What changed in this filing

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Item 1. Business

2025-03-24 compared with 2024-03-14 · 215 added, 182 removed, 565 unchanged (41% of the section changed)

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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, 2023, we had cash, cash equivalents and marketable securities of $86.8 million.

In February 2024,we raised net proceeds of $161.6 million in an underwritten public offering of common stock, We anticipate the $161.6 million in net proceeds, together with $86.8 million of cash, cash equivalents and marketable securities on hand will fund operations into 2026.

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.

Nomlabofusp Program Update

Clinical Trials

We have completed two Phase 1 clinical trials and a Phase 2 dose exploration trial, and recently initiated a Phase 2 OLE trial in patients with FA.

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.

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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, following the FDA’s review of our complete response to the partial clinical hold, 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 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 our four-week, placebo-controlled Phase 2 dose exploration study of nomlabofusp in participants with FA.

Nomlabofusp was generally well tolerated and 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.

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.

Participants treated with 50 mg had individual frataxin levels in skin increase from less than 17% relative to healthy volunteers at baseline, 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.

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.

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

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 trial, or who previously completed a prior clinical trial of nomlabofusp are potentially eligible to screen for the OLE.

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

Clinical measures collected during the trial will be compared to data from a matched control arm derived from participants in the Friedreich’s Ataxia Clinical Outcome Measures Study (FACOMS) database.

Dose escalation in the OLE trial will be considered based on safety, tolerability, PK, and tissue FXN levels from the Phase 2 trial’s 50 mg cohort as well as available data from the 25 mg dose of nomlabofusp in the OLE trial, and is contingent on FDA review as part of the partial clinical hold.

Initial data from the OLE trial is expected in the fourth quarter of 2024.

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.

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.

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.

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 initiated an OLE study in the U.S with patients age 18 or older to be dosed 25 mg of nomlabofusp daily.

Expansion of this OLE to doses above 25 mg as well as the initiation of additional U.S.

clinical trials evaluating nomlabofusp are contingent on FDA review as part of the FDA’s partial clinical hold.

We do not know if, or when, the FDA will lift the partial clinical hold on our nomlabofusp program or if it will ever allow further clinical development of nomlabofusp beyond the current OLE study that we recently initiated.

We also are planning to include in our clinical studies, individuals between the ages of 2 and 17 and are currently in discussions with FDA as to what additional clinical trial data in adults would inform inclusion of those pediatric individuals in our studies.

We are continuing to collaborate with key opinion leaders and seek guidance from regulatory authorities 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.

• 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.

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 .

Recently, we had discussions with the FDA regarding the potential use of tissue FXN levels as a novel surrogate endpoint.

The FDA has 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.

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 beginning to plan for a confirmatory study and are targeting a BLA submission in the second half of 2025.

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.

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See Figure 1.

We have completed two Phase 1 nomlabofusp clinical trials, and a Phase 2 dose exploration trial and have initiated an OLE study in the U.S with patients to be dosed 25 mg of nomlabofusp daily.

The nomlabofusp program remains under a partial clinical hold imposed by the FDA, and expansion of the OLE study above the 25 mg dose level as well as further clinical development of nomlabofusp is contingent upon FDA agreement based on its review of data from the 50 mg cohort of the Phase 2 dose exploration study and review of the available data from the OLE study at the current 25 mg dose level.

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:

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Data from the study were collected throughout the second half of 2021 and included in the complete response to the clinical hold submitted to the FDA in January 2022.

In February 2022, in response to the complete response to the clinical hold we submitted to the FDA, the FDA stated that it was maintaining the clinical hold and that additional data were needed to resolve the clinical hold.

subsequently submitted a request to the FDA for a Type C meeting, which was granted and held in July 2022.

We submitted a complete response to clinical hold incorporating additional information requested by the FDA at the meeting as well as information on the proposed study in August 2022.

In September 2022, following the Type C meeting and the submission of the Company's complete response to clinical hold, the FDA allowed the 25 mg cohort of a Phase 2, four-week, placebo-controlled, dose exploration trial of nomlabofusp in FA patients discussed above to proceed.

In connection with this decision, the FDA lifted its full clinical hold on the nomlabofusp clinical development program and imposed a partial clinical hold.

In June 2023, we met with the FDA.

Following that meeting, we submitted a complete response to the FDA’s partial clinical hold that included unblinded safety, PK and frataxin data from the Phase 2 trial’s completed 25 mg cohort.

In July 2023, following the FDA’s review of our complete response to the partial clinical hold, the FDA cleared initiation of a second cohort at 50 mg of our four-week, placebo-controlled, Phase 2 dose exploration trial and initiation of our OLE trial with daily dosing of 25 mg.

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.

Clinical Development

Non-Interventional Studies

We have conducted non-interventional studies to examine the range of tissue FXN concentrations in individuals who are homozygous for the normal FXN gene.

Non-Interventional Study

In 2021, we conducted a non-interventional study that enrolled 60 healthy adults to examine the range of tissue FXN concentrations in individuals who are homozygous for the normal FXN gene.

Tissue samples in these studies were collected using the same sampling techniques and proprietary assay used in the interventional studies.

In a 2020 study we obtained data from 8 healthy adults, but the study was then terminated early by the study site due to competing priorities during the COVID-19 pandemic.

In 2021 we initiated a second study that enrolled approximately 60 healthy adults.

Enrollment in this study was completed in 2022 and data has been used for comparison purposes in the Phase 2 clinical study described below.

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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").

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").

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.

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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 appears to be proportional to dose.

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;

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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 Phase 2 trial.

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

In June 2023, we met with the FDA.

Following that meeting, we submitted a complete response to the FDA’s partial clinical hold that included unblinded safety, PK and frataxin data from the Phase 2 trial’s completed 25 mg cohort.

In July 2023, following the FDA’s review of our complete response to the partial clinical hold, the FDA cleared initiation of the second cohort (50 mg) of our four-week, placebo-controlled, Phase 2 dose exploration trial 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 our four-week, placebo-controlled Phase 2 dose exploration study of nomlabofusp in participants with FA.

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.

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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 show a dose dependent increase in frataxin levels after 14 days of treatment.

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 grey, the 25 mg cohort in aqua, and the 50 mg cohort in blue.

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.

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Participants who completed treatment in the Phase 2 dose exploration trial, or who previously completed a prior clinical trial of

nomlabofusp are potentially eligible to screen for the OLE.

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

Further dose expansion in the OLE trial will be considered based on safety, tolerability, PK, FXN levels from the 25 mg dose of nomlabofusp in the OLE trial, as well as data from the Phase 2 trial's 50 mg cohort and is contingent on FDA review as part of the partial clinical hold.

Initial data from the OLE trial is expected in the fourth quarter of 2024.

We also are planning to include in our clinical studies, individuals between the ages of 2 and 17 and are currently in discussions with FDA as to what additional clinical data in adults would inform inclusion of those pediatric individuals in our studies.

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.

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 who 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;

• 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;

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.

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 package exclusivity), which is separate and distinct from the protection afforded by patents, to protect our products.

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 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.

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

As of February 23, 2024, our intellectual property portfolio was composed of numerous international Patent Cooperation Treaty ("PCT"), foreign, and United States non-provisional patent applications, a United States patent and United States provisional patent applications that we own or co-own, and six 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.

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.

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

The additional patent applications we own or co-own which include PCT, foreign and United States non-provisional patent applications a United States patent, and United States provisional patent applications are related to the development of nomlabofusp, including methods of use of nomlabofusp, and to our peptide-delivery platform technology.

The additional patent applications we own or co-own, which include PCT, foreign and United States non-provisional patent applications, United States patents, and United States provisional patent applications are related to the development of nomlabofusp, including methods of use of nomlabofusp, and to our peptide-delivery platform technology.

A provisional patent application allows for an effective filing date to be established with regard to an invention, but once a provisional patent application is filed, either a corresponding non-provisional patent application or a petition to convert the provisional patent application into a non-provisional patent application must be filed within 12 months or such effective filing date will be lost.

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 2044 or 2025, without taking potential patent term adjustment or patent term extension into consideration.

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 2045, 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.

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We are also obligated to reimburse WFUHS and 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.

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.

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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.

Many of our competitors have significantly greater financial, technical and human resources than we do.

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.

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

Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated amongst a smaller number of our competitors.

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Nomlabofusp is a biologic fusion protein that is produced in E.

We have worked with contract manufacturers to develop, in accordance with cGMPs a manufacturing process and analytical methods for drug substance to support clinical trials.

We also use third party manufacturers for the clinical packaging, storage and

distribution of nomlabofusp.

We have worked with contract manufacturers and research organizations to develop, in accordance with current Good Manufacturing Practices (“cGMP”) a manufacturing process and analytical methods for drug substance and drug product to support clinical trials.

We also use third party manufacturers for the clinical packaging, storage and distribution of nomlabofusp.

We rely on third parties to store the nomlabofusp master cell bank and working cell bank, each stored at a different location.

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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 currently produce a frozen liquid form of drug product at another manufacturer.

We have also begun a program with a third-party manufacturer to produce a lyophilized version of the drug product from the same KBI drug substance, that, once available, we intend to use in certain of our future planned clinical trials and ultimately, commercial use, assuming nomlabofusp receives required regulatory approvals.

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 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.

Human Capital Resources

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To facilitate talent attraction and retention, we strive to make our company a safe and rewarding workplace, with opportunities for our employees to grow and develop in their careers, supported by strong compensation, benefits, paid time-off and health and wellness programs, including programs that build connections between our employees.

As of December 31, 2023, we employed 42 full-time employees in the United States, of which 32 are directly engaged in research and development with the rest providing administrative, business and operations support.

As of December 31, 2024, we employed 65 full-time employees in the United States, of which 48 are directly engaged in research and development with the rest providing administrative, business, commercial and operations support.

None of our employees are represented by a labor organization or under any collective-bargaining arrangements.

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The principal purposes of our equity and cash incentive plans are to attract, retain and reward personnel through the granting of stock-based and cash-based compensation awards, in order to increase stockholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.

Diversity and Inclusion

We value the diversity of our employees and take pride in our commitment to diversity and inclusion across all levels of our organizational structure and with respect to our board of directors.

We are committed to developing strategies for building diverse teams and promoting the advancement of employees from diverse backgrounds.

Scientific Advisors

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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 1,750 square feet located in Bala Cynwyd, PA and Philadelphia, PA, respectively.

We are currently on a month-to-month lease on this Philadelphia lab space.

We, as well as our landlord, can terminate the lease with four months notice.

We have entered into a lease for 3,927 square feet of new laboratory space in King of Prussia, PA to replace the Philadelphia lab space, but this lease has not yet commenced with expected occupancy in the second quarter of 2024.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").

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.

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").

The Boston Lease expires on October 30, 2029.

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Copies of each of our filings with the SEC on Form 10-K, Form 10-Q and Form 8-K and all amendments to those reports, can be viewed and downloaded free of charge at our website, www.larimartx.com as soon as reasonably practicable after the reports and amendments are electronically filed with or furnished to the SEC.

Our code of ethics, other corporate policies and procedures, and the charters of our Audit Committee, Compensation Committee and Nominating and Corporate Governance Committee are available through our website

at www.larimartx.com .

We intend to post information regarding any amendments to, or waivers from, our code of ethics on our website.

Government Regulation

In the United States, drug and biologic products are subject to extensive regulation by the FDA.

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, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products.

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.

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• performance of adequate and well-controlled human clinical trials according to Good Clinical Practices ("GCPs") and any additional requirements for the protection of human research subjects and their health information, to establish the safety, purity, potency, and efficacy, of the proposed drug or biological product for its intended use;

• submission to the FDA of an NDA or BLA for marketing approval that includes substantive evidence of safety, purity, potency, and efficacy from results of non-clinical testing and clinical trials;

• submission to the FDA of an NDA or BLA for marketing approval that includes evidence of safety, purity, potency, and efficacy from results of non-clinical testing and clinical trials;

• 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;

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Before testing any drug or biological product candidate in humans, the product candidate enters the non-clinical testing stage.

Non-clinical tests include laboratory evaluations of product chemistry, pharmacology, toxicity

and formulation, as well as animal studies to assess the potential safety and activity of the product candidate.

Non-clinical tests include laboratory evaluations of product chemistry, pharmacology, toxicity and formulation, as well as animal studies to assess the potential safety and activity of the product candidate.

The conduct of the non-clinical tests must comply with federal regulations and requirements including GLPs.

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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.

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

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 most cases, the FDA requires two adequate and well-controlled Phase 3 clinical trials to demonstrate the safety and efficacy of the drug or biologic.

In rare instances, a single Phase 3 trial may be sufficient when either (1) the trial is a large, multicenter trial demonstrating internal consistency and a statistically very persuasive finding of a clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with a potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible, or (2) the single trial is supported by other confirmatory evidence.

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.

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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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In this event, the NDA or BLA must be resubmitted with the additional information.

The resubmitted application is

also subject to review before the FDA files it.

The resubmitted application is also subject to review before the FDA files it.

Once the submission is filed, the FDA begins an in-depth substantive review of the NDA or BLA.

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Prior to the institution of any manufacturing changes, a determination needs to be made whether FDA approval is required in advance.

in accordance with FDA expectations, the FDA may restrict supply and may take further action.

If not done in accordance with FDA expectations, the FDA may restrict supply and may take further action.

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, 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, 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.

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

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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 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 indication or the same

product for a different indication but that could be used off-label in the orphan indication.

Orphan drug exclusivity also could block the approval of our products for seven years if a competitor obtains approval before we do for the same product as defined by the FDA for the same indication we are seeking approval, or if our product is determined to be contained within the competitor’s scope of product for the same indication or disease.

If we pursue marketing approval for an indication broader than the orphan drug designation we have received, we may not be entitled to orphan drug exclusivity.

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 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.

Expedited Review and Approval Programs

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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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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;

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.

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 September 30, 2024, with the potential for priority review vouchers to be granted through September 30, 2026.

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.

Pediatric Information and Pediatric Exclusivity

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Under the Best Pharmaceuticals for Children Act (“BPCA”), a drug or biologic product can also obtain pediatric market exclusivity in the United States.

Pediatric exclusivity, if granted, adds six months to existing exclusivity periods for all formulations, dosage forms, and indications of the active moiety and patent terms for drugs and six months to exclusivity periods for all formulations, dosage forms, and indications for biologic products.

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 remaining.

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 via an approved BLA.

Biosimilarity to an approved reference product requires that there be no differences in conditions of use, route of administration, dosage form, and strength, and no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.

Biosimilarity is demonstrated in steps beginning with rigorous analytical studies or "fingerprinting", in vitro studies, in vivo animal studies, and generally at least one clinical study, absent a waiver from the Secretary of the U.S.

Department of Health and Human Services ("HHS").

The biosimilarity exercise tests the hypothesis that the investigational product and the reference product are the same.

If at any point in the stepwise biosimilarity process a significant difference is observed, then the products are not biosimilar, and the development of a stand-alone BLA is necessary.

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 result as the reference product, and for a product that is administered more than once, that the risk of switching between the reference product and biosimilar product is not greater than the risk of maintaining the patient on the reference product.

Pediatric exclusivity, if granted, adds six months to existing exclusivity periods for all formulations, dosage forms, and indications of the active moiety and to patent terms for drugs;

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

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.

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

The first biologic product submitted under the biosimilar abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against a finding of interchangeability for other biologics for the same condition of use for the lesser of (i) one year after first commercial marketing of the first interchangeable biosimilar, (ii) 18 months after the first interchangeable biosimilar is approved if there is no patent challenge, (iii) 18 months after resolution of a lawsuit over the patents of the reference biologic in favor of the first interchangeable biosimilar applicant, or (iv) 42 months after the first interchangeable biosimilar is approved if a patent lawsuit is ongoing within the 42-month period.

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.

During the 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a BLA for the competing product that does not rely on the reference product;

the BLA must be based on the sponsor’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity, and potency of the other company’s product.

Finally, the first biologic product submitted under the biosimilar abbreviated approval pathway that is determined to be interchangeable with the reference product may obtain exclusivity against a finding of interchangeability for other biologics for the same condition of use for the lesser of (i) one year after first commercial marketing of the first interchangeable biosimilar, (ii) 18 months after the first interchangeable biosimilar is approved if there is no patent challenge, (iii) 18 months after resolution of a lawsuit over the patents of the reference biologic in favor of the first interchangeable biosimilar applicant, or (iv) 42 months after the first interchangeable biosimilar is approved if a patent lawsuit is ongoing within the 42-month period.

Regulation Outside of the United States

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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.

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 ("EU/EEA") countries at the same time and with a single set of documentation.

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).

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Part II is assessed separately by each Member State concerned.

The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the Member State concerned, however overall related timelines are defined by the Clinical Trials Regulation.

The new Clinical Trials Regulation also provides for simplified reporting procedures for clinical trial sponsors.

The role of the relevant ethics committees in the assessment procedure is governed by the national law of the Member State concerned, however overall related timelines are defined by the Clinical Trials Regulation.

The Clinical Trials Regulation also provides for simplified reporting procedures for clinical trial sponsors.

In addition, whether or not we obtain FDA approval for a product, we must obtain approval of a product by the comparable regulatory authorities of countries outside the U.S.

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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 submit a Marketing Authorization Application ("MAA"), to be assessed in the centralized procedure.

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").

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.

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.

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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.

Full copies of the MAA are sent to a rapporteur and a co-rapporteur designated by the competent EMA scientific committee.

They coordinate the EMA's scientific assessment of the medicinal product and prepare draft reports.

Once the draft reports are prepared (other experts might be called upon for this purpose), they are sent to the CHMP, whose comments or objections are communicated to the applicant.

The rapporteur and co-rapporteur then assess the applicant's replies, submit them for discussion to the CHMP and, taking into account the conclusions of this debate, prepare a final assessment report.

Once the evaluation is completed, the CHMP gives a favorable or unfavorable opinion as to whether to grant the authorization.

When the opinion is favorable, it shall include the draft summary of the product's characteristics, the package leaflet and the texts proposed for the various packaging materials.

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 European Commission has fifteen days to prepare a draft decision.

The medicinal product is assigned an EU registration number, which will be placed on its packaging if the MA is granted.

During this period, various European Commission directorates-general are consulted on the draft MA decision.

There are two other procedures in the European Union for the grant of an MAA in multiple European Union Member States.

The decentralized procedure provides for approval by one or more other, or concerned, Member States of an assessment of an application performed by one member state, known as the Reference Member State.

Under this procedure, an applicant submits an application, or dossier, and related materials including a draft summary of product characteristics, and draft labeling and package leaflet, to the Reference Member State and Concerned Member States.

The Reference Member State prepares a draft assessment and drafts of the related materials within 120 days after receipt of a valid application.

Within 90 days of receiving the reference member state's assessment report, each Concerned Member State must decide whether to approve the assessment report and related materials.

If a member state cannot approve the assessment report and related materials on the grounds of potential serious risk to the public health, the disputed points may eventually be referred to the European Commission, whose decision is binding on all member states.

Where a product has already received an MA in one Member State, another Member State can recognize that MA under the mutual recognition procedure.

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.

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.

If a product has already been authorized for marketing in a European Union Member State, this national MA can be recognized in another European Union Member State through the mutual recognition procedure.

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.

Regulation (EC) No.

141/2000, as amended, 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 conditions that affect not more than 5 in 10,000 persons in the European Union when the application is made.

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.

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

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 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" similar drug for the same indication for a period of 10 years.

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 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 if:

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.

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.

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;

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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, 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 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.

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.

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

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:

• Appoints a rapporteur from the CHMP or from the Committee for Advanced Therapies ("CAT") to provide continuous support and to build up knowledge of the medicine in advance of the filing of an MAA;

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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 and covered by intellectual property rights.

Several rewards and incentives for the development of pediatric medicines for children are available in the E.U.

Medicines authorized across the E.U.

with the results of studies from a PIP included in the product information are eligible for an extension of their supplementary protection certificate by six months.

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).

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 Agency are free of charge for questions relating to the development of pediatric medicines.

The aforementioned European Union rules are generally applicable in the EEA.

The UK left the European Union on January 31, 2020 and the UK and the European Union concluded a trade and cooperation agreement (“TCA”), which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of cGMP, inspections of manufacturing facilities for medicinal products and cGMP documents issued, but does not provide for wholesale mutual recognition of UK and European Union pharmaceutical regulations.

At present, Great Britain has implemented European Union legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the European Union regulatory framework continues to apply in Northern Ireland).

Except in respect of the new European Union Clinical Trials Regulation, the regulatory regime in Great Britain therefore largely aligns with current European Union medicines regulations, however it is possible that these regimes will diverge more significantly in future now that Great Britain’s regulatory system is independent from the European Union and the TCA does not provide for mutual recognition of UK and European Union pharmaceutical legislation.

However, notwithstanding that there is no wholesale recognition of European Union pharmaceutical legislation under the TCA, under the new framework mentioned below which will be put in place by the Medicines and Healthcare products Regulatory Agency (“MHRA”), the UK’s medicines regulator, from January 1, 2024, the MHRA has stated that it will take into account decisions on the approval of MAs from the EMA (and certain other regulators) when considering an application for a Great Britain MA.

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

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 existing system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the UK.

In particular, the MHRA will be responsible for approving all medicinal products destined for the UK market (Great Britain and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland.

Once the Windsor Framework is approved by the EU-UK Joint Committee, the UK Government and the European Union will enact legislative measures to enact it into law.

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.

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.

All existing E.U.

MAs for centrally authorized products were automatically converted (grand fathered) into UK MAs free-of-charge on January 1, 2021.

For a period of three years from January 1, 2021, the MHRA may rely on a decision taken by the European Commission on the approval of a new MA in the centralized procedure, in order to more quickly grant a new Great Britain MA.

A separate application will, however, still be required.

On January 24, 2023, the MHRA announced that a new international recognition framework will be put in place from January 1, 2024, which will have regard to decisions on the approval of MAs made by the EMA and certain other regulators when determining an application for a new Great Britain MA.

There is now no pre-marketing authorization orphan designation in Great Britain.

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.

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

The criteria are essentially the same, but have been tailored for the GB market, i.e.

the prevalence of the condition in GB (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 GB or EU/European Economic Area, wherever is earliest.

We may also apply for access to the UK’s Innovative Licensing and Access Pathway (“ILAP”) which 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.

The criteria are essentially the same, but have been tailored for the UK market, i.e.

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.

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.

To access the ILAP, an applicant applies for an Innovation Passport designation.

Once an Innovation Passport designation is granted, the MHRA and its partner agencies (including The All Wales Therapeutics and Toxicology Centre, National Institute for Health and Care Excellence and the Scottish Medicines Consortium) will work with the Innovation Passport designee to define a Target Development Profile, (“TDP”).

TDP sets out a unique product-specific roadmap towards patient access in the UK and provides access to a toolkit to support all stages of the design, development and approvals process, including continuous benefit-risk assessment, increased support for novel development approaches and enhanced patient engagement.

The TDP sets out a unique product-specific roadmap towards patient access in the UK and provides access to a toolkit to support all stages of the design, development and approvals process, including continuous benefit-risk assessment, increased support for novel development approaches and enhanced patient engagement.

However, although the goal of the ILAP is to reduce the time to market and enable earlier patient access, access does not accelerate conduct of clinical trials or mean that the regulatory requirements are less stringent, nor does it ensure that a marketing authorization application will be approved or that any approval will be granted within a particular timeframe or at all.

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Each of these laws is subject to varying interpretations and new laws continue to be proposed.

At the state level, numerous states have or are in the process of enacting or considering comprehensive

state-level data privacy and security laws, rules and regulations while other states have focused on more narrow aspects of privacy.

At the state level, numerous states have or are in the process of enacting or considering comprehensive state-level data privacy and security laws, rules and regulations while other states have focused on more narrow aspects of privacy.

In the state of Washington, for example, the My Health My Data Act will require regulated entities to obtain consent to collect health information, grant consumers certain rights, including to request deletion of their information, and provide for robust enforcement mechanisms, including enforcement by the Washington state attorney-general and a private right of action for consumer claims.

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Among other things, the Affordable Care Act expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program, expanded the 340B program, and increased the amount of Medicaid drug rebates manufacturers are required to pay to states.

Since that time, several healthcare reform proposals recently culminated in the enactment of the Inflation Reduction Act (“IRA”) in August 2022, which, among other things, allows HHS to directly negotiate the selling price of a statutorily specified number of drugs and biologics each year that CMS reimburses under Medicare Part B and Part D.

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

Negotiations for Medicare Part D products take place in 2024 with the negotiated price taking effect in 2026, and negotiations for Medicare Part B products will begin in 2026 with the negotiated price taking effect in 2028.

In August 2023, HHS announced the ten Medicare Part D drugs and biologics that it selected for negotiations.

HHS will announce the negotiated maximum fair prices by September 1, 2024, and this price cap, which cannot exceed a statutory ceiling price, will go into effect on January 1, 2026.

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.

Since that time, there have been multiple healthcare reform measures, including the Inflation Reduction Act of 2022 (“IRA”) which, among other things, allows HHS to directly negotiate the selling price of a statutorily specified number of drugs and biologics each year that CMS reimburses under Medicare Part B and Part D.

The negotiated price may not exceed a statutory ceiling price.

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.

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.

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

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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.

For example, the FDA released a final rule in

September 2020 providing guidance for states to build and submit plans for importing drugs from Canada, and FDA authorized the first such plan in Florida in January 2024.

For example, the FDA released a final rule in September 2020 providing guidance for states to build and submit plans for importing drugs from Canada, and FDA authorized the first such plan in Florida in January 2024.

In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.

We expect that additional federal, state and foreign healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in limited coverage and reimbursement and reduced demand for our products, once approved, or additional pricing pressures.

Additional federal, state and foreign healthcare reform measures may be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in limited coverage and reimbursement and reduced demand for prescription drug products, once approved, or additional pricing pressures.

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