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Item 1. Business

2026-03-19 compared with 2025-03-24 · 332 added, 280 removed, 500 unchanged (55% of the section changed)

We are a clinical-stage biotechnology company focused on developing treatments for patients suffering from complex rare diseases using our novel cell penetrating peptide (“CPP”) technology platform.

Our lead product candidate, nomlabofusp (nomlabofusp is the International Nonproprietary Name ("INN") and the United States Adopted Name ("USAN") for CTI-1601), is a subcutaneously administered, recombinant fusion protein intended to deliver tissue frataxin ("FXN"), an essential protein, to the mitochondria of patients with Friedreich's ataxia (“FA”).

Our lead product candidate, nomlabofusp, is a subcutaneously administered, recombinant fusion protein intended to deliver frataxin (“FXN”), an essential protein, to the mitochondria of patients with Friedreich's ataxia (“FA”).

FA is a rare, progressive, and fatal disease in which patients are unable to produce sufficient FXN due to a genetic abnormality.

Currently, there are no treatment options that address the core deficit of FA, low levels of FXN.

Nomlabofusp represents the first potential therapy designed to increase FXN levels in patients with FA.

We believe that our CPP platform, which enables a therapeutic molecule to cross a cell membrane in order to reach intracellular targets, has the potential to enable the treatment of other rare and orphan diseases.

Nomlabofusp represents the first potential therapy designed to systemically increase FXN levels in patients with FA.

We believe that our CPP platform, which enables a therapeutic molecule to cross a cell membrane in order to reach intracellular targets, also has the potential to enable the treatment of other rare and orphan diseases.

We intend to use our proprietary platform to target additional orphan indications characterized by deficiencies in or alterations of intracellular content or activity.

Since our inception, we have devoted substantially all of our resources to developing nomlabofusp, building our intellectual property portfolio, developing third-party manufacturing capabilities, business planning, raising capital, and providing general and administrative support for such operations.

As of December 31, 2024, we had cash, cash equivalents and marketable securities of $183.5 million, which we anticipate will fund operations into the second quarter of 2026.

As of December 31, 2025, we had cash, cash equivalents, and marketable securities of $136.9 million, which, together with the net proceeds of $107.6 million from our February 2026 public offering of common stock, we anticipate will fund operations into the second quarter of 2027.

Nomlabofusp Program Update

We have completed two Phase 1 clinical trials and a Phase 2 dose exploration trial and have an ongoing Phase 2 OLE trial in patients with FA and an ongoing pharmacokinetic (PK) run-in study in adolescent patients with FA.

In May 2021, we reported positive top-line data from our Phase 1 FA program after completing dosing of the single ascending dose ("SAD") trial in December 2020 and of the multiple ascending dose ("MAD") trial in March 2021.

Data from these trials demonstrated proof-of-concept by showing that daily subcutaneous injections of nomlabofusp for up to 13 days resulted in dose-dependent increases in FXN levels from baseline compared to placebo in all evaluated tissues (buccal cells, skin, and platelets).

There were no serious adverse events associated with either the MAD or SAD trials.

In May 2023, we reported preliminary unblinded top-line data from the 25 mg cohort of our Phase 2 four-week, placebo-controlled, dose exploration trial of nomlabofusp in FA patients.

Data from the cohort indicated nomlabofusp was generally well tolerated and showed increases in FXN levels from baseline compared to placebo in all evaluated tissues (skin and buccal cells) at day 14.

In July 2023, the FDA cleared initiation of a second cohort (50 mg) of our four-week, placebo-controlled, Phase 2 dose exploration trial of nomlabofusp in patients with FA and the initiation of our OLE trial with daily dosing of 25 mg.

In February 2024, we reported positive top-line data and successful completion of the Phase 2 dose exploration study.

Nomlabofusp was generally well tolerated throughout the four-week treatment periods, had a predictable pharmacokinetic profile and led to dose dependent increases in FXN levels in all evaluated tissues (skin and buccal cells) after daily dosing of 14 days followed by every other day dosing until day 28 in the 25 mg and 50 mg cohorts.

Participants in the 25 mg (n=13) and 50 mg (n=15) cohorts were randomized 2:1 to receive subcutaneous injections of nomlabofusp or placebo.

Patients who completed treatment in our Phase 2 dose exploration study or who previously completed a prior clinical trial of nomlabofusp are eligible to screen and possibly participate in the OLE study.

In March 2024, we dosed the first patient in our OLE trial, evaluating daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver.

The OLE study will evaluate the safety and tolerability, pharmacokinetics, and frataxin levels in peripheral tissues as well as other exploratory pharmacodynamic markers (lipid profiles and gene expression data) following long-term subcutaneous administration of nomlabofusp.

In addition, following the completion of enrollment, as well as at least one

participant completing one year of dosing, clinical assessments collected during the study will be compared to data from a matched control arm derived from participants in the Friedreich’s Ataxia Clinical Outcome Measures Study ("FACOMS") database.

On May 30, 2024, we announced that the FDA's Center for Drug Evaluation and Research ("CDER") had selected nomlabofusp as one of a few programs for participation in the Support for Clinical Trials Advancing Rare Disease Therapeutics ("START") Pilot Program.

We have Orphan Drug Designation, Fast Track Designation, Pediatric Rare Disease Designation and Breakthrough Therapy Designation from the FDA and have been granted Orphan Drug Designation and access to the European Medicines Agency’s (“EMA’s”) Priority Medicines Program (“PRIME”) scheme in the European Union (the “EU”).

We have also received access in the United Kingdom (the “UK”) to the Medicines and Healthcare Regulatory Agency’s (“MHRA”) Innovative Licensing and Access Pathway (“ILAP”).

These programs are designed to facilitate development of certain therapeutics such as those for rare and serious diseases, and those that have the potential to meet an unmet medical need.

The FDA’s Center for Drug Evaluation and Research selected nomlabofusp as one of a few drug development programs for participation in the Support for Clinical Trials Advancing Rare Disease Therapeutics (“START”) Pilot Program.

The objective of the program is to accelerate the development of drugs for rare diseases that lead to significant disability or death by facilitating frequent advice and regular communication with the FDA staff to expedite the review process of biologics and drugs.

In September 2024, we received access to the Medicines and Healthcare Regulatory Agency ("MHRA") Innovative Licensing and Access Pathway (“ILAP”) for the treatment of adults and children with FA.

The ILAP is facilitating patient access to novel treatments by accelerating time to market through opportunities for enhanced engagements with UK regulatory authorities and other stakeholders.

Along with the receipt of the ILAP designation, nomlabofusp has already been granted orphan drug designations in the U.S.

and the European Union (the “EU”), and access to the PRIME scheme in the EU.

In December 2024, we reported positive initial data from our ongoing OLE study.

This data included safety, FXN levels, clinical, pharmacokinetic data and dose escalation:

• Nomlabofusp was generally well tolerated for up to 260 days in subjects.

The most common adverse events were injection site reactions, with most being mild, brief in duration, and self-limited.

Two participants had serious adverse events (one seizure and one anaphylactic reaction) that resolved within 24 hours and withdrew from the study;

• Long-term 25 mg tissue FXN levels showed positive mean change from baseline of 1.32 pg/μg in buccal cells and 9.28 pg/μg in skin cells at Day 90 and that 25 mg of nomlabofusp increased and maintained tissue FXN levels over time, increasing from a mean level of 15% of healthy volunteers ("HV") at baseline to 30% in buccal cells and from 16% to 72% in skin cells at Day 90;

• Tissue FXN levels appear to reach steady-state levels by Day 30 in buccal cells;

• Early clinical data showed trends toward improvement across a number of clinical outcomes for long-term 25 mg daily nomlabofusp including:

(1) decreased values indicating early trends towards improvement in the Modified Friedreich Ataxia Rating Scale ("mFARS") and the FARS-Activities of Daily Living ("ADL"), Modified Fatigue Impact Scale and 9-hole peg test at 90 days relative to baseline;

• Key pharmacokinetic data showed rapid absorption after subcutaneous administration with exposure appearing to reach steady state in plasma by day 30 with no further accumulation, which is consistent with data from our Phase 1 and Phase 2 studies.

Also in December 2024, we announced that we were increasing the dose in the OLE to 50 mg of nomlabofusp daily for then currently enrolled and all future OLE study participants.

In March 2025, we announced that our Safety Monitoring Team has deemed anaphylaxis as an adverse drug reaction likely associated with nomlabofusp and therefore, we expect to see additional reactions.

To reduce the risk of allergic reactions, including anaphylaxis, we amended the OLE protocol to administer premedication for the first month of dosing.

The OLE study is ongoing with seven sites activated and participants continuing to enroll.

All study participants are currently receiving the 50 mg dose of nomlabofusp.

We plan to provide an update on OLE data on at least 30 to 40 study participants, some of whom have been receiving nomlabofusp for more than a year, in September 2025.

We have engaged in multiple discussions and interactions with the FDA in connection with our clinical development of nomlabofusp and communications remain ongoing.

We have also had numerous interactions with the EMA, the MHRA, and Canada’s Health Canada regarding the clinical development of nomlabofusp.

We have completed four clinical studies:

(i) two Phase 1 clinical studies in adults, (ii) a Phase 2 dose exploration study in adults and (iii) a Phase 1 pharmacokinetic (“PK”) run-in study in adolescents (12-17 years old).

We currently have an ongoing open label ("OL") study (previously referred to as the Open Label Extension, (“OLE”) study) in adults and adolescents with FA.

Approximately 8,000 doses of nomlabofusp have been administered to patients throughout the clinical development program.

Recent significant developments are as follows:

• In December 2024, we reported initial data from our ongoing OL study.

This data included safety, FXN levels, clinical and PK data in 14 participants administered 25 mg nomlabofusp daily for up to 260 days (mean 99 days).

Tissue FXN levels increased and were maintained at day 90 and there were early trends towards improvement in clinical outcomes observed at day 90.

The most common adverse events were injection site reactions and two participants experienced serious adverse events (one seizure and one

anaphylactic reaction) that resolved within 24 hours and they were withdrawn from the study.

Also in December 2024, we announced that we were increasing the dose in the OL study to 50 mg of nomlabofusp daily for then currently enrolled participants and would be starting all new patients on 50 mg daily and in March 2025 we announced that all participants had transitioned to the 50 mg daily dose.

In March 2025 we also announced that our Safety Monitoring Team had identified anaphylaxis as an adverse drug reaction likely associated with nomlabofusp.

• In January 2025, we initiated dosing of adolescents (12-17 years old) in a PK run-in study for pediatric patients with FA.

Study participants in the PK run-in study are randomized 2:1 to receive either nomlabofusp at a weight-base dose expected to match the PK of adults receiving the 50 mg dose, or placebo, daily for seven days.

Following assessment of safety and PK data, participants will be eligible to screen for the OLE study.

The data from this cohort is expected to be presented during the nomlabofusp program update in September 2025.

In March 2025, we announced that FDA stated in written correspondence associated with a meeting through the START pilot program that they are open to considering the use of FXN concentration as a reasonably likely surrogate endpoint (“RLSE”) and the acceptability of FXN’s use as an RLSE would ultimately be a matter of review of the data in a future marketing application.

FDA recommended focusing on assessments of skin FXN concentrations rather than buccal FXN concentrations due to more consistent sampling and less variability.

FDA acknowledged that data we recently submitted appear to support a relationship between increased FXN

concentrations in skin cells and relevant tissues such as the heart, dorsal root ganglion and skeletal muscle.

FDA also acknowledged that the nonclinical studies we submitted were performed at relevant human doses.

FDA also suggested that we consider exploring the relationship between increases in FXN in skin and changes in pharmacodynamic (PD) markers such as lipid profiles and/or clinical measures to provide additional support for the use of FXN as an RLSE.

We plan to continue discussions with FDA regarding the adequacy of the safety data set for a BLA submission seeking accelerated approval targeted for year-end 2025.

Additionally, we have obtained feedback from both FDA and EMA on the global Phase 3 study protocol and we are on track to initiate the study by mid-2025 with potential sites in the U.S., E.U., U.K, Canada, and Australia.

Our strategy is to become a leader in the treatment of rare diseases by leveraging our technology platform and applying our management team’s know-how and expertise to the development of nomlabofusp and other future pipeline programs.

Study participants in the PK run-in study were randomized 2:1 to receive either nomlabofusp at a weight-base dose expected to match the PK of adults receiving the 50 mg dose, or placebo, daily for seven days.

We completed dosing in 14 adolescents in March 2025.

The PK and exposure data were similar to adults and the participants became eligible to enroll in the OL study.

The PK results from the adolescent cohort also supported the predictive value of our exposure modeling and will facilitate direct enrollment of children (2-11 years old) into the OL study which would eliminate any pause in study drug administration between the PK study and the OL study.

Therefore, it was not necessary to perform a cohort for children in the PK study and we terminated the study.

We are now planning to initiate enrollment of children directly into the ongoing OL study.

• In February 2025, the FDA accepted the data supporting the comparability of the lyophilized drug product to the frozen solution and agreed with our plans to introduce the lyophilized product into our clinical development program.

In July 2025, we began introducing the lyophilized product formulation into the OL study.

This is the formulation intended for commercialization.

• In March 2025, we announced that the FDA stated as part of the START pilot program, that it is open to considering the use of FXN concentration as a reasonably likely surrogate endpoint (“RLSE”) and the acceptability of FXN concentration as an RLSE to support accelerated approval will be a matter of review in a future marketing application.

The FDA recommended focusing on assessments of skin FXN concentrations rather than buccal FXN concentrations due to more consistent sampling and less variability.

The FDA acknowledged that data we submitted appeared to support a relationship between increased FXN concentrations in skin and relevant tissues such as the heart, dorsal root ganglion and skeletal muscle.

The FDA also acknowledged that the nonclinical studies we submitted were performed at relevant human doses.

The FDA also suggested that we consider exploring the relationship between increases in FXN in skin and changes in pharmacodynamic (“PD”) markers such as lipid profiles and/or clinical measures to provide additional support for the use of FXN as an RLSE.

• In June 2025, the FDA provided recommendations regarding the safety data set that might be needed to support a Biologics License Application (“BLA”) seeking accelerated approval, which included evaluating safety in at least 30 participants with continuous study drug exposure for six months and a subset of at least 10 of those participants with continuous study drug exposure for one year, with the large majority of data coming from participants receiving the 50 mg dose.

• In July 2025, we announced the publication of nonclinical data evaluating the mechanism of action, pharmacodynamics and pharmacology of nomlabofusp as a novel FXN protein replacement therapy designed to address the underlying cause of FA in two peer-reviewed articles.

These data were included in the briefing package reviewed by the FDA in support of using skin FXN concentrations as a RLSE for our registrational program seeking accelerated approval for nomlabofusp.

• In September 2025, we announced positive 25 mg and 50 mg data from the OL study evaluating daily subcutaneous injections of nomlabofusp self-administered or administered by a caregiver in participants with FA.

Ten out of 10 participants with data at six months achieved skin FXN levels that were higher than 50% of median levels in healthy volunteers and similar to levels expected in asymptomatic carriers.

We also observed consistent directional improvements across four key clinical outcomes relative to a worsening in a Friedreich's Ataxia Clinical Outcomes Measure study (“FACOMS”) natural history study reference population.

In participants receiving long term continuous treatment, including 14 participants on nomlabofusp for at least six months, eight of whom continued to be on nomlabofusp for over one year, daily administration of nomlabofusp was generally well-tolerated.

Anaphylaxis was reported in seven participants, with most events occurring on the initial day of administration and all occurring within the first 6 weeks of dosing.

As a result, we consulted experts and decided to modify the starting dose regimen

and the FDA agreed with our approach.

The most common adverse events continued to be local injection site reactions that are mostly mild, brief in duration and self-limited.

• In September 2025 we also announced that we amended the previous OLE study protocol (which had only included participants from previous clinical trials of nomlabofusp) to include adolescent and adult patients who have not previously participated in a prior nomlabofusp study and the study is now being referred to as the OL study.

In addition to risk mitigation measures against anaphylaxis that are already in place such as pre-medicating with antihistamines and supplying epinephrine auto-injectors to study participants, we introduced a new dosing regimen in which participants initially receive a 5 mg dose followed by a 25 mg dose one hour later under observation.

Nomlabofusp 25 mg is then administered once daily through day 30 and then the dose is increased to 50 mg once daily.

• In February 2026, the FDA granted the nomlabofusp program Breakthrough Therapy Designation (“BTD”).

BTD is intended to expedite the development and regulatory review of a drug intended to treat a serious condition.

A drug is eligible for BTD if preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available treatments in one or more clinically significant endpoints.

• Also in February 2026, as a result of a START pilot program meeting with the FDA, we announced continued alignment with the FDA to consider the use of skin FXN as a novel surrogate endpoint reasonably likely to predict clinical benefit to support a planned Biologics License Application (BLA) submission seeking accelerated approval and that the use of FXN as a novel surrogate endpoint to support accelerated approval.

There was also agreement on the type of analyses required to support the exposure response relationships for the nomlabofusp program.

The FDA stated that the adequacy of the safety database will be a matter of review at the time of BLA submission.

We are targeting to provide topline study data from our OL study in the second quarter of 2026 and we plan to submit a BLA seeking accelerated approval in June 2026.

For our global confirmatory Phase 3 study, we are planning sites in the U.S., E.U., U.K., Canada and Australia.

We have obtained feedback from both the FDA and the EMA on the study protocol.

Our clinical trial application was recently approved by Health Canada Authorities and now will undergo Ethics Committee review.

We have also filed our CTIS application with the EMA and it is currently under review.

Submission to the U.K.

regulatory authorities is expected to follow soon.

We plan to initiate screening in the U.S.for the study in the second quarter of 2026, with dosing of the first patient expected in mid-2026.

Our strategy is to become a leader in the treatment of rare diseases by leveraging our CPP technology platform and applying our management team’s know-how and expertise to the development of nomlabofusp and other future pipeline programs.

Key elements of our strategy include:

• Advance nomlabofusp through clinical development and regulatory approval in the United States the European Union and other foreign jurisdictions We have completed two Phase 1 clinical trials and a Phase 2 dose exploration trial in patients with FA in the United States and have an ongoing OLE study in the U.S with patients age 18 or older with initial dosing of 25 mg of nomlabofusp daily, which, in November 2024, we began increasing to 50 mg daily.

In January 2025, we started dosing adolescents (12-17 years old) in a nomlabofusp pediatric PK run-in study.

Study participants in the PK run-in study are randomized 2:1 to receive either nomlabofusp or placebo daily for seven days.

Adolescents receive a weight-based dose expected to match the PK of adults receiving the 50 mg dose.

Adolescents who complete participation in the PK run-in study will be eligible to screen in the ongoing OLE study following assessment of safety and PK data.

• Advance nomlabofusp through clinical development and regulatory approval in the United States the European Union and other foreign jurisdictions.

We have completed two Phase 1 clinical trials in adults along with a Phase 1 PK run-in study in adolescents and a Phase 2 dose exploration trial in adults with FA.

We also have an ongoing OL study in adults and adolescents with FA in which participants receive 50 mg nomlabofusp daily.

Enrollment in this study is now open to adolescents and adult patients regardless of whether they participated in a previous nomlabofusp trial.

We are continuing to develop and execute a clinical development plan for regulatory approval of nomlabofusp in the United States, the European Union, the United Kingdom (“UK”), Australia, Canada and potentially other countries.

We have obtained feedback from both FDA and EMA on the global Phase 3 study protocol and we are on track to initiate the study by mid-2025 with potential sites in the U.S., E.U., U.K, Canada, and Australia.

We are continuing discussions with FDA regarding the adequacy of the safety data set required to support BLA submission and we are targeting BLA submission by the end of 2025 to seek accelerated approval.

• Intend to pursue the use of tissue frataxin levels as a novel surrogate endpoint to support a potential Biologics License Application (“BLA”) submission for accelerated approval .

We have had discussions with the FDA regarding the potential use of tissue FXN levels as a novel surrogate endpoint.

The FDA acknowledged that frataxin deficiency appears to be critical to the pathogenic mechanism of FA, and that there continues to be an unmet need for treatments for FA patients that address the underlying disease pathophysiology.

In March 2025, we announced that FDA stated in written correspondence associated with a meeting through the START pilot program that they are open to considering the use of FXN concentration as an RLSE and the acceptability of FXN’s use as an RLSE would ultimately be a matter of review of the data in a future marketing application.

We intend to pursue an accelerated approval using FXN levels, supportive PD and clinical information, and safety data from the OLE study, along with additional non-clinical pharmacology information needed to support the novel surrogate endpoint approach.

We are continuing to plan for a confirmatory study and have received feedback from FDA on the design of this study.

We are targeting a BLA submission by the end of 2025.

• If nomlabofusp receives regulatory approval(s), commercialize nomlabofusp in the United States, the European Union, and other relevant countries independently or with third parties.

We intend to evaluate commercialization options in the United States, the European Union, the United Kingdom and in other foreign jurisdictions throughout the world where FA patients can benefit, if we are successful in obtaining regulatory approval.

We may build our own internal sales force;

partner with a contract sales organization, and/or enter into a joint marketing partnership with another pharmaceutical or biotechnology company, whereby we may jointly sell and market nomlabofusp, if approved;

or we may seek to out-license nomlabofusp, whereby other pharmaceutical or biotechnology companies sell and market nomlabofusp and pay us milestone and/or royalty payments on sales.

We have obtained feedback from both FDA and EMA on the global Phase 3 confirmatory study protocol and continue to qualify sites in the U.S., E.U., U.K, Canada, and Australia and we plan to initiate screening in this Phase 3 study in the second quarter of 2026, with dosing of the first patient expected in mid-2026.

We are targeting nomlabofusp BLA submission in June 2026 seeking accelerated approval using tissue FXN levels as a novel surrogate endpoint.

• If nomlabofusp receives regulatory approval(s), we intend to commercialize nomlabofusp in the United States, the European Union, and other relevant countries independently or with third parties.

We may build our own internal sales force, partner with a contract sales organization, enter into a joint marketing partnership with another pharmaceutical or biotechnology company, or we may seek to out-license nomlabofusp.

• Expand our product candidate pipeline to treat a variety of rare diseases.

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This approach is inefficient, as there are thousands of diseases, each with a distinct patient population, that cannot be addressed by traditional therapeutic approaches and are in need of treatment options.

Our understanding of our therapeutics derived from proprietary gene expression data across several disease models supports the concept that product candidates based on our platform technology could significantly impact common pathological mechanisms in various diseases with comparable etiologies.

Our understanding of our platform and our bioengineering capabilities support the concept that product candidates based on our platform technology could significantly impact common pathological mechanisms in various diseases with comparable etiologies.

We are utilizing this approach to identify therapeutic opportunities where our molecules and technology are more likely to be impactful.

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Friedreich’s ataxia

Friedreich’s ataxia is a rare genetic disease that is the most commonly inherited ataxia in humans, with approximately 20,000 individuals living with Friedreich’s ataxia globally, and of these individuals, approximately 5,000 are in the United States and the majority of the remaining individuals are primarily in Europe.

Friedreich’s ataxia results from a deficiency of the mitochondrial protein, FXN.

FXN is an essential and phylogenetically conserved protein that is found in cells throughout the body, with the highest levels found in the heart, spinal cord, liver, pancreas, and skeletal muscle.

FA is a rare genetic disease that is the most commonly inherited ataxia in humans, with approximately 20,000 individuals living with Friedreich’s ataxia globally, and of these individuals, approximately 5,000 are in the United States and the majority of the remaining individuals are primarily in Europe.

Friedreich’s ataxia results from a deficiency of the mitochondrial protein, frataxin, (“FXN”).

FXN is an essential and phylogenetically conserved protein that is found in cells throughout the body, with higher levels found in the heart, spinal cord, liver, pancreas, and skeletal muscle.

FXN is encoded in the nucleus of the cell, expressed in the cytoplasm and transported into the mitochondria, where it is processed to the mature form.

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Nomlabofusp, an investigational biologic fusion protein that is administered subcutaneously, consists of a CPP genetically fused to human FXN, and includes a mitochondrial targeting sequence.

Using our proprietary peptide delivery technology, nomlabofusp is designed to carry the molecule from the intravascular space across the cell membrane and into the mitochondria where the CPP and the mitochondrial targeting sequence are cleaved off to yield mature FXN.

See Figure 1.

We have completed two Phase 1 nomlabofusp clinical trials, and a Phase 2 dose exploration trial and have an ongoing OLE study in the U.S with patients with initial dosing of 25 mg of nomlabofusp daily, which in November 2024 we increased to 50 mg daily.

In January 2025, we started dosing of adolescents (12-17 years old) in a nomlabofusp pediatric PK run-in study.

Study participants in the PK run-in study are randomized 2:1 to receive either nomlabofusp or placebo daily for seven days.

Adolescents receive a weight-based dose equivalent to the 50 mg adult dose.

Adolescents who complete participation in the PK run-in study will be eligible to screen in the ongoing OLE study.

Following assessment of safety and PK data of each successive cohort, participants will be eligible to screen for the OLE study.

Based on the results of our non-clinical development program as well as results from our Phase 2 clinical trials, we believe that administering nomlabofusp may increase FXN levels in the mitochondria of patients with Friedreich’s ataxia and patients could potentially experience:

We have completed two Phase 1 clinical trials and a Phase 2 dose exploration trial in adults with FA, along with a Phase 1 PK run-in study in adolescents with FA (12-17 years old).

We also have our ongoing Phase 2 OL trial in adults and adolescents with FA in which participants receive 50 mg nomlabofusp daily.

Enrollment in this study is now open to adolescents and adult patients regardless of whether they participated in a previous nomlabofusp trial.

• improved cellular function;

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In our Phase 1 clinical trials, nomlabofusp appeared to increase FXN levels in the peripheral tissues that were tested (buccal cells, skin biopsies and platelets) and data from our Phase 2 dose exploration study demonstrated dose dependent increases in FXN levels in all evaluated tissues (skin and buccal cells) after daily dosing of 14 days followed by every other day dosing until day 28 in the 25 mg and 50 mg cohorts.

Based on this, we believe that our technology may allow us to address other rare genetic diseases that either require the replacement of molecules that need to target specific intracellular organelles, or that share similar clinical symptoms that overlap with Friedreich’s ataxia.

Data from the ongoing OL study showed increases in skin FXN levels in 10 of 10 participants with data at six months.

These skin FXN levels were higher than 50% of median levels in healthy volunteers similar to levels expected in asymptomatic carriers.

We also observed consistent directional improvement across four key clinical outcomes after one year of nomlabofusp treatment relative to a worsening observed in a FACOMS natural history study reference population.

The most common adverse events were mild/moderate injection site reactions and we have identified anaphylaxis as an adverse event likely associated with nomlabofusp administration and have implemented several risk mitigation measures.

We believe that our technology may allow us to address other rare genetic diseases that either require the replacement of molecules that need to target specific intracellular organelles, or that share similar clinical symptoms that overlap with Friedreich’s ataxia.

Finally, the use of nomlabofusp to improve mitochondrial function in other rare diseases that demonstrate evidence of mitochondrial dysfunction is also being explored.

Development of Nomlabofusp

Non-clinical Development

Knock-Out Mice and Other Non-clinical Studies

Nomlabofusp has been demonstrated to prolong the life of knock-out ("KO") mice whose heart and skeletal muscles were deficient in FXN.

Non-clinical Pharmacology

Following nomlabofusp dosing in multiple non-clinical studies in rodents and non-human primates (“NHPs”), human FXN was found to be distributed into all tissues tested, as shown in Figure 2.

Observed hFXN across all tissue and cell types tested:

Cardiac Mitochondria

CSF (Cerebrospinal Fluid)

Dorsal Root Ganglia

Skeletal Muscle

In a study in Sprague Dawley rats in which nomlabofusp was administered daily via SC injection for 7 days, a dose‑dependent increase in hFXN was observed in skin and disease-related target tissues (heart, dorsal root ganglion and skeletal muscle).

Furthermore, increases in rat skin hFXN after administration of nomlabofusp were correlated with increases in hFXN in these tissues.

These results demonstrate that changes in skin FXN concentrations can be used to predict changes in FXN concentrations of other tissues following administration of nomlabofusp.

Correlations were observed not only with skin, but also between tissues, corroborating that hFXN measurements in one tissue are indicative of concentrations in other tissues (De Toni, F., Ragaglia, V., Schecter, D.

Pharmacokinetics and Pharmacodynamics of Nomlabofusp in Non-clinical Studies of Friedreich’s Ataxia.

AAPS J 27, 112 (2025)).

Nomlabofusp was demonstrated to prolong the life of knock-out (“KO”) mice whose heart and skeletal muscles were deficient in FXN.

These mice, when untreated, develop a severe hypertrophic cardiomyopathy similar to patients with Friedreich’s ataxia and, like many Friedreich’s ataxia patients, die early in life.

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Using a neurologic mouse model, treatment with nomlabofusp prevented the development of ataxia in mice whose nervous system was deficient in FXN compared to those treated with placebo.

In multiple non-clinical studies in rodents and non-human primates ("NHPs"), human FXN was found to be distributed into all tissues tested following nomlabofusp dosing.

See Figure 7.

Observed hFXN across all tissue and cell types tested:

Cardiac Mitochondria

CSF (Cerebrospinal Fluid)

Dorsal Root Ganglia

Skeletal Muscle

In other non-clinical pharmacology studies it was demonstrated that SC administration of nomlabofusp distributed in a dose-dependent manner to several organs known to be predominantly affected in FA, including the dorsal root ganglion, heart, and skeletal muscle, as well as to other tissues, including skin.

Plasma nomlabofusp concentrations correlated with levels of human FXN delivered by nomlabofusp into tissues, and the increases in frataxin were correlated amongst tissues, especially with skin.

In KO mice, the pharmacokinetics and processing of nomlabofusp were comparable with wild type animals and treatment with nomlabofusp halted the progression of cardiac dysfunction and significantly increased survival.

Together, the findings from these non-clinical studies demonstrate that nomlabofusp exposure increased hFXN in FA-relevant tissues and provide evidence of pharmacologic effects.

(De Toni, F., Ragaglia, V., Schecter, D.

Pharmacokinetics and Pharmacodynamics of Nomlabofusp in Non-clinical Studies of Friedreich’s Ataxia.

AAPS J 27, 112 (2025)).

Non-Human Primate and Rat Toxicology Studies

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The NHP 28-day study showed no systemic toxicity.

The NHP 13-week study showed no systemic toxicity in the low and mid-dose groups, and minimal to mild histopathological findings in the high dose group.

The NHP 13-week study showed no systemic toxicity in the low and mid-dose groups, and minimal to mild histopathological

findings in the high dose group.

There were also several episodes of occasional transient muscle rigidity in some animals observed immediately after dosing in the two highest dose groups at very high exposures.

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After additional interactions and submission of additional information requested by FDA, in September 2022, the FDA lifted its full clinical hold on the nomlabofusp clinical development program and imposed a partial clinical hold.

Following additional interactions

and submission of clinical data, in May 2024, the FDA removed the partial clinical hold on the development of nomlabofusp.

Following additional interactions and submission of clinical data, in May 2024, the FDA removed the partial clinical hold on the development of nomlabofusp.

Clinical Development

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Clinical Trials

Completed Phase 1 Clinical Studies in Adults with Friedreich’s Ataxia

We submitted our Investigational New Drug application ("IND") application for nomlabofusp and began Phase 1 clinical trials in 2019 in patients with FA.

We completed two clinical studies of nomlabofusp in adult subjects with FA, a SAD study (completed in 2020) and a MAD study (completed in 2021).

The primary objective for the SAD and MAD studies was to assess the tolerability of nomlabofusp at doses ranging from 25 mg to 100 mg administered via subcutaneous injection ("SC").

Completed Phase 1 and Phase 2 Clinical Studies in Adults with Friedreich’s Ataxia

In 2019, we submitted our Investigational New Drug application (“IND”) application for nomlabofusp and began Phase 1 clinical trials in 2019 in patients with FA.

We have completed three clinical studies in adult patients, with FA;

a Phase 1 SAD study (completed in 2020), a Phase 1 MAD study (completed in 2021), and a Phase 2 Dose Exploration study (completed in 2023).

The primary objective for the phase 1 SAD and MAD studies was to assess the tolerability of nomlabofusp at doses ranging from 25 mg to 100 mg administered via SC injection.

The secondary objectives were to establish the PK of nomlabofusp administration in humans and to explore the PD of nomlabofusp administration by measuring tissue FXN concentrations in accessible tissues, namely buccal and skin cells, and in platelets.

In the MAD study, patients in the 25 mg cohort were dosed once a day for the first 4 days followed by 1 dose every third day through day 13 for a total of 7 doses, while the patients in the 50 mg cohort were dosed once a day for the first 7 days followed by 1 dose every other day through day 13 for a total of 10 doses, and patients in the 100 mg cohort were dosed once a day for 13 days consecutively for a total of 13 doses.

Administration of nomlabofusp via SC injection appeared to be well tolerated up to doses of 100 mg administered daily for up to 13 days.

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The most common treatment emergent adverse events (“TEAEs”) were injection site reactions (“ISRs”) that were generally mild, self-limited, and usually resolved within approximately 1 hour.

Patients in the 25 mg cohort were dosed once a day for the first 4 days followed by 1 dose every third day through day 13 for a total of 7 doses, while the patients in the 50 mg cohort were dosed once a day for the first 7 days followed by 1 dose every other day through day 13 for a total of 10 doses, and patients in the 100 mg cohort were dosed once a day for 13 days consecutively for a total of 13 doses (see Figures 9 and 10).

The study was designed in this fashion to ensure that the PK of nomlabofusp in patients with FA were characterized at the lower doses before the dose was escalated.

This is typical of first in human studies such as multiple-ascending dose trials that evaluate a study drug’s clinical safety profile.

There was rapid uptake of nomlabofusp into the circulation following subcutaneous injection, and exposure appeared to be proportional to dose.

*FXN levels measured via detection of peptide derived from mature FXN;

FXN concentrations are normalized to total cellular protein content in each sample;

Data represent median and 25th and 75th percentiles;

FXN levels from day 4, & day 13 measurements are shown for data derived from the 25 mg cohort;

FXN levels from day 7 & day 13 measurements are shown for data derived from the 50 & 100 mg cohorts.

Completed Phase 2 Dose Exploration Study

Increased FXN concentrations were observed in buccal cells, skin, and platelets, with higher and more frequent nomlabofusp administration.

The Phase 2 randomized, double-blind, placebo-controlled dose exploration study evaluated the safety, tolerability, PK and PD of two doses of nomlabofusp.

Cohort 1 evaluated 25 mg and Cohort 2 evaluated 50 mg.

Participants in either the 25 mg or 50 mg cohorts were randomized 2:1 to receive daily subcutaneous injections of either nomlabofusp or placebo for 14 days, and then every other day for an additional 14 days for a total 28-day dosing period.

In May 2023, we reported preliminary unblinded top-line data from the 25 mg cohort of the dose exploration study.

In July 2023, the FDA cleared initiation of the second cohort (50 mg) of the study.

In February 2024, we reported positive top-line data and successful completion of the dose exploration study.

Nomlabofusp was generally well tolerated and demonstrated dose response in FXN levels in all evaluated tissues (skin and buccal cells) after daily dosing of 14 days followed by every other day dosing until day 28 in the 25 mg and 50 mg cohorts.

With regard to safety in the Phase 2 dose exploration trial, there were a total of 28 participants (19 received nomlabofusp and 9 received placebo).

Participants in either the 25 mg or 50 mg cohorts were randomized 2:1 to receive daily SC injections of either nomlabofusp or placebo for 14 days, and then every other day for an additional 14 days for a total 28-day dosing period.

Substantial increases in tissue FXN concentrations were observed after daily SC administration of both the 25 mg and 50 mg doses.

The majority of treated patients in both cohorts with quantifiable levels of frataxin at baseline and day 14 achieved at least a 100% increase in tissue frataxin in skin cells, and at least a 30% increase in tissue frataxin levels in buccal cells.

Participants treated with 50 mg for 14 days daily had frataxin levels in skin cells increase from less than 17% at baseline relative to healthy volunteers, to 33% to 59% of healthy volunteers after 14 days of treatment.

Patients treated with placebo showed no increase in their frataxin levels during this period.

Increases in skin and buccal FXN concentrations were dose-dependent and the increases were not maintained when the dosing regimen was changed to alternate day dosing.

Abnormal lipid profiles were identified in adults with FA at baseline with directional dose-dependent normalization observed post nomlabofusp treatment.

Nineteen adults with FA received nomlabofusp in the Phase 2 study and 9 received placebo.

There were no serious adverse events reported.

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The most common adverse events reported were mild and moderate injection site reactions which resolved without any intervention and there were no study discontinuations due to injection site reactions.

Consistent with findings in our Phase 1 study, nomlabofusp demonstrated quick absorption after subcutaneous administration and had dose proportional increases in exposure.

Patients treated with placebo showed no increase in their frataxin levels during this period.

Additionally, the majority of treated patients in both cohorts with quantifiable levels of frataxin at baseline and day 14 achieve at least a 100% increase in tissue frataxin in skin cells, and at least a 30% increase in tissue frataxin levels in buccal cells.

Figures 11 and 14 show a clear dose response and increase from baseline in skin tissue and buccal tissue frataxin levels, respectively.

The graph on the left in both Figures 12 and 15 shows a dose dependent increase in frataxin levels after 14 days of treatment.

With both skin and buccal cells, when dosing is switched to every other day the magnitude of the increase in frataxin levels declines.

The waterfall plots on the right in both Figures 12 and 15 depict the individual changes in frataxin levels from baseline in skin cells and buccal cells at day 14 respectively.

Each bar represents an individual patient, with placebo treated participants in gray, the 25 mg cohort in aqua, and the 50 mg cohort in blue.

The majority of patients treated with nomlabofusp had significant increases in frataxin levels while placebo patients were basically unchanged.

Importantly, there also appears to be a dose response as frataxin levels are notably increased in most of the 50 mg cohort over the 25 mg cohort.

Only participants with quantifiable levels at baseline and day 14 and day 28 are included in the tables.

*FXN levels measured via detection of peptide derived from mature FXN;

FXN concentrations are normalized to total cellular protein content in each sample.

Data represent median and 25th and 75th percentiles.

Only participants with quantifiable levels at both baseline and day 14 are included in the figures.

**Median baseline FXN levels in patients were 3.5 pg/µg for the placebo, 3.7 pg/µg for the 25 mg cohort and 2.1 pg/µg for the 50 mg cohort.

Figures 13 and 16 depict how many people had a shift in frataxin levels in skin cells and buccal cells as a percentage of average healthy volunteers after 14 days of treatment.

On the left is the 25 mg cohort and on the right is the 50 mg cohort.

On the far left of each figure are categories of the percentage of average healthy volunteers.

Figures in black to the left of the black vertical line represent patients at baseline.

Figures to the right of the black

vertical line represent day 14 frataxin levels as a percentage of average healthy volunteers.

In blue are individuals that increase by 25% to 50% and in green are individuals that exceeded 50% of average healthy volunteers.

Only participants with quantifiable levels at baseline and day 14 are included in the figures.

*% of healthy volunteer FXN level is calculated by dividing each participant's FXN level by the average FXN level (16.34 pg/µg) from the noninterventional healthy volunteer study (N=60).

Only participants with quantifiable levels at baseline and day 14 and day 28 are included in the tables.

*FXN levels measured via detection of peptide derived from mature FXN;

FXN concentrations are normalized to total cellular protein content in each sample.

Data represent median and 25th and 75th percentiles.

Only participants with quantifiable levels at both baseline and Day 14 are included in the figures.

**Median baseline FXN level in patients were 2.1 pg/µg for the placebo, 1.8 pg/µg for the 25 mg cohort and 1.6 pg/µg for the 50 mg cohort.

Only participants with quantifiable levels at baseline and day 14 are included in the figures.

*% of healthy volunteer FXN level is calculated by dividing each participant's FXN level by the average FXN level (8.24 pg/µg) from the noninterventional healthy volunteer study (N=60).

Open Label Extension

In January 2024, we initiated the OLE trial evaluating daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver, with the first patient dosed in March 2024.

Participants who completed treatment in the Phase 2 dose exploration study, or who previously completed a prior clinical trial of nomlabofusp, are potentially eligible to screen for the OLE study.

In addition, following the completion of enrollment, as well as at least one participant completing one year of dosing, clinical assessments collected during the study will be compared to data from a matched control arm derived from participants in the Friedreich’s Ataxia Clinical Outcome Measures Study ("FACOMS") database.

Consistent with findings in our Phase 1 study, nomlabofusp demonstrated quick absorption after SC administration and had dose proportional increases in exposure.

Completed Phase 1 PK Run-In Study in Adolescents (12-17 years old) with FA

In January 2025, we initiated dosing of adolescents (12-17 years old) in a PK run-in study for pediatric patients with FA.

Study participants in the PK run-in study were randomized 2:1 to receive either nomlabofusp at a weight-based dose expected to match the PK of adults receiving the 50 mg dose, or placebo, daily for seven days.

We completed dosing in 14 adolescents in March 2025.

The PK and exposure data were similar to adults and the participants became eligible to enroll in the OL study.

The PK results from the adolescent cohort also supported the predictive value of our exposure modeling and thus the planned dosing of a cohort of children (2-11 years of age) will facilitate direct enrollment of children (2-11 years old) was cancelled and will now be enrolled directly into the OL study, This eliminates any pause in study drug administration between the PK study and the open label study.

Open Label Study

In January 2024, we initiated the OL trial evaluating daily SC injections of 25 mg of nomlabofusp self-administered or administered by a caregiver, with the first patient dosed in March 2024.

Participants who completed treatment in the Phase 2 dose exploration study, or who previously completed a prior clinical trial of nomlabofusp, were eligible to screen for the OL study.

Subjects were allowed to take omaveloxolone during the trial.

The OL study is evaluating the safety and tolerability, PK, and FXN levels in peripheral tissues as well as other exploratory PD markers (lipid profiles and gene expression data) following long-term subcutaneous administration of nomlabofusp.

In addition, clinical assessments collected during the study will be compared to data from a matched control arm derived from participants in the FACOMS database.

In December 2024, we reported positive initial data from our ongoing OLE study.

This data included safety, FXN levels, clinical, pharmacokinetic data and dose escalation:

This data included safety, FXN levels, clinical, PK data and dose escalation:

• Nomlabofusp was generally well tolerated for up to 260 days in subjects.

The most common adverse events were injection site reactions, with most being mild, brief in duration, and self-limited.

Two participants had serious adverse events (one seizure and one anaphylactic reaction) that resolved within 24 hours who withdrew from the study;

Two participants had serious adverse events (one seizure and one anaphylactic reaction) that resolved within 24 hours and these participants withdrew from the study;

• Long-term 25 mg tissue FXN levels showed positive mean change from baseline of 1.32 pg/μg in buccal cells and 9.28 pg/μg in skin cells at Day 90 and that 25 mg of nomlabofusp increased and maintained tissue FXN levels over time, increasing from a mean level of 15% of HV at baseline to 30% in buccal cells and from 16% to 72% in skin cells at Day 90;

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• Early clinical data showed trends toward improvement across a number of clinical outcomes for long-term 25 mg daily nomlabofusp including:

(1) decreased values indicating early trends towards improvement in the Modified Friedreich Ataxia Rating Scale (mFARS) and the FARS-Activities of Daily Living ("ADL"), Modified Fatigue Impact Scale and 9 hole peg test at 90 days relative to baseline;

Also in December 2024, we announced that we were increasing the dose in the OLE to 50 mg of nomlabofusp daily for then currently enrolled and all future OLE study participants.

In March 2025, we announced that our Safety Monitoring Team has deemed anaphylaxis as an adverse drug reaction likely associated with nomlabofusp and therefore, we expect to see additional reactions.

To reduce the risk of allergic reactions, including anaphylaxis, we amended the OLE protocol to administer premedication for the first month of dosing.

The OLE study is ongoing with seven sites activated and participants continuing to enroll, and all study participants are currently receiving the 50 mg dose of nomlabofusp.

We plan to provide an update on OLE data on at least 30 to 40 study participants, some of whom have been receiving nomlabofusp for more than a year, in September 2025.

(1) decreased values indicating early trends towards improvement in the Modified Friedreich Ataxia Rating Scale (mFARS) and the FARS-Activities of Daily Living (“ADL”), Modified Fatigue Impact Scale and nine hole peg test at 90 days relative to baseline;

• Key PK data showed rapid absorption after SC administration with exposure appearing to reach steady state in plasma by day 30 with no further accumulation, which is consistent with data from our Phase 1 and Phase 2 studies.

Also in December 2024, we announced that we were increasing the dose in the OL study to 50 mg of nomlabofusp daily for then currently enrolled and all future study participants.

In March 2025, we announced that our Safety Monitoring Team has deemed anaphylaxis as an adverse drug reaction likely associated with nomlabofusp.

To reduce the risk of allergic reactions, including anaphylaxis, we amended the OL study protocol to administer premedication for the first month of dosing.

In June 2025, the FDA provided recommendations regarding the safety data that might be needed to support a Biologics License Application.(“BLA”) seeking accelerated approval, which included evaluating safety in at least 30 participants with continuous study drug exposure for six months and a subset of at least 10 of those participants with continuous study drug exposure for one year, with the large majority of data coming from participants receiving the 50 mg dose.

In July 2025, we announced the publication of two peer-reviewed articles highlighting nonclinical data on the therapeutic potential, pharmacology, and mechanism of action of nomlabofusp as a novel FXN protein replacement therapy designed to address the underlying cause of FA.

These data were included in the briefing package reviewed by the FDA in support of potentially using skin FXN concentrations as a RLSE for Larimar’s registrational program seeking accelerated approval for nomlabofusp.

In September 2025, we announced additional data from the ongoing OL study:

• In 4 completed studies and the ongoing OL study, 65 participants received at least 1 dose of nomlabofusp.

• Of the 65 participants receiving at least one dose of nomlabofusp, 39 have been dosed as part of the open label study, with 14 on treatment for at least 6 months and 8 for over 1 year in the OL study.

• Consistent directional improvement was observed across 4 key clinical outcomes (mFARS, FARS-ADL, 9-HPT, MFIS) after 1 year of nomlabofusp treatment relative to a worsening in a FACOMS natural history study reference population.

See Figure 8.

• 10/10 participants with data at 6 months achieved skin FXN levels over 50% of median levels in healthy volunteers (which is similar to levels in asymptomatic carriers).

See Figure 9.

• Of the 39 participants in the OL study (and of 65 total participants who received at least 1 dose in all nomlabofusp studies), 7 experienced anaphylaxis in the first 6 weeks of dosing and returned to their usual state of health after standard treatment.

In the OL study, of the 10 participants who had not had prior exposure to nomlabofusp, only 1 experienced anaphylaxis.

Excluding these events, long term dosing of nomlabofusp was generally well tolerated, including 14 on treatment for at least 6 months and 8 on treatment for over 1 year.

IQR = interquartile range

1 - Based on the range of baseline characteristics of participants in the OL study, Larimar identified patients from the FACOMS dataset with similar characteristics using data recorded over the last 4 years for each patient.

2 - Modified Fatigue scale presented here is at Month 24 because it was not assessed at Month 12.

Data presented is based on the September 2025 data release.

*Data include all participants with quantifiable levels at each measurement point who had received 25 mg, 50 mg or had the dose increased from 25 mg to 50 mg.

**8.2 pg/µg represents 50% of the average FXN concentration average FXN concentration of healthy volunteers.

Data presented is based on the September 2025 data release.

We believe that these data, as well as the improvement in abnormal lipid profiles observed in prior completed studies, provide support that nomlabofusp increases FXN in patients with FA and that the strategy of FXN replacement has the potential to result in a clinical benefit.

Changes observed in skin FXN levels, and clinical outcomes after nomlabofusp administration across diverse participants with FA including individuals with advanced disease, are all directionally consistent and suggest a potential treatment effect.

In addition to the risk mitigation measures for anaphylaxis already in place such as pre-medicating with antihistamines and supplying epinephrine auto-injectors to study participants, we have introduced a new dosing regimen in which participants initially receive a 5 mg dose followed by a 25 mg dose 1 hour later under observation.

Nomlabofusp 25 mg is then administered once daily through Day 30 and then the dose is increased to 50 mg once daily.

We have amended the open label extension (“OLE”) study protocol to include adolescent and adult patients who have not previously participated in a prior nomlabofusp study and the study is now being referred to as the open label (“OL”) study.

We are also making plans to enroll children (2 to 11 years old) directly into the OL study.

In February 2026, we announced that the FDA granted Breakthrough Therapy Designation to nomlabofusp for the treatment of adults and children with FA.

Additionally, following a START pilot program meeting with FDA, we announced continued alignment with the FDA to consider the use of skin FXN concentration as a novel surrogate endpoint reasonably likely to predict clinical benefit to support a planned BLA, seeking accelerated approval.

The FDA stated that the adequacy of the safety data base will be a matter of review at the time of the BLA submission, which is targeted for June 2026.

Intellectual Property

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Patent and Trademark Office and its foreign counterparts.

We also intend to rely on regulatory exclusivity (also called data exclusivity), which is separate and distinct from the protection afforded by patents, to protect our products.

We also intend to rely on market and data exclusivities, which is separate and distinct from the protection afforded by patents, to protect our products.

We further protect our proprietary information by requiring our employees, consultants, contractors and other advisors to execute nondisclosure and assignment of invention agreements upon commencement of their respective employment or engagement.

Agreements with our employees also prevent them from bringing the proprietary rights of third parties to us.

Agreements with our employees

also prevent them from bringing the proprietary rights of third parties to us.

In addition, we require confidentiality or service agreements from third parties that receive our confidential information or materials.

As of March 17, 2025, our intellectual property portfolio was composed of numerous international Patent Cooperation Treaty ("PCT"), foreign, United States non-provisional patent applications, issued United States patents and United States provisional patent applications that we own or co-own, and five issued United States patents and additional non-provisional patent applications in the United States and in certain foreign jurisdictions that we license from academic institutions.

The issued patents in the United States licensed by us, which include issued patents covering the composition of matter for nomlabofusp and methods for treating FA, have expiration dates between 2025 and 2040 without taking potential patent term extension into consideration.

As of March 17, 2026, our intellectual property portfolio was composed of numerous international Patent Cooperation Treaty (“PCT”), foreign, United States non-provisional patent applications, issued United States patents, one EU patent and United States provisional patent applications that we own or co-own, and four issued United States patents and additional non-provisional patent applications in the United States and in certain foreign jurisdictions that we license from academic institutions.

The issued patents in the United States and the E.U.

licensed by us, which include issued patents covering the composition of matter for nomlabofusp and methods for treating FA, have expiration dates between 2033 and 2040 without taking potential patent term extension into consideration.

The international and the United States non-provisional patent applications licensed by us relate to composition of matter and methods of use for nomlabofusp.

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If we or our licensor timely files non-provisional patent applications in the United States and in countries outside of the United States with regard to our provisional patent applications and these non-provisional patent applications result in issued patents, such patents are expected to expire in 2046, without taking potential patent term adjustment or patent term extension into consideration.

Nomlabofusp is covered by licensed issued patents (composition of matter and methods of use) in the United States which, if properly maintained, will expire in 2025 and 2040, excluding any patent term extensions that might be available following the grant of marketing authorizations.

Nomlabofusp is covered by licensed issued patents (composition of matter and methods of use) in the United States and the E.U., which, if properly maintained, will expire in 2040, excluding any patent term extensions that might be available following the grant of marketing authorizations.

We also possess an exclusive license to non-provisional applications in the United States and certain countries outside the United States for nomlabofusp (composition of matter and methods of use).

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The actual protection afforded by a patent, which can vary from country to country, depends on the type of patent, the scope of its coverage and the availability of legal remedies in the country.

We also use other forms of protection besides patent protection and regulatory exclusivity, such as trademark, copyright, and trade secret protection, to enhance our intellectual property, particularly where we do not believe patent protection is appropriate or obtainable.

We also use other forms of protection besides patent protection and market and data exclusivity, such as trademark, copyright, and trade secret protection, to enhance our intellectual property, particularly where we do not believe patent protection is appropriate or obtainable.

We aim to take advantage of all of the intellectual property rights that are available to us and believe that this comprehensive approach will provide us with proprietary exclusive positions for our product candidates, such as nomlabofusp, where available.

In-License Agreements

We are party to a License Agreement dated November 30, 2016 with Wake Forest University Health Sciences ("WFUHS") and a License Agreement dated November 30, 2016, as amended, with Indiana University ("IU").

We are party to a License Agreement dated November 30, 2016, as amended, with Indiana University (“IU”).

Such agreements provide for a transferable, worldwide license to certain patent rights regarding technology used by us with respect to the development of nomlabofusp.

In partial consideration for the right and license granted under these agreements, we will pay each of WFUHS and IU a royalty of a low single digit percentage of net sales of licensed products depending on whether there is a valid patent covering such products.

As additional consideration for these agreements, we are obligated to pay each of WFUHS and IU certain milestone payments of up to $2.6 million in the aggregate upon the achievement of certain developmental milestones, commencing on the enrollment of the first patient in a Phase 1 clinical trial.

We will also pay each of WFUHS and IU sublicensing fees ranging up to a low double-digit percentage of sublicense consideration depending on our achievement of certain regulatory milestones as of the time of receipt of the sublicense consideration.

We are also obligated to reimburse WFUHS and IU for patent-related expenses.

event that we dispute the validity of any of the licensed patents, the royalty rate would be tripled during such dispute.

In partial consideration for the right and license granted under these agreements, we will pay IU a royalty of a low single digit percentage of net sales of licensed products depending on whether there is a valid patent covering such products.

As additional consideration for this agreement, we are obligated to pay IU certain milestone payments of up to $2.0 million in the aggregate upon the achievement of certain developmental milestones, commencing on the enrollment of the first patient in a Phase 1 clinical trial.

We will also pay IU sublicensing fees ranging up to a low double-digit percentage of sublicense consideration depending on our achievement of certain

regulatory milestones as of the time of receipt of the sublicense consideration.

We are also obligated to reimburse IU for patent-related expenses.

In the event that we dispute the validity of any of the licensed patents, the royalty rate would be tripled during such dispute.

We are also obligated to pay to IU a minimum annual royalty of less than $0.1 million per annum starting in the 2020 calendar year for the term of the agreement.

In the event that we are required to pay IU consideration, then we may deduct 20% of such IU consideration on a dollar-for-dollar basis from the consideration due to WFUHS.

In the event that we are required to pay WFUHS consideration, then we may deduct 60% of such WFUHS consideration on a dollar-for-dollar basis from the consideration due to IU.

We were previously a party to License Agreement dated November 30, 2016, with Wake Forest University Health Sciences (“WFUHS”), which licensed certain patent rights regarding technology used by us with respect to the development of nomlabofusp in consideration for an obligation to pay WFUHS a royalty of a low single digit percentage of net sales of licensed products, certain milestones, and certain sublicensing revenue.

The WFUHS license expired in December 2025 with the last to expire licensed patent.

The biopharmaceutical industry is characterized by intense and dynamic competition to develop new technologies and proprietary therapies.

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We expect to compete with Biogen’s SKYCLARYS TM (omaveloxolone), which was approved for the treatment of FA in adults and adolescents aged 16 and older by the FDA and the European Commission in February 2023 and February 2024, respectively.

Other competitors currently developing therapeutics to treat FA include, but are not limited to Design Therapeutics, Lexeo Therapeutics, Neurocrine Biosciences/Voyager Therapeutics and PTC Therapeutics ("PTC").

The FDA has accepted for filing PTC’s NDA for vatiquinone for the treatment of children and adults living with FA with a target action date of August 19, 2025.

On August 19, 2025, PTC received a complete response letter and was not approved by the FDA.

PTC had a Type C meeting with the FDA in December, 2025 and were advised that an additional study (open label or single arm study with natural history control) would be necessary to support NDA resubmission.

Many of our competitors have significantly greater name recognition, longer operating histories and financial, technical manufacturing, marketing and human resources than we do.

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We are continually trying to optimize our manufacturing process to increase yields, decrease costs and increase reliability in supply chains.

The final process will need to be successfully scaled up to support commercial manufacturing.

We are currently at full scale for the US launch and filing but will need to scale up one more time to have adequate supply for the expansion into other territories.

The drug substance which is in frozen liquid form for nomlabofusp is currently manufactured for us by KBI Biopharma, Inc.

We are party to a Master Services Agreement, as amended, with KBI, pursuant to which KBI provides biological development and clinical manufacturing services with respect to nomlabofusp.

We are no longer producing the frozen liquid form of drug product.

We are producing a lyophilized version of the drug product from the same KBI drug substance at Bora Pharmaceutical Services, Inc.

We are party to a Master Services Agreement with Bora, pursuant to which Bora provides biological development and clinical manufacturing services with respect to nomlabofusp.

In February 2025, FDA accepted the data supporting the comparability of the lyophilized drug product to the frozen solution and agreed with our plans to introduce the lyophilized product into our clinical development program in mid-2025.

The frozen solution is the dosage form currently being used in the OLE.

The lyophilized drug product is the formulation that we intend to commercialize.

To supply nomlabofusp drug substance commercially, we intend to scale up the manufacturing process.

We are producing a lyophilized version of the drug product from the same KBI drug substance at another supplier.

The drug product previously used in our clinical studies has been in a frozen solution dosage form.

In February 2025, FDA accepted the data supporting the comparability of a lyophilized drug product to the frozen solution and we are currently integrating the lyophilized formulation into the OL study.

The lyophilized drug product is the formulation that we intend for the long-term commercialization of nomlabofusp, if approved.

Process performance qualification (PPQ) of the commercial scale drug substance and drug product manufacturing is nearing completion in preparation for the BLA submission and these batches are planned to support the U.S.

commercial launch demand, if nomlabofusp is approved.

We intend to further scale up our manufacturing process to support potential worldwide commercial demand, if nomlabofusp is approved.

We have selected Lonza to support this scale-up effort.

We are currently tech transferring the process to Lonza and are making adaptations to the process that enable facility fit.

We are party to a Master Services Agreement with Lonza, pursuant to which Lonza provides biological development and clinical manufacturing services with respect to nomlabofusp.

We intend to demonstrate the comparability of the drug substance manufactured by Lonza and submit

this data to the FDA for their review in 2026.

Acceptance of this comparability will allow for the use of drug substance manufactured by Lonza in the clinical development of nomlabofusp.

We have received concurrence from the FDA that our proposed matrixed potency control strategy appears reasonable, pending review of the BLA.

We are in the process of implementing this assay at a third-party testing lab and intend to provide a comprehensive data package that supports our ongoing clinical and commercial development.

As development of this assay is scientific in nature, efforts may prove to be unsuccessful and will require further discussions with FDA on an appropriate strategy.

We have completed tech transferring and scale-up of the process to Lonza.

We are party to a Master Services Agreement with Lonza, pursuant to w h ich Lonza provides manufacturing services with respect to nomlabofusp.

Additional comparability of the drug substance manufactured by Lonza will need to be performed and reviewed by the FDA and other regulatory authorities in order to use the Lonza-manufactured drug substance in clinical and commercial activities.

We have received concurrence from the FDA that our proposed potency control strategy appears reasonable, pending review of the BLA.

Human Capital Resources

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Professor of Pediatrics, Indiana University School of Medicine

We lease office and laboratory space, which consists of approximately 8,000 square feet and 4,000 square feet located in Bala Cynwyd, PA and King of Prussia, PA, respectively.

The office lease currently expires on August 31, 2026 and the lab lease expires on May 9, 2028.

We currently lease office and laboratory space, which consists of approximately 8,000 square feet and 4,000 square feet located in Bala Cynwyd, PA and King of Prussia, PA, respectively.

On November 24, 2025, we entered into a lease for an additional 7,100 square feet of office space through January 31, 2030 in our Bala Cynwyd PA location and extended the term of all our other Bala Cynwyd space through January 31, 2030.

We expect to occupy the additional 7,100 of additional office space when renovations are complete, which is expected to be around April 1, 2026.

As part of the Merger (as defined below) with Zafgen, Inc (“Zafgen”), we acquired a non-cancellable operating lease for approximately 17,705 square feet of office space at 3 Center Plaza, Boston, Massachusetts (the “Boston Lease”).

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The Federal Food, Drug, and Cosmetic Act (“FDCA”) and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, record keeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products.

Biological products used for the prevention, treatment, or cure of a disease or condition of a human being are subject to regulation under the FDCA, with the exception that the section of the FDCA that governs the approval of drugs via new drug applications (“NDAs”), does not apply to the approval of biologics.

Biological products used for the prevention, treatment, or cure of a disease or condition of a human being

are subject to regulation under the FDCA, with the exception that the section of the FDCA that governs the approval of drugs via new drug applications (“NDAs”), does not apply to the approval of biologics.

In contrast, biologics are approved for marketing under provisions of the Public Health Service Act (“PHS Act”), via a Biologics License Application (“BLA”).

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• satisfactory completion of an FDA inspection prior to NDA or BLA approval of the manufacturing facility or facilities where the drug or biological product is produced to assess compliance with cGMPs, to assure that the facilities, methods and controls are adequate to preserve the biological product’s identity, strength, quality and purity;

• potential FDA audit of the non-clinical and clinical study sites that generated the data in support of the NDA or BLA;

• potential FDA audits of the non-clinical and clinical study sites that generated the data in support of the NDA or BLA and of the application sponsor’s oversight of the studies and sites;

• potential FDA Advisory Committee meeting to elicit expert input on critical issues and including a vote by external committee members;

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In such a case, the IND sponsor must resolve any deficiencies to the satisfaction of the FDA, and the FDA must lift the clinical hold before the clinical trial can begin.

The FDA may also impose clinical holds on a drug or biological product candidate at any time before or during clinical trials due to safety concerns or non-compliance.

also impose clinical holds on a drug or biological product candidate at any time before or during clinical trials due to safety concerns or non-compliance.

If the FDA imposes a clinical hold, trials may not re-commence without FDA authorization and then only under terms authorized by the FDA.

Clinical trials may involve the administration of the drug or biological product candidate to healthy volunteers or subjects under the supervision of qualified investigators, generally physicians not employed by or under the study sponsor’s control.

Clinical trials involving some products for certain diseases, including some rare diseases may

begin with testing in patients with the disease.

Clinical trials involving some products for certain diseases, including some rare diseases may begin with testing in patients with the disease.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety, including stopping rules that assure a clinical trial will be stopped if certain adverse events should occur.

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In drugs and biologics for rare diseases where patient populations are small, Phase 3 trials might not be required if substantial evidence of effectiveness and an acceptable risk/benefit profile can be demonstrated from Phase 2 trials.

An OLE study may also be conducted.

An OLE study typically enrolls participants from previous clinical trials and is designed to gather the long-term safety and tolerability data on a potential new medicine beyond the time period of the original studies.

An OL study may also be conducted.

An OL study typically enrolls participants from previous clinical trials or patients who would otherwise not qualify for other clinical studies such as a Phase 3 study and is designed to gather the long-term safety and tolerability data on a potential new medicine beyond the time period of the original studies.

Post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.

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Written IND safety reports must be promptly submitted to the FDA and the investigators for serious and unexpected adverse events, any findings from other studies, tests in laboratory animals or in vitro testing that suggest a significant risk for human subjects, or any clinically important increase in the rate of a serious suspected adverse reactions over that listed in the protocol or investigator brochure.

The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting.

must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting.

The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information.

The FDA or the sponsor or its data safety monitoring board may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or

terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug or biological product has been associated with unexpected serious harm to patients.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug or biological product has been associated with unexpected serious harm to patients.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the physical characteristics of the drug or biological product as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

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Information about certain clinical trials must be submitted within specific timeframes to the NIH for public dissemination on its clinicaltrials.gov website.

Although sponsors are obligated to disclose the results of their clinical trials after completion, disclosure of the results can be delayed in some cases for up to two years after the date of completion of the trial.

Failure to timely register a covered clinical study or to submit study results as provided for in the law can give rise to public notifications of noncompliance, civil monetary penalties, and also prevent the non-compliant party from receiving future grant funds from the federal government.

Sponsors or distributors of investigational products for the diagnosis, monitoring, or treatment of one or more serious diseases or conditions must also have a publicly available policy on evaluating and responding to requests for expanded access requests.

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The FDA reviews the NDA or BLA to determine, among other things, whether the proposed product is safe and effective (for drugs) or safe, potent, and effective (for biologics), for its intended use, and has an acceptable purity profile, and whether the product is being manufactured in accordance with cGMPs to assure and preserve the product’s identity, safety, strength, quality, potency and purity.

One of the performance goals agreed to by the FDA under the PDUFA is to review standard NDAs or BLAs in ten months from filing and priority NDAs or BLAs in six months from filing, whereupon a review decision is to be made.

One of the performance goals agreed to by the FDA under the PDUFA is to review standard NDAs or BLAs in ten months from filing and

priority NDAs or BLAs in six months from filing, whereupon a review decision is to be made.

The review process may be extended by three months if the FDA classifies a response to an FDA request for additional information or clarification as a major amendment.

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The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving an NDA or BLA, the FDA will typically inspect one or more clinical trial sites to assure that the clinical trials were conducted in compliance with IND study requirements and GCP requirements and may inspect the sponsor to ensure appropriate oversight and documentation related to the clinical trials.

To assure cGMP and GCP compliance, an applicant must incur significant expenditure of time, money and effort in the areas of training, record keeping, production, and quality control.

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If a complete response letter is issued, the applicant may either resubmit the NDA or BLA, addressing all of the deficiencies identified in the letter, or withdraw the application.

In September 2025, the FDA began publishing complete response letters soon after issuing them to the respective sponsors, breaking with long standing agency tradition of publishing complete response letters with approval documentation after the product is approved.

If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product.

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Annual product reports are required to be submitted annually.

Other post-approval requirements applicable to drug and biological products, include reporting of cGMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, product tracing requirements, registration and listing, record-keeping requirements, reporting of adverse events, reporting updated safety and efficacy information, and complying with electronic record and signature requirements.

Other post-approval requirements applicable to drug and biological

products, include reporting of cGMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, registration and listing, record-keeping requirements, reporting of adverse events, reporting updated safety and efficacy information, and complying with electronic record and signature requirements.

In addition, the Drug Supply Chain Security Act, or DSCSA, was enacted in 2013 with the aim of building an electronic system to identify and trace certain prescription drugs and biologics distributed in the United States.

The stabilization period for building and validating interoperable electronic tracing systems has ended and trading partners who have not achieved compliance with these requirements must secure an exemption from the FDA.

After an NDA or BLA is approved, the product may also be subject to official lot release.

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Defects in manufacturing of commercial products can result in product recalls.

For products with approved REMS, manufacturers must submit periodic assessment reports to the FDA to demonstrate that the goals of the REMS are being met.

FDA reviews the REMS assessment reports, determines if the REMS assessment report is complete, if the REMS is meeting its goals, and if the REMS goals, elements, tools or assessment plan should be modified.

Manufacturers must also comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities, and promotional activities involving the internet.

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Any agency or judicial enforcement action could have a material adverse effect.

Additionally, new learnings related to the safety profile of a product that occur post-approval, whether from post-marketing reports or ongoing clinical research, may prompt label updates and revisions, including to modify or add safety or risk information.

For products approved without a boxed warning, serious safety risks discovered post-approval could lead to the addition of a boxed warning on approved product labeling.

Drug and biologic product manufacturers and other entities involved in the manufacture and distribution of approved drug and biological products are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMPs and other laws.

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Orphan Drug Designation

Under the Orphan Drug Act, the FDA may grant Orphan Drug Designation ("ODD") to a drug or biologic product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making a drug or biologic product available in the United States for this type of disease or condition will be recovered from sales of the product.

Under the Orphan Drug Act, the FDA may grant Orphan Drug Designation (“ODD”) to a drug or biologic product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than

200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making a drug or biologic product available in the United States for this type of disease or condition will be recovered from sales of the product.

ODD must be requested before submitting an NDA or BLA.

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ODD does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has ODD receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same drug or biological product for the same disease or condition for seven years, except in limited circumstances, such as showing clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety or providing a major contribution to patient care or in instances of drug supply issues.

Competitors, however, may receive approval of either a different product for the same disease or condition or the same product for a different disease or condition but that could be used off-label in the orphan indication.

Orphan drug exclusivity also could block the approval of a product for seven years if a competitor obtains approval first for the same product as defined by the FDA for the same disease or condition, or if the second product is determined to be encompassed within the competitor’s scope of product for the same disease.

If a product that has ODD receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same drug or biological product for the same approved use or indication for seven years, except in limited circumstances, such as showing clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety or providing a major contribution to patient care or in instances of drug supply issues.

Competitors, however, may receive approval of either a different product for the same approved use or indication or the same product for a different approved use or indication but that could be used off-label in the orphan indication.

Orphan drug exclusivity also could block the approval of a product for seven years if a competitor obtains approval first for the same product as defined by the FDA for the same approved use or indication, or if the second product is determined to be encompassed within the competitor’s scope of exclusivity.

If a company pursues marketing approval for an indication broader than the orphan drug designation it has received, it may not be entitled to orphan drug exclusivity.

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The FDA will determine that a product will fill an unmet medical need if it will provide a therapy where none exists or provide a therapy that may be potentially superior to existing therapy based on efficacy or safety factors.

In addition to other benefits, such as the ability to have greater

interactions with the FDA, the FDA may initiate review of sections of a fast track NDA or BLA before the application is complete, a process known as rolling review.

In addition to other benefits, such as the ability to have greater interactions with the FDA, the FDA may initiate review of sections of a fast track NDA or BLA before the application is complete, a process known as rolling review.

The FDA may give a priority review designation to drug or biological products that treat a serious condition and, if approved, would provide a significant improvement in safety or effectiveness.

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As a condition of approval, the FDA may require a sponsor of a drug or biological product receiving accelerated approval to perform post-marketing studies with due diligence to verify and describe the predicted effect on irreversible morbidity or mortality or other clinical endpoint, and the drug or biological product may be subject to accelerated withdrawal procedures.

The Food and Drug Omnibus Reform Act (“FDORA”) was recently enacted, which included provisions related to the accelerated approval pathway.

Pursuant to FDORA, the FDA is authorized to require a post-approval study to be underway prior to approval or within a specified time period following approval.

FDORA also requires the FDA to specify conditions of any required post-approval study, which may include milestones such as a target date of study completion and requires sponsors to submit progress reports for required post-approval studies and any conditions required by the FDA not later than 180 days following approval and not less frequently than every 180 days thereafter until completion or termination of the study.

FDORA also provides the FDA increased authority for expedited procedures to withdraw approval of a drug or biologic or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product.

FDORA also enables the FDA to initiate enforcement actions for the failure to conduct with due diligence a required post-approval study, including a failure to meet any required conditions specified by the FDA or to submit timely reports.

The FDA is authorized to require a post-approval study to be underway prior to approval or within a specified time period following approval and the FDA is required to specify conditions of any required post-approval study, which may include milestones such as a target date of study completion and requires sponsors to submit progress reports for required post-approval studies and any conditions required by the FDA not later than 180 days following approval and not less frequently than every 180 days thereafter until completion or termination of the study.

The FDA may use expedited procedures to withdraw approval of a drug or biologic or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product.

The FDA may initiate enforcement actions for the failure to conduct with due diligence a required post-approval study, including a failure to meet any required conditions specified by the FDA or to submit timely reports.

In addition, the FDA generally requires, unless otherwise informed by the agency, pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

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A rare pediatric disease is defined as a disease that is a serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years, including age groups often called neonates, infants, children, and adolescents;

developing and making available the product in the United States can be recovered from sales of the product in the United States.

and is a rare disease or condition as defined in the FDCA, which includes diseases and conditions that affect fewer than 200,000 persons in the United States and diseases and conditions that affect a larger number of persons and for which there is no reasonable expectation that the costs of developing and making available the product in the United States can be recovered from sales of the product in the United States.

The sponsor of an application for a drug product that obtains rare pediatric disease designation may be eligible for a voucher that can be used or sold to obtain a priority review for a subsequent application submitted under section 505(b)(1) of the FDCA or section 351 of the PHS Act.

A rare pediatric disease drug product must meet certain eligibility requirements for a priority voucher at the time the sponsor seeks approval.

The rare pediatric disease priority review voucher program was most recently re-authorized by Congress through December 31, 2024, with the potential for priority review vouchers to be granted through September 30, 2026.

Under the amended statutory sunset provisions, after December 20, 2024, the FDA may award a priority review voucher for an approved rare pediatric disease product application only if the sponsor has rare pediatric disease designation for the drug and if that designation was granted by December 20, 2024.

After September 30, 2026, the FDA may not award any rare pediatric disease priority review vouchers unless the program is re-authorized by Congress.

On February 3, 2026, the FDA's priority voucher program which was set to expire on September 30, 2026 was extended through September 30, 2029.

Pediatric Information and Pediatric Exclusivity

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A sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must submit an initial Pediatric Study Plan (“PSP”) within 60 days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase 3 or Phase 2/3 study.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups,

relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

The FDA and the sponsor must reach an agreement on the PSP.

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for biologic products, pediatric exclusivity adds six months only to exclusivity periods for all formulations, dosage forms, and indications.

This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study, provided that at the time pediatric exclusivity is granted there is not less than nine months of term of the patent or exclusivity remaining at the time of approval.

This six-month exclusivity, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study, provided that at the time pediatric exclusivity is granted there is not less than nine months of term of the patent or exclusivity remaining at the time of approval.

The Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) created an abbreviated approval pathway for biological products that are demonstrated to be “biosimilar” or “interchangeable” with an FDA-licensed reference biological product.

Biosimilarity requires that the proposed biological product be highly similar to the reference product not withstanding minor differences in clinically inactive components;

that there be no differences in conditions of use, route of administration, dosage form, and strength;

and that no clinically meaningful differences between the product and the reference product in terms of safety, purity, and potency as shown through analytical studies, animal studies and a clinical trial or trials.

that there be no differences in route of administration, dosage form, and strength;

and that no clinically meaningful differences between the product and the reference product in terms of safety, purity, and potency as shown through analytical studies and animal studies with the possibility of a clinical trial or trials.

In order to meet the higher hurdle of interchangeability, a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical results as the reference product, and for a product that is administered more than once, that the safety and efficacy risk of switching between the reference product and biosimilar product is not greater than the risk of maintaining the patient on the reference product.

Complexities associated with the larger, and often more complex, structures of biological products, as well as the process by which such products are manufactured, pose significant hurdles to implementation that are still being evaluated by the FDA.

Under the BPCIA, a reference biologic is granted 12 years of exclusivity from the time of first licensure or BLA approval, of the reference product during which FDA cannot approve an application for a biosimilar or

interchangeable product relying on the reference product.

Additionally, no application for a biosimilar can be submitted for four years from the date of licensure of the reference product.

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Most countries outside of the United States require that clinical trial applications be submitted to and approved by the local regulatory authority for each clinical study.

In the European Union, for example, an application must be submitted to the national competent authority and an independent ethics committee in each country in which we intend to conduct clinical trials, much like the FDA and IRB, respectively.

In the European Union, for example, an application must be made to the national competent authority and an independent ethics committee in each country in which we intend to conduct clinical trials, much like the FDA and IRB, respectively.

Under the Clinical Trials Regulation (EU) No 536/2014, which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022, a single application is now made through the Clinical Trials Information System (“CTIS”), for clinical trial authorization in up to 30 European Union/European Economic Area countries at the same time and with a single set of documentation.

The assessment of applications for clinical trials is divided into two parts (Part I contains scientific and medicinal product documentation and Part II contains the national and patient-level documentation).

Part I is assessed by a coordinated review by the competent authorities of all European Union Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned) of a draft report prepared by a Reference Member State.

Part II is assessed separately by each Member State concerned.

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The approval process and requirements vary from country to country, so the number and type of non-clinical, clinical, and manufacturing studies needed may differ, and the time may be longer or shorter than that required for FDA approval.

To obtain regulatory approval of a product under the European Union's regulatory system, we are required to submit a marketing authorization application ("MAA"), to be assessed in either the centralized procedure or a national authorization procedure.

The centralized procedure allows applicants to obtain a marketing authorization ("MA") that is valid throughout the European Union and the additional Member States of the European Area (Iceland, Liechtenstein and Norway) ("EEA").

It is compulsory for medicinal products manufactured using biotechnological processes, for orphan medicinal products, for advance therapy medicinal products (gene-therapy, somatic cell-therapy or tissue-engineered medicines) and for human products containing a new active substance which are not authorized in the European Union and which are intended for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, auto-immune and other immune dysfunctions, viral diseases or diabetes.

The centralized procedure is optional for any other products containing new active substances not authorized in the European Union or for products which constitute a significant therapeutic, scientific or technical innovation or for which a centralized authorization is in the interests of patients in the European Union.

To obtain regulatory approval of a product under the European Union's regulatory system, we are required to submit a marketing authorization application (“MAA”), to be assessed through the centralized procedure or, as applicable, national, decentralized or mutual recognition procedures.

The centralized procedure allows applicants to obtain a marketing authorization (“MA”) that is valid throughout the European Union and the additional countries of the European Economic Area (Iceland, Liechtenstein and Norway) (“EEA”).

It is compulsory for medicinal products manufactured using biotechnological processes, for orphan medicinal products, for advanced therapy medicinal products (gene-therapy, somatic cell-therapy or tissue-engineered medicines) and for medicinal products containing a new active substance which are not authorized in the European Union and which are intended for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, auto-immune and other immune dysfunctions, viral diseases or diabetes.

When a company wishes to place on the market a medicinal product that is eligible for the centralized procedure, it sends an application directly to the EMA, to be assessed by the Committee for Medicinal Products for Human Use (“CHMP”).

The CHMP is responsible for conducting the assessment of whether a medicine meets the required quality, safety and efficacy requirements, and whether the product has a positive risk/benefit/risk profile.

The time limit for the evaluation procedure is 210 days (excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP).

The EMA then has

fifteen days to forward its opinion to the European Commission which will make a binding decision on the grant of an MA within 67 days of the receipt of the CHMP.

The CHMP is responsible for conducting the assessment of whether a medicine meets the required quality, safety and efficacy requirements, and whether the product has a positive risk/benefit profile.

The time limit for the evaluation procedure by the CHMP is 210 days (excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP).

The EMA then has fifteen days to forward the CHMP opinion to the European Commission, which will make a binding decision on the grant of an MA within 67 days of the receipt of the CHMP opinion.

There are two other procedures in the European Union for the grant of an MA in multiple European Union Member States, where a product does not fall within the mandatory scope of the centralized procedure.

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If the product has not received a national MA in any European Union Member State at the time of application, it can be approved simultaneously in various Member States through the decentralized procedure.

In the European Union, a “conditional” MA may be granted in cases where all the required safety and efficacy data are not yet available.

The European Commission may grant a conditional MA for a medicinal product if it is demonstrated that all of the following criteria are met:

(i) the benefit-risk balance of the medicinal product is positive;

(ii) it is likely that the applicant will be able to provide comprehensive data post-authorization;

(iii) the medicinal product fulfils an unmet medical need;

and (iv) the benefit of the immediate availability to patients of the medicinal product is greater than the risk inherent in the fact that additional data are still required.

The conditional MA is subject to conditions to be fulfilled for generating the missing data or ensuring increased safety measures.

It is valid for one year and must be renewed annually until all related conditions have been fulfilled.

Once such conditions have been fulfilled, the conditional MA can be converted into a traditional MA.

However, if the conditions are not fulfilled within the timeframe set by the EMA and approved by the European Commission, the MA will cease to be renewed.

An MA may also be granted “under exceptional circumstances” where the applicant can show that it is unable to provide comprehensive data on efficacy and safety under normal conditions of use even after the product has been authorized and subject to specific procedures being introduced.

These circumstances may arise in particular when

the intended indications are very rare and, in the state of scientific knowledge at that time, it is not possible to provide comprehensive information, or when generating data may be contrary to generally accepted ethical principles.

Like a conditional MA, an MA granted in exceptional circumstances is reserved to medicinal products intended to be authorized for treatment of rare diseases or unmet medical needs for which the applicant does not hold a complete data set that is required for the grant of a standard MA.

However, unlike the conditional MA, an applicant for authorization in exceptional circumstances is not subsequently required to provide the missing data.

Although the MA “under exceptional circumstances” is granted definitively, the risk-benefit balance of the medicinal product is reviewed annually, and the MA will be withdrawn if the risk-benefit ratio is no longer favorable.

Regulation (EC) No.

141/2000, provides that a product may be designated as an orphan medicinal product if its sponsor can establish that it is intended for the diagnosis, prevention, or treatment of life-threatening or chronically debilitating condition that affects not more than 5 in 10,000 persons in the European Union when the application is made.

In addition, orphan designation can be granted if the product is intended for a life threatening, seriously debilitating, or serious and chronic condition in the European Union where without incentives derived from orphan designation.it is unlikely that sales of the product in the European Union would be sufficient to justify the necessary investment in its development.

Orphan designation is only available if there is no other satisfactory method approved in the European Union of diagnosing, preventing, or treating the condition, or if such a method exists, the proposed orphan product will be of significant benefit to patients over the existing options.

141/2000 provides that a medicinal product may be designated as an orphan medicinal product by the European Commission, following an opinion of the EMA's Committee for Orphan Medicinal Products, if its sponsor can establish that it is intended for the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating condition that affects not more than 5 in 10,000 persons in the European Union when the application is made.

In addition, orphan designation can be granted if the product is intended for a life-threatening, seriously debilitating or serious and chronic condition in the European Union and where, without the incentives derived from orphan designation, it is unlikely that sales of the product in the European Union would be sufficient to justify the necessary investment in its development.

Orphan designation is only available if there is no other satisfactory method authorized for marketing in the European Union for diagnosing, preventing or treating the condition, or if such a method exists, the proposed orphan product will be of significant benefit to patients over the existing options.

We have obtained orphan designation in the European Union for nomlabofusp.

Orphan designation provides opportunities for fee reductions, protocol assistance and access to the centralized procedure in the European Union.

Fee reductions are not limited to the first year after an MA is granted, except for small and medium enterprises.

In addition, if a product which has an orphan designation subsequently receives a centralized MA for the indication for which it has such designation, the product is entitled to orphan market exclusivity, which means the regulatory authorities in the European Union may not approve any other application to market a "similar medicinal product" for the same indication as the authorized orphan product for a period of 10 years.

Small and medium enterprises are typically eligible for the most significant fee reductions.

In addition, if a product which has an orphan designation subsequently receives a centralized MA for the indication for which it has such designation, the product is entitled to orphan market exclusivity, which means the regulatory authorities in the European Union may not approve any other application to market a “similar medicinal product” for the same indication as the authorized orphan product for a period of 10 years from authorization of the orphan product (subject to certain exceptions).

A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

The exclusivity period may be reduced to six years if, at the end of the fifth year, its is determined that the designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.

The exclusivity period may be reduced to six years if, at the end of the fifth year, it is determined that the designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.

Additionally, an MA may be granted to a similar medicinal product for the same indication as an authorized orphan product if:

• the second applicant can establish that its product, although similar to the authorized orphan product, is safer, more effective or otherwise clinically superior;

• the MA holder of the authorized orphan product consents to a second orphan medicinal product application;

• the MA holder of the authorized orphan product cannot supply enough orphan medicinal product.

• the MA holder of the authorized orphan product consents to a second medicinal product application;

• the MA holder of the authorized orphan product cannot supply sufficient quantities of the orphan medicinal product.

The EMA offers a scheme to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist.

The PRIority MEdicines, or PRIME, scheme is intended to encourage drug development in areas of unmet medical need and is intended to reinforce early dialogue with, and regulatory support from, the EMA in order to stimulate innovation, optimize development and enable accelerated assessment of such product candidates.

The PRIority MEdicines, or PRIME, scheme is intended to encourage drug development in areas of unmet medical need and to reinforce early dialogue with, and regulatory support from, the EMA in order to stimulate innovation, optimize development and support accelerated assessment, where eligible, of such product candidates.

It is intended to build upon the scientific advice scheme and accelerated assessment procedure offered by the EMA.

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Applicants will typically be at the exploratory clinical trial phase of development and will have preliminary clinical evidence in patients to demonstrate the promising activity of the medicine and its potential to address to a significant extent an unmet medical need.

In exceptional cases, applicants from the academic sector or SMEs (small and medium sized enterprises) may submit an eligibility request at an earlier stage of development if compelling non-clinical data in a

relevant model provide early evidence of promising activity to establish proof of principle, and first in man studies indicate adequate exposure for the desired pharmacotherapeutic effects and tolerability.

In exceptional cases, applicants from the academic sector or SMEs (small and medium sized

enterprises) may submit an eligibility request at an earlier stage of development if compelling non-clinical data in a relevant model provide early evidence of promising activity to establish proof of principle, and first in man studies indicate adequate exposure for the desired pharmacotherapeutic effects and tolerability.

If a medicine is selected for the PRIME scheme, the EMA:

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A Pediatric Investigation Plan (“PIP”) in the European Union is aimed at ensuring that the necessary data are obtained to support the authorization of a medicine for children, through studies in children.

All applications for marketing authorization for new medicines have to include the results of studies as described in an agreed PIP, unless the study results are deferred, or the medicine is exempt because of a waiver.

This requirement also applies when a marketing-authorization holder wants to add a new indication, pharmaceutical form, or route of administration for a medicine that is already authorized.

Several rewards and incentives for the development of pediatric medicines for children are available in the EU Medicines authorized across the EU with the results of studies from a PIP included in the product information are eligible for an extension of their supplementary protection certificate ("SPC")by six months(provided an application for such extension is made at the same time as filing the SPC application for the product, or at any point up to two years before the SPC expires).

All applications for marketing authorization for new medicines must include either the results of studies conducted in compliance with an agreed PIP or evidence of a waiver or deferral, as applicable.

This requirement also applies when a marketing authorization holder seeks to add a new indication, pharmaceutical form or route of administration for a medicine that is already authorized.

Several rewards and incentives for the development of pediatric medicines are available in the EU.

Medicines with the results of studies from an agreed PIP appropriately reflected in the product information are eligible for a six-month extension of their supplementary protection certificate (“SPC”), provided the applicable requirements are met and the extension request is filed within the applicable deadlines (including, for SPCs already granted, generally no later than two years before SPC expiry).

This is the case even when the studies’ results are negative.

For orphan medicines, the incentive is an additional two years of market exclusivity.

Scientific advice and protocol assistance at the EMA are free of charge for questions relating to the development of pediatric medicines.

For orphan medicines, this may extend the orphan market exclusivity period by an additional two years.

Certain pediatric regulatory procedures (including PDCO assessments of PIPs, waivers, deferrals and compliance) are free of charge.

All of the aforementioned European Union rules are generally applicable in the EEA.

The UK left the European Union on January 31, 2020.

As a result of the Northern Ireland protocol following Brexit, the EMA remained responsible for approving novel medicines for supply in Northern Ireland, the European Union regulatory framework continues to apply in Northern Ireland under the EU centralized procedure, and as separate authorization was required to supply the same medicine in Great Britain (England, Wales and Scotland).

On February 27, 2023, the UK government and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”.

This new framework fundamentally changes the previous system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the UK.

In particular, the MHRA is now responsible for approving all medicinal products destined for the UK market (Great Britain and Northern Ireland), and the EMA no longer has any role in approving medicinal products destined for Northern Ireland through the EU centralized procedure.

A single UK-wide MA will be granted by the MHRA for all novel medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.

The European Commission introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the European Union for all medicines (including those for rare diseases and for children).

In April 2024, the European Parliament adopted its position on the legislative proposals and, in June 2024, the Council of the European Union adopted its position.

A common position on the text has been agreed upon on December 11, 2024, in the context of subsequent inter-institutional trilogue negotiations.

The proposed revisions remain to be adopted, and are not expected to become applicable before 2028.

Following Brexit the UK is not generally subject to EU laws in respect of medicines.

EU laws that have been transposed into UK law through secondary legislation remain applicable in the UK, however new EU legislation is not applicable in the UK.

As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency (“MHRA”) became the UK's standalone medicines and medical devices regulator.

On January 1, 2025, a new arrangement called the “Windsor Framework” came into effect and reintegrated Northern Ireland under the regulatory authority of the MHRA with respect to the regulation of medicinal products.

The Windsor Framework removes EU licensing processes and EU labeling and serialization requirements relation to and introduces a UK-wide licensing process for medicines.

A single UK-wide MA is granted by the MHRA for all novel medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.

In addition, the new arrangements require all medicines placed on the UK market to be labeled “UK only” indicating they are not for sale in the EU.

The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, an accelerated assessment procedure and new routes of evaluation for novel products and biotechnological products.

On January 1, 2024, a new international recognition framework came

into effect in the UK under which the MHRA may have regard to decisions on the approval of MAs made by the EMA and certain other regulators when determining an application for a new UK MA.

There is now no pre-marketing authorization orphan designation in the UK.

On January 1, 2024, a new international recognition framework came into effect in the UK under which the MHRA may have regard to decisions on the approval of MAs made by the EMA and certain other regulators when determining an application for a new UK MA.

There is no pre-marketing authorization orphan designation in the UK.

Instead, the MHRA will review applications for orphan designation in parallel to the corresponding MA application.

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the prevalence of the condition in the UK (rather than the EU) must not be more than 5 in 10,000.

Should an orphan designation be granted, the period or market exclusivity will be set from the date of first approval of the product in the UK.

In September 2024, we received access to the UK’s Medicines and Healthcare Regulatory Agency ("MHRA") Innovative Licensing and Access Pathway (“ILAP”) which for the treatment of adults and children with FA.

We may also apply for access to the UK’s Innovative Licensing and Access Pathway (“ILAP”) for the treatment of adults and children with FA.

Should an orphan designation be granted, the period of market exclusivity will be set from the date of first approval of the product in the UK.

In September 2024, we received access to the MHRA’s Innovative Licensing and Access Pathway (“ILAP”) for the treatment of adults and children with FA.

This Scheme aims to accelerate the time to market and facilitate patient access to certain types of medicinal products in development which target a life-threatening or seriously debilitating condition, or where there is a significant patient or public health need in the UK.

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Sales of our product candidate, if approved, or any other future product candidate will be subject to healthcare regulation and enforcement by the federal government and the states and foreign governments in which we might conduct our business.

The healthcare laws and regulations that may affect our ability to operate include the following:

In the U.S., the healthcare laws and regulations that may affect our ability to operate include the following:

• the federal Anti-Kickback Statute prohibits, among other things knowingly and willfully, directly or indirectly, soliciting, receiving, offering, or paying any remuneration that is in exchange for or to induce the referral of business, including the purchase, order, lease of any good, facility, item or service for which payment may be made under a federal healthcare program, such as Medicare or Medicaid.

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Other states have also enacted, proposed, or are considering proposing, data privacy laws, which could further complicate compliance efforts, increase our potential liability and adversely affect our business.

Additionally, to the extent that our product is sold in a foreign country, we may be subject to similar foreign laws.

Additionally, to the extent that our product is sold in a foreign country, we may be subject to similar foreign laws, such as the EU General Data Protection Regulation ("EU GDPR"), the UK General Data Protection Regulation ("UK GDPR"), Canada’s Personal Information Protection and Electronic Documents Act, and Australia’s Privacy Act, and any other applicable country, state and/or territory health privacy legislation and regulation.

Healthcare Reform

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Only high-expenditure single-source biologics that have been approved for at least 11 years (7 years for small molecule drugs) can be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.

For 2026, the first year in which negotiated prices become effective, CMS selected 10 high-cost Medicare Part D products in 2023, negotiations began in 2024, and the negotiated maximum fair price for each product has been announced.

CMS has selected 15 additional Medicare Part D drugs for negotiated maximum fair pricing in 2027.

For 2028, an additional 15 drugs, which may be covered under either Medicare Part B or Part D, will be selected, and for 2029 and subsequent years, 20 Part B or Part D drugs will be selected.

A drug or biological product that has an orphan drug designation for only one rare disease or condition will be excluded from the IRA’s price negotiation requirements, but will lose that exclusion if it receives designations for more than one rare disease or condition, or if is approved for an indication that is not within that single designated

rare disease or condition, unless such additional designation or such disqualifying approvals are withdrawn by the time CMS evaluates the drug for selection for negotiation.

The IRA also imposes rebates on Medicare Part B and Part D drugs whose prices have increased at a rate greater than the rate of inflation, and in November 2024, CMS finalized regulations for these inflation rebates.

To date, CMS has selected and negotiated prices for 25 Medicare Part D drugs for the initial years 2026 and 2027.

For 2028, an additional 15 drugs, which may be covered under either Medicare Part B or Part D, will be selected, and for 2029 and subsequent years, 20 Part B or Part D drugs will be

A drug or biological product that has one or more orphan drug designations will be excluded from the IRA’s price negotiation requirements, but will lose that exclusion if it receives approvals from FDA for an indication that is not for a rare disease or condition.

The IRA also imposes rebates on Medicare Part B and Part D drugs whose prices have increased at a rate greater than the rate of inflation.

The IRA also extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

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Thus, while it is unclear how the IRA will be implemented, it will likely have a significant impact on the biopharmaceutical industry and the pricing of prescription drug products.

In addition, on July 4, 2025, Public Law 119-21 became effective and imposes significant reductions in Medicaid funding, additional work requirements for Medicaid recipients, and more frequent reenrollment requirements, which are expected to place substantial pressure on state Medicaid budgets, reduce enrollment, and limit covered services, which could decrease utilization of, and reimbursement for, prescription drug products.

The costs of prescription drug products have also been the subject of considerable discussion in the United States.

To date, there have been several recent U.S.

congressional inquiries, as well as proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products.

The Trump Administration has issued executive orders and supported proposed regulatory initiatives in 2025 that could have a significant impact on the prices that we, or any collaborators, may receive for any approved products.

On May 12, 2025, the President signed an executive order directing the Secretary of HHS to set and communicate most-favored-nation (“MFN”) price targets to manufacturers and propose a rulemaking plan to impose MFN pricing if “significant progress” is not made, and also directing the federal government to support regulatory paths to allow direct-to-patient sales for companies that meet these targets.

The executive order further states that the Administration will take additional action (for example, examining whether marketing approvals should be modified or rescinded or considering individual drug importation waiver authorities) should manufacturers fail to offer American consumers the MFN lowest price.

In July 2025, President Trump sent letters to certain pharmaceutical companies demanding that these companies extend MFN pricing to Medicaid and newly launched drugs as well as move to direct-to-consumer models priced at MFN pricing, and soliciting binding commitments by September 29, 2025.

Since this time, multiple drug manufacturers have announced plans to, for certain of their drugs, lower prices to reflect similar pricing around the world, and to sell these reduced-price drugs on a direct-to-consumer purchasing platform developed by the federal government;

however, it is not known what results will occur to the extent the recipients of these letters do not reduce their U.S.

On December 19, 2025, CMS released two proposed rules that would incorporate MFN pricing principles into federal reimbursement for prescription drugs.

The first proposal, the Global Benchmark for Efficient Drug Pricing Model (“GLOBE”) for Medicare Part B, would require manufacturers of specified single source drugs and sole source biologics to pay incremental rebates based on international benchmark prices, with participation triggered for products meeting CMS’s spending and eligibility criteria.

The second proposal, the Guarding U.S.

Medicare Against Rising Drug Costs (“GUARD”) model for Medicare Part D, would similarly mandate manufacturer rebates for qualifying sole source drugs where the Medicare net price exceeds an MFN benchmark derived from international reference pricing methodologies.

As proposed, GLOBE would begin a five year performance period on October 1, 2026 and GUARD would begin its performance period in 2027.

These proposals will likely be subject to legal challenges that could delay their implementation or modify their impact on manufacturer pricing and revenue.

Additionally, in November 2025, CMS introduced the GENErating cost Reductions for U.S.

Medicaid (“GENEROUS”) Model, a voluntary MFN framework for manufacturers participating in the Medicaid Drug Rebate Program.

Although it is voluntary, the GENEROUS Model could also impact the drug pricing landscape for manufacturers.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business