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What changed in Korro Bio, Inc.'s 10-K — 2024 vs 2025

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Paragraph-level year-over-year comparison of Korro Bio, 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.

+872 added−858 removedSource: 10-K (2026-03-12) vs 10-K (2024-12-31)

Top changes in Korro Bio, Inc.'s 2025 10-K

872 paragraphs added · 858 removed · 631 edited across 8 sections

Item 1. Business

Business — how the company describes what it does

211 edited+139 added−127 removed272 unchanged
Biggest changeThese modification approaches can unlock validated target classes that have historically been difficult to drug, enabling us to pursue a broad range of diseases with potentially large addressable patient populations traditionally out-of-scope for other genetic medicine approaches and current traditional drug modalities. 2 Each of our programs demonstrates the versatility of the oligonucleotide-based ADAR-mediated RNA editing approach to bring additional precision and tunability to address a broad range of rare and highly prevalent diseases. • Repairing pathogenic variants: A SNV that is a G to A mutation on DNA, leading to an aberrant amino acid on a protein can be repaired using RNA editing.
Biggest changeOur pipeline has multiple programs, all of which are focused on modifying proteins to provide clinical benefit. These modification approaches can unlock validated target classes that have historically been difficult to drug, enabling us to pursue a broad range of diseases with potentially large addressable patient populations traditionally out-of-scope for other genetic medicine approaches and current traditional drug modalities.
These studies are typically designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, excretion the side effects associated with increasing doses, and, if possible, to gain early evidence of effectiveness. • Phase 2 – Phase 2 clinical trials typically involve administration of the investigational product to a limited patient population with a specified disease or condition to evaluate the drug’s potential efficacy, to determine the optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks. 31 • Phase 3 – Phase 3 clinical trials typically involve administration of the investigational product to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites.
These studies are typically designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, excretion the side effects associated with increasing doses, and, if possible, to gain early evidence of effectiveness. • Phase 2 – Phase 2 clinical trials typically involve administration of the investigational product to a limited patient population with a specified disease or condition to evaluate the drug’s potential efficacy, to determine the optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks. • Phase 3 – Phase 3 clinical trials typically involve administration of the investigational product to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites.
For more information regarding the risks related to our intellectual property, see Item 1A “ Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property .” 29 Governmental Regulation The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, clinical trial, testing, manufacture, quality control, import, export, safety, efficacy, labeling, packaging, storage, distribution, recordkeeping, approval, distribution, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs.
For more information regarding the risks related to our intellectual property, see Item 1A “ Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property .” Governmental Regulation The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, clinical trial, testing, manufacture, quality control, import, export, safety, efficacy, labeling, packaging, storage, distribution, recordkeeping, approval, distribution, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs.
Such uncertainties include, but are not limited to the level of editing efficiency needed in a target tissue type to achieve a clinical benefit, and associated safety of our edits in humans. • Specificity : Oligonucleotide-based ADAR-mediated RNA editing enables highly precise edits at the target single nucleotide level on the RNA with low risk of off-target or bystander edits, addressing a key safety concern associated with other DNA editing approaches that carry the risk of permanent insertions and deletions as well as chromosomal integration.
Such uncertainties include but are not limited to the level of editing efficiency needed in a target tissue type to achieve a clinical benefit, and associated safety of our edits in humans. • Specificity : Oligonucleotide-based ADAR-mediated RNA editing enables highly precise edits at the target single nucleotide level on the RNA with low risk of off-target or bystander edits, addressing a key safety concern associated with other DNA editing approaches that carry the risk of permanent insertions and deletions as well as chromosomal 8 integration.
In addition, the U.S. government has the right, under certain limited circumstances, to require the licensor to grant exclusive, partially exclusive, or non-exclusive licenses to any of these inventions to a third party if it determines that: (1) adequate steps have not been taken to commercialize the invention; (2) government action is necessary to meet public health or safety needs; or (3) government action is necessary to meet requirements for public use under federal regulations (also referred to as “march-in rights”).
In addition, the U.S. government has the right, under certain limited circumstances, to require the licensor to grant exclusive, partially exclusive, or non-exclusive licenses to any of these inventions to a third party if it determines that: (1) adequate steps have not been taken to commercialize the invention; (2) government action is necessary to meet public health or safety needs; or (3) government action is necessary to meet requirements for public use under federal regulations (also referred to 31 as “march-in rights”).
The GDPR also imposes strict rules on the transfer of personal data to countries outside of the EEA and the UK that do not ensure an adequate level of protection, including the United States in certain circumstances, unless derogation exists or a 36 valid GDPR transfer mechanism (for example, the European Commission approved Standard Contractual Clauses, or the SCCs, and the UK International Data Transfer Agreement or Addendum, or the UK IDTA, have been put in place.
The GDPR also imposes strict rules on the transfer of personal data to countries outside of the EEA and the UK that do not ensure an adequate level of protection, including the United States in certain circumstances, unless derogation exists or a valid GDPR transfer mechanism (for example, the European Commission approved Standard Contractual Clauses, or the SCCs, and the UK International Data Transfer Agreement or Addendum, or the UK IDTA, have been put in place.
We intend to continue to incorporate new data into these machine learning models to improve their ability to predict editing efficiency and to more expeditiously optimize and nominate new product candidates, although there is no guarantee that this will result in an accelerated development or approval timeline, if at all. • Maximize the potential of our OPERA platform through collaborations and strategic partnerships.
We intend to continue to incorporate new data into these machine learning models to improve their ability to predict editing efficiency and to more expeditiously optimize and nominate new development candidates, although there is no guarantee that this will result in an accelerated development or approval timeline, if at all. • Maximize the potential of our OPERA platform through collaborations and strategic partnerships.
These levels of normal AAT have the potential to prevent further lung damage and reduce the risk of dysfunctional AAT aggregating in the liver. • Potential to enable physiologic regulation of AAT using endogenous ADAR: Augmentation therapy and other treatments targeting static thresholds for AAT expression do not address the underlying mechanism of AAT regulation, which is endogenously regulated by inflammation and can sometimes lead to as much as 90uM of AAT in humans.
These levels of normal AAT have the potential to prevent further lung damage and reduce the risk of dysfunctional AAT aggregating in the liver. • Potential to enable physiologic regulation of AAT using endogenous ADAR: Augmentation therapy and other treatments targeting static thresholds for AAT expression do not address the underlying mechanism of AAT 23 regulation, which is endogenously regulated by inflammation and can sometimes lead to as much as 90uM of AAT in humans.
Given the versatility and broad potential of our OPERA platform across therapeutic areas, especially in diseases with high prevalence, we may enter into additional strategic partnerships with external parties that have complementary capabilities to broaden and accelerate access to our RNA editing therapies. • Invest in human capital and encourage innovation to maintain a leading position and advance the frontiers of genetic medicines.
Given the versatility and broad potential of our OPERA platform across therapeutic areas, especially 6 in diseases with high prevalence, we may enter into additional strategic partnerships with external parties that have complementary capabilities to broaden and accelerate access to our RNA editing therapies. • Invest in human capital and encourage innovation to maintain a leading position and advance the frontiers of genetic medicines.
Legally mandated price controls on payment amounts by third-party payors or other restrictions could harm our business, financial condition, results of operations and prospects. In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.
Legally mandated price controls on payment amounts by 46 third-party payors or other restrictions could harm our business, financial condition, results of operations and prospects. In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.
Next generation DNA editing approaches have recently entered the clinic and hold the promise to edit DNA at the single nucleotide level. Despite these advances, significant risks exist with DNA editing approaches. A key concern is the introduction of unwanted DNA modifications (“off-target” edits) which could have permanent adverse effects such as chromosomal integration and non-specific insertions, deletions and substitutions.
Next generation DNA editing approaches have entered the clinic and hold the promise to edit DNA at the single nucleotide level. Despite these advances, significant risks exist with DNA editing approaches. A key concern is the introduction of unwanted DNA modifications (“off-target” edits), which could have permanent adverse effects such as chromosomal integration and non-specific insertions, deletions and substitutions.
Factors that increase lung inflammation, such as smoking or infections, increase the elastase burden in the lung, leading to severe and potentially life-threatening lung damage in AATD patients. Genotypes of AATD AATD is an inherited, autosomal recessive genetic disorder that is most frequently caused by a single nucleotide variant, or SNV, mutation in the SERPINA1 gene.
Factors that increase lung inflammation, such as smoking or 20 infections, increase the elastase burden in the lung, leading to severe and potentially life-threatening lung damage in AATD patients. Genotypes of AATD AATD is an inherited, autosomal recessive genetic disorder that is most frequently caused by a single nucleotide variant, or SNV, mutation in the SERPINA1 gene.
If we fail to comply with applicable FDA or other requirements at any time with respect to product development, clinical testing, approval or any other legal requirements relating to product manufacture, processing, handling, storage, quality control, safety, marketing, advertising, promotion, packaging, labeling, export, import, distribution, or sale, we may become subject to administrative or judicial sanctions or other legal consequences.
If we fail to comply with applicable FDA or other requirements at any time with respect to product development, clinical testing, approval or any other legal requirements relating to product manufacture, processing, handling, storage, quality control, safety, marketing, advertising, promotion, packaging, labeling, export, import, distribution, or sale, we may become subject to administrative or 32 judicial sanctions or other legal consequences.
Studies of PiMZ prevalence suggest as many as one in 49 individuals in the United States and one in 58 individuals across Europe. The only FDA-approved treatment for patients with lung manifestations of AATD (co-indicated with COPD) is augmentation therapy, which utilizes AAT protein purified from pooled human plasma.
Studies of PiMZ prevalence suggest as many as one in 49 individuals in the United States and one in 58 individuals across Europe. 22 The only FDA-approved treatment for patients with lung manifestations of AATD (co-indicated with COPD) is augmentation therapy, which utilizes AAT protein purified from pooled human plasma.
ADARs bind double-stranded RNA structures, and convert a single base of adenosine (A) on RNA, into an inosine (I) that is typically translated as a guanosine (G), using an enzymatic process. ADAR mediated editing is found at high levels in cephalopods both on the coding and non-coding regions of the RNA.
ADARs bind double-stranded RNA structures, and convert a single base of adenosine (A) on RNA, into an inosine (I) that is typically translated as a guanosine (G), using an 7 enzymatic process. ADAR mediated editing is found at high levels in cephalopods both on the coding and non-coding regions of the RNA.
Further, if there are any modifications to the drug, including changes in indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA approval of a new NDA or NDA supplement, which may require the development of additional data or preclinical studies and clinical trials.
Further, if there are any modifications to the drug, 37 including changes in indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA approval of a new NDA or NDA supplement, which may require the development of additional data or preclinical studies and clinical trials.
Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted.
Many benefits accrue to sponsors of development candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted.
Given the versatility and broad potential of our OPERA platform across therapeutic 25 areas, especially in diseases with high prevalence, we may enter into additional strategic partnerships with external parties that have complementary capabilities to broaden and accelerate access to our RNA editing therapies.
Given the versatility and broad potential of our OPERA platform across therapeutic areas, especially in diseases with high prevalence, we may enter into additional strategic partnerships with external parties that have complementary capabilities to broaden and accelerate access to our RNA editing therapies.
Other Regulatory Matters Manufacturing, labeling, packaging, distribution, sales, promotion and other activities of product candidates following product approval, where applicable, or commercialization are also potentially subject to federal and state consumer protection and unfair competition laws, among other requirements to which we may be subject.
Other Regulatory Matters Manufacturing, labeling, packaging, distribution, sales, promotion and other activities of development candidates following product approval, where applicable, or commercialization are also potentially subject to federal and state consumer protection and unfair competition laws, among other requirements to which we may be subject.
As a result, the coverage determination 41 process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.
As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.
Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the product candidate and finalize a process for manufacturing the drug product in commercial quantities in accordance with cGMP requirements.
Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the development candidate and finalize a process for manufacturing the drug product in commercial quantities in accordance with cGMP requirements.
Changes in statutes, regulations, or interpretations of existing regulations could impose additional requirements on our operations, such as modifications to data processing arrangements, changes to privacy policies, recall or discontinuation of certain data processing methods, or additional recordkeeping requirements. These changes could adversely affect the operation of our business.
Changes in statutes, regulations, or interpretations of existing 40 regulations could impose additional requirements on our operations, such as modifications to data processing arrangements, changes to privacy policies, recall or discontinuation of certain data processing methods, or additional recordkeeping requirements. These changes could adversely affect the operation of our business.
The 7 ADARs are essential enzymes for normal physiologic function. ADAR-driven RNA editing has been found to be critical for the function of a number of proteins, such as the glutamate ionotropic receptor, which has been found to be almost always RNA-edited in humans.
The ADARs are essential enzymes for normal physiologic function. ADAR-driven RNA editing has been found to be critical for the function of a number of proteins, such as the glutamate ionotropic receptor, which has been found to be almost always RNA-edited in humans.
Furthermore, Fast Track designation, Breakthrough Therapy designation, Priority Review and Accelerated Approval do not change the scientific or medical standards for approval or the quality of evidence necessary to support approval, though they may expedite the development or review process. 34 U.S.
Furthermore, Fast Track designation, Breakthrough Therapy designation, Priority Review and Accelerated Approval do not change the scientific or medical standards for approval or the quality of evidence necessary to support approval, though they may expedite the development or review process. U.S.
The TGA describes its remit as being to safeguard and enhance the health of the Australian community through effective and timely regulation of therapeutic goods. The TGA administers two pathways for 40 clinical trials, the Clinical Trials Notification, or CTN, and Clinical Trials Approval, or CTA, schemes.
The TGA describes its remit as being to safeguard and enhance the health of the Australian community through effective and timely regulation of therapeutic goods. The TGA administers two pathways for clinical trials, the Clinical Trials Notification, or CTN, and Clinical Trials Approval, or CTA, schemes.
Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent. The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.
Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent. The USPTO, in consultation with the FDA, reviews and approves the application for any patent term 38 extension or restoration.
To address this knowledge gap, we developed a robust in-house process using our high-throughput cell-based assay and machine learning capabilities to design and synthesize up to approximately 1,200 oligonucleotides per month and generate up to 6,000 assay data points for any given target. • Machine learning optimization of oligonucleotides and target identification: We have built data science capabilities and a dedicated team to extract lessons from existing and newly generated experimental data to expeditiously and efficiently design and optimize RNA editing product candidates.
To address this knowledge gap, we developed a robust in-house process using our high-throughput cell-based assay and machine learning capabilities to design and synthesize up to approximately 1,200 oligonucleotides per month and generate up to 6,000 assay data points for any given target. • Machine learning optimization of oligonucleotides and target identification: We have built data science capabilities and a dedicated team to extract lessons from existing and newly generated experimental data to expeditiously and efficiently design and optimize RNA editing oligonucleotides.
If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to a seven-year period of marketing exclusivity during which the FDA may not approve any other applications to market the same therapeutic agent for the same indication, except in limited circumstances, such as a subsequent product’s showing of clinical superiority over the product with orphan exclusivity or where the original applicant cannot produce sufficient quantities of product.
If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to a seven-year period of marketing exclusivity during which the FDA may not approve any other applications to market the same therapeutic agent for the same approved use or indication, except in limited circumstances, such as a subsequent product’s showing of clinical superiority over the product with orphan exclusivity or where the original applicant cannot produce sufficient quantities of product.
The extended patent term cannot exceed the shorter of five years beyond the non-extended expiration of the patent or 14 years from the date of the FDA approval of the drug, and a patent cannot be extended more than once or for more than a single 28 product.
The extended patent term cannot exceed the shorter of five years beyond the non-extended expiration of the patent or 14 years from the date of the FDA approval of the drug, and a patent cannot be extended more than once or for more than a single product.
During the development of a new drug product, sponsors have the opportunity to meet with the FDA at certain points, including prior to submission of an IND, at the end of Phase 2 and before submission of an NDA.
During the development of a new drug product, sponsors have the opportunity to meet with the FDA at certain points, including prior to submission of an IND, at the end of Phase 2 and 34 before submission of an NDA.
American Taxpayer Relief Act of 2012 further reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
American Taxpayer Relief Act of 2012 also further reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
As transient editing is not permanent in nature, we have the ability to adjust dosing and even cease dosing as needed, providing a meaningful benefit in potential safety profile. • Provides a disease modifying therapy for both lung and liver manifestations: By transiently editing over 50% of RNA transcripts in hepatocytes, we believe we can restore levels of normal AAT protein consistent with a PiMZ to PiMM phenotype.
As transient editing is not permanent in nature, we have the ability to adjust dosing and even cease dosing as needed, providing a meaningful benefit in potential safety profile. • Provides a disease modifying therapy for both lung and liver manifestations: By transiently editing over 90% of RNA transcripts in hepatocytes, we believe we can restore levels of normal AAT protein consistent with a PiMZ to PiMM phenotype.
The manufacturing process must be capable of consistently producing quality batches of the product candidate and manufacturers must develop, among other things, methods for testing the identity, strength, quality and purity of the final drug product.
The manufacturing process must be capable of consistently producing quality batches of the development candidate and manufacturers must develop, among other things, methods for testing the identity, strength, quality and purity of the final drug product.
While we believe we can demonstrate many of the key advantages of RNA editing, we are very early in our development efforts and not yet certain of the results we may achieve.
While we 14 believe we can demonstrate many of the key advantages of RNA editing, we are very early in our development efforts and not yet certain of the results we may achieve.
Other potential consequences include, among other things: • restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls; • the issuance of safety alerts, Dear Healthcare Provider letters, press releases or other communications containing warnings or other safety information about the product; • fines, warning letters or holds on post-approval clinical trials; • refusal of the FDA to approve applications or supplements to approved applications, or suspension or revocation of product approvals; • product seizure or detention, or refusal to permit the import or export of products; • injunctions or the imposition of civil or criminal penalties; • consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs; and • mandated modification of promotional materials and labeling and issuance of corrective information. 35 U.S.
Other potential consequences include, among other things: • restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls; • the issuance of safety alerts, Dear Healthcare Provider letters, press releases or other communications containing warnings or other safety information about the product; • fines, warning letters or holds on post-approval clinical trials; • refusal of the FDA to approve applications or supplements to approved applications, or suspension or revocation of product approvals; • product seizure or detention, or refusal to permit the import or export of products; • injunctions or the imposition of civil or criminal penalties; • consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs; and • mandated modification of promotional materials and labeling and issuance of corrective information.
While we believe that our differentiated technology, scientific expertise, and intellectual property position provide us with competitive advantages, we face potential competition from a variety of companies in these fields. There are several companies using synthetic oligonucleotide or base editing technology, including Beam Therapeutics, Verve Therapeutics, Prime Medicine, AIRNA, ProQR, and Wave Life Sciences.
While we believe that our differentiated technology, scientific expertise, and intellectual property position provide us with competitive advantages, we face potential competition from a variety of companies in these fields. There are several companies using synthetic oligonucleotide or base editing technology, including AIRNA, Beam Therapeutics, Prime Medicine, ProQR, Tessera Therapeutics, Verve Therapeutics, Wave Life Sciences, and YolTech Therapeutics.
OPERA relies on the following key components that enable us to generate the proprietary RNA editing oligonucleotides that form the basis of our differentiated product candidates: • Expertise in ADAR biology , supported by extensive preclinical research using in vitro assays and proprietary mouse models as well as the fundamental work of our scientific advisors and founders to elucidate key insights and know-how of ADAR biology.
OPERA relies on the following key components that enable us to generate the proprietary RNA editing oligonucleotides that form the basis of our differentiated development candidates: • Expertise in ADAR biology , supported by extensive preclinical research using in vitro assays and proprietary mouse models as well as the fundamental work of our scientific advisors and founders to elucidate key insights and know-how of ADAR biology.
The process generally involves the following: • completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice, or GLP, requirements and applicable requirements for the humane use of laboratory animals or other applicable regulations; • completion of the manufacture, under current good manufacturing practice, or cGMP, conditions, of the drug substance and drug product that the sponsor intends to use in human clinical trials along with required analytical and stability testing; • submission to the FDA of an IND which must become effective before clinical trials may begin; • payment of user fees for FDA review of the NDA; • approval by an institutional review board, or IRB, or independent ethics committee at each clinical trial site before each trial may be initiated; • performance of adequate and well-controlled clinical trials in accordance with applicable IND regulations, good clinical practice, or GCP, requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational product for each proposed indication; • preparation and submission to the FDA of an NDA; • a determination by the FDA within 60 days of its receipt of an NDA to file the application for review; • satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the drug will be produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the drug product’s identity, strength, quality and purity; • satisfactory completion of potential FDA audit of the preclinical study clinical trial sites that generated the data in support of the NDA; and • FDA review and approval of the NDA, including, where applicable, consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug in the United States. 30 Preclinical Studies and Clinical Trials for Drugs Before testing any drug in humans, the product candidate must undergo rigorous preclinical testing.
The process generally involves the following: • completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with GLP requirements and applicable requirements for the humane use of laboratory animals or other applicable regulations; • completion of the manufacture, under current good manufacturing practice, or cGMP, conditions, of the drug substance and drug product that the sponsor intends to use in human clinical trials along with required analytical and stability testing; • submission to the FDA of an IND which must become effective before clinical trials may begin; • payment of user fees for FDA review of the NDA; • approval by an institutional review board, or IRB, or independent ethics committee at each clinical trial site before each trial may be initiated; • performance of adequate and well-controlled clinical trials in accordance with applicable IND regulations, good clinical practice, or GCP, requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational product for each proposed indication; • preparation and submission to the FDA of an NDA; • a determination by the FDA within 60 days of its receipt of an NDA to file the application for review; • satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the drug will be produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the drug product’s identity, strength, quality and purity; • satisfactory completion of potential FDA audit of the preclinical study clinical trial sites that generated the data in support of the NDA; and • FDA review and approval of the NDA, including, where applicable, consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug in the United States.
There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our product candidates. Historically, products launched in the European Union do not follow U.S. price structures and generally prices tend to be significantly lower.
There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our development candidates. Historically, products launched in the European Union do not follow U.S. price structures and generally prices tend to be significantly lower.
Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future that are approved to treat the same diseases for which we may obtain approval for our product candidates. This may include other types of therapies, such as small molecule, antibody, and/or protein therapies.
Any development candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future that are approved to treat the same diseases for which we may obtain approval for our development candidates. This may include other types of therapies, such as small molecule, antibody, and/or protein therapies.
Mammals and other lower species like cephalopods have an endogenous process of modifying single bases on RNA, referred to as RNA editing. RNA editing is a natural physiological process, similar to RNA interference, or RNAi, that occurs in cells, including a mechanism mediated by an enzyme called Adenosine Deaminase Acting on RNA, or ADAR.
Mammals and other lower species like cephalopods have an endogenous process of modifying single nucleosides on RNA, referred to as RNA editing. RNA editing is a natural physiological process, similar to RNA interference, or RNAi, that occurs in cells, including a mechanism mediated by an enzyme called Adenosine Deaminase Acting on RNA, or ADAR.
If an orphan designated product receives 33 marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity.
If an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity.
Guidance for the development of oligonucleotide therapeutics by global agencies, including the FDA, provides for an established pathway for the approval of this class of therapeutics. However, regulators have not yet established any definitive guidelines related to overall development considerations for RNA editing therapies and on clinical data has been generated to date.
Guidance for the development of oligonucleotide therapeutics by global agencies, including the FDA, provides for an established pathway for the approval of this class of therapeutics. However, regulators have not yet established any definitive guidelines related to overall development considerations for RNA editing therapies and limited clinical data has been generated to date.
We, along with our vendors, contract research organizations, or CROs, clinical investigators and CMOs will be required to navigate the various preclinical, clinical, manufacturing and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval of our product candidates.
We, along with our vendors, contract research organizations, or CROs, clinical investigators and CMOs will be required to navigate the various preclinical, clinical, manufacturing and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval of our development candidates.
This enables an understanding of ADAR activity translation among different species and disease states, allowing us to develop novel product candidates. • Expertise in oligonucleotide chemistry , enabled by the ability to identify and incorporate chemical modifications to generate a fully modified synthetic oligonucleotide.
This enables an understanding of ADAR activity translation among different species and disease states, allowing us to develop novel lead candidates. • Expertise in oligonucleotide chemistry , enabled by the ability to identify and incorporate chemical modifications to generate a fully modified synthetic oligonucleotide.
OPERA relies on the following key components that enable us to generate our differentiated RNA editing product candidates: • Expertise in ADAR biology: Our insights and know-how of ADAR biology allow us to design oligonucleotides that efficiently recruit ADARs and promote deamination while maintaining selectivity and stability.
OPERA relies on the following key components that enable us to generate our differentiated RNA editing oligonucleotides: • Expertise in ADAR biology: Our insights and know-how of ADAR biology allow us to design oligonucleotides that efficiently recruit ADARs and promote deamination while maintaining selectivity and stability.
Part I is assessed by a coordinated review by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted, 38 or Member States concerned of a draft report prepared by a Reference Member State. Part II is assessed separately by each Member State concerned.
Part I is assessed by a coordinated review by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted, or Member States concerned of a draft report prepared by a Reference Member State. Part II is assessed separately by each 41 Member State concerned.
Manufacturing processes for oligonucleotide-based therapies are well established, cost efficient and scalable to effectively address highly prevalent indications. • Regulatory : Precedence of marketed oligonucleotide drugs with similar size and types of chemical modifications that therapeutic RNA editing product candidates exhibit.
Manufacturing processes for oligonucleotide-based therapies are well established, cost efficient and scalable to effectively address highly prevalent indications. • Regulatory : Precedence of marketed oligonucleotide drugs with similar size and types of chemical modifications that therapeutic RNA editing lead candidates exhibit.
Additionally, the activities associated with the commercialization of product candidates are subject to regulation by numerous regulatory authorities in the United States in addition to the FDA, which may include the Centers for Medicare and Medicaid Services, or CMS, other divisions of the U.S.
Additionally, the activities associated with the commercialization of development candidates are subject to regulation by numerous regulatory authorities in the United States in addition to the FDA, which may include the Centers for Medicare and Medicaid Services, or CMS, other divisions of the U.S.
Median Levels of AAT and link to outcomes in liver and lung In Figure 13 below, the Odds Ratios, or OR, associated with developing COPD and cirrhosis of the liver are compared across the two genotypes, with key findings summarized below: • COPD: PiMZ individuals have minimal increased risk of developing COPD relative to healthy PiMM individuals, while PiZZ individuals are at very high risk with an OR of 8.8 • Cirrhosis of the liver: PiMZ individuals have mildly elevated risk of developing cirrhosis of the liver with an OR of 1.5, while PiZZ individuals have significantly elevated risk with an OR of 7.8 17 Figure 13.
Median Levels of AAT and link to outcomes in liver and lung In Figure 16 below, the Odds Ratios, or OR, associated with developing COPD and cirrhosis of the liver are compared across the two genotypes, with key findings summarized below: • COPD: PiMZ individuals have minimal increased risk of developing COPD relative to healthy PiMM individuals, while PiZZ individuals are at very high risk with an OR of 8.8 • Cirrhosis of the liver: PiMZ individuals have mildly elevated risk of developing cirrhosis of the liver with an OR of 1.5, while PiZZ individuals have significantly elevated risk with an OR of 7.8 Figure 16.
Item 1. B usiness. Overview We are a clinical-stage biopharmaceutical company with a mission to discover, develop and commercialize a new class of genetic medicines based on editing RNA, enabling the treatment of both rare and highly prevalent diseases.
Item 1. B usiness. Overview We are a biopharmaceutical company with a mission to discover, develop and commercialize a new class of genetic medicines based on editing RNA, enabling the treatment of both rare and highly prevalent diseases.
A Complete Response Letter indicates that the review cycle of the application is complete and the application is not ready for approval.
A Complete Response Letter indicates that the review cycle of the application is complete and 35 the application is not ready for approval.
Our ability to successfully commercialize our product candidates will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.
Our ability to successfully commercialize our development candidates will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.
Figure 10. PiMM genotype (normal liver and lung) Impact of Z mutations on liver and lung function The presence of a single Z allele can lead to insufficient production of normal AAT, as well as the production of dysfunctional AAT, causing manifestations of disease in both the lungs and liver.
Figure 13. PiMM genotype (normal liver and lung) Impact of Z mutations on liver and lung function The presence of a single Z allele can lead to insufficient production of normal AAT, as well as the production of dysfunctional AAT, causing manifestations of disease in both the lungs and liver.
For additional information relating to the financial terms of such agreement, see Note 13 to our audited consolidated financial statements included elsewhere in this Annual Report on Form 10-K. Competition The pharmaceutical and biotechnology industries, including the gene therapy and gene editing fields, are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on intellectual property.
For additional information relating to the financial terms of such agreement, see Note 12 to our audited consolidated financial statements included elsewhere in this Annual Report on Form 10-K. 28 Competition The pharmaceutical and biotechnology industries, including the gene therapy and gene editing fields, are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on intellectual property.
Our product candidates must be approved for therapeutic indications by the FDA before they may be marketed in the United States. For drug product candidates regulated under the FD&C Act, FDA must approve a New Drug Application, or an NDA.
Our development candidates must be approved for therapeutic indications by the FDA before they may be marketed in the United States. For drug development candidates regulated under the FD&C Act, FDA must approve a New Drug Application, or an NDA.
Given the importance of TDP-43’s role in maintaining healthy neurons, the generation of a protein variant with the desired non-aggregating property could potentially have therapeutic benefit for the majority of ALS and FTD patients.
Given the importance of the role of TDP-43 in maintaining healthy neurons, the generation of a protein variant with the desired non-aggregating property could potentially have therapeutic benefit for the majority of ALS and FTD patients.
For our initial wave of clinical programs, we intend to use qualified third-party CMOs with relevant manufacturing experience in genetic medicines. we plan to partner with suppliers and CMOs to produce or process critical raw materials, bulk compounds, formulated compounds, viral vectors or engineered cells for IND-supporting activities and early-stage clinical trials.
For our initial wave of clinical programs, we intend to use qualified third-party CMOs with relevant manufacturing experience in genetic medicines. We plan to partner with suppliers and CMOs to produce or process critical raw materials, bulk compounds, formulated compounds, viral vectors or engineered cells for investigational new drug, or IND, -supporting activities and early-stage clinical trials.
In the future, if and when our product candidates receive FDA approval, we expect to apply, if appropriate, for patent term extension on patents directed to those product candidates, their methods of use and/or methods of manufacture.
In the future, if and when our development candidates receive FDA approval, we expect to apply, if appropriate, for patent term extension on patents directed to those development candidates, their methods of use and/or methods of manufacture.
These normal proteins can be uniquely expressed at desired levels and duration to address both rare and highly prevalent diseases caused by a pathogenic SNV. This approach is especially relevant when the same underlying genetic SNV manifests in a broad disease phenotype from mild to severe forms of the disease. Figure 7.
These normal proteins can be uniquely expressed at desired levels and duration to address both rare and 12 highly prevalent diseases caused by a pathogenic SNV. This approach is especially relevant when the same underlying genetic SNV manifests in a broad disease phenotype from mild to severe forms of the disease.
Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life. U.S.
Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the development candidate does not undergo unacceptable deterioration over its shelf life. U.S.
Scientific advice and protocol assistance at the EMA are free of charge for questions relating to the development of pediatric medicines. 39 In March 2016, the EMA launched an initiative, the Priority Medicines scheme, or the PRIME scheme, to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist.
Scientific advice and protocol assistance at the EMA are free of charge for questions relating to the development of pediatric medicines. 42 In March 2016, the EMA launched an initiative, the Priority Medicines scheme, or the PRIME scheme, to facilitate development of development candidates in indications, often rare, for which few or no therapies currently exist.
To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost effectiveness of a particular product candidate to currently available therapies.
To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost effectiveness of a particular development candidate to currently available therapies.
Our RNA editing product candidates are oligonucleotides capable of forming Watson-Crick base pairing with the target RNA and efficiently inducing the deamination reaction by endogenously recruiting ADAR enzymes. We have assembled a suite of technologies and capabilities to build our RNA editing platform, Oligonucleotide Promoted Editing of RNA, or OPERA.
Our oligonucleotides capable of forming Watson-Crick base pairing with the target RNA and efficiently inducing the deamination reaction by endogenously recruiting ADAR enzymes. We have assembled a suite of technologies and capabilities to build our RNA editing platform, Oligonucleotide Promoted Editing of RNA, or OPERA.
Our RNA editing product candidates show no evidence of interference with endogenous ADAR editing as demonstrated at the above endogenous sites • Expertise in oligonucleotide chemistry: We have a differentiated ability to create oligonucleotide designs capable of efficiently recruiting endogenous ADAR with chemical modifications that direct high specificity editing.
Our RNA editing oligonucleotides show no evidence of interference with endogenous ADAR editing as demonstrated at the above endogenous sites • Expertise in oligonucleotide chemistry: We have a differentiated ability to create oligonucleotide designs capable of efficiently recruiting endogenous ADAR with chemical modifications that direct high specificity editing.
We have demonstrated the utility of our machine learning models through an increase in overall editing efficiency of new product candidates. In some cases, we have been able to go from design-to-data in as little as five weeks. However, there is no guarantee that this will result in an accelerated development or approval timeline, if at all. Figure 4.
We have demonstrated the utility of our machine learning models through an increase in overall editing efficiency of new RNA editing oligonucleotides. In some cases, we have been able to go from design-to-data in as little as five weeks. However, there is no guarantee that this will result in an accelerated development or approval timeline, if at all. Figure 4.
For more information regarding the risks related to our intellectual property, see Item 1A “ Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property .” Patent Portfolio We strive to protect our proprietary RNA editing platform OPERA and related technologies and our product candidates, including seeking and maintaining patent protection intended to cover various target-specific editing strategies, the composition of matter of our product candidates, their methods of use, related delivery technologies, and other inventions.
For more information regarding the risks related to our intellectual property, see Item 1A “ Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property .” Patent Portfolio We strive to protect our proprietary RNA editing platform, OPERA, and related technologies, and our lead candidates and development candidates, including seeking and maintaining patent protection intended to cover various target-specific editing strategies, the composition of matter of our lead candidate and development candidates, their methods of use, related delivery technologies, and other inventions.
These laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used. 43 Other U.S.
These laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any development candidates for which we may obtain regulatory approval or the frequency with which any such development candidate is prescribed or used. Other U.S.
Our oligonucleotides increase the potency and durability of ADAR activation, thereby increasing the editing efficiency and translational efficacy of our product candidates. We have identified critical structural, sequence, and chemistry requirements for our product candidates that drive efficient recruitment of ADARs and subsequent A-to-I editing.
Our oligonucleotides increase the potency and durability of ADAR activation, thereby increasing the editing efficiency and translational efficacy of our RNA editing oligonucleotides. We have identified critical structural, sequence, and chemistry requirements for our RNA editing oligonucleotides that drive efficient recruitment of ADARs and subsequent A-to-I editing.
Orphan product exclusivity could block the approval of one of our products for seven years if a competitor obtains approval for the same therapeutic agent for the same indication before we do, unless we are able to demonstrate that our product is clinically superior.
Orphan product exclusivity could block the approval of one of our products for seven years if a competitor obtains approval for the same therapeutic agent for the same approved use or indication before we do, unless we are able to demonstrate that our product is clinically superior.
We are leveraging significant advances in the understanding of the correlation between DNA, RNA and disease phenotypes to develop novel therapeutic approaches across a range of validated biological targets. This novel class of RNA editing therapeutics combines the precision of genomic therapies with the properties associated with traditional approved drugs, such as titratability and ability to re-dose.
We are leveraging significant advances in the understanding of the relationship between DNA, RNA and disease phenotypes to develop novel therapeutic approaches across a range of validated biological targets. Our novel class of RNA editing therapeutics combines the precision of genomic therapies with the properties associated with traditional approved drugs, such as titratability and ability to re-dose.
The SEC maintains an Internet site, http://www.sec.gov, containing reports, proxy and information statements, and other information regarding issuers that file electronically with the SEC. 44
The SEC maintains an Internet site, http://www.sec.gov, containing reports, proxy and information statements, and other information regarding issuers that file electronically with the SEC. 47
RNA editing mediated by adenosine deaminase acting on RNA, or “ADAR-mediated” RNA editing, has recently emerged as a differentiated approach that can generate product candidates having features that combine the precision of genomic therapies with the properties commonly associated with current approved drugs such as titratability and ability to re-dose.
RNA editing mediated by adenosine deaminase acting on RNA, or “ADAR-mediated” RNA editing, has emerged as a differentiated approach that can generate oligonucleotide having features that combine the precision of genomic therapies with the properties commonly associated with current approved drugs such as titratability and ability to re-dose.
The majority of ALS patients die from respiratory failure within three to five years after symptom appearance, with a small percentage of patients surviving beyond 10 years. Despite being classified as a rare disease by the FDA and the EMA, ALS is considered one of the more common neurodegenerative diseases worldwide.
The majority of ALS patients die from respiratory failure within three to five years after symptom appearance, with a small percentage of patients surviving beyond 10 years. Despite being classified as a rare disease by the FDA and the European Medicines Agency, or EMA, ALS is considered one of the more common neurodegenerative diseases worldwide.
Patent Term Restoration and Marketing Exclusivity Depending upon the timing, duration and specifics of FDA approval of our future product candidates, some of our United States patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments.
U.S. Patent Term Restoration and Marketing Exclusivity Depending upon the timing, duration and specifics of FDA approval of our future development candidates, some of our United States patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments.
In contrast to treatments targeting liver hepatocytes where there is a need for a delivery system, our RNA editing product candidates have been delivered intrathecally to the central nervous system without a need for any delivery system in preclinical mouse models.
In contrast to treatments targeting liver hepatocytes where there is a need for a delivery system, our RNA editing oligonucleotides have been delivered intrathecally to the central nervous system without a need for any delivery system in preclinical mouse models.
Our RNA editing approach involves co-opting this endogenous editing system via a proprietary engineered oligonucleotide to introduce precise edits to RNA. We iteratively optimize the editing efficiency of our product candidates using a combination of ADAR biology, chemistry and machine learning expertise. Using this approach, we can edit the transcriptome with high efficiency and specificity.
Our RNA editing approach involves co-opting this endogenous editing system via proprietary engineered oligonucleotides to introduce precise edits to RNA. We iteratively optimize the editing efficiency of our oligonucleotides using a combination of ADAR biology, chemistry and machine learning expertise. Using this approach, we can edit the transcriptome with high efficiency and specificity.
In particular, in 2010, the ACA was enacted, which, among other things, addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected; increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program; extended the Medicaid Drug Rebate program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations; subjected manufacturers to new annual fees and taxes for certain branded prescription drugs; created a Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D; and provided incentives to programs that increase the federal government’s comparative effectiveness research.
In particular, in 2010, the ACA was enacted, which, among other things, addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected; increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program; extended the Medicaid Drug Rebate program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations; subjected manufacturers to new annual fees and taxes for certain branded prescription drugs; created a Medicare Part D coverage gap discount program, in which manufacturers were required to agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D (later replaced under the Inflation Reduction Act with the Manufacturer Discount Program); and provided incentives to programs that increase the federal government’s comparative effectiveness research.
We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or at all, whether the claims of any patent applications, should they issue, will cover our product candidates, or whether the claims of any issued patents will provide sufficient protection from competitors or otherwise provide any competitive advantage.
We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or at all, whether the claims of any patent applications, should they issue, will cover our lead candidates and development candidates, or whether the claims of any issued patents will provide sufficient protection from competitors or otherwise provide any competitive advantage.
Further, the Budget Control Act of 2011 and subsequent legislation, among other things, created measures for spending reductions by Congress that include aggregate reductions of Medicare payments to providers of 2% per fiscal year, which remain in effect through 2031.
Further, the Budget Control Act of 2011 and subsequent legislation, among other things, created measures for spending reductions by Congress that include aggregate reductions of Medicare payments to providers of 2% per fiscal year, which remain in effect through fiscal year 2032. The U.S.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeFor more information on these laws, see Item 1 “ Business—Governmental Regulation—Other Healthcare Laws .” 66 If our operations are found to be in violation of any such requirements, we may be subject to penalties, including civil or criminal penalties, criminal prosecution, monetary damages, the curtailment or restructuring of our operations, loss of eligibility to obtain approvals from the FDA, exclusion from participation in federal healthcare programs including Medicare and Medicaid, the imposition of a corporate integrity agreement with the Office of Inspector General of the Department of Health and Human Services, disgorgement, individual imprisonment, contractual damages, reputational harm, and diminished profits and future earnings, any of which could adversely affect our financial results and adversely affect our ability to operate our business.
Biggest changeIf our operations are found to be in violation of applicable requirements, we may be subject to penalties and other sanctions, which may include civil or criminal penalties, criminal prosecution, monetary damages, disgorgement, contractual damages, reputational harm, curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs (including Medicare and Medicaid), the imposition of a corporate integrity agreement, suspension or withdrawal of product approvals, restrictions or prohibitions on marketing, and other enforcement actions.
Our ability to generate revenue from product sales and achieve profitability depends on our ability, alone or with collaborative partners, to successfully complete the development of, and obtain the regulatory approvals necessary to commercialize, product candidates we may identify for development. We do not anticipate generating revenues from product sales for many years, if ever.
Our ability to generate revenue from product sales and achieve profitability depends on our ability, alone or with collaborative partners, to successfully complete the development of, and obtain the regulatory approvals necessary to commercialize, candidates we may identify for development. We do not anticipate generating revenues from product sales for many years, if ever.
Our ability to generate product revenue, which we do not expect will occur for many years, if ever, will depend heavily on the successful development and eventual commercialization of any product candidates we may discover, which may never occur.
Our ability to generate product revenue, which we do not expect will occur for many years, if ever, will depend heavily on the successful development and eventual commercialization of any development candidates we may discover, which may never occur.
Our ability to generate product revenues, which we do not expect will occur for many years, if ever, will depend heavily on the successful development, marketing approval and eventual commercialization of our product candidates, which may never occur.
Our ability to generate product revenues, which we do not expect will occur for many years, if ever, will depend heavily on the successful development, marketing approval and eventual commercialization of our development candidates, which may never occur.
If we do not successfully conduct clinical development, we will not be able to market and sell products derived from our product candidates or generate product revenues.
If we do not successfully conduct clinical development, we will not be able to market and sell products derived from our development candidates or generate product revenues.
Any product candidates we may develop will be based on a novel technology that makes it difficult to predict the time and cost of development and of subsequently obtaining regulatory approval. No RNA editing therapeutic product has been approved in the United States or in Europe.
Any development candidates we may develop will be based on a novel technology that makes it difficult to predict the time and cost of development and of subsequently obtaining regulatory approval. No RNA editing therapeutic product has been approved in the United States or in Europe.
Our ability to generate future revenues from product sales depends heavily on our, or our collaborators’, ability to successfully: • identify product candidates and successfully complete research and development of such product candidates; • seek and obtain regulatory and marketing approvals for any product candidates for which we complete clinical trials; • launch and commercialize any product candidates for which we may obtain regulatory and marketing approval by establishing a sales force, marketing and distribution infrastructure, or alternatively, collaborating with a commercialization partner; • qualify for adequate coverage and reimbursement by government and third-party payors for any product candidates for which we may obtain regulatory and marketing approval; • establish and maintain supply and manufacturing relationships with third parties that can provide adequate, in both amount and quality, products and services to support clinical development and the market demand for any product candidates for which we obtain regulatory and marketing approval; • develop, maintain and enhance a sustainable, scalable, reproducible and transferable manufacturing process for the product candidates we may develop; • address competing technological and market developments; • negotiate favorable terms in any existing or future collaboration, licensing or other arrangements and perform our obligations in such collaborations; • receive market acceptance by physicians, patients, healthcare payors, and others in the medical community; • maintain, protect, enforce, defend and expand our portfolio of intellectual property and other proprietary rights, including patents, trade secrets and know-how; • defend against third party intellectual property claims of infringement, misappropriation or other violation; and • attract top talent and retain qualified personnel.
Our ability to generate future revenues from product sales depends heavily on our, or our collaborators’, ability to successfully: • identify lead candidates and successfully complete research and development of such lead candidates; • seek and obtain regulatory and marketing approvals for any development candidates for which we complete clinical trials; • launch and commercialize any development candidates for which we may obtain regulatory and marketing approval by establishing a sales force, marketing and distribution infrastructure, or alternatively, collaborating with a commercialization partner; • qualify for adequate coverage and reimbursement by government and third-party payors for any development candidates for which we may obtain regulatory and marketing approval; • establish and maintain supply and manufacturing relationships with third parties that can provide adequate, in both amount and quality, products and services to support clinical development and the market demand for any development candidates for which we obtain regulatory and marketing approval; • develop, maintain and enhance a sustainable, scalable, reproducible and transferable manufacturing process for the development candidates we may develop; • address competing technological and market developments; • negotiate favorable terms in any existing or future collaboration, licensing or other arrangements and perform our obligations in such collaborations; • receive market acceptance by physicians, patients, healthcare payors, and others in the medical community; • maintain, protect, enforce, defend and expand our portfolio of intellectual property and other proprietary rights, including patents, trade secrets and know-how; • defend against third party intellectual property claims of infringement, misappropriation or other violation; and • attract top talent and retain qualified personnel.
For example: • any product candidates we may develop will eventually become commercially available in generic or biosimilar product forms; • others may be able to make gene therapy products that are similar to any product candidates we may develop or utilize similar base editing technology but that are not covered by the claims of the patents that we may own in the future; • We, or our future license partners or collaborators, might not have been the first to make the inventions covered by the issued patent or pending patent application that we license or may own in the future; • We, or our future license partners or collaborators, might not have been the first to file patent applications covering certain of our or their inventions; • We, or our future license partners or collaborators, may fail to meet our obligations to the U.S. government regarding any in-licensed patents and patent applications funded by U.S. government grants, leading to the loss or unenforceability of patent rights; 85 • others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our owned or licensed intellectual property rights; • it is possible that our pending patent applications or those that we may own in the future will not lead to issued patents; • it is possible that there are prior public disclosures that could invalidate our patents, or parts of our owned or in-licensed patents; • it is possible that there are unpublished applications or patent applications maintained in secrecy that may later issue with claims covering our product candidates or technology similar to ours; • it is possible that our patents or patent applications omit individual(s) that should be listed as inventor(s) or include individual(s) that should not be listed as inventor(s), which may cause these patents or patents issuing from these patent applications to be held invalid or unenforceable; • issued patents that we hold rights to may be held invalid, unenforceable, or narrowed in scope, including as a result of legal challenges by our competitors; • the claims of our issued patents or patent applications, if and when issued, may not cover our product candidates; • the laws of foreign countries may not protect our proprietary rights or the proprietary rights of our future license partners or collaborators to the same extent as the laws of the United States; • the inventors of our patents or patent applications may become involved with competitors, develop products or processes that design around our patents, or become hostile to us or the patents or patent applications on which they are named as inventors; • our competitors may conduct research and development activities in countries where we do not have patent rights or enforceable patent rights and then use the information learned from such activities to develop competitive products for sale in our major commercial markets; • we have been engaged in scientific collaborations and will continue to do so in the future and our collaborators may develop adjacent or competing products that are outside the scope of our patents; • we may not develop additional proprietary technologies that are patentable; • any product candidates we develops may be covered by third parties’ patents or other exclusive rights; • a third party may challenge, invalidate, circumvent or weaken our patents, and as a result, a court could hold that our patents are not valid, enforceable and infringed; • the patents of others may harm our business; or • 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 intellectual property.
For example: • any development candidates we may develop will eventually become commercially available in generic or biosimilar product forms; • others may be able to make gene therapy products that are similar to any development candidates we may develop or utilize similar base editing technology but that are not covered by the claims of the patents that we may own in the future; • we, or our future license partners or collaborators, might not have been the first to make the inventions covered by the issued patent or pending patent application that we license or may own in the future; • we, or our future license partners or collaborators, might not have been the first to file patent applications covering certain of our or their inventions; • we, or our future license partners or collaborators, may fail to meet our obligations to the U.S. government regarding any in-licensed patents and patent applications funded by U.S. government grants, leading to the loss or unenforceability of patent rights; • others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our owned or licensed intellectual property rights; • it is possible that our pending patent applications or those that we may own in the future will not lead to issued patents; 89 • it is possible that there are prior public disclosures that could invalidate our patents, or parts of our owned or in-licensed patents; • it is possible that there are unpublished applications or patent applications maintained in secrecy that may later issue with claims covering our development candidates or technology similar to ours; • it is possible that our patents or patent applications omit individual(s) that should be listed as inventor(s) or include individual(s) that should not be listed as inventor(s), which may cause these patents or patents issuing from these patent applications to be held invalid or unenforceable; • issued patents that we hold rights to may be held invalid, unenforceable, or narrowed in scope, including as a result of legal challenges by our competitors; • the claims of our issued patents or patent applications, if and when issued, may not cover our development candidates; • the laws of foreign countries may not protect our proprietary rights or the proprietary rights of our future license partners or collaborators to the same extent as the laws of the United States; • the inventors of our patents or patent applications may become involved with competitors, develop products or processes that design around our patents, or become hostile to us or the patents or patent applications on which they are named as inventors; • our competitors may conduct research and development activities in countries where we do not have patent rights or enforceable patent rights and then use the information learned from such activities to develop competitive products for sale in our major commercial markets; • we have been engaged in scientific collaborations and will continue to do so in the future and our collaborators may develop adjacent or competing products that are outside the scope of our patents; • we may not develop additional proprietary technologies that are patentable; • any development candidates we develops may be covered by third parties’ patents or other exclusive rights; • a third party may challenge, invalidate, circumvent or weaken our patents, and as a result, a court could hold that our patents are not valid, enforceable and infringed; • the patents of others may harm our business; or • 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 intellectual property.
Some of the factors that may cause the market price of our common stock to fluctuate include: • results of clinical trials and preclinical studies of our product candidates, or those of our competitors or our existing or future collaborators; • failure to meet or exceed financial and development projections we may provide to the public; • failure to meet or exceed the financial and development projections of the investment community; • announcements of significant acquisitions, strategic collaborations, joint ventures or capital commitments by us or our competitors; • actions taken by regulatory agencies with respect to our product candidates, clinical studies, manufacturing process or sales and marketing terms; • disputes or other developments relating to proprietary rights, including patents, litigation matters, and our ability to obtain patent protection for our technologies; • additions or departures of key personnel; • significant lawsuits, including patent or stockholder litigation; • if securities or industry analysts do not publish research or reports about our business, or if they issue adverse or misleading opinions regarding our business and stock; • changes in the market valuations of similar companies; • general market or macroeconomic conditions or market conditions in the pharmaceutical and biotechnology sectors; • sales of securities by us or our securityholders in the future; • if we fail to raise an adequate amount of capital to fund our operations or continued development of our product candidates; • trading volume of our common stock; • announcements by competitors of new commercial products, clinical progress or lack thereof, significant contracts, commercial relationships or capital commitments; • adverse publicity relating to precision medicine product candidates, including with respect to other products in such markets; • the introduction of technological innovations or new therapies that compete with our products and services; and • period-to-period fluctuations in our financial results.
Some of the factors that may cause the market price of our common stock to fluctuate include: • results of clinical trials and preclinical studies of our lead candidates and development candidates, or those of our competitors or our existing or future collaborators; • failure to meet or exceed financial and development projections we may provide to the public; • failure to meet or exceed the financial and development projections of the investment community; • announcements of significant acquisitions, strategic collaborations, joint ventures or capital commitments by us or our competitors; • actions taken by regulatory agencies with respect to our development candidates, clinical studies, manufacturing process or sales and marketing terms; • disputes or other developments relating to proprietary rights, including patents, litigation matters, and our ability to obtain patent protection for our technologies; • additions or departures of key personnel; • significant lawsuits, including patent or stockholder litigation; • if securities or industry analysts do not publish research or reports about our business, or if they issue adverse or misleading opinions regarding our business and stock; • changes in the market valuations of similar companies; • general market or macroeconomic conditions or market conditions in the pharmaceutical and biotechnology sectors; • sales of securities by us or our securityholders in the future; • if we fail to raise an adequate amount of capital to fund our operations or continued development of our development candidates; • trading volume of our common stock; • announcements by competitors of new commercial products, clinical progress or lack thereof, significant contracts, commercial relationships or capital commitments; • adverse publicity relating to precision medicine development candidates, including with respect to other products in such markets; • the introduction of technological innovations or new therapies that compete with our products and services; and • period-to-period fluctuations in our financial results.
If a third party claims that we infringe, misappropriate or otherwise violate our intellectual property rights, we may face a number of issues, including, but not limited to: • infringement and other intellectual property claims that, regardless of merit, may be expensive and time-consuming to litigate and may divert our management’s attention from our core business; • substantial damages for infringement, which we may have to pay if a court decides that the product candidate or technology at issue infringes on or violates the third party’s rights, and, if the court finds that the infringement was willful, we could be ordered to pay treble damages plus the patent owner’s attorneys’ fees; • a court prohibiting us from developing, manufacturing, marketing or selling our product candidates, or from using our proprietary technologies, unless the third party licenses its product rights to us, which it is not required to do, on commercially reasonable terms or at all; • if a license is available from a third party, we may have to pay substantial royalties, upfront fees and other amounts, and/or grant cross-licenses to intellectual property rights for our product candidates; • the requirement that we redesign our product candidates or processes so they do not infringe, which may not be possible or may require substantial monetary expenditures and time; and • there could be public announcements of the results of hearings, motions, or other interim proceedings or developments, and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.
If a third party claims that we infringe, misappropriate or otherwise violate our intellectual property rights, we may face a number of issues, including, but not limited to: • infringement and other intellectual property claims that, regardless of merit, may be expensive and time-consuming to litigate and may divert our management’s attention from our core business; • substantial damages for infringement, which we may have to pay if a court decides that the development candidates or technology at issue infringes on or violates the third party’s rights, and, if the court finds that the infringement was willful, we could be ordered to pay treble damages plus the patent owner’s attorneys’ fees; • a court prohibiting us from developing, manufacturing, marketing or selling our development candidates, or from using our proprietary technologies, unless the third party licenses its product rights to us, which it is not required to do, on commercially reasonable terms or at all; • if a license is available from a third party, we may have to pay substantial royalties, upfront fees and other amounts, and/or grant cross-licenses to intellectual property rights for our development candidates; • the requirement that we redesign our development candidates or processes so they do not infringe, which may not be possible or may require substantial monetary expenditures and time; and • there could be public announcements of the results of hearings, motions, or other interim proceedings or developments, and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.
Many of our competitors have: • much greater financial, technical and human resources than we have at every stage of the discovery, development, manufacture and commercialization of products; • more extensive experience in designing and conducting preclinical studies and clinical trials, obtaining regulatory approvals, and manufacturing, marketing and selling pharmaceutical products; • product candidates that are based on previously tested or accepted technologies; • products that have been approved or are in late stages of development; and • collaborative arrangements in our target markets with leading companies and research institutions.
Many of our competitors have: • much greater financial, technical and human resources than we have at every stage of the discovery, development, manufacture and commercialization of products; • more extensive experience in designing and conducting preclinical studies and clinical trials, obtaining regulatory approvals, and manufacturing, marketing and selling pharmaceutical products; • development candidates that are based on previously tested or accepted technologies; • products that have been approved or are in late stages of development; and • collaborative arrangements in our target markets with leading companies and research institutions.
Our competitors may develop or commercialize products with significant advantages over any products we are able to develop and commercialize based on many different factors, including: • the safety and effectiveness of our products relative to alternative products, if any; • the ease with which our products can be administered and the extent to which patients accept relatively new routes of administration; • the timing and scope of regulatory approvals for these products; • the availability and cost of manufacturing, marketing and sales capabilities; • price; • more extensive coverage and higher levels of reimbursement; and • patent position.
Our competitors may develop or commercialize products with significant advantages over any products we are able to develop and commercialize based on many different factors, including: • the safety and effectiveness of our products relative to alternative products, if any; • the ease with which our products can be administered and the extent to which patients accept relatively new routes of administration; • the timing and scope of regulatory approvals for these products; • the availability and cost of manufacturing, marketing and sales capabilities; • price; 61 • more extensive coverage and higher levels of reimbursement; and • patent position.
As we are initially seeking to identify and develop product candidates to treat diseases in which there is little clinical experience using new technologies, and while we may have opportunities to discuss our clinical development plans with regulatory authorities prior to commencing clinical development, there is heightened risk that the FDA, the EMA, HREC, TGA or other regulatory authorities may not consider the clinical trial endpoints that we propose to provide clinically meaningful results (reflecting a tangible benefit to patients).
As we are initially seeking to identify and develop development candidates to treat diseases in which there is little clinical experience using new technologies, and while we may have opportunities to discuss our clinical development plans with regulatory authorities prior to commencing clinical development, there is heightened risk that the FDA, the EMA, HREC, TGA or other regulatory authorities may not consider the clinical trial endpoints that we propose to provide clinically meaningful results (reflecting a tangible benefit to patients).
Any interruption of the development or operation of the manufacturing of our product candidates, such as order delays for equipment or materials, equipment malfunction, quality control and quality assurance issues, regulatory delays and possible negative effects of such delays on supply chains and expected timelines for product availability, production yield issues, shortages of qualified personnel, discontinuation of a facility or business or failure or damage to a facility resulting from natural disasters, could result in the cancellation of shipments, loss of product in the manufacturing process or a shortfall in available product candidates or materials.
Any interruption of the development or operation of the manufacturing of our development candidates, such as order delays for equipment or materials, equipment malfunction, quality control and quality assurance issues, regulatory delays and possible negative effects of such delays on supply chains and expected timelines for product availability, production yield issues, shortages of qualified personnel, discontinuation of a facility or business or failure or damage to a facility resulting from natural disasters, could result in the cancellation of shipments, loss of product in the manufacturing process or a shortfall in available lead and development candidates or materials.
In addition, the FDA has the authority to require a REMS as a condition of approval, which may impose further requirements or restrictions on the distribution or safe use of an approved drug, such as limiting prescribing rights to certain physicians or medical centers that have undergone specialized training, limiting treatment to patients as specially defined by the indication statement or who meet 62 certain safe-use criteria, and requiring treated patients to enroll in a registry, among other requirements.
In addition, the FDA has the authority to require a REMS as a condition of approval, which may impose further requirements or restrictions on the distribution or safe use of an approved drug, such as limiting prescribing rights to certain physicians or medical centers that have undergone specialized training, limiting treatment to patients as specially defined by the indication statement or who meet certain safe-use criteria, and requiring treated patients to enroll in a registry, among other requirements.
For more information regarding PRIME and the EU regulatory framework, see Item 1 “ Business—Government Regulation—Regulation Outside of the United States .” 59 Risks Related to Regulatory, Legal, and Clinical Trials Because we are developing oligonucleotides, which are considered a relatively new class of drugs, there is increased risk that the outcome of our clinical trials will not be sufficient to obtain regulatory approval.
For more information regarding PRIME and the EU regulatory framework, see Item 1 “ Business—Government Regulation—Regulation Outside of the United States .” Risks Related to Regulatory, Legal, and Clinical Trials Because we are developing oligonucleotides, which are considered a relatively new class of drugs, there is increased risk that the outcome of our clinical trials will not be sufficient to obtain regulatory approval.
Among other things, these provisions: • establish a classified board of directors such that all members of the board are not elected at one time; • allow the authorized number of our directors to be changed only by resolution of our board of directors; 89 • limit the manner in which stockholders can remove directors from the board; • establish advance notice requirements for nominations for election to the board of directors or for proposing matters that can be acted on at stockholder meetings; • require that stockholder actions must be effected at a duly called stockholder meeting and prohibit actions by our stockholders by written consent; • limit who may call a special meeting of stockholders; • authorize our board of directors to issue preferred stock without stockholder approval, which could be used to institute a “poison pill” that would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our board of directors; and • require the approval of the holders of at least 66.67% of the votes that all our stockholders would be entitled to cast to amend or repeal certain provisions of our charter or bylaws.
Among other things, these provisions: • establish a classified board of directors such that all members of the board are not elected at one time; 93 • allow the authorized number of our directors to be changed only by resolution of our board of directors; • limit the manner in which stockholders can remove directors from the board; • establish advance notice requirements for nominations for election to the board of directors or for proposing matters that can be acted on at stockholder meetings; • require that stockholder actions must be effected at a duly called stockholder meeting and prohibit actions by our stockholders by written consent; • limit who may call a special meeting of stockholders; • authorize our board of directors to issue preferred stock without stockholder approval, which could be used to institute a “poison pill” that would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our board of directors; and • require the approval of the holders of at least 66.67% of the votes that all our stockholders would be entitled to cast to amend or repeal certain provisions of our charter or bylaws.
In addition, our approach, which focuses on using oligonucleotides for drug development, as opposed to multiple or other, more advanced proven technologies, and new products and technologies that may enter the market, may expose us to additional financial risks and make it more difficult to raise additional capital if we are not successful in developing one or more product candidates that receive regulatory approval.
In addition, our approach, which focuses on using oligonucleotides for drug development, as opposed to multiple or other, more advanced proven technologies, and new products and technologies that may enter the market, may expose us to additional financial risks and make it more difficult to raise additional capital if we are not successful in developing one or more development candidates that receive regulatory approval.
In order for the FDA to grant orphan drug exclusivity to one of our product candidates, the agency must find that the product candidate is indicated for the treatment of a condition or disease that affects fewer than 200,000 individuals in the United States or that affects more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making the product candidate available for the disease or condition will be recovered from sales of the product in the United States.
In order for the FDA to grant orphan drug exclusivity to one of our development candidates, the agency must find that the development candidates is indicated for the treatment of a condition or disease that affects fewer than 200,000 individuals in the United States or that affects more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making the development candidate available for the disease or condition will be recovered from sales of the product in the United States.
If we are unable to establish effective alliances to enable the sale of our product candidates to healthcare professionals and in geographical regions, including the United States, that will not be covered by our own marketing and sales force, or if our potential future strategic alliance partners do not successfully commercialize the product candidates, our ability to generate revenues from product sales will be adversely affected.
If we are unable to establish effective alliances to enable the sale of our development candidates to healthcare professionals and in geographical regions, including the United States, that will not be covered by our own marketing and sales force, or if our potential future strategic alliance partners do not successfully commercialize the development candidates, our ability to generate revenues from product sales will be adversely affected.
The risks we face in connection with acquisitions, include: • diversion of management time and focus from operating our business to addressing acquisition integration challenges; • program divestitures due to potential exclusivity obligations; • coordination of research and development efforts; • retention of key employees from the acquired company; • changes in relationships with strategic partners as a result of product acquisitions or strategic positioning resulting from the acquisition; 71 • cultural challenges associated with integrating employees from the acquired company into ours; • the need to implement or improve controls, procedures, and policies at a business that prior to the acquisition may have lacked sufficiently effective controls, procedures and policies; • liability for activities of the acquired company before the acquisition, including intellectual property infringement claims, violation of laws, commercial disputes, tax liabilities, and other known liabilities; • unanticipated write-offs or charges; and • litigation or other claims in connection with the acquired company, including claims from terminated employees, customers, former stockholders or other third parties.
The risks we face in connection with acquisitions, include: • diversion of management time and focus from operating our business to addressing acquisition integration challenges; • program divestitures due to potential exclusivity obligations; • coordination of research and development efforts; • retention of key employees from the acquired company; 75 • changes in relationships with strategic partners as a result of product acquisitions or strategic positioning resulting from the acquisition; • cultural challenges associated with integrating employees from the acquired company into ours; • the need to implement or improve controls, procedures, and policies at a business that prior to the acquisition may have lacked sufficiently effective controls, procedures and policies; • liability for activities of the acquired company before the acquisition, including intellectual property infringement claims, violation of laws, commercial disputes, tax liabilities, and other known liabilities; • unanticipated write-offs or charges; and • litigation or other claims in connection with the acquired company, including claims from terminated employees, customers, former stockholders or other third parties.
For example, we source certain materials used in the manufacture of our products from China and other countries outside of the United States; supply chain disruptions (including as a result of recently announced tariffs, other geopolitical events or global health pandemics) could impact our business. Additionally, our cost of goods development is at an early stage.
For example, we source certain materials used in the manufacture of our products from China and other countries outside of the United States; supply chain disruptions (including as a result of announced tariffs, other geopolitical events or global health pandemics) could impact our business. Additionally, our cost of goods development is at an early stage.
The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of 82 patents, trade secrets, and other intellectual property protection, particularly those relating to biotechnology and pharmaceutical products, which could make it difficult for us to stop the infringement of our patents or marketing of competing products against third parties in violation of our intellectual property and proprietary rights generally.
The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets, and other intellectual property protection, particularly those relating to biotechnology and pharmaceutical products, which could make it difficult for us to stop the infringement of our patents or marketing of competing products against third parties in violation of our intellectual property and proprietary rights generally.
This would include results from any post-marketing studies or surveillance to monitor the safety and efficacy of the drug product required as a condition of approval or agreed to by us. Any regulatory approvals that we receive for our product candidates may also be subject to limitations on the approved uses for which the product may be marketed.
This would include results from any post-marketing studies or surveillance to monitor the safety and efficacy of the drug product required as a condition of approval or agreed to by us. Any regulatory approvals that we receive for our development candidates may also be subject to limitations on the approved uses for which the product may be marketed.
The complex processes associated with the manufacture of our product candidates expose us to various manufacturing challenges and risks, which may include delays in manufacturing adequate supply of our product candidates, limits on our ability to increase manufacturing capacity, and the potential for product failure and product variation in quality that may interfere with preclinical studies and clinical trials, along with additional costs.
The complex processes associated with the manufacture of our development candidates expose us to various manufacturing challenges and risks, which may include delays in manufacturing adequate supply of our development candidates, limits on our ability to increase manufacturing capacity, and the potential for product failure and product variation in quality that may interfere with preclinical studies and clinical trials, along with additional costs.
To market any products that 56 may be approved, we must build our sales, marketing, managerial and other non-technical capabilities or make arrangements with third parties to perform these services. With respect to certain of our current programs as well as future programs, we may rely completely on an alliance partner for sales and marketing.
To market any products that may be approved, we must build our sales, marketing, managerial and other non-technical capabilities or make arrangements with third parties to perform these services. With respect to certain of our current programs as well as future programs, we may rely completely on an alliance partner for sales and marketing.
We believe a significant number of drugs are currently under development, and may become commercially available in the future, for the treatment of conditions that our current or future product candidates are or may be designed to treat. These drugs may be more effective, safer, less expensive, or marketed and sold more effectively, than any products we develop.
We believe a significant number of drugs are currently under development, and may become commercially available in the future, for the treatment of conditions that our current or future development candidates are or may be designed to treat. These drugs may be more effective, safer, less expensive, or marketed and sold more effectively, than any products we develop.
There can be no assurance that FDA would allow any of the product candidates we may develop to proceed on an accelerated approval pathway or grant priority review, and even if FDA did allow such pathway, there can be no assurance that such submission or application will be accepted or that any expedited development, review or approval will be granted on a timely basis, or at all.
There can be no assurance that FDA would allow any of the development candidates we may develop to proceed on an accelerated approval pathway or grant priority review, and even if FDA did allow such pathway, there can be no assurance that such submission or application will be accepted or that any expedited development, review or approval will be granted on a timely basis, or at all.
The ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding levels, statutory, regulatory, and policy changes, the FDA’s ability to hire and retain key personnel and accept the payment of user fees, and other events that may otherwise affect the FDA’s ability to perform routine functions.
The ability of the FDA to review and approve new products can be affected by a variety of factors, including staffing, government budget and funding levels, statutory, regulatory, and policy changes, the FDA’s ability to hire and retain key personnel and accept the payment of user fees, and other events that may otherwise affect the FDA’s ability to perform routine functions.
Proceedings to enforce our patents and intellectual property rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing, and could provoke third parties to assert claims against us.
Proceedings to enforce our patents and intellectual property rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other 86 aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing, and could provoke third parties to assert claims against us.
The success of our product candidates will depend on many factors, including the following: • timely and successful completion of preclinical studies, including toxicology studies, biodistribution studies and minimally efficacious dose studies in animals, where applicable; • effective INDs or comparable foreign applications that allow commencement of our planned clinical trials or future clinical trials for any product candidates we may develop; • successful enrollment and completion of clinical trials, including under the FDA’s current GCPs, current GLPs, and any additional regulatory requirements from foreign regulatory authorities; • positive results from our future clinical trials that support a finding of safety and effectiveness and an acceptable risk-benefit profile in the intended populations; • receipt of marketing approvals from applicable regulatory authorities; • establishment of arrangements through our own facilities or with third-party manufacturers for clinical supply and, where applicable, commercial manufacturing capabilities; • establishment, maintenance, defense and enforcement of patent, trademark, trade secret and other intellectual property protection or regulatory exclusivity for any product candidates we may develop; • commercial launch of any product candidates we may develop, if approved, whether alone or in collaboration with others; • acceptance of the benefits and use of the product candidates we may develop, including method of administration, if and when approved, by patients, the medical community and third-party payors; • effective competition with other products; • maintenance of a continued acceptable safety, tolerability and efficacy profile of any product candidates we may develop following approval; and • establishment and maintenance of healthcare coverage and adequate reimbursement by payors.
The success of our development candidates will depend on many factors, including the following: • timely and successful completion of preclinical studies, including toxicology studies, biodistribution studies and minimally efficacious dose studies in animals, where applicable; • effective INDs or comparable foreign applications that allow commencement of our planned clinical trials or future clinical trials for any development candidates we may develop; • successful enrollment and completion of clinical trials, including under the FDA’s current GCPs, current GLPs, and any additional regulatory requirements from foreign regulatory authorities; • positive results from our future clinical trials that support a finding of safety and effectiveness and an acceptable risk-benefit profile in the intended populations; • receipt of marketing approvals from applicable regulatory authorities; • establishment of arrangements through our own facilities or with third-party manufacturers for clinical supply and, where applicable, commercial manufacturing capabilities; • establishment, maintenance, defense and enforcement of patent, trademark, trade secret and other intellectual property protection or regulatory exclusivity for any development candidates we may develop; 55 • commercial launch of any development candidates we may develop, if approved, whether alone or in collaboration with others; • acceptance of the benefits and use of the development candidates we may develop, including method of administration, if and when approved, by patients, the medical community and third-party payors; • effective competition with other products; • maintenance of a continued acceptable safety, tolerability and efficacy profile of any development candidates we may develop following approval; and • establishment and maintenance of healthcare coverage and adequate reimbursement by payors.
In addition, our estimates regarding the potential market size may be materially different from what we currently expect by the time we commence commercialization, which could result in significant changes in our business plan and may significantly harm our results of operations and financial condition. 57 The pharmaceutical industry is intensely competitive.
In addition, our estimates regarding the potential market size may be materially different from what we currently expect by the time we commence commercialization, which could result in significant changes in our business plan and may significantly harm our results of operations and financial condition. The pharmaceutical industry is intensely competitive.
If we fail in defending such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel. A loss of key research personnel or their work product could hamper our ability to commercialize, or prevent us from commercializing, our product candidates, which could severely harm our business.
If we fail in defending such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel. A loss of key research personnel or their work product could hamper our ability to commercialize, or prevent us from commercializing, our development candidates, which could severely harm our business.
If securities analysts or investors perceive these results to be negative, it could have a material adverse effect on the price of our common stock. 78 Third-party claims of intellectual property infringement may prevent, delay or otherwise interfere with our product discovery and development efforts.
If securities analysts or investors perceive these results to be negative, it could have a material adverse effect on the price of our common stock. Third-party claims of intellectual property infringement may prevent, delay or otherwise interfere with our product discovery and development efforts.
Failure to comply with these requirements could result in warning or untitled letters, criminal or civil penalties, recalls, or product withdrawals. In addition, we intend to seek approval to market our product candidates in jurisdictions outside of the United States, and therefore will be subject to, and must comply with, regulatory requirements in those jurisdictions.
Failure to comply with these requirements could result in warning or untitled letters, criminal or civil penalties, recalls, or product withdrawals. In addition, we intend to seek approval to market our development candidates in jurisdictions outside of the United States, and therefore will be subject to, and must comply with, regulatory requirements in those jurisdictions.
In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements.
In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict 70 or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements.
In September 2024 we entered into a collaboration agreement with Novo Nordisk and in the future, we may decide to collaborate with non-profit organizations, universities, pharmaceutical and other biotechnology companies for the development and potential commercialization of existing and new product candidates. We face significant competition in seeking appropriate collaborators.
In September 2024 we entered into a collaboration agreement with Novo Nordisk and in the future, we may decide to collaborate with non-profit organizations, universities, pharmaceutical and other biotechnology companies for the development and potential commercialization of existing and new development candidates. We face significant competition in seeking appropriate collaborators.
If we are unable to do so, we may have to curtail the development of the product candidate for which we are seeking to collaborate, reduce or delay our development program or one or more of our other development programs, delay our potential commercialization or reduce the scope of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense.
If we are unable to do so, we may have to curtail the development of the development candidate for which we are seeking to collaborate, reduce or delay our development program or one or more of our other development programs, delay our potential commercialization or reduce the scope of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense.
As a result, capital appreciation, if any, of our common stock will be your sole source of gain, if any, for the foreseeable future. An active trading market for our common stock may not continue to develop or be sustained and our stockholders may not be able to resell their shares of common stock for a profit, if at all.
As a result, capital appreciation, if any, of our common stock will be your sole source of gain, if any, for the foreseeable future. 94 An active trading market for our common stock may not continue to develop or be sustained and our stockholders may not be able to resell their shares of common stock for a profit, if at all.
If we are unable to demonstrate that any adverse events were caused by the administration process or related procedures, the FDA, the EMA, HREC, TGA or other regulatory authorities could order us to cease further development of, or deny approval of, any product candidates for any or all targeted indications.
If we are unable to demonstrate that any adverse events were caused by the administration process or related procedures, the FDA, the EMA, HREC, TGA or other regulatory authorities could order us to cease further development of, or deny approval of, any development candidates for any or all targeted indications.
While we intend to seek designations for our product candidates with the FDA and comparable foreign regulatory authorities that are intended to confer benefits such as a faster development process or an accelerated regulatory pathway, there can be no assurance that we will successfully obtain such designations.
While we intend to seek designations for our development candidates with the FDA and comparable foreign regulatory authorities that are intended to confer benefits such as a faster development process or an accelerated regulatory pathway, there can be no assurance that we will successfully obtain such designations.
If preclinical and/or clinical data are not ultimately comparable to those seen in the earlier trials, we may be required to make further changes to our process and/or undertake additional clinical testing, either of which could significantly delay the clinical development or commercialization of the associated product candidate.
If preclinical and/or clinical data are not ultimately comparable to those seen in the earlier trials, we may be required to make further changes to our process and/or undertake additional clinical testing, either of which could significantly delay the clinical development or commercialization of the associated development candidate.
To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability, our competitive position could be harmed and the further development and commercialization of our product candidates could be significantly delayed.
To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability, our competitive position could be harmed and the further development and commercialization of our development candidates could be significantly delayed.
In addition, trade secrets may be independently developed by others in a manner that could prevent us from receiving legal recourse. If any of our 84 confidential or proprietary information, such as our trade secrets, were to be disclosed or misappropriated, or if any of that information was independently developed by a competitor, our competitive position could be harmed.
In addition, trade secrets may be independently developed by others in a manner that could prevent us from receiving legal recourse. If any of our confidential or proprietary information, such as our trade secrets, were to be disclosed or misappropriated, or if any of that information was independently developed by a competitor, our competitive position could be harmed.
We must perform system and process evaluation and testing of our internal control over financial reporting to allow management to report on the effectiveness of our internal controls over financial reporting in our annual report on Form 10-K filing for that year, as required by Section 404 of the Sarbanes-Oxley Act.
We must perform system and process evaluation and testing of our internal control over financial reporting to allow management to report on the effectiveness of our internal control over financial reporting in our annual report on Form 10-K filing for that year, as required by Section 404 of the Sarbanes-Oxley Act.
There is no guarantee, however, that our product candidates would be deemed eligible for the PRIME scheme and even if we do participate in the PRIME scheme, where during the course of development a medicine no longer meets the eligibility criteria, support under the PRIME scheme may be withdrawn.
There is no guarantee, however, that our development candidates would be deemed eligible for the PRIME scheme and even if we do participate in the PRIME scheme, where during the course of development a medicine no longer meets the eligibility criteria, support under the PRIME scheme may be withdrawn.
In addition, later discovery of previously unknown adverse events or other problems with our product candidates, manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may yield various results, including: • restrictions on such product candidates, manufacturers or manufacturing processes; • restrictions on the labeling or marketing of a product; • restrictions on product distribution or use; • requirements to conduct post-marketing studies or clinical trials; • warning or untitled letters; • withdrawal of any approved product from the market; • refusal to approve pending applications or supplements to approved applications that we may submit; • recall of product candidates; • fines, restitution or disgorgement of profits or revenues; • suspension or withdrawal of marketing approvals; • refusal to permit the import or export of our product candidates; • product seizure; or • injunctions or the imposition of civil or criminal penalties.
In addition, later discovery of previously unknown adverse events or other problems with our development candidates, manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may yield various results, including: • restrictions on such development candidates, manufacturers or manufacturing processes; • restrictions on the labeling or marketing of a product; • restrictions on product distribution or use; • requirements to conduct post-marketing studies or clinical trials; • warning or untitled letters; 66 • withdrawal of any approved product from the market; • refusal to approve pending applications or supplements to approved applications that we may submit; • recall of development candidates; • fines, restitution or disgorgement of profits or revenues; • suspension or withdrawal of marketing approvals; • refusal to permit the import or export of our development candidates; • product seizure; or • injunctions or the imposition of civil or criminal penalties.
Moreover, if we elect, or are required, to not initiate, delay, suspend or terminate any future clinical trial of any of our product candidates, the commercial prospects of such product candidates may be harmed and our ability to generate product revenues from any of these product candidates may be delayed or eliminated.
Moreover, if we elect, or are required, to not initiate, delay, suspend or terminate any future clinical trial of any of our development candidates, the commercial prospects of such development candidates may be harmed and our ability to generate product revenues from any of these development candidates may be delayed or eliminated.
The applicable period is seven years in the United States and ten years in the European Union. The 65 exclusivity period in the European Union can be reduced to six years if a product no longer meets the criteria for orphan designation, in particular if the product is sufficiently profitable so that market exclusivity is no longer justified.
The applicable period is seven years in the United States and ten years in the European Union. The exclusivity period in the European Union can be reduced to six years if a product no longer meets the criteria for orphan designation, in particular if the product is sufficiently profitable so that market exclusivity is no longer justified.
Due to our limited financial resources and the limited experience of our management team in managing a company with such anticipated growth, we may not be able to effectively manage the expected expansion of our operations or recruit and train additional qualified personnel.
Due to our limited financial resources and the limited experience of our management team in managing a company with such anticipated growth, we may not be able to effectively manage the expected future expansion of our operations or recruit and train additional qualified personnel.
Commercialization of any product candidates we may develop will require preclinical and clinical development; regulatory and marketing approval in multiple jurisdictions, including by the FDA, the EMA, HREC and TGA; manufacturing supply, capacity and expertise; a commercial organization; and significant marketing efforts.
Commercialization of any development candidates we may develop will require preclinical and clinical development; regulatory and marketing approval in multiple jurisdictions, including by the FDA, the EMA, HREC and TGA; manufacturing supply, capacity and expertise; a commercial organization; and significant marketing efforts.
Such changes carry the risk that they will not achieve their intended objectives, and any of these changes could cause our product candidates to perform differently and affect the results of current or future clinical trials, or the performance of the product, once commercialized.
Such changes carry the risk that they will not achieve their intended objectives, and any of these changes could cause our development candidates to perform differently and affect the results of current or future clinical trials, or the performance of the product, once commercialized.
Our product candidates and the activities associated with their development and potential commercialization, including their testing, manufacturing, recordkeeping, labeling, storage, approval, advertising, promotion, sale and distribution, are subject to comprehensive regulation by the FDA and other U.S. and international regulatory authorities.
Our development candidates and the activities associated with their development and potential commercialization, including their testing, manufacturing, recordkeeping, labeling, storage, approval, advertising, promotion, sale and distribution, are subject to comprehensive regulation by the FDA and other U.S. and international regulatory authorities.
Because our product candidates represent new approaches to the treatment of genetic-based diseases, we cannot be sure that coverage and reimbursement will be available for, or accurately estimate the potential revenue from, our product candidates or assure that coverage and reimbursement will be available for any product that we may develop.
Because our development candidates represent new approaches to the treatment of genetic-based diseases, we cannot be sure that coverage and reimbursement will be available for, or accurately estimate the potential revenue from, our development candidates or assure that coverage and reimbursement will be available for any product that we may develop.
Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that could weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future. We cannot predict 83 how future decisions by the courts, the U.S.
Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that could weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future. We cannot predict how future decisions by the courts, the U.S.
In order to commence clinical development, we will need to identify success criteria and endpoints such that the FDA, the EMA or other regulatory authorities will be able to determine the clinical efficacy and safety profile of any product candidates we may develop.
In order to commence clinical development, we will need to identify success criteria and endpoints such that the FDA, the EMA or other regulatory authorities will be able to determine the clinical efficacy and safety profile of any development candidates we may develop.
Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of these materials, this insurance may not provide adequate coverage against potential liabilities.
Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of these materials, this insurance may not provide adequate coverage 69 against potential liabilities.
If a third party were to prevail on a legal assertion of invalidity or unenforceability, we would lose at least part, and perhaps all, of the patent protection on one or more of our products or certain aspects of our platform technology.
If a third party were to prevail on a legal assertion of invalidity or unenforceability, we would lose at least part, and perhaps all, of the patent protection on one or 81 more of our products or certain aspects of our platform technology.
Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and development programs and product candidates for specific indications may not yield any commercially viable products.
Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and development programs and development candidates for specific indications may not yield any commercially viable products.
If we are unable to raise additional capital in sufficient amounts or on terms acceptable to us, we may have to significantly delay, scale back or discontinue the development or commercialization of any product candidates or other research and development initiatives.
If we are unable to raise additional capital in sufficient amounts or on terms acceptable to us, we may have to significantly delay, scale back or discontinue the development or commercialization of any development candidates or other research and development initiatives.
For additional information regarding the risks that may apply to our and our licensors’ intellectual property rights, see “—Risks Related to Intellectual Property. ” We are very early in our development efforts, and our preclinical studies and clinical trials may not be successful.
For additional information regarding the risks that may apply to our and our licensors’ intellectual property rights, see “—Risks Related to Intellectual Property. ” 54 We are very early in our development efforts, and our preclinical studies and clinical trials may not be successful.
Our product candidates are subject to extensive governmental regulations relating to, among other things, research, testing, development, manufacturing, quality, safety, efficacy, approval, recordkeeping, reporting, labeling, storage, packaging, advertising and promotion, pricing, marketing and distribution of drugs.
Our development candidates are subject to extensive governmental regulations relating to, among other things, research, testing, development, manufacturing, quality, safety, efficacy, approval, recordkeeping, reporting, labeling, storage, packaging, advertising and promotion, pricing, marketing and distribution of drugs.
A failure of one or more clinical trials can occur at any stage of testing. The outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials, and interim results of a clinical trial do not necessarily predict final results.
A failure of one or more clinical trials can occur at any stage of development. The outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials, and interim results of a clinical trial do not necessarily predict final results.
Furthermore, given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates, their manufacture or their use might expire before or shortly after those candidates receive regulatory approval and are commercialized.
Furthermore, given the amount of time required for the development, testing and regulatory review of new development candidates, patents protecting such candidates, their manufacture or their use might expire before or shortly after those candidates receive regulatory approval and are commercialized.
Congress or the USPTO may impact the value of our patents. Any adverse changes in the patent laws of other jurisdictions could also have a material adverse effect on our business, financial condition, results of operations and prospects.
Congress or the USPTO may impact the value of our patents. Any adverse changes in 87 the patent laws of other jurisdictions could also have a material adverse effect on our business, financial condition, results of operations and prospects.
We, our CMOs, and the manufacturing facilities we use to make our product candidates will also be subject to ongoing assessment of product quality, compliance with cGMP, and periodic inspection by the FDA and potentially other regulatory agencies.
We, our CMOs, and the manufacturing facilities we use to make our development candidates will also be subject to ongoing assessment of product quality, compliance with cGMP, and periodic inspection by the FDA and potentially other regulatory agencies.
We expect to expand our research, development, delivery, manufacturing, commercialization, regulatory and future sales and marketing capabilities over time, and as a result, we may encounter difficulties in managing our growth, which could disrupt our operations.
We expect to need to expand our research, development, delivery, manufacturing, commercialization, regulatory and future sales and marketing capabilities over time, and as a result, we may encounter difficulties in managing our future growth, which could disrupt our operations.
Other factors that we believe will materially affect market acceptance of our product candidates include: • the timing of our receipt of any regulatory approvals, the terms of any approvals and the countries in which approvals are obtained; • the ability to consistently manufacture our products within acceptable quality standards; • the safety and efficacy of our product candidates, as demonstrated in clinical trials and as compared with alternative treatments, if any; • the incidence, seriousness and severity of any side effects; • the relative convenience and ease of administration of our product candidates; • the willingness of patients to accept potentially new routes of administration and their risk tolerance as it relates to potentially serious side effects; • the success of our physician education programs; • the availability of government and third-party payor coverage and adequate reimbursement; • the pricing of our products, particularly as compared to alternative treatments; and • the availability of alternative effective treatments for the diseases that product candidates we develop are intended to treat and the relative risks, benefits and costs of those treatments.
Other factors that we believe will materially affect market acceptance of our development candidates include: • the timing of our receipt of any regulatory approvals, the terms of any approvals and the countries in which approvals are obtained; • the ability to consistently manufacture our products within acceptable quality standards; 60 • the safety and efficacy of our development candidates, as demonstrated in clinical trials and as compared with alternative treatments, if any; • the incidence, seriousness and severity of any side effects; • the relative convenience and ease of administration of our development candidates; • the willingness of patients to accept potentially new routes of administration and their risk tolerance as it relates to potentially serious side effects; • the success of our physician education programs; • the availability of government and third-party payor coverage and adequate reimbursement; • the pricing of our products, particularly as compared to alternative treatments; and • the availability of alternative effective treatments for the diseases that development candidates we develop are intended to treat and the relative risks, benefits and costs of those treatments.
Approval of any of our product candidates may be delayed or refused for many reasons, including: • the FDA or comparable foreign regulatory authorities may disagree with the design or implementation of our clinical trials; • We may be unable to demonstrate, to the satisfaction of the FDA or comparable foreign regulatory authorities, that our product candidates are safe and effective for any of their proposed indications; 61 • the results of clinical trials may not meet the level of statistical significance required by the FDA or comparable foreign regulatory authorities for approval; • We may be unable to demonstrate that our product candidates’ clinical and other benefits outweigh their safety risks; • the FDA or comparable foreign regulatory authorities may disagree with our interpretation of data from preclinical programs or clinical trials; • the data collected from clinical trials of our product candidates may not be sufficient to support the submission of an NDA or other comparable submission in foreign jurisdictions or to obtain regulatory approval in the United States or elsewhere; • the facilities of third-party manufacturers with which we contract or procure certain service or raw materials, may not be adequate to support approval of our product candidates; and • the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval.
Approval of any of our development candidates may be delayed or refused for many reasons, including: • the FDA or comparable foreign regulatory authorities may disagree with the design or implementation of our clinical trials; • We may be unable to demonstrate, to the satisfaction of the FDA or comparable foreign regulatory authorities, that our development candidates are safe and effective for any of their proposed indications; • the results of clinical trials may not meet the level of statistical significance required by the FDA or comparable foreign regulatory authorities for approval; • We may be unable to demonstrate that our development candidates’ clinical and other benefits outweigh their safety risks; • the FDA or comparable foreign regulatory authorities may disagree with our interpretation of data from preclinical programs or clinical trials; • the data collected from clinical trials of our development candidates may not be sufficient to support the submission of an NDA or other comparable submission in foreign jurisdictions or to obtain regulatory approval in the United States or elsewhere; • the facilities of third-party manufacturers with which we contract or procure certain service or raw materials, may not be adequate to support approval of our development candidates; and • the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval.
Our failure, or the failure of our CMOs, to comply with applicable regulations could result in regulatory actions, such as the issuance of FDA Form 483 notices of observations, warning letters or sanctions being imposed on us, including clinical holds, fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of product candidates or drugs, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect supplies of our products.
Our failure, or the failure of our CMOs, to comply with applicable regulations could result in regulatory actions, such as the issuance of FDA Form 483 notices of observations, warning letters or sanctions being imposed on us, including clinical holds, fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of development candidates or drugs, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect supplies of our products.
We face an inherent risk of product liability exposure related to the testing in human clinical trials of any product candidates we may develop and will face an even greater risk if we commercially sell any products that we may develop.
We face an inherent risk of product liability exposure related to the testing in human clinical trials of any development candidates we may develop and will face an even greater risk if we commercially sell any products that we may develop.
If we, or any third parties that we engage to assist us, are unable to successfully identify such patients, or experience delays in doing so, then: • our ability to develop any product candidates may be adversely affected if we are unable to appropriately select patients for enrollment in our clinical trials; and • we may not realize the full commercial potential of any product candidates we develop that receive marketing approval if, among other reasons, we are unable to appropriately select patients who are likely to benefit from therapy with our products.
If we, or any third parties that we engage to assist us, are unable to successfully identify such patients, or experience delays in doing so, then: • our ability to develop any development candidates may be adversely affected if we are unable to appropriately select patients for enrollment in our clinical trials; and • we may not realize the full commercial potential of any development candidates we develop that receive marketing approval if, among other reasons, we are unable to appropriately select patients who are likely to benefit from therapy with our products.
The FDA and comparable foreign regulatory authorities offer certain designations for product candidates that are designed to encourage the research and development of product candidates that are intended to address conditions with significant unmet medical need.
The FDA and comparable foreign regulatory authorities offer certain designations for development candidates that are designed to encourage the research and development of development candidates that are intended to address conditions with significant unmet medical need.
Further, if we encounter delays in development, testing, and regulatory review of new product candidates, the period of time during which we could market our product candidates under patent protection would be reduced.
Further, if we encounter delays in development, testing, and regulatory review of new development candidates, the period of time during which we could market our development candidates under patent protection would be reduced.
Litigation to defend ourself against claims by third parties, or to enforce any rights that we may have against third parties, may continue to be necessary, which could result in substantial costs and diversion of our resources, causing a material adverse effect on our business, financial condition, results of operations or cash flows. 87 The price of our common stock is volatile and fluctuates substantially, which could result in substantial losses for our stockholders.
Litigation to defend ourself against claims by third parties, or to enforce any rights that we may have against third parties, may continue to be necessary, which could result in substantial costs and diversion of our resources, causing a material adverse effect on our business, financial condition, results of operations or cash flows. 91 The price of our common stock is volatile and fluctuates substantially, which could result in substantial losses for our stockholders.
Furthermore, if we or others later identify undesirable side effects caused by any of our product candidates, several potentially significant negative consequences could result, including: • regulatory authorities may suspend or withdraw approvals of such product candidate; • we may be required to change the way a product candidate is administered or conduct additional clinical trials; • we could be sued and held liable for harm caused to patients; and • our reputation may suffer.
Furthermore, if we or others later identify undesirable side effects caused by any of our development candidates, several potentially significant negative consequences could result, including: • regulatory authorities may suspend or withdraw approvals of such development candidate; • we may be required to change the way a development candidate is administered or conduct additional clinical trials; • we could be sued and held liable for harm caused to patients; and • our reputation may suffer.
Similarly, if any third-party patent were held by a court of competent jurisdiction to cover aspects of our formulations, processes for manufacture or methods of use, including combination therapy or patient selection methods, the holders of that patent may be able to block our ability to develop and commercialize the product candidate unless we obtain a license or until such patent expires or is finally determined to be invalid or unenforceable.
Similarly, if any third-party patent were held by a court of competent jurisdiction to cover aspects of our formulations, processes for manufacture or methods of use, including combination therapy or patient selection methods, the holders of that patent may be able to block our ability to develop and commercialize the development candidate unless we obtain a license or until such patent expires or is finally determined to be invalid or unenforceable.
Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting our product candidates might expire before or shortly after we or our partners commercialize those candidates.
Given the amount of time required for the development, testing and regulatory review of new development candidates, patents protecting our development candidates might expire before or shortly after we or our partners commercialize those candidates.
If our CMOs were to encounter any of these difficulties, our ability to provide our product candidate to patients in clinical trials, or to provide product for treatment of patients once approved, would be jeopardized.
If our CMOs were to encounter any of these difficulties, our ability to provide our development candidate to patients in clinical trials, or to provide product for treatment of patients once approved, would be jeopardized.
Because the product candidates we identify are based on novel gene-editing technology, we may be unsuccessful in obtaining clearance from regulatory authorities to proceed into clinical development.
Because the development candidates we identify are based on novel gene-editing technology, we may be unsuccessful in obtaining clearance from regulatory authorities to proceed into clinical development.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeAdditionally, we have implemented an enterprise risk management process, which addresses cybersecurity risks. This process is led by our General Counsel and includes participation by the board of directors, as appropriate. Our General Counsel reports regularly on the enterprise risk management process to executive leadership and the audit committee.
Biggest changeThe management team will also update the full board of directors on matters related to cybersecurity as needed. 97 Additionally, we have implemented an enterprise risk management process, which addresses cybersecurity risks. This process is led by our General Counsel and includes participation by the board of directors, as appropriate.
With the input of the executive team, the Vice President provides annual presentations to the audit committee on our cybersecurity program, including updates on cybersecurity testing and assessments, cybersecurity risks, and related cybersecurity strategy as applicable. The management team will also update the full board of directors on matters related to cybersecurity as needed.
With the input of the executive team, the Vice President provides annual presentations to the audit committee on our cybersecurity program, including updates on cybersecurity testing and assessments, cybersecurity risks, and related cybersecurity strategy as applicable.
Added
Our General Counsel reports regularly on the enterprise risk management process to executive leadership and the audit committee.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeItem 2. Pro perties. Our principal office is located at 60 First Street, 2nd Floor, Suite 250, Cambridge, MA 02141, where we lease approximately 50,453 square feet of office and laboratory space.
Biggest changeItem 2. Pro perties. Our principal office is located at 60 First Street, 2nd Floor, Suite 250, Cambridge, MA 02141, where we lease approximately 50,453 square feet of office and laboratory space. The lease term began in May 2023 and will end in April 2034 with an option to extend the term of the lease for an additional five years.
If required, we believe that suitable additional or substitute space will be available in the future on commercially reasonable terms to accommodate any such expansion of our operations.
We believe that our existing office and laboratory space is adequate for our needs for the foreseeable future. If required, we believe that suitable additional or substitute space will be available in the future on commercially reasonable terms to accommodate any such expansion of our operations.
Removed
The lease term began in May 2023 and will end in April 2034 with an option to extend the term of the lease for an additional five years. 93 We believe that our existing office and laboratory space is adequate for our needs for the foreseeable future.

Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

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Biggest changeItem 3. Lega l Proceedings. From time to time, we may be involved in various other claims and legal proceedings relating to claims arising out of our operations. We are not currently a party to any material legal proceedings other than as disclosed below.
Biggest changeItem 3. Lega l Proceedings. From time to time, we may be involved in various other claims and legal proceedings relating to claims arising out of our operations. We are not currently a party to any material legal proceedings. Item 4. M ine Safety Disclosures. Not applicable. 98 PART II
Removed
On June 3, 2021 and June 22, 2021, purported stockholders of Frequency filed putative class action lawsuits in the U.S. District Court for the District of Massachusetts against Frequency and Frequency’s Chief Executive Officer, President, and Director, David Lucchino. On March 21, 2022, the two lawsuits were consolidated into a single lawsuit, Quinones et al. v.
Removed
Frequency Therapeutics, Inc. et al. and on May 16, 2022, Frequency’s Chief Development Officer, Dr. Carl Le Bel, was added as a defendant.
Removed
The plaintiffs alleged violations of Sections 10(b), 20(a) and Rule 10b5 of the Exchange Act due to allegedly false and misleading statements and omissions about Frequency’s Phase 2a clinical trial (FX-322-202) for its product candidate FX-322 in Frequency’s public disclosures between October 29, 2020 and March 22, 2021.
Removed
The lawsuit sought, among other things, damages in connection with Frequency’s allegedly artificially inflated stock price between October 29, 2020 and March 22, 2021 as a result of those allegedly false and misleading statements and omissions, as well as interest, attorneys’ fees and costs.
Removed
On March 29, 2023, Frequency’s motion to dismiss was granted and the lawsuit was dismissed in its entirety. On April 27, 2023, plaintiff filed a notice of appeal to the United States Court of Appeals for the First Circuit from the order dismissing the lawsuit. On August 2, 2023, plaintiff-appellant submitted its opening brief to the First Circuit.
Removed
Frequency filed its opposition brief on October 27, 2023, and plaintiff-appellant filed its reply brief on December 14, 2023. The First Circuit heard oral argument on January 8, 2024. On July 2, 2024, the First Circuit issued an opinion and judgment affirming dismissal of the lawsuit in its entirety. On July 18, 2024, plaintiff filed a motion in the U.S.
Removed
District Court for the District of Massachusetts requesting that the court vacate its prior order and judgment dismissing the plaintiff’s lawsuit. We filed an opposition to that motion on August 8, 2024, and on November 1, 2024 the U.S.
Removed
District Court for the District of Massachusetts denied the plaintiff's request that the court vacate its prior order and judgment dismissing the plaintiff’s lawsuit. The deadline for the plaintiff to appeal such decision has passed and the plaintiff did not file an appeal before such deadline. Item 4. M ine Safety Disclosures. Not applicable. 94 PART II

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeItem 5. Mar ket for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities. Market Information Our common stock is listed on the Nasdaq Capital Market under the symbol “KRRO”. Holders of Our Common Stock As of March 14, 2025, we had 9,388,902 shares of common stock issued and outstanding held of record by 87 holders.
Biggest changeItem 5. Mar ket for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities. Market Information Our common stock is listed on the Nasdaq Capital Market under the symbol “KRRO”. Holders of Our Common Stock As of March 10, 2026, we had 14,422,571 shares of common stock issued and outstanding held of record by 104 holders.
Recent Sales of Unregistered Securities None. Equity Compensation Plan Information Information about our equity compensation plans will be included in our definitive proxy statement to be filed with the SEC with respect to our 2025 Annual Meeting of Stockholders and is incorporated herein by reference. Purchases of Equity Securities by the Issuer or Affiliated Purchasers None. Item 6. [Reserved] 95
Recent Sales of Unregistered Securities None. Equity Compensation Plan Information Information about our equity compensation plans will be included in our definitive proxy statement to be filed with the SEC with respect to our 2026 Annual Meeting of Stockholders and is incorporated herein by reference. Purchases of Equity Securities by the Issuer or Affiliated Purchasers None. Item 6. [Reserved] 99

Item 7. Management's Discussion & Analysis

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

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Biggest changeIf we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit, reduce or terminate our product research and development or grant rights to develop and market our product candidates even if we would otherwise prefer to develop and market such product candidates ourselves. 101 Cash Flows Comparison of the Years Ended December 31, 2024 and 2023 The following table summarizes our cash flows for the years ended December 31, 2024 and 2023: Year Ended December 31, (in thousands) 2024 2023 Net cash used in operating activities $ (60,074 ) $ (67,283 ) Net cash (used in) provided by investing activities (123,347 ) 11,164 Net cash provided by financing activities 69,355 187,761 Effect of foreign exchange rate changes (4 ) — Net (decrease) increase in cash, cash equivalents and restricted cash $ (114,070 ) $ 131,642 Cash Used in Operating Activities Net cash used in operating activities was $60.1 million for the year ended December 31, 2024, which consisted of $83.6 million of net loss, $9.9 million of non-cash adjustments to net loss and an increase of $13.6 million in the net change in operating assets and liabilities.
Biggest changeCash Flows Comparison of the Years Ended December 31, 2025 and 2024 The following table summarizes our cash flows for the years ended December 31, 2025 and 2024: Year Ended December 31, (in thousands) 2025 2024 Net cash used in operating activities $ (78,561 ) $ (60,074 ) Net cash provided by (used in) investing activities 43,993 (123,347 ) Net cash provided by financing activities 685 69,355 Effect of foreign exchange rate changes 64 (4 ) Net decrease in cash, cash equivalents and restricted cash $ (33,819 ) $ (114,070 ) Cash Used in Operating Activities Net cash used in operating activities was $78.6 million for the year ended December 31, 2025, primarily resulted from our net loss of $117.3 million, which was primarily attributable to our research and development activities and our general and administrative expenses, along with changes in our operating assets and liabilities of $4.4 million, offset by $43.1 million of non-cash items, primarily the $30.9 million impairment of long-lived assets.
Our net losses may fluctuate significantly from quarter-to-quarter and year-to-year, depending on the timing of our preclinical studies, initiation and conduct of any clinical trials, and our expenditures on other research and development activities, including the expansion of our pipeline. We do not have any product candidates approved for sale and have not generated any revenue from product sales.
Our net losses may fluctuate significantly from quarter-to-quarter and year-to-year, depending on the timing of our preclinical studies, initiation and conduct of any clinical trials, and our expenditures on other research and development activities, including the expansion of our pipeline. We do not have any development candidates approved for sale and have not generated any revenue from product sales.
We will not generate revenue from product sales unless and until we successfully obtain regulatory approval for our product candidates, if ever, and as appropriate, move pipeline candidates into the clinic and complete clinical development.
We will not generate revenue from product sales unless and until we successfully obtain regulatory approval for our development candidates, if ever, and as appropriate, move pipeline candidates into the clinic and complete clinical development.
If we obtain regulatory approval for our product candidates and do not enter into third-party commercialization partnerships, we expect to incur significant expenses related to developing commercialization capabilities to support product sales, marketing, manufacturing and distribution activities. As a result, we will need substantial additional funding to support our continuing operations and pursue our development and growth strategy.
If we obtain regulatory approval for our development candidates and do not enter into third-party commercialization partnerships, we expect to incur significant expenses related to developing commercialization capabilities to support product sales, marketing, manufacturing and distribution activities. As a result, we will need substantial additional funding to support our continuing operations and pursue our development and growth strategy.
For example, if the FDA, EMA, HREC, TGA or another regulatory authority were to delay the planned start of clinical trials or require us to conduct clinical trials or other testing beyond those that we currently expect or if we experience significant delays in enrollment in any planned clinical trial, we could be required to expend significant additional financial resources and time on the completion of clinical development of that product candidate.
For example, if the FDA, EMA, HREC, TGA or another regulatory authority were to delay the planned start of clinical trials or require us to conduct clinical trials or other testing beyond those that we currently expect or if we experience significant delays in enrollment in any planned clinical trial, we could be required to expend significant additional financial resources and time on the completion of clinical development of that development candidate.
Our actual results may differ from these estimates under different assumptions or conditions. On an ongoing basis, 102 we evaluate our judgments and estimate in light of changes in circumstances, facts, and experience. The effects of material revisions in estimates, if any, will be reflected in the consolidated financial statements prospectively from the date of change in estimates.
Our actual results may differ from these estimates under different assumptions or conditions. On an ongoing basis, we evaluate our judgments and estimate in light of changes in circumstances, facts, and experience. The effects of material revisions in estimates, if any, will be reflected in the consolidated financial statements prospectively from the date of change in estimates.
We will remain a smaller reporting company until the last day of the fiscal year in which (i) the market value of our common stock held by non-affiliates exceeds $250 million as of the prior June 30, or (ii) our annual revenues exceed $100 million during such completed fiscal year and the market value of our common stock held by non-affiliates exceeds $700 million as of the prior June 30.
We will remain a smaller reporting company until the last day of the fiscal year in which (i) the market value of our common stock held by non-affiliates exceeds $250 million as of the prior June 30, or (ii) our annual revenues exceed $100 108 million during such completed fiscal year and the market value of our common stock held by non-affiliates exceeds $700 million as of the prior June 30.
We anticipate that our expenses will increase substantially, particularly due to the numerous risks and uncertainties associated with developing product candidates, including the uncertainty of: • the scope, rate of progress, and expenses of our ongoing research activities as well as any preclinical studies, clinical trials and other research and development activities; • establishing an appropriate safety profile with IND enabling studies; • successful enrollment in and completion of clinical trials; • whether our product candidates show safety and efficacy in our clinical trials; • receipt of marketing approvals from applicable regulatory authorities; • making arrangements with third-party manufacturers; • obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our product candidates; • commercializing product candidates, if and when approved, whether alone or in collaboration with others; and • continued acceptable safety profile of products following any regulatory approval.
We anticipate that our expenses will increase substantially, particularly due to the numerous risks and uncertainties associated with developing development candidates, including the uncertainty of: • the scope, rate of progress, and expenses of our ongoing research activities as well as any preclinical studies, clinical trials and other research and development activities; • establishing an appropriate safety profile with IND enabling studies; • successful enrollment in and completion of clinical trials; • whether our development candidates show safety and efficacy in our clinical trials; • receipt of marketing approvals from applicable regulatory authorities; 102 • making arrangements with third-party manufacturers; • obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our development candidates; • commercializing development candidates, if and when approved, whether alone or in collaboration with others; and • continued acceptable safety profile of products following any regulatory approval.
Since inception, we have focused primarily on organizing and staffing our company, business planning, raising capital, securing related intellectual property, and conducting research and development activities for our potential programs and product candidates. Since inception, we have funded our operations primarily through the private placement of our equity securities.
Since inception, we have focused primarily on organizing and staffing our company, business planning, raising capital, securing related intellectual property, and conducting research and development activities for our potential programs and development candidates. Since inception, we have funded our operations primarily through the private placement of our equity securities.
We cannot determine with certainty the timing of initiation, the duration or the completion costs of current or future preclinical studies and clinical trials of our product candidates due to the inherently unpredictable nature of preclinical and clinical development. Clinical and preclinical development timelines, the probability of success and development costs can differ materially from expectations.
We cannot determine with certainty the timing of initiation, the duration or the completion costs of current or future preclinical studies and clinical trials of our development candidates due to the inherently unpredictable nature of preclinical and clinical development. Clinical and preclinical development timelines, the probability of success and development costs can differ materially from expectations.
In addition, we expect to continue to incur costs associated with operating as a public company. Because of the numerous risks and uncertainties associated with research, development and commercialization of our product candidates, we are unable to estimate the exact amount of our working capital requirements.
In addition, we expect to continue to incur costs associated with operating as a public company. Because of the numerous risks and uncertainties associated with research, development and commercialization of our development candidates, we are unable to estimate the exact amount of our working capital requirements.
Any changes in the outcome of any of these variables with respect to the development of our product candidates in preclinical and clinical development could mean a significant change in the costs and timing associated with the development of these product candidates. We may never succeed in achieving regulatory approval for any of our product candidates.
Any changes in the outcome of any of these variables with respect to the development of our development candidates in preclinical and clinical development could mean a significant change in the costs and timing associated with the development of these development candidates. We may never succeed in achieving regulatory approval for any of our development candidates.
Operating Expenses Research and Development Expenses Research and development expenses consist primarily of costs incurred for our research and development activities, including our discovery of novel genetic medicines and the development of our product candidates, salaries and benefits, and third-party license fees.
Operating Expenses Research and Development Expenses Research and development expenses consist primarily of costs incurred for our research and development activities, including our discovery of novel genetic medicines and the development of our development candidates, salaries and benefits, and third-party license fees.
If we raise funds through collaborations, or other similar arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates or grant licenses on terms that may not be favorable to us and/or may reduce the value of our common shares.
If we raise funds through collaborations, or other similar arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or development candidates or grant licenses on terms that may not be favorable to us and/or may reduce the value of our common shares.
See also “Cautionary Statement Regarding Forward-Looking Statements.” Overview We are a clinical-stage biopharmaceutical company with a mission to discover, develop and commercialize a new class of genetic medicines based on editing RNA, enabling the treatment of both rare and highly prevalent diseases.
See also “Cautionary Statement Regarding Forward-Looking Statements.” Overview We are a biopharmaceutical company with a mission to discover, develop and commercialize a new class of genetic medicines based on editing RNA, enabling the treatment of both rare and highly prevalent diseases.
While our significant accounting policies are described in more detail in Note 2 to our audited consolidated financial statements appearing elsewhere in this Annual Report on Form 10-K, we believe that the following accounting policies are those most critical to the judgments and estimates used in the preparation of our consolidated financial statements.
While our significant accounting policies are described in more detail in Note 2 to our audited consolidated financial statements appearing elsewhere in this Annual Report on Form 10-K, we believe that the following accounting policy is most critical to the judgments and estimates used in the preparation of our consolidated financial statements.
We may obtain unexpected results from our clinical trials. We may elect to discontinue, delay or modify clinical trials of some product candidates or focus on other product candidates.
We may obtain unexpected results from our clinical trials. We may elect to discontinue, delay or modify clinical trials of some development candidates or focus on other development candidates.
See Note 14, "Commitments and Contingencies" to our audited consolidated financial statements appearing elsewhere in this Annual Report on Form 10-K.
See Note 13, "Commitments and Contingencies" to our audited consolidated financial statements appearing elsewhere in this Annual Report on Form 10-K.
We expect to continue to incur significant and increasing expenses and operating losses and negative operating cash flows 96 for the foreseeable future as we continue our research and development efforts, advance product candidates into and through clinical development, and seek regulatory approvals for our pipeline candidates.
We expect to continue to incur significant and increasing expenses and operating losses and negative operating cash flows for the foreseeable future as we continue our research and development efforts, advance development candidates into and through clinical development, and seek regulatory approvals for our development candidates.
We anticipate that we will make determinations as to which product candidates to pursue and how much funding to direct to each product candidate on an ongoing basis in response to the results of ongoing and future preclinical studies and clinical trials, regulatory developments and our ongoing assessments as to each product candidate’s commercial potential.
We anticipate that we will make determinations as to which lead candidates and development candidates to pursue and how much funding to direct to each on an ongoing basis in response to the results of ongoing and future preclinical studies and clinical trials, regulatory developments and our ongoing assessments as to each development candidate’s commercial potential.
Cash Provided by Investing Activities Net cash used in investing activities was $123.3 million for the year ended December 31, 2024 and consisted primarily of $146.3 million of purchase of marketable securities and $17.9 million of purchase of property and equipment, offset by $40.9 million of proceeds from maturities of marketable securities.
Net cash used in investing activities was $123.3 million for the year ended December 31, 2024 and consisted primarily of the purchase of marketable securities and the purchase of property and equipment, offset by proceeds from maturities of marketable securities.
Our future capital requirements will depend on many factors, including: • the scope, progress, results, and costs of discovery, preclinical development, laboratory testing, manufacturing and clinical trials for KRRO-110 and other product candidates we may develop; • the cost of continuing to build our OPERA platform and discover additional novel genetic medicines; • the extent to which we partner our programs, acquires or in-licenses other product candidates and technologies or enters into additional collaborations; • the outcome, timing and cost of meeting regulatory requirements established by the FDA, EMA and other regulatory authorities; • the timing and amount of milestone and royalty payments that we are required to make or eligible to receive under any future collaboration and license agreements; • our headcount growth and associated costs as we expand our research and development efforts; • the cost of expanding, maintaining and enforcing our intellectual property portfolio, including filing, prosecuting, defending and enforcing our patent claims and other intellectual property rights; • the cost of defending potential intellectual property disputes, including patent infringement actions brought by third parties against us or any of our product candidates; • the costs and timing of future commercialization activities, including product manufacturing, marketing, sales and distribution, for any product candidates for which we receive marketing approval; • the cost and timing of completion of commercial-scale manufacturing activities; • the effect of competing technological and market developments; and • the costs of operating as a public company.
Our future capital requirements will depend on many factors, including: • the scope, progress, results, and costs of discovery, preclinical development, laboratory testing, manufacturing and clinical trials for KRRO-121 and other candidates we may develop; • the cost of continuing to build our OPERA platform and discover additional novel genetic medicines; • the extent to which we partner our programs, acquire or in-license other lead candidates, development candidates and technologies or enter into additional collaborations; • the outcome, timing and cost of meeting regulatory requirements established by the FDA, EMA and other regulatory authorities; • the timing and amount of milestone and royalty payments that we are required to make or eligible to receive under any future collaboration and license agreements; • any future headcount growth and associated costs, should we expand our research and development efforts; • the cost of expanding, maintaining and enforcing our intellectual property portfolio, including filing, prosecuting, defending and enforcing our patent claims and other intellectual property rights; • the cost of defending potential intellectual property disputes, including patent infringement actions brought by third parties against us or any of our lead candidates or development candidates; • the costs and timing of future commercialization activities, including product manufacturing, marketing, sales and distribution, for any development candidates for which we receive marketing approval; • the cost and timing of completion of commercial-scale manufacturing activities; • the effect of competing technological and market developments; and • the costs of operating as a public company. 106 Until such time, if ever, as we can generate substantial product revenues to support our cost structure, we expect to finance our cash needs through a combination of equity offerings, debt financings, collaborations and other similar arrangements.
To date, we have raised approximately $223.6 million of aggregate gross proceeds from the sale of our convertible preferred stock, and $117.3 million from the sale of shares of common stock issued in a private placement that closed immediately prior to the November 2023 business combination and $70.0 million from the April 2024 private placement of shares of our common stock.
To date, we have raised approximately $223.6 million of aggregate gross proceeds from the sale of our convertible preferred stock, $117.3 million from the sale of shares of common stock issued in a private placement that closed immediately 100 prior to the November 2023 business combination, $70.0 million from the April 2024 private placement of shares of our common stock, $5.1 million from sales under our at-the-market offering program, and $85.0 million from the March 2026 private placement.
We plan to substantially increase our research and development expenses for the foreseeable future as we continue the development of our product candidates, conduct discovery and research activities for our preclinical programs, and expands our pipeline.
The successful development of our development candidates is highly uncertain. We plan to substantially increase our research and development expenses for the foreseeable future as we continue the development of our candidates, conduct discovery and research activities for our preclinical programs, and expand our pipeline.
As of December 31, 2024, we had cash, cash equivalents and marketable securities of $163.1 million. Since inception, we have incurred significant operating losses and, as of December 31, 2024, had an accumulated deficit of $266.6 million. We expect to continue to incur significant expenses, operating losses, and negative operating cash flows for the foreseeable future.
As of December 31, 2025, we had cash, cash equivalents and marketable securities of $85.2 million. Since inception, we have incurred significant operating losses and, as of December 31, 2025, had an accumulated deficit of $383.8 million. We expect to continue to incur significant expenses, operating losses, and negative operating cash flows for the foreseeable future.
To date, we have raised approximately $223.6 million of aggregate gross proceeds from the sale of convertible preferred stock, $117.3 million from the sale of shares of common stock issued in a private placement that closed immediately prior to the November 2023 business combination and $70.0 million from the April 2024 private placement of shares of our common stock.
To date, we have raised approximately $223.6 million of aggregate gross proceeds from the sale of convertible preferred stock, $117.3 million from the sale of shares of common stock issued in a private placement that closed immediately prior to the November 2023 business combination, $70.0 million from the April 2024 private placement of shares of our common stock, $5.1 million from the January 105 2026 sales under our at-the-market offering program, and $85.0 million from the March 2026 private placement.
We have incurred significant operating losses since inception. Our net losses were $83.6 million and $81.2 million for the years ended December 31, 2024 and 2023, respectively. We had an accumulated deficit of $266.6 million as of December 31, 2024.
We have incurred significant operating losses since inception. Our net losses were $117.3 million and $83.6 million for the years ended December 31, 2025 and 2024, respectively. We had an accumulated deficit of $383.8 million as of December 31, 2025.
We also expect to continue to incur costs associated with being a public company and maintaining controls over financial reporting, including costs of accounting, audit, legal, regulatory, compliance and director and officer insurance costs as well as investor and public relations expenses.
However, should we grow our operations, we anticipate that such personnel-related expenses would increase. We also expect to continue to incur costs associated with being a public company and maintaining controls over financial reporting, including costs of accounting, audit, legal, regulatory, compliance and director and officer insurance costs as well as investor and public relations expenses.
Net cash provided by investing activities was $11.2 million for the year ended December 31, 2023 and consisted primarily of $19.0 million proceeds from maturity of marketable securities, offset by $7.8 million of purchase of property and equipment.
Cash Provided by (Used in) Investing Activities Net cash provided by investing activities was $44.0 million for the year ended December 31, 2025 and consisted primarily of the proceeds from maturities of marketable securities, offset by purchase of marketable securities and the purchase of property and equipment.
There is no assurance that we will be successful in obtaining sufficient financing on acceptable terms to continue funding our operations. 100 Funding Requirements We expect to continue to incur significant expenses, operating losses, and negative operating cash flows for the foreseeable future as we continue our novel genetic medicine discovery efforts, advance our pipeline candidates into the clinic and through clinical trials, seek regulatory approval of our product candidates and pursue commercialization of any approved product candidates.
Funding Requirements We expect to continue to incur significant expenses, operating losses, and negative operating cash flows for the foreseeable future as we continue our novel genetic medicine discovery efforts, advance our pipeline candidates into the clinic and through clinical trials, seek regulatory approval of our development candidates and pursue commercialization of any approved development candidates.
As of December 31, 2024, we have not sold any shares of common stock under our at-the-market equity offering program. As of December 31, 2024, we had cash, cash equivalents and marketable securities of $163.1 million.
As of December 31, 2025, we had not sold any shares of common stock under our at-the-market equity offering program. In January 2026, we issued 501,861 shares of common stock under the at-the-market offering program for gross proceeds of $5.1 million. As of December 31, 2025, we had cash, cash equivalents and marketable securities of $85.2 million.
General and administrative expenses also include facility costs not otherwise included in research and development expenses. We anticipate that our general and administrative expenses will increase in the future as we increase our headcount to support our continued research activities and development of our product candidates.
General and administrative expenses also include facility costs not otherwise included in research and development expenses. We anticipate that our general and administrative expenses will decrease or remain flat in the near future to support our current planned research activities and development of our lead candidates and development candidates at current personnel levels.
During the year ended December 31, 2023, we recognized no collaboration revenue. For additional information about our revenue recognition policy, see Note 2 and Note 13 in the consolidated financial statements included in this Annual Report on Form 10-K.
For additional information about our revenue recognition policy, see Note 2 and Note 12 to our audited consolidated financial statements included in this Annual Report on Form 10-K.
General and Administrative Expenses The following table summarizes our general and administrative expenses for the years ended December 31, 2024 and 2023: Year Ended December 31, (in thousands) 2024 2023 Change Personnel expenses $ 13,160 $ 13,443 $ (283 ) Professional services 9,640 8,507 1,133 Facilities expenses 3,732 3,253 479 Other 4,013 2,081 1,932 Total general and administrative expenses $ 30,545 $ 27,284 $ 3,261 General and administrative expenses were $30.5 million for the year ended December 31, 2024, compared to $27.3 million for the year ended December 31, 2023.
General and Administrative Expenses The following table summarizes our general and administrative expenses for the years ended December 31, 2025 and 2024: Year Ended December 31, (in thousands) 2025 2024 Change Personnel-related expenses $ 14,394 $ 13,160 $ 1,234 Professional services 7,021 9,640 (2,619 ) Facilities expenses 2,874 3,732 (858 ) Other 3,870 4,013 (143 ) Total general and administrative expenses $ 28,159 $ 30,545 $ (2,386 ) General and administrative expenses were $28.2 million for the year December 31, 2025, compared to $30.5 million for the year ended December 31, 2024.
We are generating a portfolio of differentiated programs that are designed to harness the body’s natural RNA editing process to effect a precise yet transient single base edit. By editing RNA instead of DNA, we are expanding the reach of genetic medicines by delivering additional precision and tunability, which has the potential for increased specificity and improved long-term tolerability.
By editing RNA instead of DNA, we are expanding the reach of genetic medicines by delivering additional precision and tunability, which has the potential for increased specificity and improved long-term tolerability.
Our internal research and development expenses are primarily personnel-related expenses, including stock-based compensation expense and facility expenses, mainly including office rent expenses and depreciation expenses.
Our internal research and development expenses are primarily personnel-related expenses, including stock-based compensation expense and facility expenses, mainly including office rent expenses and depreciation expenses. We do not allocate our internal research and development expenses to specific development candidate programs as they are deployed across multiple projects under research and development.
Moreover, regulators have not yet established any definitive guidelines related to overall development considerations for RNA editing therapies and limited clinical data has been generated to date. The versatility of RNA editing combined with our OPERA platform broadens the therapeutic target space significantly.
However, the scientific evidence to support the feasibility of developing our development candidates using our RNA editing technology is both preliminary and limited. Moreover, regulators have not yet established any definitive guidelines related to overall development considerations for RNA editing therapies and limited clinical data has been generated to date.
Critical Accounting Policies and Estimates Our management’s discussion and analysis of our financial condition and results of operations is based on our consolidated financial statements, which have been prepared in accordance with generally accepted accounting principles in the United States, or GAAP.
Net cash provided by financing activities was $69.4 million for the year ended December 31, 2024 and consisted of net proceeds from the April 2024 private placement and proceeds from exercises of stock options. 107 Critical Accounting Policies and Estimates Our management’s discussion and analysis of our financial condition and results of operations is based on our consolidated financial statements, which have been prepared in accordance with generally accepted accounting principles in the United States, or GAAP.
Other Income, Net Other income, net primarily consists of interest income earned on money market fund accounts and marketable securities. 98 Results of Operations Comparison of the Years Ended December 31, 2024 and 2023 The following table summarizes our results of operations for the years ended December 31, 2024 and 2023: Year Ended December 31, (in thousands) 2024 2023 Change Collaboration revenue $ 2,271 $ — $ 2,271 Operating expenses: Research and development 63,636 57,250 6,386 General and administrative 30,545 27,284 3,261 Total operating expenses 94,181 84,534 9,647 Loss from operations (91,910 ) (84,534 ) (7,376 ) Other income, net Other income, net 8,470 3,389 5,081 Total other income, net 8,470 3,389 5,081 Loss before provision for income taxes (83,440 ) (81,145 ) (2,295 ) Provision for income taxes (141 ) (27 ) (114 ) Net loss $ (83,581 ) $ (81,172 ) $ (2,409 ) Collaboration Revenue During the year ended December 31, 2024, we recognized $2.3 million of collaboration revenue from our research collaboration and license agreement with Novo Nordisk.
Other Income, Net Other income, net primarily consists of interest income earned on money market fund accounts and marketable securities. 103 Results of Operations Comparison of the Years Ended December 31, 2025 and 2024 The following table summarizes our results of operations for the years ended December 31, 2025 and 2024: Year Ended December 31, (in thousands) 2025 2024 Change Collaboration revenue $ 6,392 $ 2,271 $ 4,121 Operating expenses: Research and development 65,575 63,636 1,939 General and administrative 28,159 30,545 (2,386 ) Long-lived asset impairment charge 30,886 — 30,886 Restructuring charge 3,627 — 3,627 Total operating expenses 128,247 94,181 34,066 Loss from operations (121,855 ) (91,910 ) (29,945 ) Other income, net Other income, net 5,232 8,470 (3,238 ) Total other income, net 5,232 8,470 (3,238 ) Loss before provision for income taxes (116,623 ) (83,440 ) (33,183 ) Provision for income taxes (637 ) (141 ) (496 ) Net loss $ (117,260 ) $ (83,581 ) $ (33,679 ) Collaboration Revenue During the year ended December 31, 2025 and 2024, we recognized $6.4 million and $2.3 million of collaboration revenue, respectively, from our research collaboration and license agreement with Novo Nordisk.
We have not yet commercialized any product and we do not expect to generate revenue from sales of any products for several years, if at all. Since inception, we have funded our operations primarily through proceeds from the issuance of convertible preferred stock and common stock.
Liquidity and Capital Resources Sources of Liquidity Since our inception, we have generated recurring net losses. We have not yet commercialized any products and we do not expect to generate revenue from sales of any products for several years, if at all.
Cash Provided by Financing Activities Net cash provided by financing activities was $69.4 million for the year ended December 31, 2024 and consisted primarily of net proceeds of $67.4 million from the April 2024 private placement of shares of our common stock.
Cash Provided by Financing Activities Net cash provided by financing activities was $0.7 million for the year ended December 31, 2025 and consisted of proceeds from exercises of stock options.
Financial Operations Overview Revenue We have not generated any revenue from product sales, and do not expect to generate any revenue from the sale of products in the near future. During the year ended December 31, 2024, we recognized $2.3 million of collaboration revenue, which is related to our research collaboration and license agreement with Novo Nordisk.
During the year ended December 31, 2025 and 2024, we recognized $6.4 million and $2.3 million of collaboration revenue, respectively, which is related to our research collaboration and license agreement with Novo Nordisk.
Using an oligonucleotide-based approach, we expect to bring our medicines to patients by leveraging our proprietary platform with precedented delivery modalities, manufacturing know-how, and established regulatory pathways of approved oligonucleotide medicines. However, the scientific evidence to support the feasibility of developing product candidates using our RNA editing technology is both preliminary and limited.
We use an oligonucleotide-based approach and expect to bring our medicines to patients by leveraging our proprietary platform with precedented delivery modalities, including N-acetylgalactosamine, or GalNAc, -conjugated delivery for subcutaneous administration, manufacturing know-how, and established regulatory pathways of approved oligonucleotide medicines.
We expect that our cash, cash equivalents and marketable securities outstanding as of December 31, 2024, will be sufficient to fund our operating expenses and capital expenditure requirements into the second half of 2026 (including completion of the Phase 1/2a REWRITE clinical trial of KRRO-110 and progress additional product candidates).
We expect that our cash, cash equivalents and marketable securities outstanding as of December 31, 2025, together with the net proceeds raised under the January at-the-market offering program sales and March 2026 private placement, will be sufficient to fund our operating expenses and capital expenditure requirements into the second half of 2028.
Other Income, Net Total other income, net was $8.5 million for the year ended December 31, 2024, compared to $3.4 million for the year ended December 31, 2023.
Other Income, Net Total other income, net was $5.2 million for the year ended December 31, 2025, compared to $8.5 million for the year ended December 31, 2024. The decrease of $3.3 million was primarily due to lower interest income generated from a lower cash, cash equivalent and marketable securities balance in 2025 compared to 2024.
To date, we have not made any material adjustments to our prior estimates of accrued research and development expenses. Contractual Obligations and Other Commitments Our contractual obligations and commitments relate primarily to our operating leases and non-cancelable purchase obligations under agreements with various research and development organizations and suppliers in the ordinary course of business.
See Note 3 to our audited consolidated financial statements included in this Annual Report on Form 10-K for further discussion of our impairment analysis. Contractual Obligations and Other Commitments Our contractual obligations and commitments relate primarily to our operating leases and non-cancelable purchase obligations under agreements with various research and development organizations and suppliers in the ordinary course of business.
Research and Development Expenses The following table summarizes our research and development expenses for the years ended December 31, 2024 and 2023: Year Ended December 31, (in thousands) 2024 2023 Change Development candidate expenses KRRO-110 (AATD) external expenses (a) $ 20,906 $ 1,561 $ 19,345 Unallocated research and development expenses Other research and pre-development candidate expenses 12,928 31,139 (18,211 ) Personnel expenses 18,477 15,298 3,179 Facilities expenses 11,325 9,252 2,073 Total research and development expenses $ 63,636 $ 57,250 $ 6,386 (a) We started to break out KRRO-110 external expenses upon its development candidate nomination in December 2023.
Research and Development Expenses The following table summarizes our research and development expenses for the years ended December 31, 2025 and 2024: Year Ended December 31, (in thousands) 2025 2024 Change Development candidate expenses KRRO-110 (AATD) external expenses $ 17,870 $ 20,906 $ (3,036 ) KRRO-121 (UCD) external expenses 5,429 617 4,812 Unallocated research and development expenses Other research and pre-development candidate expenses 10,824 12,311 (1,487 ) Personnel expenses 21,010 18,477 2,533 Facilities expenses 10,442 11,325 (883 ) Total research and development expenses $ 65,575 $ 63,636 $ 1,939 104 Research and development expenses were $65.6 million for the year ended December 31, 2025, compared to $63.6 million for the year ended December 31, 2024.
Net cash used in operating activities was $67.3 million for the year ended December 31, 2023, which consisted of $81.2 million of net loss, $9.6 million of non-cash adjustments to net loss and an increase of $4.3 million in the net change in operating assets and liabilities.
Net cash used in operating activities was $60.1 million for the year ended December 31, 2024, primarily resulted from our net loss of $83.6 million, which was primarily attributable to our research and development activities and our general and administrative expenses, along with changes in our operating assets and liabilities of $13.6 million, offset by $9.9 million of non-cash items.
Our most advanced program is a development candidate, KRRO-110, which is in clinical development for the treatment of AATD where, using our proprietary RNA editing approach, we are repairing a pathogenic variant on RNA. KRRO-110 has the potential to be disease-modifying and provide a differentiated therapeutic option.
We are developing a next-generation GalNAc-conjugated RNA editing oligonucleotide for the treatment of AATD that has the potential to be disease-modifying and provide a differentiated therapeutic option. In May 2025, we announced a strategic plan to streamline our operations, including a reduction in workforce by 19%, or 21 positions.
The increase was primarily due to a $19.3 million increase in KRRO-110 external expenses, which was primarily attributable to higher manufacturing activities in 2024 to produce the clinical drug product and an increase in clinical trial activities in 2024 for the Phase 1/2a REWRITE clinical trial.
The increase was primarily due to the following: • a $4.8 million increase in KRRO-121 external expenses, primarily due to exploratory and manufacturing costs; and • a $2.5 million increase in personnel-related expenses, primarily due to the expansion of our clinical development function and stock-based compensation; • offset by a $3.0 million decrease in KRRO-110 external expenses, primarily due to a reduction in non clinical costs partially offset by an increase in clinical costs for the Phase 1/2a REWRITE clinical trial as it progressed during 2025; and • a $1.5 million decrease in other research and pre-development candidate expenses.
Removed
While our approach can be used to repair pathogenic single nucleotide variants, or SNVs, as demonstrated by our most advanced clinical-stage program, our AATD product candidate, we can also engineer de novo SNVs and change amino acids on proteins to endow them with desired properties while preserving their broader functional capabilities, as exemplified by three of our other programs (an undisclosed rare metabolic disorder, ALS, and pain).
Added
We are generating a portfolio of differentiated programs that are designed to harness the body’s natural RNA editing process to effect a precise yet transient change to a single nucleoside (adenosine to an inosine edit).
Removed
In preclinical studies, we have demonstrated that single RNA changes can disrupt protein-protein interactions, prevent protein aggregation, selectively modulate ion channels and activate kinases. These modification approaches can unlock validated target classes that have historically been difficult to drug, enabling us to pursue a broad range of diseases traditionally out-of-scope for other genetic medicine approaches and current traditional drug modalities.
Added
The versatility of RNA editing combined with our OPERA platform broadens the therapeutic target space significantly. The advent of large-scale genome sequencing has progressively revealed causal genetic variation underlying several human diseases, both rare and highly prevalent.
Removed
In January 2025, we announced dosing of the first participants in our REWRITE clinical program investigating KRRO-110 as a treatment for AATD. REWRITE is a two-part single and multiple dose-escalating Phase 1/2a clinical trial that will evaluate the safety and tolerability of KRRO-110 in up to 64 participants, including healthy adults and clinically stable AATD patients with the PiZZ genotype.
Added
Genetic mutations, including SNVs implicated in disease have been found to be diverse in nature and can affect the function of genes and their associated downstream biochemical pathways. Data correlating DNA to RNA to disease phenotype have demonstrated that SNVs lead to a loss-of-function or a gain-of-function of the gene.
Removed
Secondary and exploratory endpoints include pharmacokinetic and pharmacodynamic parameters that will guide optimal dose selection for later stage studies. We have completed dosing of the first two single ascending dose cohorts in healthy adult volunteers.
Added
In addition, the majority of SNVs implicated in complex diseases are due to modulation of gene function. By editing RNA to mimic a SNV, we believe we will be able to address unmet patient need by transiently modifying gene expression and the resultant protein function.
Removed
We have not observed any serious adverse events as of the date of this annual report on Form 10-K through completion of dosing of the first two cohorts. We continue to progress enrollment, site activation and expansion into other geographies beyond Australia, including the U.S.
Added
We continue to make meaningful advancements across our programs, including KRRO-121 as a potential first-in-class treatment for hyperammonemia that has the potential to address substantial unmet need in patients with poor ammonia control, including those with UCD and HE.
Removed
In March 2025, we announced that the FDA has granted orphan drug designation to KRRO-110 for the treatment of AATD. Interim data from single ascending doses in healthy volunteers and AATD patients is expected in the second half of 2025, and completion of the trial is anticipated in 2026.
Added
KRRO-121 is an RNA-editing oligonucleotide conjugated with GalNAc in development for the potential treatment of UCDs of any mutational background in adults and adolescents. Utilizing our proprietary platform, we designed KRRO-121 to edit the GLUL transcript (the gene for the GS protein), to generate a stabilized, de novo variant of GS with enhanced ammonia clearance capacity.
Removed
Based on the preclinical data, we believe KRRO-110 has best-in-class potential for the treatment of AATD. However, KRRO-110 is in early clinical development and there is no guarantee that it will be successful.
Added
This synthetic rescue approach creates a compensating protein rather than repairing the underlying urea cycle defect.
Removed
We do not allocate our internal research and development expenses to specific drug candidate programs as they are deployed across multiple projects under research and development. 97 The successful development of our product candidates is highly uncertain.
Added
By editing GS mRNA to create a de novo protein with a single amino acid change that prevents glutamine-induced proteasomal degradation, we aim to maintain consistent ammonia clearance capacity irrespective of the specific enzyme deficiency in patients with UCD and to reduce ammonia levels in patients with HE.
Removed
During the year ended December 31, 2023, we recognized no collaboration revenue.
Added
We anticipate a regulatory filing to enable commencement of a first-in-human trial in the second half of 2026. In November 2025, we announced that KRRO-110 did not reach projected levels of functional protein following a single administration and pivoted to GalNAc delivery for patients with AATD with development candidate nomination expected in the second quarter of 2026.
Removed
Research and development expenses were $63.6 million for the year ended December 31, 2024, compared to $57.2 million for the year ended December 31, 2023.
Added
In November 2025, we implemented a strategic restructuring to extend cash runway, including a further workforce reduction of approximately 34%. Please see Note 16 to our audited consolidated financial statements included elsewhere in this Annual Report on Form 10-K.
Removed
A portion of the increase was also due to a $3.2 million increase in personnel-related expenses driven by an increase in headcount to support the expansion of our research and clinical development function, and a $2.1 million increase in facility costs due to the expansion of our mixed-use office spaces and overall support of research and development activities.
Added
Recent Developments At-the-Market Offering Program In January 2026, we issued 501,861 shares of common stock under our December 2024 at-the-market sales agreement for gross proceeds of $5.1 million, before deducting estimated offering expenses.
Removed
These increases were partially offset by a $18.2 million decrease in other research and pre-development candidates expenses, which was primarily attributable to the breakout of 99 KRRO-110 external expenses upon its December 2023 development candidate nomination as well as less lab supplies and consumables purchased for research and preclinical activities.
Added
March 2026 Private Placement On March 9, 2026, we entered into a subscription agreement with certain new and existing accredited investors to issue and sell in a private placement an aggregate of 4,501,928 shares of our common stock at a purchase price of $11.11 per share and pre-funded warrants to purchase up to an aggregate of 3,148,836 shares of our common stock (at an exercise price of $0.001 per share) at a price of $11.109 per pre-funded warrant.
Removed
The increase of $3.3 million was primarily driven a $1.9 million increase in information technology, insurance and other costs, a $1.1 million increase in professional fees, and a $0.5 million increase in facility costs primarily due to the expansion of our mixed-use office spaces and overall support of the growth of our company, partially offset by a $0.3 million decrease in employee related expenses.
Added
The private placement, which closed March 10, 2026, resulted in gross proceeds of approximately $85.0 million before deducting placement agent fees and estimated offering expenses. Financial Operations Overview Revenue We have not generated any revenue from product sales, and do not expect to generate any revenue from the sale of products in the near future.
Removed
We incurred $2.5 million of severance cost for Frequency employees related to the November 2023 business combination during year ended December 31, 2023. No comparable costs occurred during year ended December 31, 2024.
Added
In 101 November 2025, we agreed to a 12 month pause on such collaboration with Novo Nordisk, and accordingly, we do not expect to recognize any material collaboration revenue under such agreement during the 12-month hold period.
Removed
The increase of $5.1 million was primarily due to an increase of $5.1 million in interest income earned from our cash, cash equivalents and marketable securities driven by interest rates and higher marketable securities balance. Liquidity and Capital Resources Sources of Liquidity Since our inception, we have generated recurring net losses.
Added
Long-lived Asset Impairment Charges We determined that indicators of impairment existed during the fourth quarter of 2025 and, as a result, our long-lived assets were reviewed for impairment. We assessed the recoverability of our single enterprise-wide asset group and determined that the assets were not fully recoverable when compared to the future undiscounted cash flows from the asset group.

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Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

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Biggest changeItem 7A. Q uantitative and Qualitative Disclosures About Market Risk. As of December 31, 2024, we had cash, cash equivalents and marketable securities of $163.1 million, which consist of bank deposits, money market funds and US treasury and other government-backed securities.
Biggest changeItem 7A. Q uantitative and Qualitative Disclosures About Market Risk. As of December 31, 2025, we had cash, cash equivalents and marketable securities of $85.2 million, which consist of bank deposits, money market funds and US treasury and other government-backed securities.
Interest income is sensitive to changes in 103 the general level of interest rates; however, due to the nature of these investments, an immediate 10% change in market interest rates would not have a material effect on the fair market value of our cash, cash equivalents or marketable securities. Our employees and operations are primarily located in the United States.
Interest income is sensitive to changes in the general level of interest rates; however, due to the nature of these investments, an immediate 10% change in market interest rates would not have a material effect on the fair market value of our cash, cash equivalents or marketable securities. Our employees and operations are primarily located in the United States.
Inflation generally affects us by increasing our cost of labor and research, manufacturing and developments costs. We believe that inflations has not had a material effect on our financial statements included elsewhere in this Annual Report on Form 10-K. However, our operations may be adversely affected by inflation in the future. 104
Inflation generally affects us by increasing our cost of labor and research, manufacturing and developments costs. We believe that inflations has not had a material effect on our financial statements included elsewhere in this Annual Report on Form 10-K. However, our operations may be adversely affected by inflation in the future. 109

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