with Takeda under the Takeda Collaboration Agreement, we have no active collaborations for any of our product candidates.
Other than our collaboration with JNJ under the JNJ License and Collaboration Agreement and our collaboration with Takeda under the Takeda Collaboration Agreement, we have no active collaborations for any of our product candidates.
In particular, the conflict in Ukraine has exacerbated market disruptions, including significant volatility in commodity prices, as well as supply chain interruptions, and has contributed to record inflation globally. The U.S. Federal Reserve and other central banks may be unable to contain inflation through more restrictive monetary policy and inflation may increase or continue for a prolonged period of time.
In particular, the conflict in Ukraine has exacerbated market disruptions, including significant volatility in commodity prices, as well as supply chain interruptions, and has contributed to inflation globally. The U.S. Federal Reserve and other central banks may be unable to contain inflation through more restrictive monetary policy and inflation may increase or continue for a prolonged period of time.
Our research programs may initially show promise in identifying potential product candidates yet fail to yield product candidates for clinical development for many reasons. Our proprietary peptide platform may not result in any products of commercial value. We have developed a proprietary peptide technology platform to enable the identification, testing, design and development of new product candidates.
Our research programs may initially show promise in identifying potential product candidates yet fail to yield product candidates for clinical development for many reasons. Our proprietary technology platform may not result in any products of commercial value. We have developed a proprietary technology platform to enable the identification, testing, design and development of new product candidates.
The following examples are illustrative: ● others may be able to make compounds or formulations that are similar to our product candidates, but that are not covered by the claims of any patents that we own, license or control; ● we or any strategic partners might not have been the first to make the inventions covered by the issued patents or pending patent applications that we own; ● we may not have been the first to file patent applications covering certain of our inventions; ● others may independently develop the same, similar, or alternative technologies without infringing, misappropriating or violating our intellectual property rights; ● it is possible that our pending patent applications will not lead to issued patents; ● issued patents may not provide us with any competitive advantages, or may be narrowed or held invalid or unenforceable, including as a result of legal challenges; 55 Table of Contents ● our competitors might conduct research and development activities in the United States and other countries that provide a safe harbor from patent infringement claims for certain research and development activities, as well as in countries where we do not have patent rights, and may then use the information learned from such activities to develop competitive products for sale in our major commercial markets; ● we may choose not to file a patent in order to maintain certain trade secrets or know-how, and a third party may subsequently file a patent covering such trade secrets or know-how; and ● the patents of others may have an adverse effect on our business.
The following examples are illustrative: ● others may be able to make compounds or formulations that are similar to our product candidates, but that are not covered by the claims of any patents that we own, license or control; ● we or any strategic partners might not have been the first to make the inventions covered by the issued patents or pending patent applications that we own; ● we may not have been the first to file patent applications covering certain of our inventions; ● others may independently develop the same, similar, or alternative technologies without infringing, misappropriating or violating our intellectual property rights; ● it is possible that our pending patent applications will not lead to issued patents; ● issued patents may not provide us with any competitive advantages, or may be narrowed or held invalid or unenforceable, including as a result of legal challenges; ● our competitors might conduct research and development activities in the United States and other countries that provide a safe harbor from patent infringement claims for certain research and development activities, as well as in countries where we do not have patent rights, and may then use the information learned from such activities to develop competitive products for sale in our major commercial markets; ● we may choose not to file a patent in order to maintain certain trade secrets or know-how, and a third party may subsequently file a patent covering such trade secrets or know-how; and ● the patents of others may have an adverse effect on our business.
If any of our product candidates fail in clinical trials or do not gain regulatory approval or fail to achieve market acceptance, we may never become profitable. Revenue we generate from our collaborations with JNJ, Takeda, and any future collaboration arrangements may not be sufficient to sustain our operations.
In addition, if any of our product candidates fail in clinical trials or do not gain regulatory approval or fail to achieve market acceptance, we may never become profitable. Revenue we generate from our collaborations with JNJ, Takeda, and any future collaboration arrangements, if any, may not be sufficient to sustain our operations.
If we are unable to submit an NDA with respect to any of our current product candidates, if any NDA we submit is not approved by the FDA, or we elect not to file an NDA, or if we are unable to obtain any required state and local distribution licenses or similar authorizations, we will be unable to commercialize that product.
If we or our collaborators are unable to submit an NDA with respect to any of our current product candidates, if any NDA we or our collaborators submit is not approved by the FDA, or we or our collaborators elect not to file an NDA, or if we or our collaborators are unable to obtain any required state and local distribution licenses or similar authorizations, we will be unable to commercialize that product.
The laws that may affect our ability to operate include, but are not limited to: ● the federal Anti-Kickback Statute; 47 Table of Contents ● the federal false claims laws, including the False Claims Act; ● the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”); ● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act and their implementing regulations, which also imposes obligations, including mandatory contractual terms, on HIPAA-covered entities, their business associates as well as their covered subcontractors with respect to safeguarding the privacy, security and transmission of individually identifiable health information; ● the federal civil monetary penalties statute; ● the federal Physician Payments Sunshine Act; and ● analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws.
The laws that may affect our ability to operate include, but are not limited to: ● the federal Anti-Kickback Statute; 45 Table of Contents ● the federal false claims laws, including the False Claims Act; ● the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”); ● HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act and their implementing regulations, which also imposes obligations, including mandatory contractual terms, on HIPAA-covered entities, their business associates as well as their covered subcontractors with respect to safeguarding the privacy, security and transmission of individually identifiable health information; ● the federal civil monetary penalties statute; ● the federal Physician Payments Sunshine Act; and ● analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws.
The degree of market acceptance of any of our product candidates, if approved for commercial sale, will depend on a number of factors, including but not limited to: ● the safety and efficacy of the product in clinical trials, and potential advantages over competing treatments; ● the publication of unfavorable safety or efficacy data concerning our product by third parties; 44 Table of Contents ● the prevalence and severity of any side effects, including any limitations or warnings contained in a product’s approved labeling; ● the clinical indications for which approval is granted; ● recognition and acceptance of our product candidates over our competitors’ products; ● prevalence of the disease or condition for which the product is approved; ● the cost of treatment, particularly in relation to competing treatments; ● the willingness of the target patient population to try our therapies and of physicians to prescribe these therapies; ● the strength of marketing and distribution support and timing of market introduction of competitive products; ● the extent to which the product is approved for inclusion on formularies of hospitals and managed care organizations; ● publicity concerning our products or competing products and treatments; ● the extent to which third-party payors provide coverage and adequate reimbursement for the product candidate, or any other product candidates we may pursue, if approved; ● our ability to maintain compliance with regulatory requirements; and ● labeling or naming imposed by FDA or other regulatory agencies.
The degree of market acceptance of any of our product candidates, if approved for commercial sale, will depend on a number of factors, including but not limited to: ● the safety and efficacy of the product in clinical trials, and potential advantages over competing treatments; ● the publication of unfavorable safety or efficacy data concerning our product by third parties; ● the prevalence and severity of any side effects, including any limitations or warnings contained in a product’s approved labeling; ● the clinical indications for which approval is granted; ● recognition and acceptance of our product candidates over our competitors’ products; ● prevalence of the disease or condition for which the product is approved; ● the cost of treatment, particularly in relation to competing treatments; ● the willingness of the target patient population to try our therapies and of physicians to prescribe these therapies; ● the strength of marketing and distribution support and timing of market introduction of competitive products; ● the extent to which the product is approved for inclusion on formularies of hospitals and managed care organizations; ● publicity concerning our products or competing products and treatments; ● the extent to which third-party payors provide coverage and adequate reimbursement for the product candidate, or any other product candidates we may pursue, if approved; ● our ability to maintain compliance with regulatory requirements; and ● labeling or naming imposed by FDA or other regulatory agencies.
We cannot be sure that, if our clinical trials for any of our product candidates are successfully completed, we will be able to submit an NDA to the FDA or that any NDA we submit will be approved by the FDA in a timely manner, if at all.
We cannot be sure that, if our clinical trials for any of our product candidates are successfully completed, we or our collaborators will be able to submit an NDA to the FDA or that any NDA we or our collaborators submit will be approved by the FDA in a timely manner, if at all.
Our product candidates could fail to receive regulatory approval for many reasons, including the following: ● the FDA or comparable foreign regulatory authorities may disagree with the design or implementation of our clinical trials, or our interpretation of the data submitted in support of regulatory approval; ● we may be unable to demonstrate to the satisfaction of the FDA or comparable foreign regulatory authorities that a product candidate is safe and effective for its proposed indication or that a product candidate’s clinical and other benefits outweigh its safety risks; ● the results of clinical trials may fail to achieve the level of statistical significance required by the FDA or comparable foreign regulatory authorities for approval; ● the data collected from pre-clinical studies and clinical trials of our product candidates may not be sufficient to support the submission of an NDA, supplemental NDA, or other regulatory submissions necessary to obtain regulatory approval; 41 Table of Contents ● we or our contractors may not meet the GMP and other applicable requirements for manufacturing processes, procedures, documentation and facilities necessary for approval by the FDA or comparable foreign regulatory authorities; and ● changes to the approval policies or regulations of the FDA or comparable foreign regulatory authorities with respect to our product candidates may result in our clinical data becoming insufficient for approval.
Our product candidates could fail to receive regulatory approval for many reasons, including the following: ● the FDA or comparable foreign regulatory authorities may disagree with the design or implementation of our clinical trials, or our interpretation of the data submitted in support of regulatory approval; ● we may be unable to demonstrate to the satisfaction of the FDA or comparable foreign regulatory authorities that a product candidate is safe and effective for its proposed indication or that a product candidate’s clinical and other benefits outweigh its safety risks; ● the results of clinical trials may fail to achieve the level of statistical significance required by the FDA or comparable foreign regulatory authorities for approval; ● the data collected from pre-clinical studies and clinical trials of our product candidates may not be sufficient to support the submission of an NDA, supplemental NDA, or other regulatory submissions necessary to obtain regulatory approval; ● we or our contractors may not meet the GMP and other applicable requirements for manufacturing processes, procedures, documentation and facilities necessary for approval by the FDA or comparable foreign regulatory authorities; and ● changes to the approval policies or regulations of the FDA or comparable foreign regulatory authorities with respect to our product candidates may result in our clinical data becoming insufficient for approval.
If we are unable to anticipate and address these risks properly, our business and financial results will be harmed. We may fail or elect not to commercialize our product candidates, even if approved.
If we are unable to anticipate and address these risks properly, our business and financial results will be harmed. We or our collaborators may fail or elect not to commercialize our product candidates, even if approved.
We have not yet successfully developed an approved product or generated revenue from product sales or successfully conducted a pivotal registration trial for one of our product candidates. Consequently, the ability to accurately assess our future operating results or business prospects is significantly more limited than if we had a longer operating history or approved products on the market.
We have not yet successfully developed an approved product or generated revenue from product sales or successfully completed a pivotal registration trial for one of our product candidates. Consequently, the ability to accurately assess our future operating results or business prospects is significantly more limited than if we had a longer operating history or approved products on the market.
As more groups become engaged in scientific research and product development in fields related to our product candidates, such as hepcidin mimetics or IL-23R, the risk of our patents, or patents that we have in-licensed, being challenged through patent interferences, derivation proceedings, oppositions, re-examinations, litigation or other means will likely increase.
As more groups become engaged in scientific research and product development in fields related to our product candidates, such as hepcidin mimetics or IL-23R, the risk of our patents, or patents that we have in-licensed, being challenged through derivation proceedings, oppositions, re-examinations, litigation or other means will likely increase.
As has been widely reported, we are currently operating in a period of macroeconomic uncertainty and capital markets disruption, which has been significantly impacted by domestic and global monetary and fiscal policy, trade regulations, including changes in trade policies, tariffs or other trade restrictions or the threat of such actions, 46 Table of Contents geopolitical instability, including ongoing military conflicts between Russia and Ukraine and in the Middle East, rising tensions between China and Taiwan, and high interest rates.
As has been widely reported, we are currently operating in a period of macroeconomic uncertainty and capital markets disruption, which has been significantly impacted by domestic and global monetary and fiscal policy, trade regulations, including changes in trade policies, tariffs or other trade restrictions or the threat of such actions, geopolitical instability, including ongoing military conflicts between Russia and Ukraine and in the Middle East, rising tensions between China and Taiwan, and high interest rates.
If we are not able to comply with the requirements of Section 404 or if we or our independent registered public accounting firm are unable to attest to the effectiveness of our internal control over 56 Table of Contents financial reporting, investors may lose confidence in the accuracy and completeness of our financial reports, the market price of our stock could decline and we could be subject to sanctions or investigations by Nasdaq, the SEC, or other regulatory authorities, which would require additional financial and management resources.
If we are not able to comply with the requirements of Section 404 or if we or our independent registered public accounting firm are unable to attest to the effectiveness of our internal control over financial reporting, investors may lose confidence in the accuracy and completeness of our financial reports, the market price of our stock could decline and we could be subject to sanctions or investigations by Nasdaq, the SEC, or other regulatory authorities, which would require additional financial and management resources.
Risks Related to Regulatory Process and Other Legal Compliance Matters The regulatory approval processes of the FDA and comparable foreign authorities are lengthy and time consuming, and if we are ultimately unable to obtain regulatory approval for our product candidates, our business will be substantially harmed.
Risks Related to Regulatory Process and Other Legal Compliance Matters The regulatory approval processes of the FDA and comparable foreign authorities are lengthy and time consuming, and if we or our collaborators are ultimately unable to obtain regulatory approval for our product candidates, our business will be substantially harmed.
We currently conduct, and intend to continue to conduct, a substantial portion of the clinical trials for our product candidates outside of the United States. If approved, we may commercialize our product candidates abroad. We will thus be subject to the risks of doing business outside of the United States.
We currently conduct, and intend to continue to conduct, a substantial portion of the clinical trials for our product candidates outside of the United States. If approved, we or our collaborators may commercialize our product candidates abroad. We will thus be subject to the risks of doing business outside of the United States.
We expect that our financial condition and operating results will fluctuate significantly from period to period due to a variety of factors, many of which are beyond our control, including the success of our programs, decisions by regulatory bodies, actions taken by competitors or current or future licensees or collaborative partners, market and macroeconomic conditions and other factors identified in these risk factors.
We expect that our financial condition and operating results will fluctuate significantly from period to period due to a variety of factors, many of which are beyond our control, including the success of our programs, decisions by regulatory bodies, actions taken by competitors or current or future licensees or collaborators, market and macroeconomic conditions and other factors identified in these risk factors.
If, and to the extent that, we or our collaboration partners are unable to comply with these regulations, our ability to earn potential royalties from sales of product candidates under our collaboration agreements would be materially and adversely impacted.
If, and to the extent that, we or our collaborators are unable to comply with these regulations, our ability to earn potential royalties from sales of product candidates under our collaboration agreements would be materially and adversely impacted.
Under Sections 382 and 383 of the Internal Revenue Code of 1986, as amended, if a corporation undergoes an “ownership change,” generally defined as a greater than fifty percentage point change (by value) in its equity ownership by certain stockholders over a three-year period, the corporation’s ability to use its pre-change net operating loss carryforwards, or NOLs, and other pre-change tax attributes (such as research and development tax credits) to offset its post-change taxable income or tax liability may be limited.
Under Sections 382 and 383 of the Internal Revenue Code of 1986, as amended, if a corporation undergoes an “ownership change,” generally defined as a greater than fifty percentage point change (by value) in its equity ownership by certain stockholders over a three-year period, the corporation’s ability to use its pre-change NOLs, and other pre-change tax attributes (such as research and development tax credits) to offset its post-change taxable income or tax liability may be limited.
Given that our proprietary position is based, in part, on our know-how and trade secrets, a competitor’s discovery of our trade secrets or other unauthorized use or disclosure would impair our competitive position and may have an adverse effect on our business and results of operations. Intellectual property rights do not necessarily address all potential threats to our business.
Given that our proprietary position is based, in part, on our know-how and trade secrets, a competitor’s discovery of our trade secrets or other unauthorized use or disclosure would impair our competitive position and may have an adverse effect on our business and results of operations. 53 Table of Contents Intellectual property rights do not necessarily address all potential threats to our business.
An adverse outcome in a patent dispute could have a material adverse effect on our business by: ● causing us to lose patent rights in the relevant jurisdiction(s); ● subjecting our collaboration partners or us to litigation, or otherwise preventing the commercialization of product candidates in the relevant jurisdiction(s); or ● requiring our collaboration partners or us to obtain licenses to the disputed patents, cease using the disputed technology or develop or obtain alternative technologies.
An adverse outcome in a patent dispute could have a material adverse effect on our business by: ● causing us to lose patent rights in the relevant jurisdiction(s); ● subjecting our collaborators or us to litigation, or otherwise preventing the commercialization of product candidates in the relevant jurisdiction(s); or ● requiring our collaborators or us to obtain licenses to the disputed patents, cease using the disputed technology or develop or obtain alternative technologies.
The incurrence of indebtedness and/or the issuance of certain equity securities could result in fixed 38 Table of Contents payment obligations and could also result in certain additional restrictive covenants, such as limitations on our ability to incur debt and/or issue additional equity, limitations on our ability to acquire or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business.
The incurrence of indebtedness and/or the issuance of certain equity securities could result in fixed payment obligations and could also result in certain additional restrictive covenants, such as limitations on our ability to incur debt and/or issue additional equity, limitations on our ability to acquire or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business.
The size and complexity of our internal computer systems and those of our CROs, contract manufacturers, collaboration partners, and other third parties on which we rely may make them potentially vulnerable to breakdown, telecommunications and electrical failures, and malicious intrusion such as ransomware and computer viruses that may result in the impairment of key business processes.
The size and complexity of our internal computer systems and those of our CROs, contract manufacturers, collaborators, and other third parties on which we rely may make them potentially vulnerable to breakdown, telecommunications and electrical failures, and malicious intrusion such as ransomware and computer viruses that may result in the impairment of key business processes.
Accordingly, the likelihood of our success must be evaluated in light of many potential challenges and variables associated with a clinical-stage biopharmaceutical company, many of which are outside of our control, and past results, including operating or financial results, should not be relied on as an indication of future results.
Accordingly, the likelihood of our success must be evaluated in light of many potential challenges and variables associated with a clinical-stage biopharmaceutical 31 Table of Contents company, many of which are outside of our control, and past results, including operating or financial results, should not be relied on as an indication of future results.
In 37 Table of Contents addition, in keeping with our organizational prioritization of rusfertide in PV, plans to initiate trials of rusfertide in additional disease indications have been paused. As a result, we may forego or delay the pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential.
In addition, in keeping with our organizational prioritization of rusfertide in PV, plans to initiate trials of rusfertide in additional disease indications have been paused. As a result, we may forego or delay the pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential.
Other companies targeting the same patient populations as our clinical trials for such medicines may make it more difficult for us to 36 Table of Contents complete enrollment in our clinical trials.
Other companies targeting the same patient populations as our clinical 32 Table of Contents trials for such medicines may make it more difficult for us to complete enrollment in our clinical trials.
We have experienced ownership changes in the past, resulting in annual limitations in our ability to use our NOLs and credits. In addition, we may experience subsequent ownership changes as a result of future equity offerings or other changes in the ownership of our stock, some of which 57 Table of Contents are beyond our control.
We have experienced ownership changes in the past, resulting in annual limitations in our ability to use our NOLs and credits. In addition, we may experience subsequent ownership changes as a result of future equity offerings or other changes in the ownership of our stock, some of which are beyond our control.
The imposition of any of these penalties or other commercial limitations could negatively impact our collaboration arrangements or cause our collaboration partners to terminate the related license and collaboration agreement, either of which would materially and adversely affect our business, financial condition and results of operations. 48 Table of Contents Our future success depends on our ability to retain our executive officers and to attract, retain and motivate qualified personnel.
The imposition of any of these penalties or other commercial limitations could negatively impact our collaboration arrangements or cause our collaborators to terminate the related license and collaboration agreement, either of which would materially and adversely affect our business, financial condition and results of operations. 46 Table of Contents Our future success depends on our ability to retain our executive officers and to attract, retain and motivate qualified personnel.
Political, economic and regulatory 43 Table of Contents developments may further complicate developments in healthcare systems and pharmaceutical drug pricing. These developments could, for example, impact our potential licensing agreements as commercial and collaborative partners may also consider the impact of these pressures on their licensing strategies.
Political, economic and regulatory developments may further complicate developments in healthcare systems and pharmaceutical drug pricing. These developments could, for example, impact our potential licensing agreements as commercial and collaborative partners may also consider the impact of these pressures on their licensing strategies.
Although we maintain such insurance, any claim that may be brought against us could result in a court judgment or settlement in an amount that is not covered, in whole or in part, by our insurance or that is in excess of the limits of our insurance coverage.
Although we maintain such insurance, any claim that may be brought against us could result in a court judgment or settlement in an amount that is 48 Table of Contents not covered, in whole or in part, by our insurance or that is in excess of the limits of our insurance coverage.
If we fail to commercialize any of our product candidates, our business, financial condition, results of operations and prospects may be materially and adversely affected. The commercial success of any current or future product candidate will depend upon the degree of market acceptance by physicians, patients, third-party payors and others in the medical community.
If we or our collaborators fail to commercialize any of our product candidates, our business, financial condition, results of operations and prospects may be materially and adversely affected. 41 Table of Contents The commercial success of any current or future product candidate will depend upon the degree of market acceptance by physicians, patients, third-party payors and others in the medical community.
Although we do not believe that inflation has had a material impact on our financial position or results of operations to date, our financial position or results of operations may be adversely affected in the future due to the macroeconomic factors discussed above, and such factors may lead to increases in the cost of manufacturing our product candidates and delays in initiating trials.
Although we do not believe that the macroeconomic factors discussed above have had a material impact on our financial position or results of operations to date, our financial position or results of operations may be adversely affected in the future due to these factors, and such factors may lead to increases in the cost of manufacturing our product candidates and delays in initiating trials.
We have not obtained regulatory approval for any product candidate and it is possible that none of our existing product candidates or any product candidates we have in development or may seek to develop in the future will ever obtain regulatory approval.
We have not obtained regulatory approval for any product candidate 37 Table of Contents and it is possible that none of our existing product candidates or any product candidates we have in development or may seek to develop in the future will ever obtain regulatory approval.
Any failure to 51 Table of Contents identify relevant prior art relating to a patent or patent applications can invalidate a patent or prevent a patent from issuing. Even if patents have been issued, third parties may challenge the validity, enforceability or scope thereof, which may result in such patents being narrowed, invalidated or held unenforceable.
Any failure to identify relevant prior art relating to a patent or patent applications can invalidate a patent or prevent a patent from issuing. Even if patents have been issued, third parties may challenge the validity, enforceability or scope thereof, which may result in such patents being narrowed, invalidated or held unenforceable.
We will have to pay any amounts awarded by a court or negotiated in a settlement that exceed our coverage limitations or that are not covered by our insurance, and we may not have, or be able to obtain, sufficient capital to pay such amounts. 50 Table of Contents Our headquarters is located near known earthquake fault zones.
We will have to pay any amounts awarded by a court or negotiated in a settlement that exceed our coverage limitations or that are not covered by our insurance, and we may not have, or be able to obtain, sufficient capital to pay such amounts. Our headquarters is located near known earthquake fault zones.
We will rely on our internal process research and development efforts and those of contract manufacturers to develop the required manufacturing processes for cost-effective, large-scale 40 Table of Contents production.
We will rely on our internal process research and development efforts and those of contract manufacturers to develop the required manufacturing processes for cost-effective, large-scale production.
Any disclosure to or misappropriation by third parties of our confidential proprietary information could enable competitors to quickly duplicate or surpass our technological achievements, thus eroding our competitive position in our market.
Any disclosure to or misappropriation by third parties of our confidential proprietary information could enable competitors to quickly duplicate or surpass our technological achievements, thus eroding our competitive position in our 50 Table of Contents market.
In addition, global credit and financial markets have experienced extreme volatility and disruptions in the past several years and the foregoing factors have led to and may continue to cause diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, uncertainty about economic stability and increased inflation.
In addition, global credit and financial markets have experienced extreme volatility and disruption in the past several years and the foregoing factors have led to and may continue to cause diminished liquidity and credit availability, declines in consumer confidence, declines in economic growth, uncertainty about economic stability and continued inflation.
Even though we expect that our product candidate will be priced responsibly, if approved, there is no guarantee that it or any other product that we bring to the market directly or through a strategic partner will gain market acceptance by physicians, patients, third-party payors and others in the medical community.
Even though we expect that our product candidates will be priced responsibly, if approved, there is no guarantee that it or any other product that we bring to the market directly or through a collaborator will gain market acceptance by physicians, patients, third-party payors and others in the medical community.
We or our collaboration partners in any potential commercial launch of our product candidates may not be successful in achieving widespread patient or physician awareness or acceptance of such product candidate.
We or our collaborators in any potential commercial launch of our product candidates may not be successful in achieving widespread patient or physician awareness or acceptance of such product candidate.
Icotrokinra, the product candidate in development pursuant to our JNJ collaboration, and rusfertide, the product candidate in development pursuant to the Takeda Collaboration Agreement, may prove to have undesirable or unintended side effects or other characteristics adversely affecting its safety, efficacy or cost effectiveness that could prevent or limit its approval for marketing and successful commercial use, or that could delay or prevent the commencement and/or completion of clinical trials.
Icotyde, the product candidate in development pursuant to the JNJ License and Collaboration Agreement, and rusfertide, the product candidate in development pursuant to the Takeda Collaboration Agreement, may prove to have undesirable or unintended side effects or other characteristics adversely affecting their safety, efficacy or cost effectiveness that could prevent or limit their approval for marketing and successful commercial use, or that could delay or prevent the commencement and/or completion of clinical trials.
Risks Related to our Reliance on Third Parties If JNJ does not elect to continue the development of icotrokinra, or if Takeda does not elect to develop and commercialize rusfertide, our business and business prospects would be adversely affected.
Risks Related to our Reliance on Third Parties If JNJ does not elect to continue the development of or successfully commercialize Icotyde, or if Takeda does not elect to commercialize rusfertide, our business and business prospects would be adversely affected.
We do not currently have, nor do we plan to develop, the infrastructure or capability internally to manufacture our drug supplies and we expect to continue to depend on contract manufacturers for the foreseeable future.
We do not currently have, nor do we plan to develop, the infrastructure or capability internally to 36 Table of Contents manufacture our drug supplies and we expect to continue to depend on contract manufacturers for the foreseeable future.
We have in the past and may in the future seek additional funding through a combination of equity offerings, including the use of the 2022 ATM Facility, debt financings, collaborations and/or licensing arrangements. Additional funding may not be available to us on acceptable terms, or at all.
We have in the past and may in the future seek additional funding through a combination of equity offerings, debt financings, collaborations and/or licensing arrangements. Additional funding may not be available to us on acceptable terms, or at all.
We currently conduct, and intend to continue to conduct, a substantial portion of our clinical trials outside of the United States and, if approved, we intend to also market our product candidates outside of the United States. We are thus subject to risks associated with doing business outside of the United States.
We currently conduct, and intend to continue to conduct, a substantial portion of our clinical trials outside of the United States and, if approved, we intend to also market our product candidates outside of the United States either directly or through our collaborators. We are thus subject to risks associated with doing business outside of the United States.
Under the terms of the JNJ License and Collaboration Agreement, JNJ may terminate the agreement for convenience and without cause on written notice of a certain period. In addition, prior to any termination of the agreement, JNJ will generally have control over the further clinical development of icotrokinra and any other licensed compounds.
Under the terms of the JNJ License and Collaboration Agreement, JNJ may terminate the agreement for convenience and without cause on written notice of a certain period. In addition, prior to any termination of the agreement, JNJ will generally have control over the further clinical development of Icotyde and any other licensed compounds and commercialization, if Icotyde is approved.
If the JNJ License and Collaboration Agreement or the Takeda Collaboration Agreement is terminated early, or if JNJ’s or Takeda’s development activities are terminated early or suspended for an extended period of time, or are otherwise unsuccessful, our business and business prospects would be materially and adversely affected.
If the JNJ License and Collaboration Agreement or the Takeda Collaboration Agreement are terminated early, if JNJ’s or Takeda’s development activities are terminated early or suspended for an extended period of time, or are otherwise unsuccessful, or if JNJ’s or Takeda’s commercialization efforts are deprioritized or unsuccessful, our business, financial condition and prospects would be materially and adversely affected.
Risks Related to our Financial Position and Capital Requirements We have incurred a cumulative net loss since our inception and anticipate that we may incur significant losses in the future. We have never generated any revenue from product sales and may never be profitable.
Risks Related to our Financial Position and Capital Requirements We have incurred a cumulative net loss since our inception and we may incur significant losses in the future. We have never generated any revenue from product sales. We have incurred a cumulative net operating loss since inception and may continue to incur operating losses in the future.
Absent the funding support obtained under these agreements, our further development of the collaboration product candidates would require significant additional capital from us, or the establishment of alternative collaborations with third parties, which may not be possible. As of December 31, 2024, we had cash, cash equivalents and marketable securities of $559.2 million.
Absent the funding support obtained under these agreements, our further development of the collaboration product candidates and our drug discovery and development programs would require significant additional capital from us, or the establishment of alternative collaborations with third parties, which may not be possible. As of December 31, 2025, we had cash, cash equivalents and marketable securities of $646.0 million.
We expect to expand the size of our organization in the future, and we may experience difficulties in managing this growth. As of December 31, 2024, we had 126 full-time equivalent employees, including 98 full-time equivalent employees engaged in research and development.
We expect to expand the size of our organization in the future, and we may experience difficulties in managing this growth. As of December 31, 2025, we had 132 full-time equivalent employees, including 103 full-time equivalent employees engaged in research and development.
A continued and prolonged public health crisis could have a material negative impact on our business, financial condition, and operating results. Unstable market and macroeconomic conditions, including elevated and sustained inflation, may have serious adverse consequences on our business, financial condition and stock price.
A continued and prolonged public health crisis could have a material negative impact on our business, financial condition, and operating results. Unstable market and macroeconomic conditions, including tariffs or trade policy, may have serious adverse consequences on our business, financial condition and stock price.
We are subject to the risk of possible disagreements with JNJ regarding the development of icotrokinra or other matters under the JNJ License and Collaboration Agreement and Takeda regarding the development of rusfertide or other matters under the Takeda Collaboration Agreement, such as the interpretation of such agreement or ownership of proprietary rights.
We are subject to the risk of possible disagreements with JNJ regarding the development or commercialization of Icotyde, if approved, or other matters under the JNJ License and Collaboration Agreement and with Takeda regarding the development or commercialization of rusfertide, if approved, or other matters under the Takeda Collaboration Agreement, such as the interpretation of such agreements, milestones or royalty payments or ownership of proprietary rights.
Our stock price has fluctuated in the past and is likely to be volatile in the future. From January 1, 2024 through December 31, 2024, the reported sale price of our common stock has fluctuated between $21.43 and $48.89 per share.
Our stock price has fluctuated in the past and is likely to be volatile in the future. From January 1, 2025 through December 31, 2025, the reported sale price of our common stock has fluctuated between $35.09 and $95.35 per share.
However, we may need to have access to additional funds in the future in order to complete clinical development or commercialize our product candidates to a point where our operations generate net cash inflows. Raising additional capital may cause dilution to our existing stockholders, restrict our operations or require us to relinquish rights to our product candidates or technologies.
However, we may need to have access to additional funds in the future in order to complete clinical development or commercialize our product candidates to a point where our operations generate net cash inflows. 34 Table of Contents If we require additional capital, there may be dilution to our existing stockholders, our operations may be restricted, or we may be required to relinquish rights to our product candidates or technologies.
Any disruption or cybersecurity incident, to the extent it was to result in the loss, destruction, unavailability, alteration or dissemination of, or damage to, our data or applications, or for it to be believed or reported that any of these occurred, could harm our reputation, compel us to comply with federal and/or state breach notification laws, subject us to mandatory corrective action, require us to verify the correctness of database contents and otherwise subject us to liability under laws and regulations that protect personal data, resulting in increased costs or loss of revenue.
Any disruption or cybersecurity incident, to the extent it was to result in the loss, destruction, unavailability, alteration or dissemination of, or damage to, our data or applications, or for it to be believed or reported that any of these occurred, could harm our reputation, compel us to comply with federal and/or state breach notification laws, subject us to mandatory corrective action, require us to verify the correctness of database contents and otherwise subject us to liability under laws and regulations that protect personal data, resulting in increased costs or loss of revenue. 47 Table of Contents ​ The risk of a cybersecurity incident or other informational technology disruption, particularly through cyberattacks, has generally increased as the number, intensity and sophistication of attempted attacks and intrusions from around the world has increased.
Our commercial success depends in part on our ability to develop, manufacture, market and sell our drug candidates and use our proprietary technologies without infringing or otherwise violating the patents and proprietary rights of third parties.
Third-party claims of intellectual property infringement may prevent or delay our drug discovery and development efforts. Our commercial success depends in part on our ability to develop, manufacture, market and sell our drug candidates and use our proprietary technologies without infringing or otherwise violating the patents and proprietary rights of third parties.
We generally contract with third parties for the disposal of these materials and waste. We cannot eliminate the risk of contamination or injury from these materials. In the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources.
In the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources.
Litigation or other legal proceedings relating to intellectual property claims, with or without merit, are unpredictable and generally expensive and time-consuming and, even if resolved in our favor, are likely to divert significant resources from our core business, including distracting our technical and management personnel from their normal responsibilities.
An adverse outcome in a patent dispute could severely harm our collaborations or cause our collaborators to terminate their respective agreements. 51 Table of Contents Litigation or other legal proceedings relating to intellectual property claims, with or without merit, are unpredictable and generally expensive and time consuming and, even if resolved in our favor, are likely to divert significant resources from our core business, including distracting our technical and management personnel from their normal responsibilities.
Because we have limited financial and managerial resources, we have historically focused on research programs and product candidates mainly on the development of rusfertide and the product candidates subject to our JNJ collaboration. We have an ongoing commitment to optimize and focus resources toward our rusfertide program in PV.
Because we have limited financial and managerial resources, we have historically focused on research programs and product candidates mainly for the development of rusfertide and the product candidates subject to our JNJ collaboration. We have an ongoing commitment to optimize and focus resources on our drug discovery and development 33 Table of Contents programs addressing biologically and commercially validated targets.
Further, in the event that the JNJ License and Collaboration Agreement or the Takeda Collaboration Agreement is terminated, we may not receive any additional fees or milestone payments under these agreements.
Further, in the event that the JNJ License and Collaboration Agreement or the Takeda Collaboration Agreement is terminated, we may not receive any additional fees or milestone payments under these agreements. In addition, if either JNJ or Takeda fail to successfully commercialize Icotyde or rusfertide, respectively, if approved, we would not receive any royalty payments under these agreements.
We are required to develop and maintain proper and effective internal controls over financial reporting and any failure to maintain the adequacy of these internal controls may adversely affect investor confidence in our company and, as a result, the value of our common stock.
If we face such litigation, it could result in substantial costs and a diversion of management’s attention and resources, which could harm our business. 54 Table of Contents We are required to develop and maintain proper and effective internal controls over financial reporting and any failure to maintain the adequacy of these internal controls may adversely affect investor confidence in our company and, as a result, the value of our common stock.
We base our estimates on historical experience and on various other assumptions that we believe to be reasonable under the circumstances. We cannot assure you, however, that our estimates, or the assumptions underlying them, will be correct. Item 1B. Unresolved Staff Comments None.
We base our estimates on historical experience and on various other assumptions that we believe to be reasonable under the circumstances. We cannot assure you, however, that our estimates, or the assumptions underlying them, will be correct. 56 Table of Contents We could be subject to additional tax liabilities.
If any of the parties to these confidentiality agreements breaches or violates the terms of such agreements, we may not have adequate remedies for any such breach or violation, and we could lose our trade secrets as a result. 52 Table of Contents Even if we are able to adequately protect our trade secrets and proprietary information, our trade secrets could otherwise become known or could be independently discovered by our competitors.
If any of the parties to these confidentiality agreements breaches or violates the terms of such agreements, we may not have adequate remedies for any such breach or violation, and we could lose our trade secrets as a result.
We are not permitted to market any product candidate in the United States until after approval of an NDA from the FDA, or in any foreign countries until approval by corresponding regulatory authorities.
In addition, even if approved, our pricing and reimbursement will be subject to further review and discussions with payors. We are not permitted to market any product candidate in the United States until after approval of an NDA from the FDA, or in any foreign countries until approval by corresponding regulatory authorities.
If we are not successful in 42 Table of Contents commercializing our product candidates, either on our own or through collaborations with one or more third parties, our future revenue will be materially and adversely impacted.
If we are not successful in commercializing our product candidates, either on our own or through collaborations with one or more third parties, our future revenue will be materially and adversely impacted. 39 Table of Contents Recently enacted and future legislation may increase the difficulty and cost for us to obtain marketing approval of and commercialize our product candidates and affect the prices we may obtain.
Also, because the period of collaborative development under the agreement has ended, JNJ has sole decision-making authority for product candidates resulting from the collaboration, which could lead to disputes with JNJ.
Also, because the period of collaborative development under the agreement has ended, JNJ has sole decision- 35 Table of Contents making authority for product candidates resulting from the collaboration, which could lead to disputes with JNJ. Disagreements with JNJ or Takeda could lead to litigation or arbitration, which would be expensive and would be time-consuming for our management and employees.
The research, testing, manufacturing, labeling, approval, sale, marketing and distribution of our product candidates will be subject to extensive regulation by the FDA and other regulatory authorities in the United States and other countries. In addition, even if approved, our pricing and reimbursement will be subject to further review and discussions with payors.
We cannot be certain that our product candidates will receive regulatory approval or, if approved, be successfully commercialized by us or our collaborators. The research, testing, manufacturing, labeling, approval, sale, marketing and distribution of our product candidates will be subject to extensive regulation by the FDA and other regulatory authorities in the United States and other countries.
In addition, there are a significant number of global clinical trials in hematologic disorders that are currently ongoing, especially in Phases 2 and 3, making it highly competitive and challenging to recruit subjects.
For example, our rusfertide clinical studies were subject to a three-week clinical hold by the FDA in September 2021. In addition, there are a significant number of global clinical trials in inflammatory and immunology disorders, hematologic disorders and metabolic disorders that are currently ongoing, especially in Phases 2 and 3, making it highly competitive and challenging to recruit subjects.
Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management. 54 Table of Contents We may be subject to claims challenging the inventorship or ownership of our issued patents, any patents issued as a result of our pending or future patent applications and other intellectual property.
We may be subject to claims challenging the inventorship or ownership of our issued patents, any patents issued as a result of our pending or future patent applications and other intellectual property.
We expect that a substantial portion of our efforts and expenditures over the next few years will be devoted to our current product candidates and the development of other product candidates. We cannot be certain that our product candidates will receive regulatory approval or, if approved, be successfully commercialized.
We expect that a substantial portion of our efforts and expenditures over the next few years will be devoted to our current product candidates and the development of other product candidates, including any product candidates resulting from our discovery and development program.
We have incurred a cumulative net operating loss since inception and may continue to incur operating losses in the future. As of December 31, 2024, we had an accumulated deficit of $340.5 million. We expect to continue to incur significant research, development and other expenses related to our ongoing operations and product development.
As of December 31, 2025, we had an accumulated deficit of $470.7 million. We expect to continue to incur significant research, development and other expenses related to our ongoing operations and product development. As a result, we may continue to incur losses in the future as we continue our development of, and seek regulatory approvals for, our product candidates.
In addition, any new product that competes with an approved product must demonstrate advantages in efficacy, convenience, tolerability or safety in order to overcome price competition and to be commercially successful.
Pharmaceutical companies may invest heavily to accelerate discovery and development of novel compounds or to in-license novel compounds that could make our product candidates less competitive. In addition, any new product that competes with an approved product must demonstrate advantages in efficacy, convenience, tolerability or safety in order to overcome price competition and to be commercially successful.
If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel.
If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management.
If approved, our product candidates are expected to face competition from commercially available drugs as well as drugs that are in the development pipelines of our competitors. Pharmaceutical companies may invest heavily to accelerate discovery and development of novel compounds or to in-license novel compounds that could make our product candidates less competitive.
If approved, our product candidates are expected to face competition from commercially available drugs as well as drugs that are in the development pipelines of our competitors.
As a result of this volatility, investors may experience losses on their investment in our common stock, including due to the factors discussed in these “Risk Factors” and elsewhere in this Annual Report. Volatility in our share price could subject us to securities class action litigation.
As a result of this volatility, payouts under, as well as the incentive value of, our stock-based compensation arrangements for employees can fluctuate and investors may experience losses on their investment in our common stock, including due to the factors discussed in these “Risk Factors” and elsewhere in this Annual Report.
If the market opportunities for our approved product candidates, if any, are smaller than we expect, it could materially adversely affect our financial condition and results of operations. ​ If the market opportunity for our products, if approved, is smaller than we expect, we may never become or remain profitable nor generate sufficient revenue growth to sustain our business even if we obtain significant market share for them.
If any product candidates we may develop in the future are approved but fail to achieve an adequate level of acceptance by physicians, patients, third-party payors and others in the medical community, we will not be able to generate sufficient revenue, either directly or through milestone and royalty payments from our collaborators, to become or remain profitable. 42 Table of Contents If the market opportunities for our approved product candidates, if any, are smaller than we expect, it could materially adversely affect our financial condition and results of operations. ​ If the market opportunity for our products, if approved, is smaller than we expect, we may never become or remain profitable nor generate sufficient revenue growth to sustain our business even if we obtain significant market share for them.
Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could have a material adverse effect on our ability to compete in the marketplace. 53 Table of Contents Third-party claims of intellectual property infringement may prevent or delay our drug discovery and development efforts.
Accordingly, despite our efforts, we may not be able to prevent third parties from infringing upon or misappropriating or from successfully challenging our intellectual property rights. Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could have a material adverse effect on our ability to compete in the marketplace.
The potentially addressable patient population for our products may be limited or may not be amenable to treatment with our products, and new patients may become increasingly difficult to identify or access, which would adversely affect our results of operations and our business. 45 Table of Contents Risks Related to our Business and Industry We face significant competition from other biotechnology and pharmaceutical companies, and our operating results will suffer if we or our collaboration partners fail to compete effectively.
The potentially addressable patient population for our products may be limited or may not be amenable to treatment with our products, and new patients may become increasingly difficult to identify or access, which would adversely affect our results of operations and our business.

… 95 more changes not shown on this page.

Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

5 edited+1 added−0 removed9 unchanged
Biggest changeIn addition, we consult with outside advisors and experts when appropriate to assist with assessing, identifying, and managing cybersecurity risks, including to help anticipate future threats and trends, and their impact on our risk environment. 58 Table of Contents Governance Our current Head of IT reports directly to our Chief Financial Officer and has over twenty years of experience managing information technology and cybersecurity matters, holds a Master of Science degree in Telecommunications and Computer Networks and is Project Management Professional, Certified Scrum Master and IT Infrastructure Library certified.
Biggest changeGovernance Our current Head of IT reports directly to our Chief Financial Officer and has over twenty years of experience managing information technology and cybersecurity matters, holds a Master of Science degree in Telecommunications 57 Table of Contents and Computer Networks and is Project Management Professional, Certified Scrum Master and IT Infrastructure Library certified.
These processes are managed and monitored by a dedicated cybersecurity team, including third-party service providers, and led by our Head of IT, and include mechanisms, controls, technologies, systems, and other processes designed to help prevent or mitigate data loss, theft, misuse, or other security incidents or vulnerabilities affecting the data and help maintain a stable information technology environment.
These processes are managed and monitored by a dedicated cybersecurity team, including third-party service providers, and led by our Head of IT, and include mechanisms, controls, technologies, systems, and other processes designed to help prevent or mitigate data loss, theft, misuse, or other security incidents or vulnerabilities affecting our data and help maintain a stable information technology environment.
Furthermore, we employ data loss prevention tools to help enforce strict data security policies, prevent unauthorized access and protect the transmission of sensitive information. These integrated technologies help us to detect, mitigate, and respond to cyber threats, with the goal of minimizing potential disruptions to our business operations.
Furthermore, we employ data loss prevention tools to help enforce strict data security policies, prevent unauthorized access and protect the transmission of sensitive information. These integrated technologies help us to detect, mitigate, and respond to cyberthreats, with the goal of minimizing potential disruptions to our business operations.
Our Board receives at least two updates each year on cybersecurity and information technology matters and related risk exposures from our Head of IT as well as other members of our senior leadership team. We consider cybersecurity, along with other significant risks that we face, within our overall enterprise risk management framework.
Our Board receives updates at least annually on cybersecurity and information technology matters and related risk exposures from our Head of IT as well as other members of our senior leadership team. We consider cybersecurity, along with other significant risks that we face, within our overall enterprise risk management framework.
Our endpoint detection and response (“EDR”) system helps monitor and analyze endpoint devices, and is designed to assist us in quickly identifying and responding to emerging threats. Complementing our EDR capabilities, our managed detection and response service assists with threat monitoring, proactive threat hunting, and rapid incident response.
Our endpoint detection and response (“EDR”) system helps monitor and analyze endpoint devices, and is designed to assist us in quickly identifying and responding to emerging threats, including those from our third-party service providers. Complementing our EDR capabilities, our managed detection and response service assists with threat monitoring, proactive threat hunting, and rapid incident response.
Added
In addition, we consult with outside advisors and experts when appropriate to assist with assessing, identifying, and managing cybersecurity risks, including to help anticipate future threats and trends, and their impact on our risk environment.

Item 2. Properties

Properties — owned and leased real estate

1 edited+0 added−0 removed0 unchanged
Biggest changeItem 2. Properties We lease approximately 75,600 square feet of office and laboratory space in Newark, California under a lease agreement, as amended, that expires in November 2029. We believe that our existing facilities are adequate to meet our current business needs. We anticipate that additional space will be available on commercially reasonable terms, if required.
Biggest changeItem 2. Properties We lease approximately 60,600 square feet of office and laboratory space in Newark, California under a lease agreement, as amended, that expires in November 2029. We believe that our existing facilities are adequate to meet our current business needs. We anticipate that additional space will be available on commercially reasonable terms, if required.

Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

1 edited+0 added−0 removed2 unchanged
Biggest changeRefer to Note 9 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information on our historical legal proceedings. Item 4. Mine Safety Disclosures Not applicable. ​ 59 Table of Contents PART II
Biggest changeRefer to Note 9 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information on our historical legal proceedings. Item 4. Mine Safety Disclosures Not applicable. ​ 58 Table of Contents PART II

Item 4. Mine Safety Disclosures

Mine Safety Disclosures — required of mining issuers

1 edited+0 added−0 removed0 unchanged
Biggest changeItem 4. ​ Mine Safety Disclosures ​ 59 ​ ​ ​ ​ ​ PART II ​ ​ ​ ​ ​ ​ ​ ​ ​ Item 5. ​ Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities ​ 60
Biggest changeItem 4. ​ Mine Safety Disclosures ​ 58 ​ ​ ​ ​ ​ PART II ​ ​ ​ ​ ​ ​ ​ ​ ​ Item 5. ​ Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities ​ 59

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

5 edited+0 added−0 removed0 unchanged
Biggest changeWe currently expect to retain all future earnings, if any, for use in the operation and expansion of our business, and therefore do not anticipate paying any cash dividends in the foreseeable future. 60 Table of Contents Performance Graph The following is not deemed “filed” with the Securities and Exchange Commission and shall not be incorporated by reference into any filing we make under the Exchange Act or the Securities Act of 1933, as amended, whether made before or after the date hereof and irrespective of any general incorporation by reference language in such filing.
Biggest changeThe declaration of any future cash dividend will be at the discretion of our Board and will depend upon our earnings, if any, our capital requirements and financial position, our general economic conditions, and other pertinent factors determined by our Board. 59 Table of Contents Performance Graph The following is not deemed “filed” with the Securities and Exchange Commission and shall not be incorporated by reference into any filing we make under the Exchange Act or the Securities Act of 1933, as amended, whether made before or after the date hereof and irrespective of any general incorporation by reference language in such filing.
The number of stockholders of record is based upon the actual number of stockholders registered at such date and does not include holders of shares in “street names” or persons, partnerships, associates, or corporations, or other entities identified in security listings maintained by depositories. Dividends We have never declared or paid any cash dividends.
The number of stockholders of record is based upon the actual number of stockholders registered at such date and does not include holders of shares in “street names” or persons, partnerships, associates, or corporations, or other entities identified in security listings maintained by depositories. Dividends To date, we have never declared or paid any cash dividends.
The graph below shows the cumulative total stockholder return assuming an investment on December 31, 2019 in each of our common stock, the Nasdaq Composite Index and the Nasdaq Biotechnology Index.
The graph below shows the cumulative total stockholder return assuming an investment on December 31, 2020 in each of our common stock, the Nasdaq Composite Index and the Nasdaq Biotechnology Index.
Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Market Information Our common stock trades on The Nasdaq Stock Market, LLC under the symbol “PTGX.” Stockholders As of the close of business on February 19, 2025, there were two stockholders of record of our common stock.
Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Market Information Our common stock trades on The Nasdaq Stock Market, LLC under the symbol “PTGX.” Stockholders As of the close of business on February 18, 2026, there were two stockholders of record of our common stock.
The graph compares the performance of a $100 investment in our common stock and in each index (assuming reinvestment of all dividends) from December 31, 2019 to December 31, 2024. ​ Recent Sales of Unregistered Securities None. Issuer Purchases of Equity Securities None. 61 Table of Contents Item 6. Reserved ​ ​
The graph compares the performance of a $100 investment in our common stock and in each index (assuming reinvestment of all dividends) from December 31, 2020 to December 31, 2025. Recent Sales of Unregistered Securities None. Issuer Purchases of Equity Securities None. Item 6. Reserved ​ ​ 60 Table of Contents

Item 6. [Reserved]

Selected Financial Data — reserved (removed by SEC in 2021)

1 edited+0 added−0 removed0 unchanged
Biggest changeItem 6. ​ Reserved ​ 62 Item 7. ​ Management’s Discussion and Analysis of Financial Condition and Results of Operations ​ 62 Item 7A. ​ Quantitative and Qualitative Disclosures about Market Risk ​ 76 Item 8. ​ Financial Statements and Supplementary Data ​ 77
Biggest changeItem 6. ​ Reserved ​ 60 Item 7. ​ Management’s Discussion and Analysis of Financial Condition and Results of Operations ​ 61 Item 7A. ​ Quantitative and Qualitative Disclosures about Market Risk ​ 73 Item 8. ​ Financial Statements and Supplementary Data ​ 74

Item 7. Management's Discussion & Analysis

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

69 edited+33 added−47 removed38 unchanged
Biggest changeThe remaining balance of $30.6 million was recorded as deferred revenue as of December 31, 2024, which will be recognized over time based on a measure of our efforts toward satisfying our performance obligation relative to the total expected efforts or inputs to satisfy the performance obligation (e.g. costs incurred compared to total budget). ​ JNJ License and Collaboration Agreement revenue represents the achievement of non-refundable milestone payments pursuant to the JNJ License and Collaboration Agreement, as amended in November 2024, of $165.0 million and $60.0 million for the years ended December 31, 2024 and 2023, respectively. ​ 69 Table of Contents We do not have any commercialized products, and our revenue is derived from licensing and collaboration agreements.
Biggest changeAs of December 31, 2025, the remaining $9.6 million in deferred revenue will be recognized through the conclusion of the development services performance obligation. ​ License and collaboration revenue for the year ended December 31, 2024 of $434.4 million included (i) $254.1 million of the $300.0 million upfront cash payment allocated to the delivery of the rusfertide license to Takeda upon effectiveness of the Takeda Collaboration Agreement in March 2024, (ii) $15.3 million allocated to development services provided by us during the period based on the cost input method under the Takeda Collaboration Agreement 68 Table of Contents and (iii) $165.0 million milestone payment pursuant to the terms of the JNJ License and Collaboration Agreement for a Phase 3 clinical trial of any licensed product for any indication meeting its primary endpoint. ​ We do not have any commercialized products, and our revenue is derived from licensing and collaboration agreements.
We have taken into consideration any known impacts in our accounting estimates to date and are not aware of any additional specific events or circumstances that would require any additional updates to our estimates or judgments or a revision of the carrying value of our assets or liabilities as of the date of the filing of this Annual Report on Form 10-K.
We have taken into consideration any known impacts to our accounting estimates to date and are not aware of any additional specific events or circumstances that would require any additional updates to our estimates or judgments or a revision of the carrying value of our assets or liabilities as of the date of the filing of this Annual Report on Form 10-K.
See Note 8 to the Consolidated Financial Statements elsewhere in this Annual Report on Form 10-K for additional information. ​ Under the Takeda Collaboration Agreement, we may share with Takeda certain development, manufacturing and commercialization costs.
See Note 8 to the Consolidated Financial Statements elsewhere in this Annual Report on Form 10-K for additional information. ​ Under the Takeda Collaboration Agreement, we may share with Takeda certain development, manufacturing and commercialization costs. See Note 3 to the Consolidated Financial Statements elsewhere in this Annual Report on Form 10-K for additional information.
Estimates related to revenue recognition include assumptions used to determine standalone selling price utilized to allocate the transaction price between distinct performance obligations, assumptions used to recognize revenue over time for certain performance obligations for which a cost-based input method is used as the measure of 65 Table of Contents progress and estimates of whether contingent consideration should be included in the transaction price at each reporting period.
Estimates related to revenue recognition include assumptions used to determine standalone selling price utilized to allocate the transaction price between distinct performance obligations, assumptions used to recognize 64 Table of Contents revenue over time for certain performance obligations for which a cost-based input method is used as the measure of progress and estimates of whether contingent consideration should be included in the transaction price at each reporting period.
These estimates may change as new events occur, circumstances change, and additional information is obtained. Actual results could differ materially from these estimates under different assumptions or conditions.
These estimates may change as new events occur, and additional information is obtained. Actual results could differ materially from these estimates under different assumptions or conditions.
Management’s judgment is required in determining the level of effort required under an arrangement and the period over which we expect to complete our performance obligations. If we determine that the performance obligation is satisfied over time, any upfront payment received is initially recorded as deferred revenue on our consolidated balance sheets.
Management’s judgment is required to determine the level of effort required under an arrangement and the period over which we expect to complete our performance obligations. If we determine that the performance obligation is satisfied over time, any upfront payment received is initially recorded as deferred revenue on our consolidated balance sheets.
However, the status and timing of actual services performed, number of patients enrolled, the rate of patient enrollment and the number and location of sites activated may vary from our estimates and may result in adjustments to our research and development expenses in future 66 Table of Contents periods.
However, the status and timing of actual services performed, number of patients enrolled, the rate of patient enrollment and the number and location of sites activated may vary from our estimates and may result in adjustments to our research and development expenses in future 65 Table of Contents periods.
The $144.6 million decrease in cash provided by financing activities for year ended December 31, 2024, as compared to the year ended December 31, 2023, was primarily due to $107.8 million of proceeds received from a public offering of our common stock in April 2023, $24.3 million of proceeds from ATM sales of our common stock in 2023, and $34.3 million in proceeds from exercises of warrants in 2023 in exchange for Pre-Funded Warrants and common stock.
The $144.6 million decrease in cash provided by financing activities for year ended December 31, 2024, as compared to the year ended December 31, 2023, was primarily due to $107.8 million of proceeds received from a public offering of our common stock in April 2023, $24.3 million of proceeds from sales of our common stock under the 2022 ATM Facility in 2023, and $34.3 million in proceeds from exercises of warrants in 2023 in exchange for Pre-Funded Warrants and common stock.
The Pre-Funded Warrants will expire upon the day they are exercised in full. The Pre-Funded Warrants are exercisable at any time prior to expiration except that the Pre-Funded Warrants cannot be exercised by the Investors if, after giving effect thereto, the Investors would beneficially 71 Table of Contents own more than 9.99% of our common stock, subject to certain exceptions.
The Pre-Funded Warrants will expire upon the day they are exercised in full. The Pre-Funded Warrants are exercisable at any time prior to expiration except that the Pre-Funded Warrants cannot be exercised by the Investors if, after giving effect thereto, the Investors would beneficially own more than 9.99% of our common stock, subject to certain exceptions.
We expect to enter into additional clinical development, contract research, clinical and commercial manufacturing, supplier and collaborative research agreements in the future, which may require upfront payments and long-term commitments of capital resources. ​ Our contractual obligations include minimum lease payments under our operating lease obligations.
We expect to enter into additional clinical development, contract research, clinical and commercial manufacturing, supplier and collaborative research agreements in the future, which may require upfront payments and long-term commitments of capital resources. 72 Table of Contents ​ Our contractual obligations include minimum lease payments under our operating lease obligations.
Proceeds from Sales of Our Common Stock ​ In April 2023, we completed an underwritten public offering of 5,000,000 shares of our common stock at a public offering price of $20.00 per share and issued an additional 750,000 shares of common stock at a price of $20.00 per share following the underwriters’ exercise of their option to purchase additional shares.
In April 2023, we completed an underwritten public offering of 5,000,000 shares of our common stock at a public offering price of $20.00 per share and issued an additional 750,000 shares of common stock at a price of $20.00 per share following the underwriters’ exercise of their option to purchase additional shares.
Our capital expenditures were $1.4 million, $0.6 million and $0.8 million for the years ended December 31, 2024, 2023 and 2022, respectively. Our primary uses of cash are to fund our operating expenses, including our research and development expenditures and general and administrative costs.
Our capital expenditures were $1.6 million, $1.4 million and $0.6 million for the years ended December 31, 2025, 2024 and 2023, respectively. Our primary uses of cash are to fund our operating expenses, including our research and development expenditures and general and administrative costs.
For product candidates in clinical development, direct costs consist primarily of clinical, pre-clinical, and drug discovery costs, costs of supplying drug substance and drug product for use in clinical and pre-clinical studies, including clinical manufacturing costs, contract research organization fees, and other contracted services pertaining to specific clinical and pre-clinical studies.
For product candidates in clinical development, direct costs consist primarily of clinical, pre-clinical, and drug discovery costs, costs of supplying drug substance and drug product for use in clinical and pre-clinical studies, including clinical manufacturing costs, contract research organization fees, and other contracted services pertaining to specific clinical and 66 Table of Contents pre-clinical studies.
Cash Provided by Financing Activities Cash provided by financing activities for the year ended December 31, 2024 was $25.9 million and consisted of net cash proceeds of $26.5 million from the issuance of common stock upon exercises of stock options and purchases of stock under our employee stock purchase plan (“ESPP”), partially offset by $0.6 million in tax withholding payments related to the net settlement of restricted stock units.
Cash provided by financing activities for the year ended December 31, 2024 was $25.9 million and consisted of net cash proceeds of $26.5 million from the issuance of common stock upon exercises of stock options and purchases of stock under our ESPP, partially offset by $0.6 million in tax withholding payments related to the net settlement of restricted stock units.
Net proceeds, after deducting underwriting commissions and offering costs paid by us, were approximately $107.8 million. ​ In August 2022, we entered into an Open Market Sale Agreement SM , pursuant to which we may offer and sell up to $100.0 million shares of our common stock from time to time in “at-the-market” offerings (the “2022 ATM Facility”).
Net proceeds, after deducting underwriting commissions and offering costs paid by us, were approximately $107.8 million for the year ended December 31, 2023. ​ In August 2022, we entered an Open Market Sale Agreement SM , pursuant to which we may offer and sell up to $100.0 million shares of our common stock from time to time in “at-the-market” offerings (the “2022 ATM Facility”).
The $254.4 million increase in cash provided by operating activities during the year ended December 31, 2024, as compared to the year ended December 31, 2023, was primarily due to the receipt of a $300.0 million one-time, non-refundable upfront payment related to the Takeda Collaboration Agreement.
The $254.4 million increase in cash provided by operating activities during the year ended December 31, 2024, as compared to the year ended December 31, 71 Table of Contents 2023, was primarily due to the receipt of a $300.0 million one-time, non-refundable upfront payment upon the effectiveness of the Takeda Collaboration Agreement in 2024.
Key assumptions to determine the standalone selling price may include forecasted revenues, development timelines, reimbursement rates for personnel costs, discount rates and probabilities of technical and regulatory success.
Key assumptions to determine the standalone selling price may include forecast revenues, development timelines, reimbursement rates for personnel costs, discount rates and probability of technical and regulatory success.
Operations We have incurred cumulative net losses from inception through December 31, 2024 of $340.5 million. Substantially all of our net losses have resulted from costs incurred in connection with our research and development programs and from general and administrative costs associated with our operations.
Operations We have incurred cumulative net losses from inception through December 31, 2025 of $470.7 million. Substantially all of our net losses have resulted from costs incurred in connection with our research and development programs and from general and administrative costs associated with our operations.
Cash (Used in) Provided by Investing Activities Cash used in investing activities for the year ended December 31, 2024 was $299.5 million and consisted of purchases of securities of $621.7 million and purchases of property and equipment of $1.4 million, partially offset by proceeds from maturities of marketable securities of $323.6 million.
Purchases of property and equipment were primarily related to laboratory equipment and furniture and fixtures. Cash used in investing activities for the year ended December 31, 2024 was $299.5 million and consisted of purchases of securities of $621.7 million and purchases of property and equipment of $1.4 million, partially offset by proceeds from maturities of marketable securities of $323.6 million.
Warrants to purchase 1,375,000 shares of our common stock had an exercise price of $10.00 per share and Warrants to purchase 1,375,000 shares of our common stock had an exercise price of $15.00 per share. ​ In August 2023, prior to the expiration of the Warrants, we entered into certain agreements with the Investors and their affiliates under which we agreed to allow the Warrants to be exercised in exchange for pre-funded warrants representing the same number of Warrant Shares underlying the Warrants with an exercise price of $0.001 per share (the “Pre-Funded Warrants”).
In August 2023, prior to the expiration of the Warrants, we entered into certain agreements with the Investors and their affiliates under which we agreed to allow the Warrants to be exercised in exchange for pre-funded warrants representing the same number of Warrant Shares underlying the Warrants with an exercise price of $0.001 per share (the “Pre-Funded Warrants”).
Our research and development programs are subject to change from time to time as we evaluate our priorities and available resources. General and Administrative Expenses General and administrative expenses consist of personnel costs, allocated facilities costs and other expenses for outside professional services, including legal, human resources, audit and accounting services, IT and pre-commercialization expenses, including selling and marketing costs.
Our research and development programs are subject to change from time to time as we evaluate our priorities and available resources. General and Administrative Expenses General and administrative expenses consist of personnel costs, allocated costs, and other expenses for outside professional services, including legal, human resources and audit and accounting services. Personnel costs consist of salaries, benefits and stock-based compensation.
Personnel costs consist of salaries, benefits and stock-based compensation. Allocated expenses consist of expenses for rent and maintenance of facilities, information technology, depreciation and amortization expense and other administrative supplies.
Allocated costs consist of expenses for rent and maintenance of facilities, information technology, depreciation and amortization expense and other administrative supplies.
Income tax expense for the year ended December 31, 2024 was a result of taxable income from the recognition of revenue in connection with the Takeda Collaboration Agreement and the JNJ License and Collaboration Agreement.
Income tax expense for the year ended December 31, 2025 consisted of adjustments related to the filing of our 2024 tax return during the period. Income tax expense for the year ended December 31, 2024 was a result of taxable income from the recognition of revenue in connection with the Takeda Collaboration Agreement and the JNJ License and Collaboration Agreement.
In accordance with Accounting Standards Topic 260, Earnings Per Share , outstanding Pre-Funded Warrants are included in the computation of basic net loss per share because the exercise price is negligible, and they are fully vested and exercisable after the original issuance date.
In accordance with Accounting Standards Topic 260, “ Earnings Per Share,” outstanding Pre-Funded Warrants are included in the computation of basic net loss (income) per share because the 70 Table of Contents exercise price is negligible, and they are fully vested and exercisable after the original issuance date. No Pre-Funded Warrants were exercised during the year ended December 31, 2025.
There has been uncertainty and disruption in the global economy and financial markets due to a number of factors, including geopolitical instability, inflationary pressures, high interest rates, a recessionary environment, domestic and global monetary and fiscal policy, changes in trade policies, including tariffs or other trade restrictions or the threat of such actions, banking and other financial institution instability and other factors.
There has been uncertainty and disruption in the global economy and financial markets due to a number of factors, including but not limited to geopolitical instability, high interest rates, and changes in trade policies, including tariffs or other trade restrictions or the threat of such actions and retaliatory actions.
This increase was primarily due to a $4.6 million increase in advisory and legal fees related to the Takeda Collaboration agreement and a $4.4 million increase in stock-based compensation expense. We had 28 and 27 full-time equivalent general and administrative employees as of December 31, 2024 and 2023, respectively.
This increase was primarily due to a $2.9 million increase in stock-based compensation expense and an increase of $2.6 million in professional services expenses, partially offset by $4.6 million in advisory and legal fees incurred during the year ended December 31, 2024 related to the Takeda Collaboration Agreement. ​ We had 29 and 28 full-time equivalent general and administrative employees as of December 31, 2025 and 2024, respectively.
Research and Development Expenses Research and development expenses represent costs incurred to conduct research, such as the discovery and development of our product candidates. We recognize all research and development costs as they are incurred unless there is an alternative future use in other research and development projects or otherwise.
We recognize all research and development costs as they are incurred unless there is an alternative future use in other research and development projects or otherwise.
Such additional funding may come from various sources, including raising additional capital, seeking access to debt, and seeking additional collaborative or other arrangements with partners, but such funding may not be available on terms acceptable to us, if at all.
Our future funding requirements will depend on many factors, including those described in Part I, Item 1A, “Risk Factors.” Such additional funding may come from various sources, including raising additional capital, seeking access to debt, and seeking additional collaborative or other arrangements with partners, but such funding may not be available on terms acceptable to us, if at all.
We expect our research and development expenses to increase in the near term as compared to prior year periods as we continue to focus our resources toward (i) progressing our rusfertide program into late stage clinical trials and preparing for regulatory filings and commercialization, and (ii) advancing our pre-clinical and drug discovery research programs, including progressing our recently nominated product development candidate PN-881 through IND-enabling studies, or foreign equivalents.
We expect our research and development expenses to increase in the near term as compared to prior year periods as we continue to focus our resources toward advancing our pre-clinical and drug discovery research and clinical programs, including progressing our product development candidates PN-881, PN-477, PN-458 and PN-8047 through IND-enabling studies, or foreign equivalents.
During the year ended December 31, 2024, Pre-Funded Warrants to purchase 1,205,252 shares were net exercised, resulting in the issuance of 1,205,225 shares of common stock. As of December 31, 2024, Pre-Funded Warrants to purchase 1,500,000 shares of common stock remained outstanding.
During the year ended December 31, 2024, Pre-Funded Warrants to purchase 84,992 shares were net exercised, resulting in the issuance of 84,989 shares of common stock.
Cash used in operating activities for the year ended December 31, 2023 was $70.2 million and consisted primarily of our net loss of $79.0 million and a net change of $19.5 million in net operating assets and liabilities, partially offset by certain non-cash items, including $29.2 million of stock-based compensation expense.
Cash provided by operating activities for the year ended December 31, 2024 was $184.2 million and consisted primarily of our net income of $275.2 million and certain non-cash items, including $37.6 million of stock-based compensation, partially offset by a net change of $122.6 million in net operating assets and liabilities.
Interest Income Interest income increased $11.4 million, or 77%, from $14.9 million for the year ended December 31, 2023 to $26.3 million for the year ended December 31, 2024.
Interest Income Interest income increased $2.5 million, or 9%, from $26.3 million for the year ended December 31, 2024 to $28.8 million for the year ended December 31, 2025.
General and Administrative Expenses General and administrative expenses increased $10.0 million, or 30%, from $33.5 million for the year ended December 31, 2023 to $43.5 million for the year ended December 31, 2024.
General and Administrative Expenses General and administrative expenses increased $1.4 million, or 3%, from $43.5 million for the year ended December 31, 2024 to $44.9 million for the year ended December 31, 2025.
We expect that our existing cash, cash equivalents and marketable securities will be sufficient to fund our operations for at least the next twelve months from the date of this Annual Report on Form 10-K based on current operating plans and financial forecasts.
We expect that our existing cash, cash equivalents and marketable securities will be sufficient to fund our operations for at least the next twelve months from the date of this Annual Report on Form 10-K based on current operating plans and financial forecasts. ​ While we do not currently anticipate a need for additional funding, we may require additional funding in the future to advance our discovery pipeline and to develop, acquire, or in-license other potential product candidates.
The potential future payments include (i) up to $2.75 million in future development milestone payments, (ii) a low single digit royalty on worldwide net sales, and (iii) sales milestones for achievement of annual net sales amounts in specific geographies.
Under the Arbitration Resolution Agreement, we are obligated to make certain payments related to rusfertide, including (i) up to $2.75 million future development milestone payments, (ii) a 1% royalty on worldwide net sales, and (iii) sales milestones for achievement of annual net sales amounts in specific geographies.
Purchases of property and equipment were primarily related to purchases of leasehold improvements and laboratory equipment. 74 Table of Contents Cash used in investing activities for the year ended December 31, 2023 was $39.3 million and consisted of purchases of marketable securities of $191.1 million and purchases of property and equipment of $0.6 million, partially offset by proceeds from maturities of marketable securities of $152.4 million.
Cash Used in Investing Activities Cash used in investing activities for the year ended December 31, 2025 was $49.3 million and consisted primarily of purchases of marketable securities of $546.6 million and purchases of property and equipment of $1.6 million, partially offset by proceeds from maturities and sales of marketable securities of $498.8 million.
There were no sales of our common stock under the 2022 ATM Facility during the years ended December 31, 2024 and 2022. ​ Pre-Funded Warrants ​ In August 2018, we entered into a Securities Purchase Agreement with certain accredited investors (each, an “Investor” and, collectively, the “Investors”), pursuant to which we sold an aggregate of 2,750,000 shares of our common stock at a price of $8.00 per share for aggregate net proceeds of $21.7 million, after deducting offering expenses payable by us.
There were no sales of our common stock under the 2022 ATM Facility during the years ended December 31, 2025 and 2024. ​ Pre-Funded Warrants ​ In August 2018, we entered into a Securities Purchase Agreement with certain accredited investors (each, an “Investor” and, collectively, the “Investors”).
For additional information, see Part I, Item 1A, “Risk Factors — Risks Related to our Financial Position and Capital Requirements.” The following table summarizes our cash flows for the periods indicated: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ 2024 2023 2022 Consolidated Statements of Cash Flows Data: ​ (Dollars in thousands) Cash provided by (used) in operating activities ​ $ 184,152 ​ $ (70,236) ​ $ (108,137) Cash (used in) provided by investing activities ​ $ (299,483) ​ $ (39,258) ​ $ 91,468 Cash provided by financing activities ​ $ 25,853 ​ $ 170,477 ​ $ 18,838 Stock-based compensation ​ $ 37,554 ​ $ 29,293 ​ $ 24,202 Deferred revenue ​ $ 30,567 ​ $ — ​ $ — ​ Cash Provided by (Used in) Operating Activities Cash provided by operating activities for the year ended December 31, 2024 was $184.2 million and consisted primarily of our net income of $275.2 million and certain non-cash items, including $37.6 million of stock-based compensation, partially offset by a net change of $122.6 million in net operating assets and liabilities.
The following table summarizes our cash flows for the periods indicated: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ ​ ​ ​ 2025 ​ ​ ​ 2024 ​ ​ ​ 2023 Consolidated Statements of Cash Flows Data: ​ (Dollars in thousands) Cash provided by (used in) operating activities ​ $ 57,671 ​ $ 184,152 ​ $ (70,236) Cash used in investing activities ​ $ (49,332) ​ $ (299,483) ​ $ (39,258) Cash provided by financing activities ​ $ 22,864 ​ $ 25,853 ​ $ 170,477 Stock-based compensation ​ $ 45,974 ​ $ 37,554 ​ $ 29,293 Change in deferred revenue ​ $ (21,017) ​ $ 30,567 ​ $ — ​ Cash Provided by (Used in) Operating Activities Cash provided by operating activities for the year ended December 31, 2025 was $57.7 million and consisted primarily of a net change of $146.2 million in net operating assets and liabilities and certain non-cash items, including $46.0 million of stock-based compensation, partially offset by a net loss of $130.1 million during the period.
We are also eligible to receive tiered royalties from 10% to 17% on ex-U.S. net sales of rusfertide and other specified second-generation injectable hepcidin memetic compounds (the “Licensed Products”). We and Takeda will also share equally in profits and losses (50% to us and 50% to Takeda) of the Licensed Products in the United States, if approved.
Under the Takeda Collaboration Agreement, we and Takeda share equally in profits and losses (50% to us and 50% to Takeda) associated with rusfertide in the United States. We also will receive tiered royalties ranging from 10% to 17% on ex-U.S. net sales of rusfertide.
The effective tax rate was 1.5% and 0.0% for the years ended December 31, 2024 and 2023, respectively. ​ Comparison of the Years Ended December 31, 2023 and 2022 See Part II, Item 7—Results of Operations—Comparison of the Years Ended December 31, 2023 and 2022 in our Annual Report on Form 10-K for the year ended December 31, 2023, filed on February 17, 2024, for a discussion of our results of operations for the year ended December 31, 2023 compared to the year ended December 31, 2022. ​ Liquidity and Capital Resources Sources of Liquidity Historically we have funded our operations primarily from net proceeds from the sale of shares of our common stock and receipt of payments under collaboration agreements.
The effective tax rate was 0.6% and 1.5% for the years ended December 31, 2025 and 2024, respectively. ​ Comparison of the Years Ended December 31, 2024 and 2023 See “Part II, Item 7—Results of Operations—Comparison of the Years Ended December 31, 2024 and 2023” in our Annual Report on Form 10-K for the year ended December 31, 2024, filed on February 21, 2025, for a discussion of our results of operations for the year ended December 31, 2024 compared to the year ended December 31, 2023. ​ Liquidity and Capital Resources Sources of Liquidity We had $646.0 million and $559.2 million in cash, cash equivalent and marketable securities as of December 31, 2025 and 2024, respectively.
We do not intend to dedicate further internal resources to clinical development or contract manufacturing activities for our PN-943 clinical program. The process of conducting research, identifying potential product candidates, conducting pre-clinical studies and clinical trials necessary to obtain regulatory approval and commencing pre-commercialization activities is costly and time intensive.
The process of conducting research, identifying potential product candidates, conducting pre-clinical studies and clinical trials necessary to obtain regulatory approval and commencing pre-commercialization activities is costly and time intensive. We may never succeed in achieving marketing approval for our product candidates regardless of our costs and efforts.
See Note 3 to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for further details related to the agreement, including our right to opt-out of the 50:50 U.S. profit and loss sharing arrangement.
In addition, we will receive tiered royalties ranging from 10% to 17% on ex-U.S. net sales of rusfertide. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report for further details related to the agreement, including our opt-out rights.
See Note 3 to the Consolidated Financial Statements elsewhere in this Annual Report on Form 10-K for additional information. In January 2020, we initiated arbitration proceedings with the International Court of Arbitration of the International Chamber of Commerce against Zealand Pharma A/S (“Zealand”) related to a collaboration agreement we and Zealand entered into in 2012 and terminated in 2014.
In January 2020, we initiated arbitration proceedings with the International Court of Arbitration of the International Chamber of Commerce against Zealand Pharma A/S (“Zealand”) related to a collaboration agreement we and Zealand entered into in 2012 and terminated in 2014. In August 2021, we and Zealand agreed to resolve the dispute and reached an Arbitration Resolution Agreement.
Following icotrokinra’s joint discovery by us and JNJ scientists pursuant to our IL-23R collaboration, we were primarily responsible for the development of icotrokinra through Phase 1, with JNJ assuming responsibility for development in Phase 2 and beyond.
Following Icotyde’s joint discovery by Protagonist and JNJ scientists, pursuant to the license and collaboration agreement, we were primarily responsible for the development of Icotyde through Phase 1, with JNJ assuming responsibility for development in Phase 2 and beyond. In July 2025 and September 2025, respectively, JNJ submitted a New Drug Application (“NDA”) to the U.S.
We expect to continue to incur significant research and development expenses and other expenses related to our ongoing operations, product development, pre-clinical discovery programs and pre-commercialization activities. As a result, we may incur losses in the future as we continue the development of, and seek regulatory approval for, our product candidates.
We expect to continue to incur significant research and development expenses and other expenses related to our ongoing operations, clinical development and pre-clinical discovery programs.
This increase was primarily due to higher invested balances, including the $300.0 million one-time, nonrefundable upfront payment received under the Takeda Collaboration Agreement in April 2024. ​ ​ ​ 70 Table of Contents Income Tax Expense ​ Income tax expense was $4.2 million and $0 for the year ended December 31, 2024 and 2023, respectively.
This increase was primarily due to higher invested balances, partially offset by lower average yields during 2025. ​ 69 Table of Contents Income Tax Expense ​ Income tax expense was $0.8 million and $4.2 million for the year ended December 31, 2025 and 2024, respectively.
(2) Includes $16.6 million and $12.2 million of non-cash stock-based compensation expense for the years ended December 31, 2024 and 2023, respectively. ​ License and Collaboration Revenue License and collaboration revenue was comprised of the following for the years presented: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ Dollar ​ % ​ 2024 2023 Change Change ​ ​ (Dollars in thousands) ​ ​ License and collaboration revenue: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Takeda Collaboration Agreement revenue ​ $ 269,433 ​ $ — ​ $ 269,433 ​ * JNJ License and Collaboration Agreement revenue ​ 165,000 ​ 60,000 ​ 105,000 175 Total license and collaboration revenue ​ $ 434,433 ​ $ 60,000 ​ $ 374,433 * *Percentage not meaningful. ​ License and collaboration revenue increased by $374.4 million from $60.0 million for the year ended December 31, 2023 to $434.4 million for the year ended December 31, 2024. ​ Takeda Collaboration Agreement revenue of $269.4 million for the year ended December 31, 2024 was comprised of (i) $254.1 million of the $300.0 million upfront cash payment allocated to the delivery of the rusfertide license to Takeda upon effectiveness of the agreement in March 2024, and (ii) $15.3 million allocated to development services provided by us during the period based on the cost input method.
(2) Includes $19.6 million and $16.6 million of non-cash stock-based compensation expense for the years ended December 31, 2025 and 2024, respectively. ​ License and Collaboration Revenue License and collaboration revenue was comprised of the following for the years presented: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ Dollar ​ % ​ ​ ​ ​ 2025 ​ ​ ​ 2024 ​ ​ ​ Change ​ ​ ​ Change ​ ​ (Dollars in thousands) ​ ​ License and collaboration revenue: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Takeda Collaboration Agreement revenue ​ $ 46,016 ​ $ 269,433 ​ $ (223,417) ​ (83) JNJ License and Collaboration Agreement revenue ​ — ​ 165,000 ​ (165,000) (100) Total license and collaboration revenue ​ $ 46,016 ​ $ 434,433 ​ $ (388,417) (89) ​ License and collaboration revenue decreased by $388.4 million from $434.4 million for the year ended December 31, 2024 to $46.0 million for the year ended December 31, 2025.
We had 98 and 85 full-time equivalent research and development employees as of December 31, 2024 and 2023, respectively. Research and development personnel-related expenses for the year ended December 31, 2024 increased by $10.0 million as compared to the year ended December 31, 2023, including increases of $6.1 million in personnel-related expenses and $3.9 million in stock-based compensation expense.
Research and development personnel-related expenses for the year ended December 31, 2025 increased by $6.5 million as compared to the year ended December 31, 2024, primarily driven by an increase in stock-based compensation expense.
Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations ​ OVERVIEW We are a discovery through late-stage development biopharmaceutical company focused on peptide therapeutics. Our clinical programs fall into two broad categories of diseases: (i) hematology and blood disorders, and (ii) inflammatory and immunomodulatory (“I&I”) diseases.
Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations ​ OVERVIEW We are an integrated discovery and development company with a validated technology platform. Our programs fall into three broad therapeutic areas: (i) inflammation and immunology (“I&I”), (ii) hematology and (iii) metabolic diseases.
Cash provided by financing activities for the year ended December 31, 2023 was $170.5 million and consisted primarily of net cash proceeds of $107.8 million from the April 2023 public offering of our common stock, $24.3 million from sales of our common stock under the 2022 ATM Facility, $34.4 million from the exercise of the Warrants in exchange for issuance of Pre-Funded Warrants and common stock, and $4.8 million in proceeds from the issuance of common stock upon exercise of stock options and purchases of common stock under our ESPP.
The $3.0 million decrease in cash provided by financing activities for year ended December 31, 2025, as compared to the year ended December 31, 2024, was primarily due to a $3.1 million decrease in proceeds from the issuance of common stock upon exercise of options and purchases of common stock under our ESPP.
Components of Our Results of Operations License and Collaboration Revenue Our license and collaboration revenue is derived from payments we receive under the Takeda Collaboration Agreement and the JNJ License and Collaboration Agreement. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report on Form 10-K for additional information.
Components of Our Results of Operations License and Collaboration Revenue Our license and collaboration revenue is derived from payments we receive from our collaboration partners under the JNJ License and Collaboration Agreement and the Takeda Collaboration Agreement.
We also have an oral peptide-based metabolic/obesity program and expect to nominate a development candidate in the second quarter of 2025. ​ Risks and Uncertainties ​ We describe the respective risks, uncertainties and assumptions that could affect our business, financial condition and/or results of operations in Part I, Item 1A. “Risk Factors” herein.
See Note 13 to the Consolidated Financial Statements included elsewhere in this Annual Report for additional information. ​ Risks and Uncertainties ​ We describe the respective risks, uncertainties and assumptions that could affect our business, financial condition and/or results of operations in Part I, Item 1A. “Risk Factors” herein.
Rusfertide, an injectable mimetic of the natural hormone hepcidin, is currently in Phase 3 development for treatment of the rare blood disorder polycythemia vera (“PV”). Rusfertide is being co-developed and will be co-commercialized with Takeda Pharmaceuticals, Inc. (“Takeda”) and the Company remains primarily responsible for development through NDA filing.
Rusfertide Rusfertide is a first-in-class investigational injectable mimetic of the natural hormone hepcidin in development for the treatment of the rare blood disorder polycythemia vera (“PV”). We discovered rusfertide, advanced it into Phase 3 development, and in early 2024 entered into a co-development and co-commercialization arrangement with Takeda Pharmaceuticals, Inc.
The increase was primarily due to an increase of $19.0 million in pre-clinical and drug discovery research expense, including costs related to PN-881, our recently nominated IL-17 development candidate, partially offset by a decrease of $0.9 million in expenses for our PN-943 program as further development work was deprioritized in 2023.
The increase was primarily due to an increase of $23.4 million in pre-clinical and drug discovery research program expenses, including costs related to our obesity program product candidates PN-477 and PN-458 and our oral hepcidin program product candidate PN-8047, and $10.5 million in costs related to IL-17 program product candidate PN-881.
We also remain eligible to receive upward tiering royalties on net product sales at percentages ranging from 6% percent to 10% percent, with 10% percent applicable for net sales over $4.0 billion. See Note 3 to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for additional information.
Our weighted average royalty rate on the first $4.0 billion in annual net sales is 7.25%, and the rate on net sales over $4.0 billion is 10%. See Note 3 to the Consolidated Financial Statements included elsewhere in this Annual Report for additional information.
Research and Development Expenses ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ Dollar ​ % ​ 2024 ​ 2023 ​ Change ​ Change ​ ​ (Dollars in thousands) ​ ​ Clinical and development expense — rusfertide ​ $ 97,862 ​ $ 98,060 ​ $ (198) ​ - Clinical and development expense — PN-943 ​ ​ 150 ​ ​ 1,058 ​ ​ (908) ​ (86) Clinical and development expense — other ​ ​ 176 ​ ​ 99 ​ ​ 77 ​ 78 Pre-clinical and drug discovery research expense ​ ​ 39,940 ​ ​ 20,944 ​ ​ 18,996 ​ 91 Total research and development expenses ​ $ 138,128 ​ $ 120,161 ​ $ 17,967 ​ 15 ​ Research and development expenses increased $18.0 million, or 15%, from $120.2 million for the year ended December 31, 2023 to $138.1 million for the year ended December 31, 2024.
Research and Development Expenses ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ Dollar ​ % ​ ​ ​ ​ 2025 ​ 2024 ​ Change ​ Change ​ ​ (Dollars in thousands) ​ ​ Clinical and development expense — rusfertide ​ $ 85,142 ​ $ 97,862 ​ $ (12,720) ​ (13) Clinical and development expense — PN-881 ​ ​ 10,513 ​ ​ — ​ ​ 10,513 ​ * Clinical and development expense — other ​ ​ 249 ​ ​ 326 ​ ​ (77) ​ (24) Pre-clinical and drug discovery research expense ​ ​ 63,386 ​ ​ 39,940 ​ ​ 23,446 ​ 59 Total research and development expenses ​ $ 159,290 ​ $ 138,128 ​ $ 21,162 ​ 15 *Percentage not meaningful. ​ Research and development expenses increased $21.2 million, or 15%, from $138.1 million for the year ended December 31, 2024 to $159.3 million for the year ended December 31, 2025.
Other Income (Expense), Net Other income (expense), net consists primarily of amounts related to foreign exchange gains and losses and related items. 68 Table of Contents Results of Operations ​ Comparison of the Years Ended December 31, 2024 and 2023 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ Dollar ​ % ​ 2024 2023 Change Change ​ ​ (Dollars in thousands) ​ ​ Revenue: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ License and collaboration revenue ​ $ 434,433 ​ $ 60,000 ​ $ 374,433 ​ * Operating expenses: ​ ​ ​ Research and development (1) ​ ​ 138,128 ​ ​ 120,161 ​ ​ 17,967 15 General and administrative (2) ​ 43,462 ​ 33,491 ​ 9,971 30 Total operating expenses ​ 181,590 ​ 153,652 ​ 27,938 18 Income (loss) from operations ​ 252,843 ​ (93,652) ​ 346,495 * Interest income ​ 26,315 ​ ​ 14,898 ​ 11,417 77 Other income (expense), net ​ ​ 250 ​ ​ (201) ​ ​ 451 ​ * Income (loss) before income tax expense ​ ​ 279,408 ​ ​ (78,955) ​ ​ 358,363 ​ * Income tax expense ​ ​ 4,220 ​ ​ — ​ ​ 4,220 ​ * Net income (loss) ​ $ 275,188 ​ $ (78,955) ​ $ 354,143 * *Percentage not meaningful.
Other Income (Expense), Net Other income (expense), net consists primarily of amounts related to foreign exchange gains and losses, realized gains and losses on marketable securities, and related items. 67 Table of Contents Results of Operations ​ Comparison of the Years Ended December 31, 2025 and 2024 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Year Ended December 31, ​ Dollar ​ % ​ ​ ​ ​ 2025 ​ ​ ​ 2024 ​ ​ ​ Change ​ ​ ​ Change ​ ​ (Dollars in thousands) ​ ​ License and collaboration revenue ​ $ 46,016 ​ $ 434,433 ​ $ (388,417) ​ (89) Operating expenses: ​ ​ ​ ​ ​ ​ ​ Research and development (1) ​ ​ 159,290 ​ ​ 138,128 ​ ​ 21,162 15 General and administrative (2) ​ 44,853 ​ 43,462 ​ 1,391 3 Total operating expenses ​ 204,143 ​ 181,590 ​ 22,553 12 (Loss) income from operations ​ (158,127) ​ 252,843 ​ (410,970) (163) Interest income ​ 28,789 ​ ​ 26,315 ​ 2,474 9 Other income, net ​ ​ 27 ​ ​ 250 ​ ​ (223) ​ (89) (Loss) income before income tax expense ​ ​ (129,311) ​ ​ 279,408 ​ ​ (408,719) ​ (146) Income tax expense ​ ​ 838 ​ ​ 4,220 ​ ​ (3,382) ​ (80) Net (loss) income ​ $ (130,149) ​ $ 275,188 ​ $ (405,337) (147) (1) Includes $26.4 million and $20.9 million of non-cash stock-based compensation expense for the years ended December 31, 2025 and 2024, respectively.
We are primarily responsible for the development of rusfertide through a potential NDA filing.
We were primarily responsible for the clinical development of rusfertide through NDA filing and remain primarily responsible for the conduct of ongoing rusfertide long-term extension studies.
We have a pre-clinical stage program to identify an orally administered hepcidin mimetic/ferroportin blocker, which we believe to be complementary to the injectable rusfertide for offering the best treatment options for PV and other potential erythropoietic and iron imbalance disorders, and we expect to nominate a development candidate in the fourth quarter of 2025.
In December 2025, we nominated development candidate PN-8047, an orally administered hepcidin functional mimetic small molecule, which we believe may be complementary to the injectable rusfertide for offering the best treatment options for PV.
On July 27, 2021, we entered into an Amended and Restated License and Collaboration Agreement with JNJ, which amended and restated the License and Collaboration Agreement, effective July 13, 2017, by and between the Company and JNJ, as amended by the first amendment, effective May 7, 2019 (together, the “JNJ License and Collaboration Agreement”) for the development and commercialization of icotrokinra.
Collaboration Agreements ​ JNJ License and Collaboration Agreement ​ We and JNJ are parties to a license and collaboration agreement related to the development and commercialization of Icotyde. We entered into the agreement in July 2017, and amended it in May 2019, July 2021 and November 2024 (as amended, the “JNJ License and Collaboration Agreement”).
PN-881 In the fourth quarter of 2024, we announced the selection of PN-881, a potential best-in-class oral peptide IL-17 antagonist, as a development candidate for the treatment of immune-mediated skin diseases. PN-881 targets three IL-17 dimers (IL-17 AA, AF and FF), which may offer potential treatment options for h idradenitis suppurativa (“HS”), spondyloarthritis, plaque psoriasis and psoriatic arthritis (“PsA”).
PN-881 targets three IL-17 dimers (IL-17 AA, AF and FF), and may offer potential treatment options for plaque psoriasis, psoriatic arthritis (“PsA”), h idradenitis suppurativa (“HS”), and spondyloarthritis. In October 2025, the first human subject was dosed in our Phase 1 trial of PN-881 (ClinicalTrials.gov identifier NCT07153146) evaluating its safety, tolerability, pharmacokinetics and pharmacodynamics in healthy adults.
We also have a number of pre-clinical stage oral drug discovery programs to address clinically and commercially validated targets, including IL-17 oral peptide antagonist PN-881, an oral metabolic/obesity peptide program, and an oral hepcidin mimetic/ferroportin blocker program. Rusfertide Rusfertide is currently in Phase 3 development for the treatment of PV.
IND-enabling studies for PN-8047 are ongoing. ​ Other Programs ​ We also have a number of pre-clinical stage drug discovery programs addressing biologically and commercially validated targets, including an oral IL-4R alpha antagonist for the treatment of atopic dermatitis and moderate-to-severe asthma, and amylinR-based oral and subcutaneous mono- and poly-agonists for the treatment of obesity.
Revenue from licensing and collaboration agreements, by its very nature, is highly variable and dependent upon factors such as the timing of when regulatory and sales milestones are achieved, if at all, and the accounting for any upfront payments and performance obligations associated with any existing or new agreements.
The decrease in revenue was primarily attributable to lower milestone and collaboration revenue, which is highly variable and dependent upon factors such as the timing of when regulatory and sales milestones are achieved, if at all, and the accounting for any upfront payments associated with any existing or new agreements. ​ License and collaboration revenue for the year ended December 31, 2025 of $46.0 million related to the Takeda Collaboration Agreement and was comprised of (i) $21.3 million representing a portion of the $25.0 million milestone payment received in September 2025 that was allocated to the rusfertide license delivery performance obligation under the agreement and (ii) $24.7 million for development services provided by us during the period based on the cost-based input method.
As discussed above, our revenue for the year ended December 31, 2024 was significantly higher than in prior years due to the partial recognition of an upfront payment of $300.0 million upon execution of the Takeda Collaboration Agreement and the achievement of a $165.0 million milestone pursuant to the terms of the JNJ License and Collaboration Agreement, as amended in November 2024.
The $126.5 million decrease in cash provided by operating activities during the year ended December 31, 2025, as compared to the year ended December 31, 2024, was primarily due to the receipt of a $300.0 million one-time, non-refundable upfront payment upon the effectiveness of the Takeda Collaboration Agreement in 2024, partially offset by the receipt of the $165.0 million milestone payment from JNJ and the $25.0 million milestone payment from Takeda in 2025.
Under the JNJ License and Collaboration Agreement, we earned a $50.0 million milestone payment upon the dosing of the third patient in the ICONIC-TOTAL Phase 3 trial in late October 2023, which we received in December 2023.
Under the terms of the agreement, we received an upfront payment of $300.0 million in April 2024 and a $25.0 million milestone payment in September 2025 upon completion of the Phase 3 VERIFY clinical trial (NCT05210790) report.
Icotrokinra is a first-in-class investigational targeted oral peptide that selectively blocks the Interleukin-23 receptor (“IL-23R”) and is licensed to J&J Innovative Medicines (“JNJ”), formerly Janssen Biotech, Inc.
Our aim is to develop medicines for biologically and commercially validated targets which demonstrate a strong differentiation compared to existing therapies. Our Development Products and Discovery Programs Icotyde™ (icotrokinra) Icotyde™ (icotrokinra) is a first-in-class investigational targeted oral peptide that selectively blocks the Interleukin-23 receptor (“IL-23R”), which underpins the inflammatory response in psoriasis and offers potential in other IL-23-mediated diseases.
The $130.7 million decrease in cash provided by investing activities for the year ended December 31, 2023, as compared to the year ended December 31, 2022, was primarily related to a decrease in the net activity of purchases and maturities of marketable securities. Purchases of property and equipment were primarily related to purchases of laboratory and computer equipment.
The $250.2 million decrease in cash used in investing activities for the year ended December 31, 2025, as compared to the year ended December 31, 2024, was primarily related to investments made with a portion of the proceeds from the $300.0 million upfront payment received from Takeda in 2024.
We earned the $165.0 million milestone payment described above during the fourth quarter of 2024. We have earned a total of $337.5 million in nonrefundable payments from JNJ from 2017 through December 31, 2024.
Pursuant to the JNJ License and Collaboration Agreement, we were primarily responsible for the discovery, IND-enabling studies and the initial Phase 1 study for Icotyde, and JNJ is primarily responsible for conducting all further development. 62 Table of Contents We have earned a total of $337.5 million in milestone payments from JNJ under the agreement, including a $165.0 million milestone payment earned in the fourth quarter of 2024.
We are eligible to receive up to $630.0 million in future development and sales milestone payments, inclusive of the following potential upcoming milestones: ● $50.0 million milestone upon approval of an NDA for icotrokinra in any indication; ● $25.0 million milestone upon the acceptance of an NDA filing by the FDA for icotrokinra in a second indication; and ● $45.0 million milestone upon the approval of an NDA for icotrokinra in a second indication.
We are eligible to receive up to $630.0 million in future development and sales milestone payments, including the following potential milestones: We will also receive upward tiering royalties on net worldwide Icotyde product sales at percentages ranging from 6% to 10%.
Removed
Two novel peptides derived from our proprietary discovery technology platform, rusfertide and icotrokinra (formerly known as JNJ-2113), are currently in advanced Phase 3 clinical development, with New Drug Application (“NDA”) submissions to the U.S. Food and Drug Administration (“FDA”) potentially in 2025.
Added
Icotyde is licensed to Janssen Biotech, Inc., a Johnson & Johnson company (“JNJ”), under a license and collaboration agreement initially entered into in 2017.
Removed
VERIFY (ClinicalTrials.gov identifier NCT05210790) is a global double-blind, placebo-controlled Phase 3 clinical trial of rusfertide in PV for approximately 250 patients. The trial evaluates the efficacy, symptom burden and safety of once-weekly, subcutaneously self-administered rusfertide in patients with uncontrolled hematocrit who are phlebotomy dependent despite standard of care treatment.
Added
Food and Drug Administration (“FDA”) and an application to the European Medicines Agency (“EMA”) seeking the first approval of Icotyde for the treatment of adults and pediatric patients 12 years of age and older with moderate-to-severe plaque psoriasis. JNJ has disclosed that it expects to launch Icotyde in the United States in 2026, subject to regulatory approval.
Removed
The trial enrolled patients across North and South America, Europe, Asia and Australia. We expect to announce top-line data for the trial’s 32-week primary efficacy endpoint in March 2025, potentially leading to an NDA filing in the fourth quarter of 2025.
Added
(“Takeda”) under a license and collaboration agreement entered into in January 2024. We remained primarily responsible for clinical development activities through rusfertide’s NDA filing for the treatment of erythrocytosis in patients with PV, which we and Takeda submitted in December 2025. Rusfertide has also received Orphan Drug status, Fast Track designation and, in August 2025, Breakthrough Therapy designation (“BTD”).
Removed
Our rusfertide Phase 2 clinical trials include the following: ● REVIVE (NCT04057040) – A Phase 2 proof of concept (“POC”) trial, was initiated in the fourth quarter of 2019.
Added
BTD is a process designed to expedite the development and review of drugs that are intended to treat a serious condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies. BTD also provides eligibility for priority NDA review, and Orphan Drug status qualifies sponsors for various incentives, including the potential for extended market exclusivity.
Removed
We completed enrollment of patients in the first quarter of 2022 and 70 patients were enrolled through the end of the randomized withdrawal portion of the trial, which was completed during the first quarter of 2023 and is continuing in an ongoing open-label extension (“OLE”); ● THRIVE (NCT06033586) – A Phase 2 long-term OLE for REVIVE patients on years three through five of treatment; and ● PACIFIC (NCT04767802) – Another Phase 2 trial for rusfertide for patients diagnosed with PV and with routinely elevated hematocrit levels (>48%), was initiated during the first quarter of 2021, and the 52-week trial was completed during the second quarter of 2023.
Added
Takeda has disclosed that it expects to launch rusfertide in the second half of 2026, subject to regulatory approval. IL-17 Program PN-881 . We are developing PN-881, a potential best-in-class oral peptide IL-17 antagonist, for the treatment of immune-mediated skin diseases.
Removed
Final results from the REVIVE trial presented at the American Society of Hematology (“ASH”) 2024 Annual Meeting in December 2024 showed that 54% of patients with PV experienced more than 2.5 years of durable hematocrit control ( 62 Table of Contents In January 2024, we entered into a worldwide license and collaboration agreement for rusfertide with Takeda (the “Takeda Collaboration Agreement”).

… 69 more changes not shown on this page.

Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

4 edited+0 added−0 removed3 unchanged
Biggest changeInterest Rate Fluctuation Risk We had $559.2 million and $341.6 million in cash, cash equivalents and marketable securities at December 31, 2024 and 2023, respectively. Our cash and cash equivalents consist of cash, money market funds, commercial paper and government bonds. Marketable securities consist of certificates of deposit, corporate bonds, commercial paper and government bonds.
Biggest changeInterest Rate Fluctuation Risk We had $646.0 million and $559.2 million in cash, cash equivalents and marketable securities at December 31, 2025 and 2024, respectively. Our cash and cash equivalents consist of cash, money market funds, certificate of deposit and commercial paper. Marketable securities consist of government and agency bonds, commercial paper and corporate bonds.
Based on our interest rate sensitivity analysis, an immediate 100 basis point increase in interest rates would increase our annual interest income by approximately $2.8 million, while an immediate 100 basis point decrease in interest rates would decrease our annual interest income by approximately $2.8 million.
Based on our interest rate sensitivity analysis, an immediate 100 basis point increase in interest rates would increase our annual interest income by approximately $3.8 million, while an immediate 100 basis point decrease in interest rates would decrease our annual interest income by approximately $3.8 million.
Inflation Fluctuation Risk Inflation generally affects us by increasing our costs, such as the cost of labor and research and development contract costs. We do not believe inflation has had a material adverse effect on the results of our operations during the year ended December 31, 2024. ​ 76 Table of Contents
Inflation Fluctuation Risk Inflation generally affects us by increasing our costs, such as the cost of labor and research and development contract costs. We do not believe inflation has had a material adverse effect on the results of our operations during the year ended December 31, 2025. ​ 73 Table of Contents
Approximately $0.6 million and $0.9 million of our cash balance was located in Australia at December 31, 2024 and 2023, respectively. Our expenses, except those related to our Australian operations, are generally denominated in U.S. dollars. For our operations in Australia, the majority of our expenses are denominated in Australian dollars.
Approximately $2.8 million and $0.6 million of our cash balance was located in Australia at December 31, 2025 and 2024, respectively. Our expenses, except those related to our Australian operations, are generally denominated in U.S. dollars. For our operations in Australia, the majority of our expenses are denominated in Australian dollars.

Other PTGX 10-K year-over-year comparisons