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Item 1. Business

2025-03-03 compared with 2024-02-27 · 512 added, 374 removed, 473 unchanged (65% of the section changed)

Company Overview

We are a biopharmaceutical company focused on discovering and developing potential best-in-class medicines for serious and rare diseases.

We are a biopharmaceutical company focused on discovering, developing, and commercializing potential best-in-class medicines for serious and rare diseases.

We target disease areas where marketed therapies often leave room for improvements in efficacy, safety, and/or dosing convenience.

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We intend to prioritize indications where a fast-follower and a potentially differentiated drug candidate, or overall product profile, could create significant medical benefit for patients.

We are engineering medicines to address unmet medical needs for patients and further advance drug innovation.

We are engineering product candidates to address unmet medical needs for patients and further advance drug innovation.

Our goal is to identify and evaluate product concepts leveraging clinically validated molecular targets using established therapeutic modalities.

We prioritize product concepts that are aligned with clinical and commercial hypotheses, which we expect will provide an attractive balance of risk and opportunity, thereby representing a compelling allocation of our resources.

We focus on advancing therapeutic proteins, including antibodies, that we either in-license or discover internally, incorporating proprietary therapeutic protein and antibody discovery and optimization platforms to advance clinical candidates with unique characteristics.

We have built relevant expertise in protein and antibody discovery and engineering, biologics manufacturing, nonclinical and clinical development for thyroid eye disease (“TED”), development of anti-neonatal Fc receptor (“FcRn”) therapies, and nonclinical and clinical development for indications in rare and autoimmune diseases.

We focus on advancing therapeutic proteins that we either in-license or discover internally, incorporating proprietary therapeutic protein and antibody discovery and optimization platforms to advance clinical candidates with unique characteristics.

We have built relevant expertise in protein and antibody discovery and engineering, biologics manufacturing, nonclinical and clinical development, and commercialization for thyroid eye disease (“TED”), development of anti-neonatal Fc receptor (“FcRn”) therapies, and nonclinical and clinical development for indications in rare and autoimmune diseases.

Our approach to rapidly discovering and developing novel therapeutics relies on our scientific expertise in evaluating pre-existing clinical proof-of-concept data for the drug targets we are pursuing, and opportunities to improve upon existing investigational and/or approved therapies.

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We believe this strategy reduces the risks associated with discovering and developing novel therapeutics.

We have first prioritized the development of therapies for the treatment of TED, a serious and debilitating rare autoimmune disease that causes inflammation within the orbit of the eye that can cause bulging of the eyes, redness and swelling, double vision, pain, and potential blindness.

Development of Therapies to Treat Thyroid Eye Disease (TED)

We are developing therapies for the treatment of TED, a serious and debilitating rare autoimmune disease that causes inflammation within the orbit of the eye that can cause bulging of the eyes, redness and swelling, double vision, pain, and potential blindness.

TED significantly impacts quality of life, imposing a high burden on activities of daily living and mental health for patients suffering from the disease.

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The only medicine approved by the FDA for TED is Tepezza® (teprotumumab), which is an intravenously administered monoclonal antibody that targets insulin-like growth factor 1 receptor (“IGF-1R”).

Tepezza® is marketed in the United States by Horizon Therapeutics plc (“Horizon”), which was acquired by Amgen in October 2023.

Tepezza is marketed in the United States (“U.S.”) by Horizon Therapeutics plc (“Horizon”), which was acquired by Amgen Inc.

(“Amgen”) in October 2023.

In 2024, Amgen gained approval for Tepezza in Japan and submitted a Marketing Authorization Application (“MAA”) to the European Medicines Agency (“EMA”).

The results from clinical trials of teprotumumab conducted by Horizon provide strong clinical validation linking the targeting of IGF-1R to clinical benefit in patients with TED.

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We believe that there are multiple opportunities to develop fast-follower therapeutics that improve on teprotumumab’s features, including dosing schedule, route of administration, and safety profile.

We are developing two product candidates, VRDN-001 for intravenous (“IV”) and VRDN-003 for subcutaneous (“SC”) administration, to treat patients who suffer from TED.

Our most advanced program, VRDN-001, is a differentiated humanized monoclonal antibody targeting IGF-1R intravenously administered for the treatment of TED.

In previously presented in vitro preclinical data, we showed that VRDN-001 is a potentially differentiated full antagonist of IGF-1R, compared to teprotumumab’s incomplete antagonism of IGF-1R.

We also conducted Phase 1/2 clinical trials of VRDN-001 in patients with active or chronic TED.

In the active TED portion of the Phase 1/2 clinical trials, data reported from all three dose cohorts of VRDN-001 (n=21) showed significant and rapid improvement in both the signs and symptoms of TED after two infusions of VRDN-001 compared to placebo.

Across all VRDN-001 treated patients in the active TED trial, 71% were proptosis responders, 67% were overall responders, 62% achieved a clinical activity score (“CAS”) of 0 or 1, and 54% had complete resolution of their diplopia.

In the chronic TED portion of the Phase 1/2 clinical trials, data reported from both dose cohorts of VRDN-001 (n=12) showed significant and rapid improvement in the signs and symptoms of TED after two infusions of

VRDN-001 compared to placebo.

Across all VRDN-001 treated patients in the chronic TED trial, 42% were proptosis responders, 40% achieved a CAS of 0 or 1, and no patients had complete resolution of their diplopia.

In the Phase 1/2 clinical trials of both active and chronic TED, VRDN-001 had a favorable safety profile and was well-tolerated by all patients treated in all dose cohorts.

We are evaluating VRDN-001 in two global Phase 3 clinical trials, THRIVE and THRIVE-2, for the treatment of active and chronic TED, respectively.

THRIVE and THRIVE-2 are each designed to compare a five-dose IV treatment arm of VRDN-001 at 10 mg/kg, dosed three weeks apart, to placebo.

This five-dose VRDN-001 regimen features fewer infusions and a shorter time per infusion compared to teprotumumab, the currently marketed IGF-1R inhibitor.

We expect to report topline THRIVE and THRIVE-2 data in the middle of 2024 and by year end 2024, respectively.

We expect that the THRIVE and THRIVE-2 Phase 3 trials, together with a safety database comprising 300 treated patients will support global health authority registration for marketing approval in both active and chronic TED, respectively.

In addition to our VRDN-001 IV program, in December 2023 we selected VRDN-003 as our prioritized subcutaneous program for pivotal development in TED following positive data in a Phase 1 clinical trial in healthy volunteers.

We believe VRDN-003 has the potential to be the best-in-class subcutaneous anti-IGF-1R program by preserving the efficacy of anti-IGF-1Rs in TED, improving safety, and maximizing convenience for patients.

VRDN-003 has the same binding domain as its parent molecule, VRDN-001, and was engineered to have a longer half-life.

VRDN-003 is designed to be a low-volume, self-administered, infrequently-dosed subcutaneous IGF-1R for TED.

The VRDN-003 Phase 1 clinical study showed VRDN-003 to have a prolonged half-life of 40 to 50 days, which is four to five times that of its parent molecule, VRDN-001.

Because of the similarities between the VRDN-001 and VRDN-003 antibodies, we expect VRDN-003 to have similar clinical responses at the exposure levels of VRDN-001 that led to robust clinical activity in its Phase 2 clinical trial in TED.

Further, pharmacokinetic modeling of VRDN-003 predicted that exposure levels of VRDN-003 could be achieved that are equivalent to exposure levels of VRDN-001 that produced clinically meaningful results with multiple dosing regimens of VRDN-003, i.e., subcutaneous injection every two, four, or eight weeks.

Based on these results, we expect to initiate a global pivotal program with VRDN-003 in mid-2024, with planned trials in both active and chronic TED patients, pending regulatory authority alignment.

In addition to developing therapies for TED, we are also developing a portfolio of engineered anti-FcRn inhibitors, including VRDN-006 and VRDN-008.

We are developing two product candidates, veligrotug (formerly known as VRDN-001) for intravenous (“IV”) and VRDN-003 for subcutaneous (“SC”) administration, to treat patients who suffer from TED.

Our most advanced program, veligrotug, is a differentiated humanized monoclonal antibody targeting IGF-1R intravenously administered for the treatment of TED.

In previously presented in vitro nonclinical data, we showed that veligrotug is a potentially differentiated full antagonist of IGF-1R, compared to teprotumumab’s incomplete antagonism of IGF-1R.

VRDN-003 has the same binding domain as veligrotug, and was engineered to have a longer half-life.

VRDN-003 is designed to be a low-volume, infrequently-dosed subcutaneous IGF-1R for TED, which we plan to launch commercially with an auto-injector to enable at-home patient self-

administration.

We believe VRDN-003 has the potential to be the best-in-class subcutaneous anti-IGF-1R product candidate by preserving the efficacy of anti-IGF-1Rs in TED, improving safety and maximizing convenience for patients.

We conducted phase 1/2 clinical trials of veligrotug in patients with active or chronic TED.

In the active TED portion of the phase 1/2 clinical trials, data reported from all three dose cohorts of veligrotug (n=21) showed significant and rapid improvement in both the signs and symptoms of TED after two infusions of veligrotug compared to placebo.

Across all veligrotug treated patients in the active TED trial, 71% were proptosis responders, 67% were overall responders, 62% achieved a clinical activity score (“CAS”) of 0 or 1, and 54% had complete resolution of their diplopia.

In the chronic TED portion of the phase 1/2 clinical trials, data reported from both dose cohorts of veligrotug (n=12) showed significant and rapid improvement in the signs and symptoms of TED after two infusions of veligrotug compared to placebo.

Across all veligrotug treated patients in the chronic TED trial, 42% were proptosis responders, 40% achieved a CAS of 0 or 1, and no patients had complete resolution of their diplopia.

In the phase 1/2 clinical trials of both active and chronic TED, veligrotug had a favorable safety profile and was well-tolerated by all patients treated in all dose cohorts.

We are conducting a global pivotal program for veligrotug, including evaluating its efficacy and safety in two global well-controlled phase 3 clinical trials, THRIVE and THRIVE-2, for the treatment of active and chronic TED, respectively.

THRIVE and THRIVE-2 are each designed to compare a five-dose IV treatment arm of veligrotug at 10 mg/kg, dosed three weeks apart, to placebo.

This five-dose veligrotug regimen features fewer infusions and a shorter time per infusion compared to teprotumumab, the currently marketed IGF-1R inhibitor.

On September 10, 2024, we announced topline data from the THRIVE study, which enrolled 113 patients, randomized to veligrotug (n=75) and placebo (n=38).

THRIVE achieved all primary and secondary endpoints with a high level of statistical significance (p < 0.0001) and was generally well-tolerated, with no treatment-related serious adverse events (“SAEs”).

Veligrotug additionally showed a rapid onset of treatment effect, with the majority (53%) of veligrotug-treated patients achieving a proptosis response as early as three weeks.

On December 16, 2024, we announced topline data from the THRIVE-2 study, which enrolled 188 patients, randomized to veligrotug (n=125) and placebo (n=63).

THRIVE-2 achieved all primary and secondary endpoints with statistical significance and was generally well-tolerated.

Veligrotug continued to demonstrate a rapid onset of treatment effect, with a statistically significant proptosis response as early as three weeks and a statistically significant reduction and resolution of diplopia as early as six weeks.

THRIVE-2 is the first global phase 3 study in patients with chronic TED to demonstrate a statistically significant and clinically meaningful diplopia responder rate and rate of diplopia complete resolution.

To meet the 300 patient standard safety database requirements for the veligrotug biologics license application (“BLA”), we are conducting our STRIVE clinical trial (safety database inclusive of patients from the THRIVE and THRIVE-2 trials).

STRIVE is a global study of veligrotug in TED patients that utilizes broad inclusion criteria (e.g., any severity or duration of disease) and is randomized 3:1 (10 mg/kg IV with an active control of 3 mg/kg IV).

In January 2025, we completed enrollment in STRIVE with a total of 231 patients, exceeding the enrollment target of 212 due to patient demand.

We have also completed enrollment of the open label extension study for non-responding patients in THRIVE and THRIVE-2.

We anticipate submitting a BLA for veligrotug in the second half of 2025 and an MAA to the EMA in the first half of 2026.

In addition to our intravenous veligrotug program, VRDN-003 is our subcutaneous product candidate currently in pivotal development in TED, which we selected in December 2023 following positive data in a phase 1 clinical trial in healthy volunteers.

The VRDN-003 phase 1 clinical study showed VRDN-003 to have a prolonged half-life of 40 to 50 days, which is four to five times that of veligrotug.

Because of the healthy volunteer data and the similarities between the veligrotug and VRDN-003 antibodies, we expect VRDN-003 to have similar clinical responses at the exposure levels of veligrotug that led to robust clinical activity in its clinical trials to date in TED.

Further, pharmacokinetic modeling of VRDN-003 based on the healthy volunteer data predicted that exposure levels of VRDN-003 could be achieved that are equivalent to exposure levels of veligrotug that produced clinically meaningful results with multiple dosing regimens of VRDN-003, i.e., subcutaneous injection every two, four, or eight weeks.

We are conducting a global pivotal program for VRDN-003, including evaluating its efficacy and safety in two global well-controlled phase 3 clinical trials, REVEAL-1 and REVEAL-2, for the treatment of active and chronic TED, respectively.

Both studies will evaluate subcutaneous VRDN-003 administered every four weeks or every eight weeks and will assess outcomes versus placebo.

Patient enrollment and dosing continues in both studies.

In addition, to enable BLA submission for VRDN-003, we have initiated a safety study to meet the 300 patient standard safety database requirement (to also include patients from the REVEAL-1 and REVEAL-2 trials) and plan to initiate an auto-injector study in 2025 to enable launching VRDN-003 in an auto-injector device, if approved.

We anticipate topline data for REVEAL-1 and REVEAL-2 in the first half of 2026, and we anticipate submitting a BLA for VRDN-003 for the treatment of TED by the end of 2026.

Development of FcRn Inhibitors

In addition to developing therapies for TED, we are also developing a portfolio of engineered FcRn inhibitors, including VRDN-006 and VRDN-008.

FcRn inhibitors have the potential to treat a broad array of autoimmune diseases, representing a possible significant commercial market opportunity.

Our multi-pronged engineering approach has resulted in a portfolio of FcRn-targeting molecules that leverage the clinically and commercially validated mechanism of FcRn inhibition while potentially addressing the limitations of current agents such as incomplete immunoglobulin G (“IgG”) suppression, safety, and inconvenience of dosing.

VRDN-006 is a FcRn-targeting Fc fragment, and in non-human primate studies, demonstrated specificity for blocking FcRn-IgG interactions while not showing decreases in albumin or increases in low-density lipoprotein (“LDL”) levels, which are known potential side effects associated with certain full-length monoclonal anti-FcRn antibodies.

In our head-to-head non-human primate studies, VRDN-006 demonstrated comparable potency and IgG lowering to Vyvgart® (efgartigimod), the current standard of care in FcRn inhibition, as well as a similar safety profile.

We plan to file an Investigational New Drug Application (“IND”) for VRDN-006 by the end of 2024 and expect healthy volunteer data for VRDN-006 in the second half of 2025.

VRDN-008 is a novel, first-in-class FcRn inhibitor that aims to pair IgG suppression with extended half-life technology, potentially enabling deeper and more durable suppression of IgG than existing anti-FcRn therapies.

Both molecules are designed to be convenient, self-administered, subcutaneous products.

VRDN-006 is a highly selective Fc fragment that inhibits FcRn and is designed to be a convenient subcutaneous and self-administered option for patients.

In non-human primate (“NHP”) studies, VRDN-006 demonstrated specificity for blocking FcRn-IgG interactions while not showing decreases in albumin or increases in low-density lipoprotein (“LDL”) levels, which are known potential side effects associated with certain full-length anti-FcRn monoclonal antibodies.

In our head-to-head NHP studies, VRDN-006 demonstrated comparable potency and IgG reductions to efgartigimod, which is the current standard of care in FcRn inhibition, as well as a similar safety profile.

We submitted an IND for VRDN-006 in December 2024, which cleared in January 2025, and we expect proof-of-concept IgG reduction data in healthy volunteers in the third quarter of 2025.

VRDN-008 is a half-life extended bispecific FcRn inhibitor comprising an Fc fragment and an albumin-binding domain designed to prolong IgG suppression and provide a potentially best-in-class subcutaneous option for patients.

In a single, high-dose, head-to-head study in NHPs, VRDN-008 demonstrated three times the half-life of efgartigimod.

Additionally, VRDN-008 showed a deeper and more sustained IgG reduction with peak IgG reductions that were 20% deeper than efgartigimod while not showing decreases in albumin or increases in LDL levels.

NHP studies are ongoing to generate additional data for VRDN-008.

Once completed, we plan to use the totality of VRDN-008’s NHP data to build a robust pharmacokinetic and pharmacodynamic model to predict potential human dosing regimens for VRDN-008.

We anticipate submitting an IND for VRDN-008 by the end of 2025.

Our mission is to create and advance new biologic medicines for patients suffering from serious and rare diseases that are underserved by today’s therapies.

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Our multidisciplinary search process evaluates scientific and clinical validation of therapeutic targets, market potential, and feasibility of efficiently developing a competitive product.

• Initial clinical development and commercial focus on thyroid eye disease (TED) :

◦ Advance intravenous VRDN-001 clinical development to enter the TED market quickly.

We are evaluating VRDN-001 in two global Phase 3 clinical trials, THRIVE and THRIVE-2, for the treatment of active and chronic TED, respectively.

THRIVE and THRIVE-2 are each designed to compare a five-dose intravenous treatment arm of VRDN-001 at 10 mg/kg, dosed three weeks apart, to placebo.

This five-dose VRDN-001 regimen features fewer infusions and a shorter time per infusion compared to teprotumumab, the currently marketed IGF-1R inhibitor for TED.

We expect to report topline THRIVE and THRIVE-2 data in the middle of 2024 and by year end 2024, respectively.

We expect that the THRIVE and THRIVE-2 Phase 3 trials, together with a safety database comprising 300 treated patients, will support global health authority registration for marketing approval in both active and chronic TED, respectively.

• Our clinical development and commercial focus on thyroid eye disease (TED) :

◦ Seek marketing approval for veligrotug.

We are evaluating veligrotug in two pivotal global phase 3 clinical trials, THRIVE and THRIVE-2, for the treatment of active and chronic TED, respectively.

THRIVE and THRIVE-2 are each designed to compare a five-dose intravenous treatment arm of veligrotug at 10 mg/kg, dosed three weeks apart, to placebo.

This five-dose veligrotug regimen features fewer infusions and a shorter time per infusion compared to teprotumumab, the currently marketed IGF-1R inhibitor for TED.

We reported positive topline THRIVE and THRIVE-2 data in September 2024 and December 2024, respectively.

We expect that the THRIVE and THRIVE-2 phase 3 trials, together with a safety database comprising 300 treated patients (safety database inclusive of patients from the THRIVE and THRIVE-2 trials), will support global health authority registration for marketing approval in both active and chronic TED.

We expect to submit a BLA for veligrotug in the second half of 2025 and an MAA to the EMA for veligrotug in the first half of 2026.

◦ Rapidly develop subcutaneous VRDN-003 as our next generation, potential best-in-class IGF-1R antibody.

In December 2023, we selected VRDN-003 for pivotal development in TED.

VRDN-003 is designed to be self-administered subcutaneously at home as an infrequent and low-volume injection to decrease the burden on TED patients.

VRDN-003 has the same binding domain as its parent molecule, VRDN-001, and was engineered to have a longer half-life.

VRDN-003 is designed to maintain the efficacy of IGF-1Rs as demonstrated by the approved teprotumumab while improving on its safety and maximizing patient convenience.

We expect to initiate a global pivotal program with VRDN-003 in mid-2024, with planned trials in both active and chronic TED patients, pending regulatory authority alignment.

VRDN-003 has the same binding domain as veligrotug and was engineered to have a longer half-life.

VRDN-003 is designed to maintain the efficacy of IGF-1Rs as demonstrated by the marketed product, teprotumumab, and by the clinical results for veligrotug in THRIVE and THRIVE-2, while improving on its safety and maximizing patient convenience.

We are evaluating VRDN-003 in two global phase 3 clinical trials, REVEAL-1 and REVEAL-2, for the treatment of active and chronic TED, respectively.

REVEAL-1 and REVEAL-2 are each designed to evaluate subcutaneous VRDN-003 administered every four weeks or every eight weeks and will assess outcomes

versus placebo.

We have initiated a safety study to meet the 300 patient standard safety database requirement (to also include patients from the REVEAL-1 and REVEAL-2 trials) and anticipate initiating an auto-injector study in 2025 to have an auto-injector device available at the time of commercial launch, if approved.

We expect to report topline REVEAL-1 and REVEAL-2 data in the first half of 2026.

We expect that the REVEAL-1 and REVEAL-2 phase 3 trials, together with a safety database of 300 treated patients (safety database inclusive of patients from the REVEAL-1 and REVEAL-2 trials), will support global health authority registration for marketing approval in both active and chronic TED, respectively.

◦ Be a trusted partner in the care of TED patients.

We plan to cultivate a network across TED stakeholders to inform our patient-centric approach, including with patients and advocacy groups, key opinion leaders, research institutions, healthcare professionals and payers.

◦ Prepare for commercialization of VRDN-001 and VRDN-003, for the treatment of patients with TED.

We hold worldwide commercialization rights, excluding the greater area of China, to VRDN-001 and VRDN-003.

◦ Prepare for commercialization of veligrotug and VRDN-003, for the treatment of patients with TED.

We hold worldwide commercialization rights, excluding the greater area of China, to veligrotug and VRDN-003.

As a result, we have the flexibility to develop and potentially commercialize products ourselves, or alternatively to enter collaborations with industry partners.

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◦ Generate VRDN-006 proof-of-concept IgG reduction data in healthy volunteers.

VRDN-006 is a highly selective Fc fragment that inhibits FcRn and is designed to be a convenient subcutaneous and self-administered option for patients.

VRDN-006 received IND clearance from the FDA in January 2025 and we expect proof-of-concept IgG reduction data in healthy volunteers in the third quarter of 2025.

◦ Advance VRDN-008 to the clinic.

VRDN-008 is a half-life extended bispecific FcRn inhibitor comprising an Fc fragment and an albumin-binding domain designed to prolong IgG suppression as a subcutaneous, self-administered and potential best-in-class option for patients.

In single, high-dose head-to-head NHP studies, VRDN-008 demonstrated three times the half-life and showed a deeper and more sustained IgG reduction than efgartigimod.

NHP studies are ongoing to generate additional data for VRDN-008.

Once completed, we plan to use the totality of VRDN-008’s NHP data to build a robust pharmacokinetic and pharmacodynamic model to predict potential human dosing regimens for VRDN-008.

We anticipate submitting an IND for VRDN-008 by the end of 2025.

• Leverage our therapeutic protein, antibody, and multi-disciplinary search expertise to continue discovering and developing novel, best-in class product candidates.

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However, proptosis, pain, diplopia, and eyelid retraction often persist throughout life for patients with chronic TED.

Patients with active and chronic TED experience significant impairment to their quality of life, including difficulties activities of daily living, trouble functioning in social situations, and decreased psychological well-being.

Patients with active and chronic TED experience significant impairment to their quality of life, including difficulties with the activities of daily living, trouble functioning in social situations, and decreased psychological well-being.

About one in every three patients experience anxiety and depression.

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One potential cause of TED is autoimmune antibodies against IGF-1R that lead to the activation of IGF-1R, resulting in increased proliferation, secretion of extracellular complex carbohydrates, and differentiation into fat cells.

These antibodies, and autoimmune antibodies to TSHR, can elicit an immune attack against the fibrocytes that surround the eye triggering the development of TED.

These antibodies, and autoimmune antibodies to TSHR, can elicit an immune attack against the fibrocytes that surround the eye triggering the

development of TED.

Inflammation associated with this attack combined with activation of IGF-1R leads to the wide spectrum of pathologies seen with this disease.

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In January 2020, Tepezza (teprotumumab), an antibody that blocks the activation of IGF-1R, was approved by the FDA for the treatment of TED.

The Tepezza® label was updated in April 2023 to specify its use for the treatment of TED regardless of TED activity or duration.

In addition, the label was updated in its warnings and precautions, adverse reactions, and patient counseling information sections in December 2022 with additional information on hyperglycemia and in July 2023 to include hearing impairment, its potential severity, and guidance for monitoring.

In two randomized, double-blind placebo-controlled trials, infusions of teprotumumab every three weeks, for a total of eight doses, led to a greater than 2 mm decrease in proptosis in 71% and 83% of patients, respectively, compared to 20% and 10% with placebo.

Treatment with teprotumumab also led to a 53% decrease in diplopia compared to a 25% decrease when patients were treated with placebo control.

The Tepezza labeling was updated in April 2023 to specify its use for the treatment of TED regardless of TED activity or duration.

In addition, the labeling was updated in its warnings and precautions, adverse reactions, and patient counseling information sections in December 2022 with additional information on hyperglycemia and in July 2023 to include hearing impairment, its potential severity, and guidance for monitoring.

In two randomized, double-blind placebo-controlled trials, infusions of teprotumumab every three weeks, for a total of eight doses, led to a greater than 2 mm decrease in proptosis in 71% and 83% of patients with active TED, respectively, compared to 20% and 10% with placebo.

Combined results from these two studies in patients with active TED showed that treatment with teprotumumab also led to a 53% decrease in diplopia compared to a 25% decrease when patients were treated with placebo control.

Thus, these data show that targeting and blockade of IGF-1R in TED provides a clinically meaningful benefit and is a de-risked approach.

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We estimate approximately 190,000 TED patients in the United States with moderate to severe TED, which includes patients with either active and chronic TED, and a similar epidemiology in Europe.

At launch, Horizon announced a price of approximately $16,300 per vial of Tepezza® which translates to a list price of approximately $375,000 based on patient weight for a six-month course of therapy.

In the first three years following launch, Tepezza® annual net sales have grown steadily from 2020 to reach almost $2.0 billion in 2022, and net sales are annualizing to $1.8 billion in 2023.

This demonstrates that TED is currently a multi-billion-dollar market in the United States alone, with the potential for additional revenue in the United States with indication expansion to chronic TED and more convenient regimens and routes of administration.

There is also potential for additional revenue following regulatory approvals and commercial expansion outside of the United States, which we believe will accommodate multiple entrants.

In 2020, Horizon launched with a price of approximately $16,300 per vial of Tepezza which translates to a list price of approximately $375,000 based on patient weight for a six-month course of therapy.

Tepezza’s 2024 net sales in the U.S.

were approximately $1.8 billion, with the potential for additional revenue in the U.S.

with further penetration into the prevalent TED population and more convenient regimens and routes of administration.

With Tepezza now approved in multiple countries outside of the U.S., including Japan, and a regulatory submission completed in Europe, we believe there is potential for meaningful additional revenue outside of the U.S., which we believe will further support multiple entrants.

Our Product Candidates

VRDN-001, a potential best-in-class intravenously administered IGF-1R antibody

VRDN-001 is a monoclonal antibody that binds to and is believed to act as a full antagonist of IGF-1R signaling pathway.

Veligrotug, a potential best-in-class intravenously administered IGF-1R antibody

Veligrotug is a monoclonal antibody that binds to and is believed to act as a full antagonist of IGF-1R signaling pathway.

This mechanism of action is clinically and commercially validated by the only FDA product approved for the treatment of TED, Tepezza.

Based on our ongoing THRIVE and THRIVE-2 Phase 3 clinical trials, our goal is for VRDN-001 to be second to market in this class of medicine, with the opportunity to offer a differentiated IV product.

We have an exclusive license to the worldwide rights to develop and commercialize VRDN-001 for all non-oncology indications that do not use radiopharmaceuticals, including the treatment of patients with TED, from ImmunoGen.

The antibody sequence that we are developing as VRDN-001 in TED had previously been developed in oncology as AVE-1642 and studied in over 100 patients.

Based on our ongoing THRIVE and THRIVE-2 phase 3 clinical trials, our goal is for veligrotug to be second to market in this class of medicine, with the opportunity to offer a differentiated IV product.

We have an exclusive license to the worldwide rights to develop and commercialize veligrotug for all non-oncology indications that do not use radiopharmaceuticals, including the treatment of patients with TED, from ImmunoGen, Inc.

(“ImmunoGen”).

The antibody sequence that we are developing as veligrotug in TED had previously been developed in oncology as AVE-1642 and studied in over 100 patients.

However, development in oncology was stopped in 2009 due to its failure to meet the primary efficacy endpoints in multiple myeloma.

As described below, we have sublicensed the right to develop, manufacture and commercialize

certain IGF-1R directed antibody products for non-oncology indications in the greater area of China to Zenas BioPharma (Cayman) Limited.

Clinical Trials for VRDN-001

Phase 1/2 Trial of VRDN-001 in Patients with Active TED

In the second half of 2022 and early 2023, we announced data from our Phase 1/2 clinical trial evaluating the safety and efficacy of VRDN-001 in patients with active TED.

The proof-of-concept portion of this double-blind, placebo-controlled Phase 1/2 trial evaluated two infusions of VRDN-001 administered intravenously, three weeks apart, with efficacy measured six weeks after the first dose.

VRDN-001 was evaluated at doses of 3, 10, and 20 mg/kg, with each cohort designed to include six patients randomized to drug, and two patients randomized to placebo.

We previously announced positive results from all three dose cohorts, and VRDN-001 demonstrated a favorable safety profile.

In the 3 mg/kg dose cohort, nine patients were randomized to receive VRDN-001 to enable all consented patients who were eligible following screening to participate in the trial, and two patients were randomized to receive placebo.

The following activity was observed across all three dose groups (n=21) at week six:

• 71% proptosis responder rate, defined as a ≥2-millimeter (“mm”) reduction in proptosis from baseline as measured by exophthalmometry

• 2.3 mm mean reduction in proptosis from baseline as measured by exophthalmometry

• 2.76 mm mean reduction in proptosis from baseline as measured by blinded, centrally reviewed magnetic resonance imaging (“MRI”, preliminary data available for 16 of the 21 patients)

• 4.1 point mean reduction in CAS from baseline on a 7-point measure of signs and symptoms of TED

• 62% maximal or near-maximal therapeutic effect on CAS, defined as reaching a CAS of 0 or 1 on the 7-point composite measure of signs and symptoms of TED

As described below, we sublicensed the right to develop, manufacture and commercialize certain IGF-1R directed antibody products for non-oncology indications in the greater area of China to Zenas BioPharma (Cayman) Limited (now Zenas BioPharma, Inc., their successor in interest, “Zenas BioPharma”).

In January 2025, Zenas BioPharma sublicensed their rights to Zai Lab (Hong King) Limited (“Zai Lab”).

Clinical Trials for veligrotug

Phase 1/2 Trial of veligrotug in Patients with Active TED

In the second half of 2022 and early 2023, we announced data from our phase 1/2 clinical trial evaluating the safety and efficacy of veligrotug in patients with active TED.

The proof-of-concept portion of this double-blind, placebo-controlled phase 1/2 trial evaluated two infusions of veligrotug administered intravenously, three weeks apart, with efficacy measured six weeks after the first dose.

Veligrotug was evaluated at doses of 3, 10, and 20 mg/kg, with each cohort designed to include six patients randomized to drug, and two patients randomized to placebo.

We previously announced positive results from all three dose cohorts, and veligrotug demonstrated a favorable safety profile.

In the 3 mg/kg dose cohort, nine patients were randomized to receive veligrotug to enable all consented patients who were eligible following screening to participate in the trial, and two patients were randomized to receive placebo.

At week 6, across all three dose groups (n=21), we observed a 71% proptosis responder rate and a 67% overall responder rate.

62% of veligrotug-treated patients achieved a CAS of 0 or 1, and 54% had complete resolution of their diplopia.

Veligrotug was generally well-tolerated.

Phase 1/2 Trial of veligrotug in Patients with Chronic TED

In July 2023, we announced data from our phase 1/2 clinical trial evaluating the safety and efficacy of veligrotug in patients with chronic TED.

Veligrotug was evaluated at doses of 3 and 10 mg/kg, with each cohort designed to include six patients randomized to drug, and two patients randomized to placebo.

We previously announced positive results from both cohorts, and veligrotug demonstrated a favorable safety profile that was generally consistent with the previously reported results in patients with active TED with veligrotug.

At week six, across both dose groups (n=12), we observed a 42% proptosis responder rate and 40% of veligrotug-treated patients achieving a CAS of 0 or 1.

No patients achieved complete resolution of their diplopia.

Veligrotug was generally well-tolerated and demonstrated a safety profile that was generally consistent with the previously reported results in patients with active TED with veligrotug.

Phase 3 Trial (THRIVE) of veligrotug in Patients with Active TED

THRIVE is a global double-masked, placebo-controlled phase 3 clinical trial evaluating the safety and efficacy of veligrotug in patients with active TED.

THRIVE evaluated five infusions of veligrotug at 10 mg/kg, dosed three weeks apart.

Patients were randomized two to drug and one to placebo.

In September 2024, we announced positive topline data from THRIVE.

THRIVE met the primary and all secondary endpoints at fifteen weeks after five infusions of veligrotug, showing highly statistically significant (p < 0.0001) improvements on all of the measured signs and symptoms of TED.

Veligrotug additionally showed a rapid onset of treatment effect, with the majority (53%) of veligrotug-treated patients achieving a proptosis response as early as three weeks.

THRIVE enrolled 113 patients, randomized to veligrotug (n=75) and placebo (n=38).

The following activity was observed in veligrotug-treated patients at week fifteen (n=75):

• 70% proptosis responder rate (“PRR”) (64% placebo-adjusted, p < 0.0001), defined as a ≥2-millimeter (“mm”) reduction in proptosis from baseline in the study eye without worsening in the fellow eye (≥2 mm increase), as measured by exophthalmometry.

PRR results as measured by MRI/CT were consistent with those measured by exophthalmometry at the primary efficacy analysis timepoint.

• 2.9mm mean reduction in proptosis from baseline (2.4mm placebo-adjusted, p < 0.0001), as measured by exophthalmometry

• 63% diplopia responder rate (43% placebo-adjusted, p < 0.0001), defined as patients with baseline diplopia who achieved a reduction of at least 1 on the Gorman subjective diplopia scale (76 patients with diplopia at baseline)

• 54% complete resolution of diplopia (43% placebo-adjusted, p < 0.0001), defined as patients with baseline diplopia who achieved a score of 0 on the Gorman subjective diplopia scale

• 64% maximal or near-maximal therapeutic effect on CAS (46% placebo-adjusted, p < 0.0001), defined as reaching a CAS of 0 or 1 on the 7-point composite measure of signs and symptoms of TED

• 3.4 point mean reduction in CAS from baseline (1.7-point placebo-adjusted, p < 0.0001), on a 7-point measure of signs and symptoms of TED

Overall response

• 67% overall responder rate, defined as a ≥2 mm reduction in proptosis and a ≥2 point reduction in CAS

• 54% complete resolution of diplopia, defined as patients with baseline diplopia who achieved a score of 0 on the Gorman subjective diplopia scale (13 patients with diplopia at baseline)

VRDN-001 had a favorable safety profile and was generally well-tolerated.

There were no reported serious adverse events (“SAEs”), and no discontinuations in patients treated with VRDN-001 as of the December 19, 2022 data cut (all patients reached 6-week visit).

Phase 1/2 Trial of VRDN-001 in Patients with Chronic TED

In July 2023, we announced data from our Phase 1/2 clinical trial evaluating the safety and efficacy of VRDN-001 in patients with chronic TED.

VRDN-001 was evaluated at doses of 3 and 10 mg/kg, with each cohort designed to include six patients randomized to drug, and two patients randomized to placebo.

We previously announced positive results from both cohorts, and VRDN-001 demonstrated a favorable safety profile that was generally consistent with the previously reported results in patients with active TED with VRDN-001.

The following activity was observed across both dose groups (n=12) at week six:

• 42% proptosis responder rate, defined as a ≥2-millimeter (“mm”) reduction in proptosis from baseline as measured by exophthalmometry

• 1.6 mm mean reduction in proptosis from baseline as measured by exophthalmometry

• 2.0 mm mean reduction in proptosis from baseline as measured by blinded, centrally reviewed magnetic resonance imaging (“MRI”, preliminary data available for 8 of the 12 patients)

• 2.3 point mean reduction in CAS from baseline on a 7-point measure of signs and symptoms of TED

• 40% maximal or near-maximal therapeutic effect on CAS, defined as reaching a CAS of 0 or 1 on the 7-point composite measure of signs and symptoms of TED

• No patients achieved complete resolution of diplopia at week 6, defined as patients with baseline diplopia who achieved a score of 0 on the Gorman subjective diplopia scale (5 patients with diplopia at baseline).

VRDN-001 demonstrated a favorable safety profile that was generally consistent with the previously reported results in patients with active TED with VRDN-001.

Phase 3 Trial (THRIVE) of VRDN-001 in Patients with Active TED

We are evaluating VRDN-001 in THRIVE, an ongoing global Phase 3 clinical study for the treatment of active TED.

THRIVE is designed to compare a five-dose treatment arm of VRDN-001 at 10 mg/kg, dosed three weeks apart, to placebo.

This five-dose VRDN-001 regimen features fewer infusions and a shorter time per infusion compared to the currently marketed IGF-1R inhibitor.

We expect to report topline results for the THRIVE trial in the middle of 2024.

Phase 3 Trial (THRIVE-2) of VRDN-001 in Patients with Chronic TED

We are also evaluating VRDN-001 in THRIVE-2, an ongoing global Phase 3 clinical study for the treatment of chronic TED.

THRIVE-2 is designed to compare a five-dose treatment arm of VRDN-001 at 10 mg/kg, dosed three weeks apart, to placebo.

This five-dose VRDN-001 regimen features fewer infusions and a shorter time per infusion compared to the currently marketed IGF-1R inhibitor.

We expect to report topline THRIVE-2 data by year end 2024.

• 67% overall responder rate (61% placebo-adjusted, p < 0.0001), defined as a ≥2 mm reduction in proptosis and a ≥2 point reduction in CAS

Veligrotug was generally well-tolerated with a safety profile consistent with previous veligrotug studies.

The majority of adverse events (“AEs”) were mild, and 96% of veligrotug-treated patients completing all doses.

There were no treatment-related serious AEs.

A 5.5% placebo-adjusted rate of hearing impairment AEs was observed.

Phase 3 Trial (THRIVE-2) of veligrotug in Patients with Chronic TED

THRIVE-2 is a global double-masked, placebo-controlled phase 3 clinical trial evaluating the safety and efficacy of veligrotug in patients with chronic TED.

THRIVE-2 evaluated five infusions of veligrotug at 10 mg/kg, dosed three weeks apart.

Patients were randomized two to drug and one to placebo.

In December 2024, we announced positive topline data from THRIVE-2.

THRIVE-2 met the primary and all secondary endpoints at fifteen weeks after five infusions of veligrotug, showing statistically significant responses on all of the measured signs and symptoms of TED.

Veligrotug continued to demonstrate a rapid onset of treatment effect, with a statistically significant proptosis response as early as three weeks and statistically significant diplopia reduction and resolution as early as six weeks.

THRIVE-2 enrolled 188 patients, randomized to veligrotug (n=125) and placebo (n=63).

The mean time since onset of TED in patients treated with veligrotug was 69.8 months.

The following activity was observed in veligrotug-treated patients at week fifteen (n=125):

• 56% proptosis responder rate (“PRR”) (48% placebo-adjusted;

p < 0.0001), defined as a ≥2-millimeter (“mm”) reduction in proptosis from baseline in the study eye without worsening in the fellow eye (≥2 mm increase), as measured by exophthalmometry.

PRR was statistically significant at all time points, including as early as 3 weeks, demonstrating a rapid onset of treatment effect.

PRR results as measured by MRI/CT were consistent with those measured by exophthalmometry at the primary efficacy analysis timepoint.

• 2.3mm mean reduction in proptosis from baseline (1.9mm placebo-adjusted, p < 0.0001), as measured by exophthalmometry

• 56% diplopia responder rate (31% placebo-adjusted, p = 0.0006), defined as patients with baseline diplopia who achieved a reduction of at least 1 on the Gorman subjective diplopia scale.

Rapid onset was observed as early as 6 weeks after just two infusions (102 patients with diplopia at baseline)

• 32% complete resolution of diplopia (18% placebo-adjusted, p = 0.0152), defined as patients with baseline diplopia who achieved a score of 0 on the Gorman subjective diplopia scale

• 54% maximal or near-maximal therapeutic effect on CAS (29% placebo-adjusted, p = 0.006), defined as reaching a CAS of 0 or 1 on the 7-point composite measure of signs and symptoms of TED, among patients with a CAS of ≥ 3 at baseline (n = 104)

• 2.9 point mean reduction in CAS from baseline (1.6-point placebo-adjusted, p < 0.0001), on a 7-point measure of signs and symptoms of TED, among patients with a CAS of ≥ 3 at baseline

• CAS outcomes are exploratory endpoints and p-values are nominally significant.

Overall response

• 56% overall responder rate (50% placebo-adjusted, p < 0.0001), defined as a ≥2 mm reduction in proptosis and a ≥1 point reduction in CAS

Veligrotug was generally well-tolerated with a safety profile consistent with previous veligrotug studies, including THRIVE.

The majority of AEs were mild, and 94% of veligrotug-treated patients completed their treatment course.

A 9.6% placebo-adjusted rate of hearing impairment AEs was observed.

To meet the 300 patient standard safety database requirements for the veligrotug BLA, we are conducting STRIVE, a global clinical study of veligrotug in TED patients that utilizes broad inclusion criteria (e.g., any severity or duration of disease) and is randomized 3:1 (10 mg/kg IV with an active control of 3 mg/kg IV).

In January 2025, we completed enrollment in STRIVE with a total of 231 patients, exceeding the enrollment target of 212 due to patient demand.

We also completed enrollment of patients in the open label extension study for non-responding patients in THRIVE and THRIVE-2.

Together, THRIVE and THRIVE-2 evaluated veligrotug in the largest and broadest population of active and chronic TED patients studied to date in global phase 3 clinical trials.

We believe that these robust and consistent clinical efficacy and safety results, after only five infusions of veligrotug, support a differentiated product profile and the potential for veligrotug to be the IV treatment-of-choice for all forms of active and chronic TED.

We expect that the THRIVE and THRIVE-2 phase 3 clinical trials, together with a safety database comprising 300 treated patients, will support global health authority registration for marketing approval in both active and chronic TED, respectively.

We expect to submit a BLA in the second half of 2025 and an MAA to the EMA in the first half of 2026.

VRDN-003, a potential best-in-class subcutaneously administered IGF-1R antibody

In December 2023, we selected VRDN-003 for pivotal development in TED following positive data in a Phase 1 clinical trial in healthy volunteers.

VRDN-003 is a monoclonal antibody that acts as a full antagonist of IGF-1R.

VRDN-003 utilizes the same binding domain as VRDN-001 and is engineered to extend the half-life of the parent antibody, and therefore potentially enabling less frequent and more convenient dosing.

VRDN-003 is designed to maintain the clinical response of VRDN-001 IV while significantly increasing patient convenience.

VRDN-003 utilizes the same binding domain as veligrotug and is engineered to extend its half-life, and therefore potentially enabling less frequent and more convenient dosing.

VRDN-003 is designed to maintain the clinical response of veligrotug IV while significantly increasing patient convenience.

We believe a later-entrant subcutaneous therapy can convert meaningful portions of an IV market.

There is precedent that subcutaneous therapies can quickly command substantial market share even when launching several years after an incumbent IV.

Although we have designed VRDN-003 to have a superior dosing profile to its parent molecule, VRDN-001, as well as to the currently marketed IV product, teprotumumab, market examples demonstrate that subcutaneous therapies have commanded market share even where such therapies have the same or worse dosing frequency than their IV counterparts.

Although we have designed VRDN-003 to have a superior dosing profile to its parent molecule, veligrotug, as well as to the currently marketed IV product, teprotumumab, market examples demonstrate that subcutaneous therapies have commanded market share even where such therapies have the same or worse dosing frequency than their IV counterparts.

Further, subcutaneous offerings can also grow the overall market size for their class.

We believe VRDN-003 has significant potential to

capture a meaningful proportion of the IV TED market and to grow the TED market as a convenient, less-frequent, low-volume subcutaneous anti-IGF-1R antibody that patients take at home.

The VRDN-003 Phase 1 healthy volunteer clinical study showed VRDN-003 to have a prolonged half-life of 40 to 50 days, which is four to five times that of its parent molecule, VRDN-001.

Because of the similarities of VRDN-001 and VRDN-003, we expect VRDN-003 to have similar clinical responses at the exposure levels of VRDN-001 that led to robust clinical activity in its Phase 2 clinical study in TED.

Based on these results, we expect to initiate a global pivotal program with VRDN-003 in mid-2024, with planned trials in both active and chronic TED patients, pending regulatory authority alignment.

We believe VRDN-003 has significant potential to capture a meaningful proportion of the IV TED market and to grow the TED market as a convenient, less-frequent, low-volume subcutaneous anti-IGF-1R antibody that patients take at home.

We are conducting a global pivotal program for VRDN-003, including evaluating its efficacy and safety in two global well-controlled phase 3 pivotal clinical trials, REVEAL-1 and REVEAL-2, for the treatment of active and chronic TED, respectively.

We selected VRDN-003 for pivotal development in TED following positive data in a phase 1 clinical trial in healthy volunteers.

This study showed VRDN-003 to have a prolonged half-life of 40 to 50 days, which is four to five times that of its parent molecule, veligrotug.

Because of the similarities of veligrotug and VRDN-003, we expect VRDN-003 to have similar clinical responses at the exposure levels of veligrotug that led to robust clinical activity in its phase 2 clinical study in TED.

Further, pharmacokinetic modeling of VRDN-003 predicted that exposure levels of VRDN-003 could be achieved that are equivalent to exposure levels of veligrotug that produced clinically meaningful results with multiple dosing regimens of VRDN-003, i.e., subcutaneous injection every two, four, or eight weeks.

Patient enrollment and dosing continues in both REVEAL-1 and REVEAL-2.

Both studies will evaluate subcutaneous VRDN-003 administered every four weeks or every eight weeks and will assess outcomes versus placebo.

We expect that the REVEAL-1 and REVEAL-2 phase 3 trials, together with a safety database of 300 patients (safety database inclusive of patients from the REVEAL-1 and REVEAL-2 trials), will support global health authority registration for marketing approval in both active and chronic TED, respectively.

We also anticipate initiating an auto-injector study in 2025 to have an auto-injector device available at the time of commercial launch, if approved.

We anticipate topline data for REVEAL-1 and REVEAL-2 in the first half of 2026, and we anticipate submitting a BLA for VRDN-003 for the treatment of TED by the end of 2026.

Phase 1 Trial of VRDN-003 in Healthy Volunteers

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• Extended Half Life :

VRDN-003 pharmacokinetics data showed an extended half-life of 40 to 50 days, which is a 4-to-5-fold increase over the half-life of VRDN-001 (which showed a half-life of 10 to 12 days).

VRDN-003 pharmacokinetics data showed an extended half-life of 40 to 50 days, which is a 4-to-5-fold increase over the half-life of veligrotug (which showed a half-life of 10 to 12 days).

• Prolonged Pharmacodynamics (“PD”) :

Following a single subcutaneous dose of VRDN-003, IGF-1 serum levels increased approximately 4-fold at peak.

This was consistent with the increases in IGF-1 levels that have been shown in the clinic following a single dose of VRDN-001 SC and IV.

This was consistent with the increases in IGF-1 levels that have been shown in the clinic following a single dose of veligrotug SC and IV.

IGF-1 is a PD biomarker for IGF-1R target engagement.

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VRDN-003 modeling demonstrated dosing flexibility for the program’s anticipated global pivotal development.

The modeling showed that dosing VRDN-003 every eight weeks, every four weeks, and every two weeks achieved a range of exposures levels that were seen for VRDN-001 after intravenous doses of 3 mg/kg, 10 mg/kg and 20 mg/kg, respectively.

The shared binding domain and pharmacology of VRDN-003 with VRDN-001 allow us to leverage the clinical activity of VRDN-001 IV at different exposure levels to select doses for VRDN-003 that we expect to demonstrate a clinical response.

We expect to initiate the VRDN-003 pivotal program in mid-2024, pending regulatory authority alignment.

Anti-FcRn Portfolio:

The modeling showed that dosing VRDN-003 every eight weeks, every four weeks, and every two weeks achieved a range of exposures levels that were seen for veligrotug after intravenous doses of 3 mg/kg, 10 mg/kg and 20 mg/kg, respectively.

FcRn Inhibitor Portfolio:

VRDN-006 and VRDN-008

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FcRn inhibitors have the potential to treat a broad array of autoimmune diseases, representing a possible significant commercial market opportunity.

Our multi-pronged engineering approach has resulted in a portfolio of FcRn-targeting molecules that leverage the clinically and commercially validated mechanism of FcRn inhibition in myasthenia gravis while potentially addressing the limitations of current agents such as incomplete IgG suppression and safety.

Our multi-pronged engineering approach has resulted in a portfolio of FcRn-targeting molecules that leverage the clinically and commercially validated mechanism of FcRn inhibition in myasthenia gravis and chronic inflammatory demyelinating polyneuropathy (“CIDP”) while potentially addressing the limitations of current agents such as incomplete IgG suppression and safety.

VRDN-006 and VRDN-008 are both designed to be convenient, self-administered, subcutaneous products.

The first FDA-approved FcRn inhibitor, Vyvgart® (efgartigimod), was developed by argenx SE (“Argenx”) and is approved for myasthenia gravis.

Efgartigimod net sales were $1.2 billion in 2023, and it is projected to generate over $4 billion in annual sales by 2028.

Furthermore, FcRn inhibitors have the potential to address additional sizable autoimmune indications such as chronic inflammatory demyelinating polyneuropathy, myositis, membranous nephropathy, Graves’ disease, lupus nephritis, and Sjogren’s syndrome.

The first FDA-approved FcRn inhibitor, Vyvgart® (efgartigimod), was developed by argenx SE (“Argenx”) and is approved for myasthenia gravis and chronic inflammatory demyelinating polyneuropathy.

Argenx reported efgartigimod net sales of approximately $2.2 billion in 2024, and it is projected to generate close to $6 billion in annual sales by 2030.

Furthermore, FcRn inhibitors have the potential to address additional sizable autoimmune indications such as myositis, membranous nephropathy, Graves’ disease, lupus nephritis, and Sjogren’s syndrome.

VRDN-006 is a highly-selective Fc fragment.

In our non-human primate studies, VRDN-006 showed specificity for blocking FcRn-IgG interactions while not showing decreases in albumin or increases in low LDL levels, which

are known potential side effects associated with certain full-length monoclonal anti-FcRn antibodies.

In our NHP studies, VRDN-006 demonstrated specificity for blocking FcRn-IgG interactions while not showing decreases in albumin or increases in LDL levels, which are known potential side effects associated with certain full-length monoclonal anti-FcRn antibodies.

With efgartigimod, Argenx has proven that an Fc fragment can achieve clinical efficacy while sparing an effect on albumin or LDL, and shows better tolerability than full length antibodies against FcRn.

VRDN-006 is the only other known Fc fragment currently in development.

Our preclinical studies show that VRDN-006 demonstrates comparable potency in vitro and comparable IgG lowering in non-human primates to efgartigimod.

In NHP studies, we showed that VRDN-006 demonstrates comparable potency in vitro and comparable IgG lowering in non-human primates to efgartigimod.

VRDN-006 also shows a similar safety profile to efgartigimod in our head-to-head non-human primate study showing that, comparable to efgartigimod, it did not lower albumin or increase LDL levels.

VRDN-008 is a novel FcRn inhibitor that aims to pair IgG suppression with extended half-life technology.

VRDN-008, with its extended half-life, has the potential to more deeply and durably suppress IgG as compared to efgartigimod and other third party candidates.

In the mouse model shown below, VRDN-008 shows a deeper and more durable IgG suppression when compared to efgartigimod.

We plan to advance this program into non-human primates with the goal of evaluating the level of IgG suppression mediated by VRDN-008 in a larger animal model.

We believe by improving persistence and depth of suppression, we may improve efficacy and offer a more convenient dosing profile compared to the current weekly IV or subcutaneous administrations of efgartigimod.

VRDN-006 received IND clearance from the FDA in January 2025 and we expect proof-of-concept IgG reduction data in healthy volunteers in the third quarter of 2025.

In a single, high-dose, head-to-head study in NHPs, VRDN-008 demonstrated three times the half-life of efgartigimod and a deeper and more sustained IgG reduction with peak IgG reductions that were 20% deeper than efgartigimod.

VRDN-008 also shows a similar safety profile to efgartigimod in our head-to-head non-human primate study showing that, comparable to efgartigimod, it did not lower albumin or increase LDL levels.

NHP studies are ongoing to generate additional data for VRDN-008.

Once completed, we plan to use the totality of VRDN-008’s NHP data to build a robust pharmacokinetic and pharmacodynamic model to enable the prediction of potential human dosing regimens for VRDN-008.

Intellectual Property

We have in-licensed and developed patents and patent applications, which include claims directed to compositions, methods of use, dosing and formulations.

We have in-licensed and owned patents and patent applications, which include claims directed to compositions, methods of use, dosing and formulations.

We possess know-how and trade secrets relating to the development and commercialization of our product candidates, including related manufacturing processes.

As of December 31, 2023, our in-licensed and owned patent portfolio consists of approximately one U.S.

issued patent, approximately nineteen U.S.

pending patent applications, no patents issued in jurisdictions outside of the United States, and approximately seventy-one patent applications pending in jurisdictions outside of the United States (including approximately five pending Patent Cooperation Treaty (PCT) applications) that, in many cases, are counterparts to the foregoing U.S.

As of January 15, 2025, our in-licensed and owned patent portfolio consists of approximately one U.S.

issued patent, approximately seventeen U.S.

pending patent applications, no patents issued in jurisdictions outside of the United States, one allowed patent in China, and approximately seventy-eight patent applications pending in jurisdictions outside of the United States (including approximately seven pending Patent Cooperation Treaty (PCT) applications) that, in many cases, are counterparts to the foregoing U.S.

patents and patent applications.

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We may also pursue patent protection with respect to manufacturing and drug development processes and technology.

When available to expand market exclusivity, our strategy is to obtain or license additional intellectual property related to core elements of technology and/or product candidates.

When available to expand

market exclusivity, our strategy is to obtain or license additional intellectual property related to core elements of technology and/or product candidates.

Individual patents extend for varying periods of time, depending upon the date of filing of the patent application, the date of patent issuance, and the legal term of patents in the countries in which they are obtained.

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The duration of patents outside of the United States varies in accordance with provisions of applicable local law, but typically is also 20 years from the earliest non-provisional filing date.

Our patents issued as of December 31, 2023, will expire no earlier than 2041.

If patents are issued on our patent applications pending as of December 31, 2023, the resulting patents are projected to expire on dates ranging from 2041 to 2044.

Our patent issued as of January 15, 2025 is expected to expire no earlier than 2041.

If patents are issued on our patent applications pending as of January 15, 2025, the resulting patents are projected to expire on dates ranging from 2041 to 2045.

However, the actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country, potential disclaimers of term, and the validity and enforceability of the patent.

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Other therapies, such as corticosteroids, have been used on an off-label basis to alleviate some of the symptoms of TED.

Argenx’s Vyvgart® and UCB’s Rystiggo® are the only FDA-approved anti-FcRn therapies, each approved in generalized myasthenia gravis.

A non-exhaustive list of other companies that are advancing therapies in clinical development for the treatment of TED or to target FcRn include:

A non-exhaustive list of companies currently advancing therapies in clinical development for the treatment of TED include:

• Amgen is developing an on-body subcutaneous formulation of Tepezza in a phase 3 study and has an early-stage candidate AMG-732 in TED.

• Argenx is developing efgartigimod (Vyvgart), an antibody fragment to target the FcRn that is subcutaneously delivered and expected to be evaluated in a registrational phase 3 trial in patients with TED.

• Immunovant, Inc.

is developing a subcutaneous formulation of batoclimab in phase 3 studies in patients with active TED.

• Roche is developing satralizumab (Enspryng), an anti-1L-6R that is subcutaneously delivered and is being evaluated in a phase 3 trial in patients with active TED.

• Sling Therapeutics, Inc.

is developing linsitinib, a small molecule IGF-1R inhibitor currently being evaluated in an ongoing phase 2b/3 study in patients with active TED and currently has plans to initiate a phase 3 trial.

• Tourmaline Bio is developing TOUR006, a subcutaneously delivered anti-IL-6, in an ongoing phase 2b clinical trial in patients with active TED.

• Lassen Therapeutics is developing LASN01, an intravenously delivered anti-1L-11R currently being evaluated in a phase 2 study in active TED.

• ACELYRIN, INC.

is developing lonigutamab (VB-421), a subcutaneously delivered anti-IGF-1R currently being evaluated in a Phase 1/2 study for TED.

• Argenx is developing efgartigimod (“Vyvgart®”), an antibody fragment to target the neonatal Fc receptor (FcRn) that is subcutaneously delivered and expected to be evaluated in a registrational Phase 3 trial in patients with TED.

• Immunovant and Harbour BioMed are developing batoclimab (IMVT-1401/HBM9161) and IMVT-1402.

is developing lonigutamab (VB-421), a subcutaneously delivered anti-IGF-1R currently being evaluated in a phase 1/2 study in patients with TED.

On January 6, 2025, ACELYRIN reported partial data from the phase 1/2 study and announced plans to initiate two phase 3 studies in patients with TED in the first quarter of 2025.

On February 6, 2025, ACELYRIN announced a decision to re-evaluate the phase 3 development program for lonigutumab.

Argenx’s Vyvgart and UCB’s Rystiggo® are the only FDA-approved anti-FcRn therapies, each approved in generalized myasthenia gravis.

A non-exhaustive list of other companies that are advancing therapies in clinical development for the treatment to target FcRn include:

• Immunovant, Inc.

is developing batoclimab (IMVT-1401/HBM9161) and IMVT-1402 with intentions to target generalized myasthenia gravis, CIDP, Graves’ disease, and Rheumatoid arthritis (“RA”).

Both are monoclonal antibodies targeting FcRn.

IMVT-1401 is currently being evaluated in ongoing Phase 3 trials in patients with TED and myasthenia gravis.

IMVT-1402 data from a Phase 1 healthy volunteers study was released in December 2023.

• Lassen Therapeutics is developing LASN01, an intravenously delivered anti-1L-11R with expected Phase 1 data in idiopathic pulmonary fibrosis and TED in 2024.

• Roche is developing satralizumab (Enspryng), a monoclonal antibody anti-1L-6R that is subcutaneously delivered and is being evaluated in a Phase 3 trial in patients with active TED.

• Sling Therapeutics, Inc.

is developing linsitinib, a small molecule IGF-1R inhibitor currently being evaluated in an ongoing Phase 2b LIDS clinical trial in patients with active TED.

• Tourmaline Bio is developing TOUR006, a subcutaneously delivered anti-IL-6, in an ongoing Phase 2b clinical trial in patients with active TED and currently has plans to initiate a Phase 3 trial.

• Johnson and Johnson is developing nipocalimab, which is in ongoing Phase 3 trials for a number of indications including generalized myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and autoimmune hemolytic anemia.

Batoclimab is currently being evaluated in ongoing phase 3 studies in TED and phase 2 studies in CIDP and Graves’ disease.

IMVT-1402 is currently being evaluated in a phase 2 study in patients with Graves’ disease and RA.

• Johnson and Johnson is developing nipocalimab, which is in ongoing phase 3 trials for a number of indications including generalized myasthenia gravis, CIDP, Sjogren’s disease and warm autoimmune hemolytic anemia.

Johnson and Johnson submitted a BLA for nipocalimab in generalized myasthenia gravis in August 2024.

• UCB continues to develop Rystiggo in an ongoing phase 3 study in Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease.

License Agreements

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In October 2020, Viridian Therapeutics, Inc.

(“Private Viridian”) entered a license agreement with Zenas BioPharma (Cayman) Limited (“Zenas BioPharma”) to license technology comprising certain materials, patent rights, and know-how to Zenas BioPharma.

(“Private Viridian”) entered a license agreement with Zenas BioPharma to license technology comprising certain materials, patent rights, and know-how to Zenas BioPharma.

On October 27, 2020, in connection with the closing of the Private Viridian acquisition, we became party to the license agreement with Zenas BioPharma.

Since February 2021, we have entered into several letter agreements with Zenas BioPharma in which we agreed to provide assistance to Zenas BioPharma with certain development activities, including manufacturing.

The license agreement, as amended, and letter agreements (collectively, the “Zenas Agreements”) were negotiated with a single commercial objective and are treated as a combined contract for accounting purposes.

In May 2022, the Company entered into a Manufacturing Development and Supply Agreement with Zenas BioPharma to manufacture and supply, or to have manufactured and supplied, clinical drug product for developmental purposes.

The license agreement and subsequent letter agreements and supply agreement (collectively, the “Zenas Agreements”) were negotiated with a single commercial objective and are treated as a combined contract for accounting purposes.

Under the terms of the Zenas Agreements, we granted Zenas BioPharma an exclusive license to develop, manufacture, and commercialize certain IGF-1R directed antibody products for non-oncology indications in the greater area of China.

In January 2025, Zenas BioPharma sublicensed their rights under the license agreement to Zai Lab and assigned the Manufacturing Development and Supply Agreement to Zai Lab in connection with the sublicense transaction.

As consideration for the Zenas Agreements, the transaction price included upfront non-cash consideration and variable consideration in the form of payment for our goods and services provided and milestone payments due upon the achievement of specified events.

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In consideration for rights granted by ImmunoGen, we are obligated to make certain development milestone payments of up to $48.0 million.

In December 2021, we paid a $2.5 million milestone payment to ImmunoGen upon the submission of an IND application for VRDN-001 with the FDA.

In May 2022, we paid a $3.0 million milestone payment to ImmunoGen related to the first patient dosed in the clinical trial for VRDN-001.

In December 2022, we recorded $10.0 million as research and development expense related to a milestone owed to ImmunoGen related to the first patient dosed in a pivotal clinical trial for VRDN-001, amount which was paid in January 2023 and which was included in accounts payable in the consolidated balance sheet as of December 31, 2022.

In December 2021, we paid a $2.5 million milestone payment to ImmunoGen upon the submission of an IND application for veligrotug with the FDA.

In May 2022, we paid a $3.0 million milestone payment to ImmunoGen related to the first patient dosed in the clinical trial for veligrotug.

In December 2022, we recorded $10.0 million as research and development expense related to a milestone owed to ImmunoGen related to the first

patient dosed in a pivotal clinical trial for veligrotug, amount which was paid in January 2023, and which was included in accounts payable in the consolidated balance sheet as of December 31, 2022.

Additionally, if we successfully commercialize any product candidate subject to the ImmunoGen License Agreement, we are responsible for royalty payments equal to a percentage in the mid-single digits of net sales and commercial milestone payments of up to $95.0 million.

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We assumed the ImmunoGen License Agreement in connection with the merger with Private Viridian in 2020.

License Agreements with Xencor, Inc.

In December 2020, we entered into a license agreement with Xencor, Inc.

(“Xencor”) (the “Xencor License Agreement”), under which Xencor granted us rights to an exclusive, worldwide, sublicensable, non-transferable, royalty-bearing license to use specified Xencor technology for the research, development, manufacturing, and commercialization of therapeutic antibodies targeting IGF-1R.

This agreement was terminated on July 25, 2023 and no further payments are owed under the Xencor License Agreement.

In December 2021, we entered into a subsequent technology license agreement with Xencor (the “2021 Xencor License Agreement”) for a non-exclusive license to certain antibody libraries developed by Xencor.

Under the 2021 Xencor License Agreement, we received a one-year research license to review the antibodies and the right to select up to three antibodies for further development.

This agreement was terminated on September 7, 2023 and no further payments are owed under the 2021 Xencor License Agreement.

Antibody and Discovery Option Agreement with Paragon Therapeutics, Inc.

In January 2022, we entered into an antibody and discovery option agreement (the “Paragon Agreement”) with Paragon Therapeutics, Inc.

Antibody and Discovery Option Agreement and License Agreement with Paragon Therapeutics, Inc.

In January 2022, we entered into an antibody and discovery option agreement (the “Paragon Research Agreement”) with Paragon Therapeutics, Inc.

(“Paragon”) under which we and Paragon will cooperate to develop one or more therapeutic proteins or antibodies.

Under the terms of the Paragon Agreement, Paragon will perform certain development activities in accordance with an agreed upon research plan, and we will pay Paragon agreed upon development fees in exchange for Paragon’s commitment of the necessary personnel and resources to perform these activities.

The Paragon Agreement stipulates a final deliverable to us comprising of a report summarizing the experiments and processes performed under the research plan (the “Final Deliverable”).

Under the terms of the Paragon Research Agreement, Paragon will perform certain development activities in accordance with an agreed upon research plan, and we will pay Paragon agreed upon development fees in exchange for Paragon’s commitment of the necessary personnel and resources to perform these activities.

The Paragon Research Agreement stipulates a final deliverable to us comprising of a report summarizing the experiments and processes performed under the research plan (the “Final Deliverable”).

Additionally, Paragon agreed to grant us an option for an exclusive license to all of Paragon’s right, title and interest in and to certain antibody technology and the Final Deliverable, and a non-exclusive license to certain background intellectual property owned by Paragon solely to research, develop, make, use, sell, offer for sale and import of the licensed intellectual property and resulting products worldwide (each, an “Option” and together, the “Options”).

Paragon also granted us a limited, exclusive, royalty-free license, without the right to sublicense, to certain antibody technology and the Final Deliverable, and a non-exclusive, royalty-free license without the right to sublicense, under certain background intellectual property owned by Paragon, solely to evaluate the antibody technology and Option and for the purpose of allowing us to determine whether to exercise the Option with respect to certain programs.

We may, at our sole discretion, exercise the Option with respect to

specified programs (“Programs”) at any time until the date that is 90 days after the Company’s receipt of the Final Deliverable the applicable program, or such longer period as agreed upon by the parties (“Option Period”) by delivering written notice of such exercise to Paragon.

We may, at our sole discretion, exercise the Option with respect to specified programs (“Programs”) at any time until the date that is 90 days after the Company’s receipt of the Final Deliverable the applicable program, or such longer period as agreed upon by the parties (“Option Period”) by delivering written notice of such exercise to Paragon.

If we fail to exercise an Option prior to expiration of the applicable Option Period, such Option for such Programs will terminate.

In consideration for Paragon’s grant of the Options to us, we paid to Paragon a non-refundable, non-creditable one-time fee of $2.5 million, which was recorded as research and development expense during the three months ended March 31, 2022.

In December 2022, we and Paragon entered into a first amendment to the Paragon Agreement, under which we obtained an additional limited license for the purpose of conducting certain activities.

In December 2022, we and Paragon entered into a first amendment to the Paragon Research Agreement, under which we obtained an additional limited license for the purpose of conducting certain activities.

In consideration for the rights and licenses obtained under the first amendment, we paid Paragon a non-refundable fee of $2.3 million (the “First Amendment Payment”), which was recorded as research and development expense during the three months ended December 31, 2022.

The non-refundable upfront fee and the First Amendment Payment are separate from any development costs or cost advance paid or owing with respect to the specified program.

In October 2023, we entered into a License Agreement with Paragon (the “Paragon License Agreement”) as a result of exercising its Option under the Paragon Agreement to obtain exclusive licenses to develop, manufacture and commercialize certain therapeutic proteins and antibodies and associated products.

In October 2023, we entered into a License Agreement with Paragon (the “Paragon License Agreement”) as a result of exercising our Option under the Paragon Research Agreement to obtain exclusive licenses to develop, manufacture and commercialize certain therapeutic proteins and antibodies and associated products.

In connection with the execution of the Paragon License Agreement, we made an initial payment of $5.3 million, which was recorded as research and development expense during the three months ended December 31, 2023.

In consideration for rights granted by Paragon, we are obligated to make certain future development milestone payments of up to $16.0 million on a program-by-program basis upon the achievement of specified clinical and regulatory milestones.

Additionally, if we successfully commercialize any product candidate subject to the Paragon License Agreement, we are responsible for royalty payments equal to a percentage in the mid-single digits of net sales.

During the year ended December 31, 2023, we recorded $12.0 million in research and development costs related to the Paragon Agreement.

As further described below, the Paragon License Agreement was amended and restated by the Amended and Restated License Agreement with Paragon in September 2024.

In January 2024, we entered into a letter agreement with Paragon pursuant to which Paragon agreed to continue to perform development activities under the existing Paragon Research Agreement and Paragon License Agreement, which we renewed in July 2024.

In consideration for the development activities to be conducted by Paragon, we agreed to reimburse Paragon for actual development costs incurred and agreed upon development fees in exchange for Paragon’s commitment of the necessary personnel and resources to perform these activities.

In September 2024, we entered into a second amendment to the Paragon Research Agreement to include additional development activities to be performed by Paragon.

Under the amended Paragon Research Agreement, we will be obligated to make a one-time non-refundable payment of $3.5 million to Paragon following the achievement of certain research and development objectives.

We achieved such objectives in February 2025 and the $3.5 million payment was recorded as research and development expense during the three months ended March 31, 2025.

In September 2024, we entered into the Amended and Restated License Agreement with Paragon (the “Amended Paragon License Agreement”) which amended and restated the Paragon License Agreement.

In connection with the execution of the

Amended Paragon License Agreement, we paid to Paragon a non-refundable fee of $4.0 million in September 2024, which was recorded as research and development expense during the three months ended September 30, 2024.

In consideration for rights granted by Paragon, we are obligated to make certain future milestone payments of up to $16.0 million on a program-by-program basis upon the achievement of specified clinical or regulatory milestones, with total milestone payments under all programs not to exceed $40.0 million.

Additionally, if the Company develops a product utilizing certain intellectual property rights granted to it under the Amended Paragon License Agreement, the Company is obligated to pay Paragon potential additional future development milestone payments of up to $3.1 million and commercial milestone payments of up to $17.0 million with respect to such product.

If the Company successfully commercializes any product candidate subject to the Amended Paragon License Agreement, it is responsible for royalty payments equal to a percentage in the mid-single digits of such product’s net sales.

During the year ended December 31, 2024, we recorded $14.2 million in research and development costs related to the Paragon Research Agreement and Amended Paragon License Agreement (collectively the “Paragon Agreements”).

Government Regulation

The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of biologics such as those we are developing.

We, along with third-party contractors, will be required to navigate the various preclinical, clinical and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidates.

We, along with third-party contractors, will be required to navigate the various requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidates.

Biologics Regulation

In the United States, biological products are subject to regulation under the Federal Food, Drug, and Cosmetic Act (“FDCA”), the Public Health Service Act (“PHSA”) and other federal, state, local, and foreign statutes and regulations.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, and local statutes and regulations requires the expenditure of substantial time and financial resources.

The process of developing a biologic and obtaining regulatory approvals and compliance with federal, state, and local statutes and regulations, both pre- and post-approval, requires the expenditure of substantial time and financial resources.

Failure to comply with the applicable U.S.

requirements at any time during the product development process, approval process or following approval may subject an applicant to administrative action and judicial sanctions .

requirements at any time during the product development process, approval process or following approval may subject an applicant to delays in development or approval, administrative action and judicial sanctions .

The regulatory requirements applicable to biological product development, approval, and marketing are subject to change, and regulations and administrative guidance often are revised or reinterpreted by the regulatory authorities in ways that may have a significant impact on our business.

We cannot predict whether legislative changes will be enacted or if regulatory authorities’ guidance or interpretations will change.

The process required by the FDA before biologic product candidates may be marketed in the United States generally involves the following:

• completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s current Good Laboratory Practices (“GLP”) regulation;

• completion of nonclinical laboratory tests, animal studies and formulation studies performed in accordance with the FDA’s current Good Laboratory Practices (“GLP”) regulation, as applicable;

• submission to the FDA of an IND, which must become effective before clinical trials may begin and must be updated annually or when significant changes are made;

• approval by an independent institutional review board (“IRB”) or ethics committee at each clinical site before the trial is commenced;

• manufacture of the proposed biologic candidate in accordance with current good manufacturing practice (“cGMP”);

• approval by an independent institutional review board (“IRB”) or ethics committee (“EC”) representing each clinical site before the trial is commenced;

• performance of adequate and well-controlled human clinical trials in accordance with good clinical practice (“GCP”) requirements to establish the safety, purity and potency of the proposed biologic product candidate for its intended purpose;

• preparation of and submission to the FDA of a biologics license application (“BLA”) after completion of all pivotal clinical trials;

• preparation of and submission to the FDA of a biologics license application (“BLA”), requesting approval to market the biological product for one or more proposed indications, and including submission of detailed information on nonclinical and clinical studies, the manufacture and composition of the product and proposed labeling;

• satisfactory completion of an FDA Advisory Committee review, if applicable;

• a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;

• satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMPs, and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency, and of selected clinical investigation sites to assess compliance with GCPs;

• satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities, including those of third-parties, at which the proposed product is produced to assess compliance with cGMPs, and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency;

• satisfactory completion of any FDA inspections of the nonclinical and clinical trial sites and any FDA Bioresearch Monitoring inspections to assure compliance with GLPs and GCPs, respectively, and the integrity of nonclinical and clinical data submitted in support of the BLA;

• payment of the application fee under the Prescription Drug User Free Act (“PDUFA”), unless exempted;

• FDA review and approval of a BLA to permit commercial marketing of the product for particular indications for use in the United States.

Preclinical and Clinical Development

Nonclinical and Clinical Development

Before testing any investigational biological product in humans, the product must undergo nonclinical testing.

Nonclinical tests include laboratory evaluations of product chemistry, formulation, and stability, as well as studies to evaluate the potential for efficacy and toxicity in animal studies.

The conduct of the nonclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements, including applicable GLP requirements and the U.S.

Department of Agriculture’s Animal Welfare Act, if applicable.

Prior to beginning the first clinical trial with a product candidate, we must submit an IND to the FDA.

An IND is a request for authorization from the FDA to administer an investigational new drug product to humans.

The central focus of an IND submission is on the general investigational plan and the protocol or protocols for preclinical studies and clinical trials.

The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology and pharmacodynamic characteristics of the product, chemistry, manufacturing and controls information, and any available human data or literature to support the use of the investigational product.

An IND submission includes the general investigational plan and the protocol or protocols for the proposed clinical trials, as well as results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology and pharmacodynamic characteristics of the product, chemistry, manufacturing and controls information, and any available human data or literature to support the use of the investigational product.

An IND must become effective before human clinical trials may begin.

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A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.

Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the study until completed.

Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives.

Furthermore, each clinical trial must be reviewed and approved by an IRB or REC either centrally or individually at each institution at which the clinical trial will be conducted before the clinical trial begins at that site, and the IRB/REC must monitor the study until completed.

Regulatory authorities, the IRB/REC or the sponsor may suspend a clinical trial at any time on various grounds, including based on a finding that the subjects are being exposed to an unacceptable health risk, noncompliance with regulatory requirements, or concern that the trial is unlikely to meet its stated objectives.

Imposition by the FDA of a partial or complete clinical hold would delay a proposed clinical study or cause suspension of an ongoing study until FDA determines that all outstanding concerns have been adequately addressed, and the FDA has notified the company that investigations may proceed.

Imposition of a clinical hold could cause significant delays or difficulties in completing planned clinical studies in a timely manner.

Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

There are also requirements governing the reporting of ongoing preclinical studies and clinical trials and clinical study results to public registries.

For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap or be combined.

The investigational product is initially introduced into healthy human subjects or patients with the target disease or condition.

These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

The investigational product is initially introduced into a limited population of healthy human subjects or, in some circumstances, patients with the target disease or condition.

These studies are designed to test the safety, dosage

tolerance, absorption, metabolism and distribution of the investigational product in humans, and the side effects associated with increasing doses.

The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.

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The investigational product is administered to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites.

These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval.

These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product labeling and approval.

In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product.

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Concurrent with clinical trials, companies may complete additional animal studies and develop additional information about the biological characteristics of the product candidate and must finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final product, or for biologics, the safety, purity and potency.

The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must include methods for testing the identity, strength, quality and purity of the final product, or for biologics, the safety, purity and potency.

Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

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When a foreign clinical study is conducted under an IND, all IND requirements must be met unless waived.

When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain FDA regulatory requirements in order to use the study as support for an IND or application for marketing approval or licensure, including that the study was conducted in accordance with GCP, including review and approval by an independent ethics committee and use of proper procedures for obtaining informed consent from subjects, and the FDA is able to validate the data from the study through an onsite inspection if the FDA deems such inspection necessary.

The GCP requirements encompass both ethical and data integrity standards for clinical studies .

Specifically, the FDA requires that the study be conducted in accordance with GCP requirements intended to ensure the protection of human subjects and the quality and integrity of the study data, including review and approval by an independent ethics committee and use of proper procedures for obtaining informed consent from subjects, and that the FDA is able to validate the data from the study through an onsite inspection if the FDA deems such inspection necessary.

In December 2022, with the passage of the Food and Drug Omnibus Reform Act amendments to the FDCA, Congress added a requirement for sponsors to develop and submit a diversity action plan for each phase 3 clinical trial or any other “pivotal study” of a new drug or biological product.

These plans are meant to encourage the enrollment of more diverse patient populations in late-stage clinical trials of FDA-regulated products.

Specifically, diversity action plans must include the sponsor’s goals for enrollment, the underlying rationale for those goals, and an explanation of how the sponsor intends to meet them.

This requirement will apply with respect to clinical investigations for which enrollment commences 180 days after the publication of a final guidance by the FDA on diversity action plans.

FDA issued draft guidance addressing diversity action plans in June 2024, and the statute directs FDA to issue final guidance within nine months of closing the comment period on this draft guidance, which is expected to be in June 2025.

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

Similar requirements for posting clinical trial information in clinical trial registries exist in the European Union and in other countries outside the United States.

BLA Submission and Review

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies and clinical trials are submitted to the FDA as part of a BLA requesting approval to market the product for one or more indications.

The BLA must include all relevant data available from pertinent preclinical studies and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things.

Data can come from company-sponsored clinical studies intended to test the safety and effectiveness of the product, or from a number of alternative sources, including studies initiated and sponsored by investigators.

The BLA must include all relevant data available from pertinent nonclinical studies and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things.

The submission of a BLA requires payment of a substantial application user fee to the FDA, unless a waiver or exemption applies.

In addition, under the Pediatric Research Equity Act (“PREA”), a BLA or supplement to a BLA must contain data to assess the safety and effectiveness of the biological product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The Food and Drug Administration Safety and Innovation Act requires that a sponsor who is planning to submit a marketing application for a biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial pediatric study plan, within sixty days after an end-of-Phase 2 meeting or as may be agreed between the sponsor and FDA.

In addition, under the Pediatric Research Equity Act (“PREA”), a BLA or certain supplements to a BLA must contain data that are adequate to assess the safety and effectiveness of the biological product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective, although deferrals or full or partial waivers may be available in some circumstances.

A sponsor who is planning

to submit a marketing application for a biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must submit an initial pediatric study plan, within sixty days after an end-of-phase 2 meeting or as may be agreed between the sponsor and FDA.

The FDA must then review the information submitted, consult with the sponsor, and agree upon a final plan.

The FDA or the sponsor may request an amendment to the plan at any time.

The FDA is required to send a PREA Non-Compliance letter to sponsors who have failed to submit their pediatric assessments required under PREA, have failed to seek or obtain a deferral or deferral extension or have failed to request approval for a required pediatric formulation, and the FDA publicly posts such PREA Non-Compliance letters and the sponsor’s response.

Unless otherwise required by regulation, PREA does not apply to any biological product for an indication for which orphan designation has been granted.

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Once a BLA has been accepted for filing, the FDA’s goal is to review standard applications within ten months after the filing date, or, if the application qualifies for priority review, six months after the FDA accepts the application for filing.

In both standard and priority reviews, the review process may also be extended by FDA requests for additional information or clarification.

The FDA reviews a BLA to determine, among other things, whether a product is safe, pure and potent and the facility in which it is manufactured, processed, packed or held meets standards designed to assure the product’s continued safety, purity and potency.

The FDA may convene an advisory committee to provide clinical insight on application review questions.

A major amendment to a BLA submitted at any time during the review cycle, including in response to a request from the FDA, may extend the goal date by three months.

The FDA does not always meet its PDUFA goal dates for standard and priority BLAs.

During its review of a BLA, the FDA may convene an advisory committee to provide clinical insight on application review questions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

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

Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCPs.

If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information.

Notwithstanding the submission of any

requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

After the FDA evaluates a BLA and conducts inspections of manufacturing facilities where the investigational product and/or its drug substance will be produced, the FDA may issue an approval letter or a Complete Response letter.

Additionally, before approving a BLA, the FDA will typically inspect one or more clinical trial sites and may also inspect the applicant to assure compliance with GCPs intended to ensure the protection of human subjects and the quality and integrity of the study data.

Under the PHSA, the FDA may approve a BLA if it determines that the product is safe, pure, and potent and that the facility where the product will be manufactured meets standards designed to ensure that it continues to be safe, pure, and potent.

On the basis of the FDA’s evaluation of the application and accompanying information, including the results of the inspection of the manufacturing facilities and any FDA inspections of nonclinical and clinical trial sites to assure compliance with GLP or GCP, and the applicant to ensure compliance with GCP, the FDA may issue an approval letter or a complete response letter (“CRL”).To reach this determination, the FDA will evaluate whether the proposed new biologic’s benefits outweigh its potential risks to patients.

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

A Complete Response letter will describe all of the deficiencies that the FDA has identified in the BLA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the Complete Response letter without first conducting required inspections, testing submitted product lots and/or reviewing proposed labeling.

In issuing the Complete Response letter, the FDA may recommend actions that the applicant might take to place the BLA in condition for approval, including requests for additional information or clarification.

The FDA may delay or refuse approval of a BLA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.

If the application is not approved, the FDA will issue a CRL which will describe all of the deficiencies that the FDA has identified in the BLA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the CRL without first conducting required inspections, testing submitted product lots and/or reviewing proposed labeling.

In issuing the CRL, the FDA may recommend actions that the applicant might take to place the BLA in condition for approval, including requests for additional information or clarification.

Applicants that receive a CRL may submit to the FDA information that represents a complete response to the issues identified by the FDA.

The FDA will not approve an application until issues identified in the CRL have been addressed.

If regulatory approval of a product is granted, such approval will be granted for particular indications and may entail limitations on the indicated uses for which such product may be marketed.

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A REMS is a safety strategy to manage a known or potential serious risk associated with a product and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls and specifications.

Once approved, the FDA may withdraw the product approval if compliance with pre- and post-marketing requirements is not maintained or if problems occur after the product reaches the marketplace.

The FDA may require one or more Phase 4 post-market studies and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization and may limit further marketing of the product based on the results of these post-marketing studies.

The FDA also may condition approval on, among other things, changes to proposed labeling, including a more limited indication or addition of warnings, precautions or contraindications, or implementation of testing and surveillance programs to monitor the product after commercialization.

The FDA may require one or more phase 4 post-market studies and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization and may limit further marketing of the product based on the results of these post-marketing studies Once approved, the FDA may withdraw the product approval if

compliance with pre- and post-marketing requirements is not maintained or if problems occur after the product reaches the marketplace.

Orphan Drug Designation

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The orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review or approval process.

If a product that has orphan drug designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug exclusive approval (or exclusivity), which means that the FDA may not approve any other applications, including a full BLA, to market the same product for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity.

If a product that has orphan drug designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same product for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity.

Orphan drug exclusivity does not prevent FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition.

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As a result, the scope of exclusivity has been narrow and protected only against competition from the same “use or indication” rather than the broader “disease or condition.” In the September 2021 case Catalyst Pharmaceuticals, Inc.

FDA, a federal circuit court set aside the FDA’s narrow interpretation and ruled that orphan drug exclusivity covers the full scope of the orphan-designated disease or condition regardless of whether the drug obtains approval only for a narrower use.

The decision concerned amifampridine, a drug used to treat Lambert-Eaton myasthenic syndrome.

Depending on how the FDA applies the decision beyond this case, it may limit the drugs that can receive exclusivity.

Becerra , a federal circuit court set aside the FDA’s narrow interpretation and ruled that orphan drug exclusivity covers the full scope of the orphan-designated disease or condition regardless of whether the drug obtains approval only for a narrower use.

Although the FDA announced in January 2023 that it will not apply the Catalyst decision beyond the facts at issue in that case, Catalyst could serve as a precedent for future challenges to FDA’s orphan drug-related decisions.

Legislation has been introduced, but has not been passed, that would codify the scope of orphan drug exclusivity set forth in the FDA’s regulations, rather than the interpretation adopted by the Eleventh Circuit in Catalyst .

Expedited Development and Review Programs

The FDA offers a number of expedited development and review programs for qualifying product candidates.

The fast track program is intended to expedite or facilitate the process for reviewing new products that meet certain criteria.

The fast track program is intended to expedite or facilitate the process for developing new products that meet certain criteria.

Specifically, new products are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

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The sponsor of a fast track product has opportunities for more frequent interactions with the review team during product development and, once a BLA is submitted, the product may be eligible for priority review.

A fast track product may also be eligible for rolling review, where the FDA may consider for review sections of the BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the BLA, the FDA agrees to accept sections of the BLA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the BLA.

A fast track product may also be eligible for rolling review, where the FDA may review sections of the BLA on a rolling basis before the complete application is submitted, if the applicant provides a schedule for the submission of the sections of the BLA, the FDA agrees to accept sections of the BLA and determines that the schedule is acceptable, and the applicant pays any required user fees upon submission of the first section of the BLA.

A product intended to treat a serious or life-threatening disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review.

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For original BLAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date (as compared to ten months under standard review).

Additionally, products studied for their safety and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

Fast track, breakthrough therapy, and priority review designations are not mutually exclusive, and a product may qualify for one or more of these programs.

While these programs are intended to expedite product development and approval, they do not alter the standards for FDA marketing approval.

Even if designation is granted, FDA may later decide that a product candidate no longer meets the conditions for designation and the designation may be rescinded.

Additionally, the FDA may grant accelerated approval to a product for a serious or life-threatening condition that provides meaningful therapeutic advantage to patients over existing treatments based upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

The FDA may also grant accelerated approval for such a condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of accelerated approval, the FDA will generally require the sponsor to perform adequate and well-controlled post-marketing clinical studies to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit.

Under the Food and Drug Omnibus Reform Act of 2022, the FDA may require, as appropriate, that such studies be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval.

Products receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required post-marketing studies or if such studies fail to verify the predicted clinical benefit.

In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

Fast track designation, breakthrough therapy designation and priority review do not change the standards for approval but may expedite the development or approval process.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

In May 2018, the Right to Try Act established a new regulatory pathway to increase access to unapproved, investigational treatments for patients diagnosed with life-threatening diseases or conditions who have exhausted approved treatment options and who are unable to participate in a clinical trial.

Failure to conduct required post-approval studies with due diligence, failure to confirm a clinical benefit during the post-approval studies, or dissemination of false or misleading promotional materials would allow the FDA to withdraw the product approval on an expedited basis.

All promotional materials for therapeutic candidates approved under accelerated approval are subject to prior review by the FDA unless FDA informs the BLA holder otherwise.

The Consolidated Appropriations Act, 2023 strengthens the FDA’s authority to require and regulate post-approval studies of accelerated approval drugs and to expedite the rescission of accelerated approval based on these post-approval studies.

Regulation of Combination Products

Certain therapeutic products are comprised of multiple components, such as drug components and device components, that would normally be subject to different regulatory frameworks by the FDA and frequently regulated by different centers at the FDA.

Certain therapeutic products comprise multiple components, such as drug components and device components, that would normally be subject to different regulatory frameworks by the FDA and frequently regulated by different centers at the FDA.

These products are known as combination products.

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The determination of which center will be the lead center is based on the “primary mode of action” of the combination product.

Thus, if the primary mode of action of a drug-

device combination product is attributable to the drug product, the FDA center responsible for premarket review of the drug product would have primary jurisdiction for the combination product.

Thus, if the primary mode of action of a drug-device combination product is attributable to the drug product, the FDA center responsible for premarket review of the drug product would have primary jurisdiction for the combination product.

The FDA has also established the Office of Combination Products to address issues surrounding combination products and provide more certainty to the regulatory review process.

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Post-Approval Requirements

Any products manufactured or distributed by us pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product.

After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval.

There also are continuing user fee requirements, under which the FDA assesses an annual program fee for each product identified in an approved BLA.

Biologic manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMPs, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.

Biologic manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies.

BLA holders and their contractors, including third-party manufacturers, are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with

ongoing regulatory requirements, including cGMPs and pharmacovigilance regulations.

Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented.

FDA regulations also require investigation and correction of any deviations from cGMPs and impose reporting requirements upon us and any third-party manufacturers that we may decide to use.

Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMPs and other aspects of regulatory compliance.

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• injunctions or the imposition of civil or criminal penalties.

The FDA closely regulates the marketing, labeling, advertising and promotion of products.

A company can make only those claims relating to safety and efficacy, purity and potency that are approved by the FDA and in accordance with the provisions of the approved label.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses.

Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters,

corrective advertising and potential civil and criminal penalties.

Physicians may prescribe legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA.

Such off-label uses are common across medical specialties.

Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances.

The FDA does not regulate the behavior of physicians in their choice of treatments.

The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.

The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products, including biological products.

Promotional claims about a product candidate are prohibited before the product is approved.

In addition, the NDA or BLA holder of an approved drug, including a biologic, in the United States may not promote that drug for unapproved, or off-label, uses, although a physician may prescribe a drug for an off-label use in accordance with laws and professional standards governing the practice of medicine.

If a company is found to have promoted off-label uses for an approved drug, it may become subject to administrative and judicial enforcement by the FDA, the DOJ or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities.

This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company may promote or distribute drug products in the future.

The federal government has levied large civil and criminal fines against companies for alleged improper promotion and has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.

Biosimilars and Reference Product Exclusivity

The Affordable Care Act (“ACA”) includes a subtitle called the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which created an abbreviated approval pathway for biological products that are highly similar, or “biosimilar,” to or interchangeable with an FDA-approved reference biological product.

The FDA has issued several guidance documents outlining an approach to review and approval of biosimilars.

Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency, is generally shown through analytical studies, animal studies, and a clinical study or studies.

Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

In order for the FDA to approve a biosimilar product, it must find that there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.

For the FDA to approve a biosimilar product as interchangeable with a reference product, the agency must find that the biosimilar product can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

A product shown to be biosimilar or interchangeable with an FDA-approved reference biological product may rely in part on the FDA’s previous determination of safety and effectiveness for the reference product for approval, which can potentially reduce the cost and time required to obtain approval to market the product.

Complexities associated with the larger, and often more complex, structures of biological products, as well as the processes by which such products are manufactured, pose significant hurdles to implementation of the abbreviated approval pathway that are still being worked out by the FDA.

In September 2021, the FDA issued two guidance documents intended to inform prospective applicants and facilitate the development of proposed biosimilars and interchangeable biosimilars, as well as to describe the FDA’s interpretation of certain statutory requirements added by the BPCIA.

Upon licensure by the FDA, an interchangeable biosimilar may be substituted for the reference product without the intervention of the health-care provider who prescribed the reference product.

The FDA approved the first interchangeable biosimilars in 2021.

However, in 2024, the agency updated its policies regarding interchangeable biosimilars to require fewer tests by the applicant to demonstrate interchangeability and to highlight that these products are not safer or more effective than biosimilars that have not been demonstrated “interchangeable” with their reference products.

In response to such scientific developments, it is possible that Congress could revisit and amend relevant provisions from the BPCIA as part of the upcoming legislative session.

Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA.

In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed.

During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product.

During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own nonclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product.

The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products.

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

At this juncture, it is unclear whether products deemed “interchangeable” by the FDA will, in fact, be readily substituted by pharmacies, which are governed by state pharmacy law.

The BPCIA is complex and continues to be interpreted and implemented by the FDA.

In July 2018, the FDA announced an action plan to encourage the development and efficient review of biosimilars, including the establishment of a new office within the agency that will focus on therapeutic biologics and biosimilars.

On December 20, 2020, Congress amended the PHSA as part of the COVID-19 relief bill to further simplify the biosimilar review process by making it optional to show that conditions of use proposed in labeling have been previously approved for the reference product, which used to be a requirement of the application.

In addition, government proposals have sought to reduce the 12-year reference product exclusivity period.

As of March 2020, certain products previously approved as drugs under the FDCA, such as insulin and human growth hormone, are now deemed to be biologics under the PHSA, which means they may face competition through the biosimilars pathway and are not eligible for the twelve-year period of exclusivity granted to new BLAs.

Other aspects of the BPCIA, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent litigation.

As a result, the ultimate impact, implementation, and impact of the BPCIA is subject to significant uncertainty.

The law also includes an extensive process for the innovator biologic and biosimilar manufacturer to litigate patent infringement, validity, and enforceability prior to the approval of the biosimilar.

As discussed below, the Inflation Reduction Act of 2022 (“IRA”) is a significant new law that intends to foster generic and biosimilar competition and to lower drug and biologic costs.

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Only one patent applicable to an approved product is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent.

The USPTO in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

The USPTO in consultation with the FDA, reviews and approves the application for any patent term extension.

Thus, for each approved product, we may apply for restoration of patent term for one of our related owned or licensed patents to add patent life beyond the original expiration date, depending on the expected length of the clinical studies and other factors involved in the filing of the relevant NDA or BLA.

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The collection and use of personal health data and other personal data in the European Union (“EU”) is governed by the provisions of the European General Data Protection Regulation 2016/679 (“GDPR”), which became applicable in May 2018, and related data protection laws in individual EU Member States.

The GDPR imposes a number of strict obligations and restrictions on the ability to process, including collecting, analyzing and transferring, personal data of individuals, in particular

with respect to health data from clinical trials and adverse event reporting.

The GDPR imposes a number of strict obligations and restrictions on the ability to process, including collecting, analyzing and transferring, personal data of individuals, in particular with respect to health data from clinical trials and adverse event reporting.

The GDPR includes requirements relating to the legal basis of the processing (such as consent of the individuals to whom the personal data relates), the information provided to the individuals prior to processing their personal data, the notification obligations to the national data protection authorities, and the security and confidentiality of the personal data.

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On June 18, 2021, the European Data Protection Board adopted recommendations to assist data exporters with such assessment and their duty to identify and implement supplementary measures where they are needed to ensure compliance with the EU level of protection to the personal data they transfer to third countries.

With regard to the transfer of personal data from the EEA to the United States, on July 10, 2023, the EC adopted its adequacy decision for the EU-US Data Privacy Framework.

With regard to the transfer of personal data from the EEA to the United States, on July 10, 2023, the European Commission adopted its adequacy decision for the EU-US Data Privacy Framework.

On the basis of the new adequacy decision, personal data can flow from the EEA to U.S.

companies participating in the framework.

Companies that have not signed up to the framework will continue to be subject to the international transfer requirements above, and will need to ensure that adequate safeguards such as the SCCs are implemented for all EEA-US data transfers.

Failure to comply with the requirements of the GDPR and the related national data protection laws of the EU Member States may result in significant monetary fines for noncompliance of up to €20 million or 4% of the annual global turnover of the noncompliant company, whichever is greater, other administrative penalties and a number of criminal offenses (punishable by uncapped fines) for organizations and, in certain cases, their directors and officers, as well as civil liability claims from individuals whose personal data was processed.

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Furthermore, there is a growing trend towards the required public disclosure of clinical trial data in the EU, which adds to the complexity of obligations relating to processing health data from clinical trials.

Such public disclosure obligations are provided in the new EU Clinical Trials Regulation No.536/2014 (“CTR”), European Medicines Agency (“EMA”) disclosure initiatives and voluntary commitments by industry.

Such public disclosure obligations are provided in the new EU Clinical Trials Regulation No.536/2014 (“CTR”), EMA disclosure initiatives and voluntary commitments by industry.

Failure to comply with these obligations could lead to government enforcement actions and significant penalties against us, harm to our reputation, and adversely impact our business and operating results.

The uncertainty regarding the interplay between different regulatory frameworks, such as the CTR and the GDPR, further adds to the complexity that we face with regard to data protection regulation.

The uncertainty regarding the

interplay between different regulatory frameworks, such as the CTR and the GDPR, further adds to the complexity that we face with regard to data protection regulation.

With regard to the transfer of personal data from the EEA to the United Kingdom (“UK”), personal data may now freely flow from the EEA to the UK since the UK is deemed to have an adequate data protection level.

However, the adequacy decisions include a ‘sunset clause’ which entails that the decisions will automatically expire four years after their entry into force.

Drug and Biologic Development Process

However, the adequacy decisions include a ‘sunset clause’ which entails that the decisions will automatically expire four years after their entry into force, and so this adequacy decision will be reviewed, and is expected – but not guaranteed - to be renewed, before or during June 2025.

Drug and Biologic Development Process in the EU

In the EU, medicinal products are primarily regulated by EU pharmaceutical law seeking to harmonize the standards for assessing the quality, safety and efficacy of medicinal products.

The process of obtaining regulatory approvals and the subsequent compliance with applicable legislation requires the expenditure of substantial time and financial resources.

Failure to comply with the applicable EU requirements at any time during the product development and post-approval may attract enforcement actions and sanctions .

The process by which medicinal products may be marketed in the EU generally involves the following:

• completion of nonclinical laboratory tests and animal studies performed consistent with the principles of GLP set out in Directive 2004/9/EC and Directive 2004/10/EC;

• submission to the relevant national competent authorities (“NCA”) in each Member State where the trial will be performed of an application for clinical trial authorization (“CTA”), which must be granted prior to the commencement of the clinical trial;

• issuance of a positive opinion on the clinical trial by a research ethics committee (“REC”) in each Member State where the trial will be performed;

• performance of adequate and well-controlled clinical trials in accordance with the principles of GCPs set out in the CTR, Directive 2005/28/EC, Commission Implementing Regulation 2017/556 or the equivalent requirements for trials conducted outside the EU, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines on GCPs, and the ethical principles set out in the Declaration of Helsinki;

• manufacture and import of the medicinal product in accordance with the principles of GMPs set out in Regulation No.

1252/2014, Directive 2001/83/EC, Directive 2017/1572 and associated legislation;

• preparation of and submission to the EMA, or the relevant NCA, of a marketing authorization application (“MAA”) after completion of all pivotal clinical trials, nonclinical studies and chemistry, manufacturing and control information;

• following satisfactory assessment of the MAA dossier, adoption by the EMA, or the relevant NCA, of a positive opinion on the approvability of the medicinal product;

• following EMA’s positive scientific assessment or that of a NCA on the approvability of the medicinal product, grant of a marketing authorization in respect of therapeutic indications by either the European Commission for centrally approved medicinal products or NCAs for nationally approved medicinal products;

• national approval for pricing and reimbursement including the need to demonstrate cost-effectiveness in each Member State for a new medicinal product to be adopted for use in the respective national health systems;

• establishment and implementation of an appropriate pharmacovigilance system which complies with principles of GVP set out in Directive 2010/84/EU, Regulation (EU) No 1235/2010 and Commission Implementing Regulation No 520/2012.

Clinical Development in the EU

Regardless of where they are conducted, all clinical trials included in applications for marketing authorization for human medicines in the EU / EEA must have been carried out in accordance with EU regulations.

This means that clinical trials conducted in the EU / EEA have to comply with EU clinical trial legislation but also that clinical trials conducted outside the EU / EEA have to comply with ethical principles equivalent to those set out in the EEA, including adhering to international good clinical practice and the Declaration of Helsinki.

The conduct of clinical trials in the EU is governed by the CTR, which entered into force on January 31, 2022.

The CTR replaced the Clinical Trials Directive 2001/20/EC, (“Clinical Trials Directive”) and introduced a complete overhaul of the existing regulation of clinical trials for medicinal products in the EU.

Under the former regime, which will expire after a transition period of one or three years, respectively, as outlined below in more detail, before a clinical trial can be initiated it must be approved in each EU member state where there is a site at which the clinical trial is to be conducted.

The approval must be obtained from two separate entities:

the National Competent Authority (“NCA”) and one or more Ethics Committees.

The NCA of the EU Member States in which the clinical trial will be conducted must authorize the conduct of the trial, and the independent Ethics Committee must grant a positive opinion in relation to the conduct of the clinical trial in the relevant EU member state before the commencement of the trial.

Any substantial changes to the trial protocol or other information submitted with the clinical trial applications must be submitted to

or approved by the relevant NCA and Ethics Committees.

Under the current regime all suspected unexpected serious adverse reactions to the investigated drug that occur during the clinical trial must be reported to the NCA and to the Ethics Committees of the EU member state where they occur.

A more unified procedure will apply under the new CTR.

A sponsor will be able to submit a single application for approval of a clinical trial through a centralized EU clinical trials portal.

One national regulatory authority (the reporting EU member state proposed by the applicant) will take the lead in validating and evaluating the application consult and coordinate with the other concerned EU Member States.

If an application is rejected, it may be amended and resubmitted through the EU clinical trials portal.

If an approval is issued, the sponsor may start the clinical trial in all concerned EU Member States.

However, a concerned EU member state may in limited circumstances declare an “opt-out” from an approval and prevent the clinical trial from being conducted in such member state.

The CTR also aims to streamline and simplify the rules on safety reporting, and introduces enhanced transparency requirements such as mandatory submission of a summary of the clinical trial results to the EU Database.

The CTR foresees a three-year transition period.

EU Member States will work in CTIS immediately after the system has gone live.

Since January 31, 2023, submission of initial clinical trial applications via CTIS is mandatory, and by January 31, 2025, all ongoing trials approved under the former Clinical Trials Directive will need to comply with the CTR and have to be transitioned to CTIS.

Under both the former regime and the new CTR, national laws, regulations, and the applicable GCP and GLP standards must also be respected during the conduct of the trials, including the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines on GCP and the ethical principles that have their origin in the Declaration of Helsinki.

During the development of a medicinal product, the EMA and national regulators within the EU provide the opportunity for dialogue and guidance on the development program.

At the EMA level, this is usually done in the form of scientific advice, which is given by the Committee for Medicinal Products for Human Use (“CHMP”) on the recommendation of the Scientific Advice Working Party.

This means that clinical trials conducted in the EU / EEA have to comply with EU clinical trial legislation but also that clinical trials conducted outside the

EU / EEA have to comply with the principles equivalent to those set out in the EEA, including adhering to GCPs and the ethical principles set out in the Declaration of Helsinki.

In accordance with the CTR, sponsors must submit a single CTA application through a centralized EU clinical trials portal, the Clinical Trials Information System (“CTIS”).

The CTA application will generally include the results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology and pharmacodynamic characteristics of the product, chemistry, manufacturing and controls information, and any available human data or literature to support the use of the investigational product.

The sponsor must propose one NCA to act as reporting member state (“RMS”) to lead the validation and evaluation of the application.

This RMS will be responsible for consulting and coordinating with the NCAs of the other EU Member States, i.e., Concerned Member States (“CMS”).

If an application is rejected, it may be amended and resubmitted through the CTIS.

If an approval is issued, the sponsor may start the clinical trial in all CMSs.

However, a CMS may in limited circumstances declare an “opt-out” from an approval and prevent the clinical trial from being conducted in such Member State.

Consistent with the position in the U.S., NCAs, RECs or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives.

During the development of a medicinal product, the EMA and NCAs provide the opportunity for dialogue and guidance on the development program.

At the EMA level, this is usually achieved in the form of scientific advice, which is given by the Committee for Medicinal Products for Human Use (“CHMP”) on the recommendation of the Scientific Advice Working Party.

A fee is incurred with each scientific advice procedure but is significantly reduced for designated orphan medicines.

Advice from the EMA is typically provided based on questions concerning, for example, quality (chemistry, manufacturing and controls testing), nonclinical testing and clinical studies, and pharmacovigilance plans and risk-management programs.

Advice is not legally binding with regard to any future Marketing Authorization Application (“MAA”) of the product concerned.

Advice is not legally binding with regard to any future MAA of the product concerned.

Drug Marketing Authorization

In the European Union, medicinal products are subject to extensive pre- and post-market regulation by regulatory authorities at both the European Union and national levels.

In the EU and EEA, after completion of all required clinical testing, pharmaceutical products may only be placed on the market after obtaining a Marketing Authorization (“MA”).

To obtain an MA of a drug under European Union regulatory systems, an applicant can submit an MAA, through, amongst others, a centralized or decentralized procedure.

Centralized Authorization Procedure

The centralized procedure provides for the grant of a single MA that is issued by the EC, following the scientific assessment of the application by the EMA that is valid for all EU Member States as well as in the three additional EEA Member States.

The centralized procedure is compulsory for specific medicinal products, including for medicines developed by means of certain biotechnological processes, products designated as orphan medicinal products, ATMP, and medicinal products with a new active substance indicated for the treatment of certain diseases (AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and viral diseases).

For medicinal products containing a new active substance not yet authorized in the EEA before May 20, 2004 and indicated for the treatment of other diseases, medicinal products that constitute significant therapeutic, scientific or technical innovations or for which the grant of a MA through the centralized procedure would be in the interest of public health at EU level, an applicant may voluntarily submit an application for a marketing authorization through the centralized procedure.

In the EU, medicinal products are subject to extensive pre- and post-market regulation by regulatory authorities at both the EU and national levels.

In the EU and EEA, after completion of all required testing, nonclinical studies, clinical trials and chemistry, manufacturing, and controls information can be included in a MAA requesting approval to market the product for one or more indications.

Pharmaceutical products may only be placed on the market after a marketing authorization has been obtained.

In the EU and EEA, there are two types of marketing authorization:

centralized and national.

Centralized Marketing Authorizations

The centralized procedure provides for the grant of a single marketing authorization that is issued by the EC, following the scientific assessment of the application by the EMA that is valid for all EU Member States as well as in the three additional EEA Member States.

The centralized procedure is compulsory for specific medicinal products, including for medicines developed by means of certain biotechnological processes, (recombinant DNA technology, controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells, and hybridoma and monoclonal antibody methods) products designated as orphan medicinal products, advanced-therapy medicinal products (gene-therapies, somatic cell-therapies or tissue-engineered medicines), and medicinal products containing a new active substance indicated for the treatment of certain diseases (AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune, other immune dysfunctions and viral diseases).

For medicinal products containing a new active substance not yet authorized in the EEA before May 20, 2004 and indicated for the treatment of other diseases, medicinal products that constitute significant therapeutic, scientific or technical innovations or for which the grant of a marketing authorization through the centralized procedure would be in the interest of public health at EU level, an applicant may request submission of an marketing authorization through the centralized procedure.

Under the centralized procedure, the CHMP established at the EMA, is responsible for conducting the initial assessment of a drug.

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However, this timeline excludes clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP, so the overall process typically takes a year or more, unless the application is eligible for an accelerated assessment.

Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is expected

to be of a major public health interest, particularly from the point of view of therapeutic innovation.

Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation.

Upon request, the CHMP can reduce the time frame to 150 days if the applicant provides sufficient justification for an accelerated assessment.

The CHMP will provide a positive opinion regarding the application only if it meets certain quality, safety and efficacy requirements.

This opinion is then transmitted to the EC, which has the ultimate authority for granting MA within 67 days after receipt of the CHMP opinion.

Decentralized Authorization Procedure

Medicines that fall outside the mandatory scope of the centralized procedure have three routes to authorization:

(i) they can be authorized under the centralized procedure if they concern a significant therapeutic, scientific or technical innovation, or if their authorization would be in the interest of public health;

(ii) they can be authorized under a decentralized procedure where an applicant applies for simultaneous authorization in more than one EU member state;

or (iii) they can be authorized in an EU member state in accordance with that state’s national procedures and then be authorized in other EU countries by a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization (mutual recognition procedure).

The decentralized procedure permits companies to file identical MA applications for a medicinal product to the competent authorities in various EU Member States simultaneously if such medicinal product has not received marketing approval in any EU Member State before.

This procedure is available for pharmaceutical products not falling within the mandatory scope of the centralized procedure.

The competent authority of a single EU Member State, the reference member state, is appointed to review the application and provide an assessment report.

The competent authorities of the other EU Member States, the concerned member states, are subsequently required to grant a marketing authorization for their territories on the basis of this assessment.

The only exception to this is where the competent authority of an EU Member State considers that there are concerns of potential serious risk to public health, the disputed points are subject to a dispute resolution mechanism and may eventually be referred to the EC, whose decision is binding for all EU Member States.

The CHMP will provide a positive opinion regarding the application only if it meets certain quality, safety and efficacy

requirements.

This opinion is then transmitted to the EC, which has the ultimate authority for granting marketing authorization within 67 days after receipt of the CHMP opinion.

National Marketing Authorizations

Medicines that fall outside the mandatory scope of the centralized procedure can be authorized nationally.

Where a product already received a national marketing authorization, applicants can request other Member States to recognize the approval via the mutual recognition procedure.

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

The decentralized procedure permits companies to file identical MAAs for a medicinal product to the NCAs of various EU Member States simultaneously.

The NCA of a single EU Member State, the reference member state, is appointed to review the application and provide an assessment report.

The NCAs of the other Member States, the concerned member states, are subsequently required to grant a marketing authorization for their territories on the basis of this assessment.

The only exception to this is where the competent authority of a CMS considers that there are concerns of potential serious risk to public health, the disputed points are subject to a dispute resolution mechanism and may eventually be referred to the EC, whose decision is binding for all EU Member States.

Risk Management Plan

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An updated RMP must be submitted:

(i) at the request of EMA or a national competent authority, or (ii) whenever the risk-management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit-risk profile or as a result of an important pharmacovigilance or risk-minimization milestone being reached.

The regulatory authorities may also impose specific obligations as a condition of the MA.

(i) at the request of EMA or a NCA, or (ii) whenever the risk-management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit-risk profile or as a result of an important pharmacovigilance or risk-minimization milestone being reached.

The regulatory authorities may also impose specific obligations as a condition of the marketing authorization.

Since October 30, 2023, all RMPs for centrally authorized products are published by the EMA subject only to limited redactions.

MA Validity Period and Exclusivity

Marketing Authorization Validity Period and Exclusivity

Marketing Authorizations have an initial duration of five years.

After these five years, the authorization may subsequently be renewed on the basis of a reevaluation of the risk-benefit balance.

Once renewed, the MA is valid for an unlimited period unless the EC or the national competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with only one additional five-year renewal.

After these five years have elapsed, the authorization may subsequently be renewed on the basis of a reevaluation of the risk-benefit balance.

Once renewed, the marketing authorization is valid for an unlimited period unless the European Commission or the NCA decides, on justified grounds relating to pharmacovigilance, to proceed with only one additional five-year renewal.

Applications for renewal must be made to the EMA at least nine months before the five-year period expires.

In the EU, new chemical entities (“NCEs”), sometimes referred to as new active substances, qualify for eight years of data exclusivity upon the product’s first MA in the EU and an additional two years of market exclusivity.

This data exclusivity, if granted, prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic (abbreviated) application for eight years, after which generic marketing authorization can be submitted, and the innovator’s data may be referenced, but not approved for two years.

The overall ten-year period will be extended to a maximum of eleven years if, during the first eight of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

Products may not be granted data exclusivity since there is no guarantee that a product will be considered by the EU’s regulatory authorities to include an NCE.

Even if a compound is considered to be a NCE and the MA applicant is able to gain the prescribed period of data exclusivity, another company could market a version of the medicinal product if such company can complete a full MAA with its own complete database of pharmaceutical tests, preclinical studies and clinical trials and obtain MA of its product.

Exceptional Circumstances/Conditional Approval

Similar to accelerated approval regulations in the United States, conditional MAs can be granted in the EU in exceptional circumstances.

A conditional MA can be granted for medicinal products where, although comprehensive clinical data referring to the safety and efficacy of the medicinal product have not been supplied, a number of criteria are fulfilled:

(i) the benefit/risk balance of the product is positive, (ii) it is likely that the applicant will be in a position to provide the comprehensive clinical data, (iii) unmet medical needs will be fulfilled by the grant of the MA and (iv) the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.

A conditional MA must be renewed annually.

In the EU, medicinal products containing a new active substance (“NAS”), qualify for eight years of data exclusivity upon the product’s first marketing authorization in the EU and an additional two years of market exclusivity.

This data exclusivity, if granted, prevents the developers of generic versions of the innovative medicinal product from referencing the innovator’s data for eight years.

After this period has expired, a generic marketing authorization can be submitted, and the innovator’s data may be referenced.

During the marketing protection period, even if a generic marketing authorization has been granted, the generic medicinal product cannot be placed on the market until the expiry of a full ten-year period from the initial authorization of the innovative medicinal product.

The overall ten-year period can be extended to a maximum of eleven years if, during the first eight of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

Products may not be granted data exclusivity since there is no guarantee that a product will be considered by the EU’s regulatory authorities to include an NAS.

Even if a compound is considered to be a NAS and the marketing authorization applicant is able to gain the prescribed period of data exclusivity, another company could market a version of the medicinal product if such company can compile a full MAA based on its own complete set of chemistry, manufacturing, and controls information, nonclinical studies and clinical trials and obtain marketing authorization of its product.

Conditional Approval

Similar to accelerated approval regulations in the United States, conditional marketing authorizations can be granted in the EU in the interest of public health and patients to address unmet medical needs.

A conditional marketing authorization can be granted for medicinal products based on less comprehensive clinical data referring to the safety and efficacy of the medicinal product than normally required.

However, for such an approval to be granted a number of criteria should be fulfilled:

benefit/risk balance of the product is positive, (ii) it is likely that the applicant will be in a position to provide the comprehensive clinical data, (iii) unmet medical needs will be fulfilled by the grant of the marketing authorization and (iv) the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.

A conditional marketing authorization must be renewed annually.

Orphan Designation and Exclusivity

The criteria for designating an orphan medicinal product in the European Union are similar in principle to those in the United States.

The EMA grants orphan drug designation if the medicinal product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting no more than five in 10,000 persons in the European Union (prevalence criterion).

In addition, Orphan Drug Designation can be granted if, for economic reasons, the medicinal product would be unlikely to be developed without incentives and 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 medicinal product is a significant benefit to patients affected by the condition.

The EMA’s Committee for Orphan Medicinal Products (“COMP”) assesses orphan drug designation if the medicinal product is:

(1) intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting no more than five in 10,000 persons in the European Union when the application is made, or without the incentives derived from orphan status, it is unlikely the medicinal product would generate sufficient return to justify the investment;

and (2) there is no other satisfactory method approved in the EU of diagnosing, preventing, or treating the condition, or if such a method exists, the proposed medicinal product is a significant benefit to patients affected by the condition.

The COMP’s assessment will form the basis for the European Commission to adopt an implementing decision on grant of an orphan designation.

An application for orphan drug designation (which is not a marketing authorization, as not all orphan-designated medicines reach the authorization application stage) must be submitted first before an application for marketing authorization of the medicinal product is submitted.

The applicant will receive a fee reduction for the MAA if the orphan drug designation has been granted, but not if the designation is still pending at the time the marketing authorization is submitted, and sponsors must submit an annual report to EMA summarizing the status of development of the medicine.

The applicant will receive a fee reduction for the MAA if the orphan drug designation is granted, but not if the designation is still pending at the time the MAA is submitted, and applicants must submit an annual report to EMA summarizing the status of development of the medicine.

Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

Designated orphan medicines are eligible for conditional marketing authorization.

The EMA’s Committee for Orphan Medicinal Products reassesses the orphan drug designation of a product in parallel with the review for a marketing authorization;

The COMP reassesses the orphan drug designation of a product in parallel with the CHMP’s review of the MAA.

For a product to benefit from market exclusivity it must maintain its orphan drug designation at the time of marketing authorization review by the EMA and approval by the EC.

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Upon the grant of a marketing authorization, orphan drug designation provides up to ten years of market exclusivity in the orphan indication.

During the 10-year period of market exclusivity, with a limited number of exceptions, the regulatory authorities of the EU Member States and the EMA may not accept applications for marketing authorization, accept an application to extend an existing marketing authorization or grant marketing authorization for other similar medicinal products for the same therapeutic indication.

During the 10-year period of market exclusivity, with a limited number of exceptions, NCAs and the EMA may not accept MAAs to extend an existing marketing authorization or grant marketing authorizations for other similar medicinal products for the same approved therapeutic indication.

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

An orphan medicinal product can also obtain an additional two years of market exclusivity for an orphan-designated condition when the results of specific studies are reflected in the Summary of Product Characteristics, addressing the pediatric population and completed in accordance with a fully compliant Pediatric Investigation Plan.

An orphan medicinal product can benefit from an additional two years of market exclusivity for an orphan-designated condition when the results of specific studies are reflected in the Summary of Product Characteristics, addressing the pediatric population and completed in accordance with a fully compliant Pediatric Investigation Plan.

No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications.

The 10-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, i.e., the condition prevalence or financial returns criteria under Article 3 of Regulation (EC) No.

141/2000 on orphan medicinal products.

The 10-year market exclusivity period may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation or that the product is sufficiently profitable to justify maintenance of the market exclusivity.

When the period of orphan market exclusivity for an indication ends, the orphan drug designation for that indication expires as well.

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PRIME Designation

In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist.

The Priority Medicines (“PRIME”) scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure.

Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies on the basis of compelling non-clinical data and tolerability data from initial clinical trials.

development program elements, and potentially accelerated MAA assessment once a dossier has been submitted.

Importantly, once a candidate medicine has been selected for the PRIME scheme, a dedicated contact point and rapporteur from the CHMP or from CAT are appointed facilitating increased understanding of the product at EMA’s Committee level.

A kick-off meeting with the CHMP/CAT rapporteur initiates these relationships and includes a team of multidisciplinary experts to provide guidance on the overall development plan and regulatory strategy.

In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no satisfactory therapies currently exist in the EU.

Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies on the basis of compelling nonclinical data and tolerability data from initial clinical trials.

Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted.

Importantly, once a candidate medicine has been selected for the PRIME scheme, a dedicated contact point and rapporteur from the CHMP or from the Committee for Advanced Therapies (“CAT”) are appointed facilitating increased understanding of the product at EMA’s Committee level.

A kick-off meeting with the CHMP/CAT rapporteur initiates these relationships and includes a team of multidisciplinary experts to provide guidance on the overall development plan and

regulatory strategy.

PRIME eligibility does not change the standards for product approval, and there is no assurance that any such designation or eligibility will result in expedited review or approval.

Regulation of Combination Products in the EU

Unlike in the U.S., there is no single definition for a combination product.

In the EU, product containing a medical device and a medicinal product are either regulated as a medicinal product or a medical device and the primary mode of action governs the regulatory pathway.

If a medical device intended to administer a medicinal product and the medicinal product and medical device are placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combination and which is not reusable, then the single integral product is regulated as a medicinal product.

In that case, the approval must take account of general safety and performance requirements for assessing the medical device component.

In contrast, where the medical device and the medicinal product are not presented as an integrated unit, then they will be regulated separately under the medical device legislation and the medicinal product legislation.

Any device which incorporates as an integral part, a medicinal substance, including a biological substance, that have an action ancillary to that the device, then the combination product is regulated as a medical device, but the notified body responsible for conformity assessment must consult a medicine authority including the EMA.

However, if the action of the medicinal substance including a biological substance is principal and not ancillary to that of the device, then the combination product is regulated as a medicinal product.

Post-Approval Requirements in the EU

EU law requires each marketing authorization holder, NCA, and the EMA to operate a pharmacovigilance system.

Collectively, these systems ensure the ongoing monitoring of the safety and benefit-risk profile of approved medicinal products.

Key responsibilities of marketing authorization holders include, but are not limited to:

the maintenance of a pharmacovigilance system master file that outlines the marketing authorization holder’s relevant processes and procedures;

the appointment of a Qualified Person for pharmacovigilance who is responsible for overseeing the marketing authorization holder’s pharmacovigilance system;

the collection, recording and reporting by the marketing authorization holder to the relevant competent authorities of suspected adverse events associated with the use of their medicinal products;

the submission by marketing authorization holders of periodic safety update reports to the relevant competent authority and to regular audits and inspections by the relevant regulatory authorities.

Post approval, any changes to the approved medicinal product, such as the addition of new indications or changes to the manufacturing process, are subject to prior review and approval by the relevant regulatory authorities.

Obtaining and maintaining such approvals requires marketing authorization holders to expend time, money and effort to ensure and demonstrate regulatory compliance.

Similar to the position in the U.S., if a marketing authorization holder does not maintain compliance with applicable regulatory requirements, or if unfavorable signals derived from post-approval use of the medicinal product are identified, the relevant regulatory authority can impose various sanctions/remedial actions, including but not limited to:

the suspension or revocation of the underlying approvals;

the imposition of market recalls;

the performance of post-authorization safety studies;

the imposition of changes to the approved labeling;

the issuance of warning letters and imposition of fines;

restrictions on the marketing of a medicinal product;

the issuance of safety alerts including Dear Healthcare Professional letters;

and the imposition of criminal penalties.

Regulation in the UK

The UK formally left the EU on January 31, 2020.

EU laws now only apply to the UK in respect of Northern Ireland as laid out in the Protocol on Ireland and Northern Ireland and as amended by the Windsor Framework agreed by the UK and EU on February 27, 2023.

Amongst other things, the Windsor Framework sets out a long-term set of arrangements for the supply of medicines into Northern Ireland.

From January 1, 2025, medicines will need to be approved and licensed on a UK-wide basis by the UK’s Medicines and Healthcare products Regulatory Agency (the “MHRA”), with medicines using the same packaging and labelling across the UK.

The European Medicines Agency will have no role in approving or licensing new drugs for provision in Northern Ireland.

After the expiry of the transition period on December 31, 2020, the UK became a “third country” for the purposes of EU law.

Until recently, certain aspects of EU pharmaceutical legislation applied in Northern Ireland by virtue of the Northern Ireland Protocol.

However, in accordance with the Windsor Framework, as of January 1, 2025, EU pharmaceutical law no longer applies in Northern Ireland.

The Windsor Framework sets out a long-term set of arrangements for the supply of medicines into Northern Ireland.

In particular, medicines need to be approved and licensed on a UK-wide basis by the UK’s Medicines and Healthcare products Regulatory Agency (the “MHRA”), with medicines using the same packaging and labeling across the UK.

The EMA has no role in approving or licensing new drugs for provision in Northern Ireland.

The European Union and the UK have agreed on a trade and cooperation agreement (“TCA”), which includes provisions affecting the life sciences sector (including on customs and tariffs).

There are some specific provisions concerning pharmaceuticals, including the mutual recognition of cGMP, inspections of manufacturing facilities for medicinal products and cGMP documents issued.

There are some specific provisions concerning pharmaceuticals, including the mutual recognition of cGMP, inspections of manufacturing facilities for medicinal products and GMP documents issued.

The TCA does not, however, contain wholesale mutual recognition of UK and EU pharmaceutical regulations and product standards.

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The IDTA and Addendum came into force on March 21, 2022 and replaced the old SCCs for the purposes of the UK regime.

However, the transitional provisions, adopted with the IDTA and the Addendum, provide that contracts concluded on or before September 21, 2022 on the basis of any old SCCs continue to provide appropriate safeguards for the purpose of the UK regime until March 21, 2024, provided that the processing operations that are the subject matter of the contract remain unchanged and reliance on those clauses ensures that the transfer of personal data is subject to appropriate safeguards.

However, the transitional provisions, adopted with the IDTA and the Addendum, provide that contracts concluded on or before September 21, 2022 on the basis of any old SCCs continued to provide appropriate safeguards for the purpose of the UK regime until March 21, 2024, provided that the processing operations that are the subject matter of the contract remain unchanged and reliance on those clauses ensures that the transfer of personal data is subject to appropriate safeguards.

With regard to the transfer of personal data from the UK to the United States, the UK government has adopted an adequacy decision for the United States, the UK-US Data Bridge, which came into force on October 12, 2023.

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company participating in the EU-US Data Privacy Framework and the UK Extension.

As with the EU equivalent, companies that are not participants in the framework and extension will continue to be subject to the international transfer requirements under the UK GDPR.

Other Regulations

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Such laws include, without limitation:

federal Anti-Kickback Statute (“AKS”);

the federal Anti-Kickback Statute (“AKS”);

the federal False Claims Act (“FCA”);

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A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

Civil and criminal false claims laws, including the FCA, and civil monetary penalty laws, which can be enforced through civil whistleblower or qui tam actions, prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment of federal government funds, including in federal healthcare programs, that are false or fraudulent.

Pharmaceutical and other healthcare companies have been prosecuted under these laws for engaging in a variety of different types of conduct that caused the submission of false claims to federal healthcare programs.

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Numerous United States state, federal, and local laws and regulations, as well as foreign legislation, govern the collection, processing, transfer, disclosure, sharing, storing, dissemination, use, confidentiality, and security of personal information.

In the United States, there are several federal and state laws and regulations, including state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws and regulations that regulate the collection, use, disclosure, protection and processing of medical and health-related information.

These laws could apply to our operations or the operations of our partners.

For example, in the United States, at the federal level, the regulations promulgated under the Health Insurance Portability and Accountability Act (“HIPAA”), as amended by the Health Information Technology for Economic and Clinical Health Act (“HITECH Act”), and their respective implementing regulations impose data privacy, security, and breach notification obligations with respect to protected health information (“PHI”) on certain health-care providers, health plans and health-care clearinghouses, known as “covered entities”, as well as on their business associates, which include persons or entities that perform certain services that involve using, disclosing, creating, receiving, maintaining, or transmitting individually identifiable PHI for or on behalf of such covered entities.

While we have determined that we are neither a covered entity nor a business associate directly subject to HIPAA, many of the U.S.

health-care providers with which we interact are subject to HIPAA, and we may have assumed obligations related to protecting the privacy of personal information.

These requirements imposed by HIPAA and the HITECH Act on covered entities and business associates include, entering into agreements that require business associates protect PHI provided by the covered entity against improper use or disclosure, among other things;

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To the extent that we submit electronic healthcare claims and payment transactions that do not comply with the electronic data transmission standards established under HIPAA and the HITECH Act, payments to us may be delayed or denied.

Even when HIPAA does not apply, according to the Federal Trade Commission, violating consumers’ privacy rights or failing to take appropriate steps to keep consumers’ personal information secure, including medical and health-related information, may constitute unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act.

Even when HIPAA does not apply, according to the Federal Trade Commission, violating consumers’ privacy rights or failing to take appropriate steps to keep consumers’ personal information secure, including medical and health-related information, may constitute unfair or deceptive acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act.

In addition, there are also several U.S.

state privacy laws, such as the California Consumer Privacy Act of 2018 (“CCPA”), as amended by the California Privacy Rights Act of 2020 (“CPRA”), govern the privacy and security of personal information, including specific medical and health-related information in certain circumstances, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

The CCPA/CPRA applies to personal data of consumers, business contacts, and employees, and imposes obligations on certain businesses that do business in California, including to provide specific disclosures in privacy notices and rights to California residents in relation to their personal information.

Health information falls under the CCPA/CPRA’s definition of personal information where it identifies, relates to, describes, or is reasonably capable of being associated with or could reasonably be linked with a particular consumer or household—unless it is subject to HIPAA—and is included under a new category of personal information, “sensitive personal information,” which is offered greater protection.

Similar comprehensive state privacy laws that provide protection of medical or health-related information are now in effect in Virginia, Colorado, Connecticut, and Utah, and many have passed in other states.

state privacy laws, such as the California Consumer Privacy Act of 2018, as amended by the California Privacy Rights Act of 2020 (together, the “CCPA”), that govern the privacy and security of personal information.

Some, such as the Washington My Health My Data Act, protect specific medical and health-related information in certain circumstances.

Some of these state laws are more stringent than HIPAA and many differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

The CCPA applies to personal data of consumers, business contacts, and employees, and imposes obligations on certain businesses that do business in California, including to provide specific disclosures in privacy notices and rights to California residents in relation to their personal information.

Health information may fall under the CCPA’s definition of personal information where it identifies, relates to, describes, or is reasonably capable of being associated with or could reasonably be linked with a particular consumer or household—unless it is subject to HIPAA—and is included under a new category of personal information, “sensitive personal information,” which is offered greater protection.

In addition, almost 20 other states have now passed comprehensive privacy laws that have taken effect or will come into effect at various times over the next few years.

Failure to comply with these laws, where applicable, can result in the imposition of significant civil and/or criminal penalties and private litigation.

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The ACA, which was enacted in March 2010, substantially changed the way healthcare is financed by both governmental and private insurers in the United States, and significantly affected the pharmaceutical industry.

The ACA contains a number of provisions of particular import to the pharmaceutical and biotechnology industries, including, but not limited to, those governing enrollment in federal healthcare programs, a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, and annual fees based on pharmaceutical companies’ share of sales to federal health care programs.

Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, and annual fees based on pharmaceutical companies’ share of sales to federal health-care programs.

Since its enactment, there have been judicial and Congressional challenges to certain aspects of the ACA, and we expect there will be additional challenges and amendments to the ACA in the future.

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Further, no uniform policy for coverage and reimbursement exists in the United States, and coverage and reimbursement can differ significantly from payor to payor.

Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement rates, but also have their

own methods and approval process apart from Medicare determinations.

Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement rates, but also have their own methods and approval process apart from Medicare determinations.

As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our product candidates to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

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We currently employ internal resources and third-party consultants to manage our manufacturing contractors.

Historically, we have relied on third-party contract development and manufacturing organizations (“CDMOs”), to manufacture and supply our preclinical and clinical materials used during the development of our product candidates.

We initially pursued three separate manufacturing paths to supply investigational product for our planned clinical trials in order to mitigate delays and uncertainties.

We currently rely on a single multi-site CDMO for manufacturing our clinical materials, WuXi AppTec (Hong Kong) Limited and WuXi Biologics (Hong Kong) Limited (together, “WuXi”), although other avenues remain available if our current manufacturer were to be negatively impacted.

Historically, we have relied on third-party contract development and manufacturing organizations (“CDMOs”), to manufacture and supply our nonclinical and clinical materials used during the development of our product candidates.

We currently rely on a single multi-site CDMO for manufacturing our clinical materials, WuXi Biologics (Hong Kong) Limited (“WuXi”), although other avenues remain available if our current manufacturer were to be negatively impacted.

We maintain a long-term master services agreement with our CDMO pursuant to which the CDMO provides biologics development and manufacturing services on a per-project basis and a related cell line license.

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The agreement includes confidentiality and intellectual property provisions to protect our proprietary rights related to our product candidates.

We do not currently have arrangements in place for redundant supply.

While any reduction or halt in supply from the CDMO could limit our ability to develop our product candidates until a replacement CDMO is found and qualified, we believe that we have

sufficient supply to support our current clinical trial programs.

We do not currently have arrangements for redundant supply and are working on building our supply chain to put these in place.

Any reduction or halt in supply from the CDMO could limit our ability to develop our product candidates until a replacement CDMO is found and qualified, although we believe that we have supply on hand that can partially support our current clinical trial programs until a replacement CDMO is secured.

In light of our reliance on WuXi, we are taking several measures to strengthen our supply chain by moving certain CDMO activities outside of WuXi’s Chinese facilities.

In light of our reliance on WuXi, we are taking several measures to strengthen our supply chain by moving certain CDMO activities outside of WuXi’s facilities.

See “Risk Factors” for additional information.

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As of December 31, 2024, we employed 143 full-time employees located in the U.S., including at our facilities in Waltham, Massachusetts and Boulder, Colorado.

As of February 22, 2024 we employed 96 full-time employees located in the U.S.

We consider our relationship with our employees to be good.

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We are committed to equality, inclusion and diversity in the workplace.

As of December 31, 2023, approximately 32% of our workforce identify as members of underrepresented ethnic communities and approximately 53% identify as female.

We strive to interview diverse candidates for our open positions.

As of December 31, 2024, approximately 24% of our workforce identify as members

of underrepresented ethnic communities and approximately 59% identify as female.

We strive to develop a diverse slate of candidates to interview for our open positions.

Attracting, developing and retaining talented employees to support the growth of our business is an integral part of our human capital strategy and critical to our long-term success.

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We offer a package of competitive employee benefits, including 401(k) plan matching contributions and an employee stock purchase plan.

We have a performance development review process in which managers provide regular feedback to assist with the development of our employees, including the use of individual plans to assist with career development.

We have a performance development review process in which managers provide regular feedback to assist with the development of our employees.

We also invest in the growth and development of our employees through various training and development programs that help build and strengthen our employees’ leadership and professional skills.

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Our Corporate Information

We were initially founded as a Delaware limited liability company in January 2010 and subsequently incorporated as a Delaware corporation in June 2014.

We were initially founded as miRagen Therapeutics, Inc.

as a Delaware limited liability company in January 2010 and subsequently incorporated as a Delaware corporation in June 2014.

On January 20, 2021, pursuant to a merger agreement under which miRagen Therapeutics, Inc.

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to Viridian Therapeutics, Inc.

Our common stock currently trades on The Nasdaq Capital Market under the ticker symbol “VRDN.” Our principal executive office is located at 221 Crescent Street, Suite 401, Waltham, MA 02453, and our telephone number is (617) 272-4600.

Our common stock currently trades on The Nasdaq Capital Market under the ticker symbol “VRDN.” Our principal executive office is located at 221 Crescent Street, Suite 103A, Waltham, MA 02453, and our telephone number is (617) 272-4600.

Our website address is www.viridiantherapeutics.com.

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We have included our website in this Annual Report solely as an inactive textual reference.

This Annual Report contains references to our trademarks and trademarks belonging to other entities.

This Annual Report contains references to our trademarks and trademarks belonging to other entities that are the property of their respective owners.

Solely for convenience, trademarks and trade names referred to in this Annual Report, including logos, artwork, and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these trademarks and trade names.

intend our use or display of other companies’ trade names or trademarks to imply a relationship with, or endorsement or sponsorship of us by, any other company.

We do not intend our use or display of other companies’ trade names or trademarks to imply a relationship with, or endorsement or sponsorship of us by, any other company.

Available Information

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The reports are also available at the SEC’s internet website at www.sec.gov.

A copy of our Corporate Governance Guidelines, Code of Business Conduct and Ethics, and the charters of the Audit Committee, Compensation Committee, Nominative and Corporate Governance Committee and Science and Technology Committee are posted on our website, www.viridiantherapeutics.com, under “Corporate Governance.”

A copy of our Corporate Governance Guidelines, Code of Business Conduct and Ethics, and the charters of the Audit Committee, Compensation Committee, Nominating and Corporate Governance Committee, and Science and Technology Committee are posted on our website, www.viridiantherapeutics.com, under “Corporate Governance.”

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