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Item 1. Business

2025-03-03 compared with 2024-02-29 · 398 added, 297 removed, 840 unchanged (45% of the section changed)

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myostatin inhibition for neuromuscular and metabolic diseases, including spinal muscular atrophy ("SMA") and obesity;

and antibody recruiting, bispecific molecules and antibody drug conjugates ("ADCs") for cancer.

and antibody recruiting bispecific molecules ("ARMs") and antibody drug conjugates ("ADCs") for cancer.

Separation from Biohaven Pharmaceutical Holding Company Ltd.

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from the Former Parent (the “Spin-Off”) described in Biohaven’s Information Statement attached as Exhibit 99.1 to Biohaven’s Registration Statement on Form 10, as amended (Reg.

Collectively, we refer to the Distribution and Spin-Off throughout this Annual Report on Form 10-K as the "Separation." As a result of the Separation, Biohaven Ltd.

Collectively, we refer to the Distribution and Spin-Off throughout this Annual Report on Form 10-K ("Annual Report") as the "Separation." As a result of the Separation, Biohaven Ltd.

became an independent, publicly traded company as of October 3, 2022, and commenced regular way trading under the symbol “BHVN”’ on the New York Stock Exchange (the "NYSE") on October 4, 2022.

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Glutamate Modulation Platform

The most advanced product candidate from our glutamate receptor antagonist platform is troriluzole (previously referred to as trigriluzole and BHV-4157), which is currently in two Phase 3 trials in OCD and, for which the Company

submitted a new drug application (“NDA”) in Spinocerebellar Ataxia Type 3 (“SCA3”) to the U.S.

FDA and marketing authorisation application ("MAA") to the European Medicines Agency ("EMA").

application (“NDA”) in Spinocerebellar Ataxia and marketing authorisation application ("MAA") have been accepted and are currently under review by the U.S.

FDA and European Medicines Agency ("EMA"), respectively.

Troriluzole is also being evaluated by the Global Coalition for Adaptive Research ("GCAR") as part of Glioblastoma Adaptive Global Innovative Learning Environment - NCT03970447 ("GBM AGILE"), a revolutionary patient-centered, adaptive platform trial for registration that tests multiple therapies for patients with newly-diagnosed and recurrent glioblastoma ("GBM").

Other product candidates include BHV-5500, which is an antagonist of the glutamate N-methyl-D-aspartate (“NMDA”) receptor and its oral prodrug BHV-5000.

Other product candidates include BHV-5500, an antagonist of the glutamate N-methyl-D-aspartate (“NMDA”) receptor and its oral prodrug BHV-5000.

Glutamate is an important neurotransmitter present in over 90% of all brain synapses.

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The proportion with decreased SARA score was 14 (50%) of 28 patients in the riluzole group versus three (11%) of 27 in the placebo group (OR 8.00, 95% CI 1.95– 32.83;

We acquired troriluzole from ALS Biopharma, LLC (“ALS Biopharma”) and Fox Chase Chemical Diversity Center, Inc.

(“FCCDC”), along with an estate of over 300 prodrugs.

We acquired troriluzole as well as an estate of over 300 prodrugs from ALS Biopharma, LLC (“ALS Biopharma”) and Fox Chase Chemical Diversity Center, Inc.

A prodrug is a compound that, after administration, is metabolized in the body into an active drug.

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SCAs are thought to be pathogenetically related but disease course and brain region involvement are known to vary between the different genotypes.

SCA3, also known as Machado-Joseph disease, is the most common genotype, with a prevalence of up to 6,000 in North America and 4,600 in the European Union (“EU”) and Japan, and accounts for approximately 30% to 50% of SCAs worldwide.

SCA affects approximately 15,000 people in the United States and 24,000 in Europe and the United Kingdom.

SCA3, also known as Machado-Joseph disease, is the most common genotype and accounts for approximately 30% to 50% of SCAs worldwide.

Currently, there are no approved symptomatic or neuroprotective treatments for SCA.

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In this trial, we observed a favorable safety and tolerability profile of troriluzole, with no drug-related serious adverse events (“SAEs”) and low discontinuation rates due to AEs.

During open-label treatment over the open-label extension phase, however, troriluzole did show slowing of disease progression in troriluzole-treated subjects in contrast to the measurable decline expected as compared to a matched cohort of untreated patients from the US natural history study (Clinical Research Consortium for Spinocerebellar Ataxias (“CRC-SCA”)).

natural history study (Clinical Research Consortium for the Study of Cerebellar Ataxia (“CRC-SCA”)).

Based on our learnings from the proof-of-concept Study BHV4157-201, including analyses from the open-label extension phase, we advanced troriluzole into a pivotal Phase 3, randomized, double-blind, placebo-controlled, parallel-group study to assess the safety and efficacy of troriluzole over 48 weeks in subjects with SCA (Study BHV4157-206).

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the scale was designed to limit subjectivity of the scale and focus on functional aspects of the disease so that significant changes would reflect a clinically meaningful change in function.

In May 2022, the Company announced top-line results from the Phase 3 clinical trial evaluating the efficacy and safety of its investigational therapy, troriluzole, in adult patients with SCA.

In May 2022, the Company announced top-line results from the Phase 3 clinical trial (Study BHV4157-206) evaluating the efficacy and safety of its investigational therapy, troriluzole, in adult patients with SCA.

The primary endpoint, change from baseline to week 48 on the f-SARA, did not reach statistical significance in the overall SCA population as there was less than expected disease progression in the placebo arm over the course of the study.

In the overall study population (n = 213), the troriluzole and placebo groups each had mean baseline scores of 4.9 on the f-SARA and the two groups showed minimal change at the 48-week endpoint with f-SARA scores of 5.1 and 5.2, respectively (p=0.76).

Preliminary post hoc analysis of

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This analysis, demonstrating that subjects who were more ambulatory with less severe disease at baseline were more likely to show a benefit from troriluzole, is consistent with the early treatment paradigm for other neurodegenerative diseases.

Two independent natural history cohorts for SCA, one in the US (CRC-SCA) and one in Europe (EUROSCA), have characterized disease progression in this genetically defined neurodegenerative disorder.

Two independent natural history cohorts for SCA, one in the U.S.

(CRC-SCA) and one in Europe (EUROSCA), have characterized disease progression in this genetically defined neurodegenerative disorder.

A Matching Adjusted Indirect Comparison (“MAIC”) was performed to match natural history subjects to subjects in BHV4157-206.

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As seen in the figure below, an additional comparative study was conducted using OLE data from up to 3 years with subjects from BHV4157-201.

Using a matched control pooled from the same two independent natural history studies (US and European), troriluzole-treated All SCA subjects showed clinically relevant benefit compared to expected progression from the external control at 1 year, 2 years, and 3 years.

Using a matched control pooled from the same two independent natural history studies (U.S.

and European), troriluzole-treated All SCA subjects showed clinically relevant benefit compared to expected progression from the external control at 1 year, 2 years, and 3 years.

Of note, there was an administrative gap in treatment in BHV4157-201 between the end of the 48-week OLE and the resumption of treatment at the start of the 96-week period.

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Given these findings and the debilitating nature of SCA, in May 2023 we announced that we submitted a New Drug Application ("NDA") to the FDA for troriluzole for the treatment of SCA3.

In July 2023, the FDA informed us that it would not review the recently submitted NDA application for troriluzole given that the study's primary endpoint was not met and thus, would not permit a substantive review.

In July 2023, the FDA informed us that it would not review the submitted NDA application for troriluzole given that the study's primary endpoint was not met and thus, would not permit a substantive review.

In followup to the regulatory decision on the NDA application, we held followup meetings with the FDA regarding the SCA data.

We continue to have constructive dialogue with the FDA regarding our SCA development program and potential future data analyses to address regulatory concerns in the previously issued refuse-to-file decision on it's NDA application for SCA3.

We will provide further updates on the SCA development program as warranted by any continued positive progress from the outcome of future regulatory interactions

on this topic.

In October 2023, the European Medicines Agency ("EMA") informed us that our Marketing Authorization Application ("MAA") for troriluzole (Dazluma) in the treatment of SCA has been validated and is now under review by EMA's Committee for Medicinal Products for Human Use ("CHMP").

We remain committed to working closely with the health authorities to bring troriluzole to people with SCA3, given no therapy is currently approved for this ultra-rare genetic disorder.

We had constructive dialogue with the FDA regarding our SCA development program and potential future data analyses to address regulatory concerns in the previously issued refuse-to-file decision on the NDA application for SCA3.

In October 2023, the European Medicines Agency ("EMA") informed us that our Marketing Authorization Application ("MAA") for troriluzole (Dazluma) in the treatment of SCA3 was validated and was now under review by EMA's Committee for Medicinal Products for Human Use ("CHMP").

In the fourth quarter of 2024, we completed a clarification meeting with the CHMP Rapporteurs.

The MAA documents were subsequently updated with a broader indication to include all SCA genotypes, in light of the new positive BHV4157-206-RWE study data (discussed below).

In September 2024, we announced positive topline results from pivotal Study BHV4157-206-RWE (NCT06529146) demonstrating the efficacy of troriluzole on the mean change from baseline in the f-SARA after 3 years of treatment.

The study achieved the primary endpoint (see figure below).

Collectively, data across multiple analyses demonstrate a robust and clinically meaningful slowing of disease progression in SCA patients.

These treatment benefits translate into a 50-70% slower rate of decline compared to untreated patients, representing 1.5-2.2 years delay in disease progression over the 3-year study period.

Additionally, in a responder sensitivity analysis, disease progression when defined by a 2 point or greater worsening on the f-SARA at 3 years showed an odds ratio ("OR") of 4.1 (95% CI:

2.1, 8.1) for the untreated external control arm versus troriluzole treated subjects (p < 0.0001;

pooled analysis).

Study BHV4157-206-RWE was designed, in discussion with the FDA, to assess the effectiveness of troriluzole in SCA after 3 years of treatment as measured by the change from baseline in the f-SARA.

The study utilized Phase 3 data and an external control of matched, untreated SCA subjects from the U.S.

CRC-SCA in accordance with FDA's Guidance on Real-World Evidence ("RWE") of effectiveness.

All endpoints were prespecified, and both the study protocol and statistical analysis plan were submitted to, and reviewed by, FDA prior to topline data analysis.

The new analysis doubled the previously available 3 year data with 63 subjects now completing 3 years of treatment with troriluzole and matched to the external control arm.

Propensity Score Matching ("PSM") was used to ensure that untreated patients from the CRC-SCA study were rigorously matched to treated patients from Study BHV4157-206 on baseline characteristics.

The primary objective was to examine the treatment effects of troriluzole for up to 3 years, by comparing data on the f-SARA from patients treated with troriluzole in Study BHV4157-206 to untreated patients from the natural history study.

Troriluzole-treated patients demonstrated statistically significant and sustained benefits at years 1, 2 and 3 on the f-SARA compared to a rigorously matched natural history control.

Additionally, prespecified analyses in the protocol employed a separate, independent natural history control from the European SCA natural history study ("EUROSCA") for global regulatory purposes.

Results using the EUROSCA patients, in addition to a pooled analysis using both CRC-SCA and EUROSCA patients, as the external controls were also statistically significant and consistent with the primary efficacy analysis at all timepoints (see figures below).

of EUROSCA data increased the external control sample size and added to the robustness of the statistically significant treatment differences at years 1, 2, and 3, favoring troriluzole.

Based upon the topline data from Study BHV4157-206-RWE, and previous safety and efficacy data from the troriluzole development program in SCA, we submitted an NDA for the treatment of all SCA genotypes to the FDA in the fourth quarter of 2024.

The troriluzole development program has generated the largest clinical trial dataset in SCA and now has follow-up in some patients treated with troriluzole for over 5 years.

We previously received both Fast-Track and Orphan drug designation ("ODD") from the FDA, and ODD from the European Medicines Agency ("EMA"), for troriluzole in SCA.

An NDA with ODD is eligible for priority FDA review.

In February 2025, the FDA accepted for review our NDA for troriluzole for the treatment of adult patients with SCA and granted priority review.

The FDA's decision regarding the NDA is expected during the third quarter of 2025.

Based on FDA priority review timelines and if ultimately approved, we are prepared to commercialize troriluzole for SCA in the U.S.

Troriluzole for OCD

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In January 2024, we announced plans to conduct a pre-planned interim analysis ("IA") to evaluate efficacy in the first of our two Phase 3 studies in OCD.

The IA is planned to be conducted by an independent Data Monitoring Committee, after 350 subjects have had the opportunity to complete the study (representing approximately 70% of subjects in the primary analysis population reach primary endpoint).

The IA is powered to detect a clinically meaningful difference between troriluzole and placebo on the Y-BOCS primary outcome that is based on the effect size observed in the Phase 2 proof of concept ("POC") study.

The potential results of the IA include (1) a highly statistically significant evidence of efficacy leading to stopping the study or (2) continuation of the study, with possible sample size re-estimation.

Last Patient Last Visit and database lock for the IA are anticipated in the first quarter of 2024, with expected IA topline results in the second quarter of 2024.

The IA was planned to be conducted by an independent Data Monitoring Committee ("DMC") after approximately 70% of subjects in the primary analysis population reached the primary endpoint.

The Data Monitoring Committee convened in the second quarter of 2024 to review the IA and informed the Company that the study may continue.

As such, we continue enrolling patients in the first Phase 3 study in OCD and expect that this study will be fully enrolled in the first quarter of 2025.

We expect to report topline data from the first Phase 3 study in OCD in the first half of 2025.

There was a similarly designed pre-planned IA for the second Phase 3 study in OCD conducted in the fourth quarter of 2024, and the DMC also informed us that this study may continue.

We expect to report topline data from the second Phase 3 study in OCD in the second half of 2025.

Troriluzole for Glioblastoma

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The primary analysis of a regimen's effect on overall survival uses all patients in both its stages and all control patients in the trial in the graduating signature, suitably adjusted for any possible time trends.

Enrollment in the study is ongoing.

The study is ongoing.

Myostatin Platform

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In September 2023, we completed enrollment in a Phase 3 clinical trial assessing the efficacy and safety of taldefgrobep alfa in SMA.

The Phase 3 placebo-controlled, double-blind trial is designed to evaluate the efficacy and safety of taldefgrobep as an adjunctive therapy for participants who are already taking a stable dose of nusinersen or risdiplam or have a history of treatment with onasemnogene abeparvovec-xioi, compared to placebo.

The primary outcome measures of the study will be efficacy of taldefgrobep alfa compared to placebo in the change in the 32 item Motor Function Measure (“MFM-32”) total score from baseline to Week 48.

The Phase 3 placebo-controlled, double-blind trial was designed to evaluate the efficacy and safety of taldefgrobep as an adjunctive therapy for participants who are already taking a stable dose of nusinersen or risdiplam or have a history of treatment with onasemnogene abeparvovec-xioi, compared to placebo.

The primary outcome measure of the study was efficacy of taldefgrobep alfa compared to placebo in the change in the 32 item Motor Function Measure (“MFM-32”) total score from baseline to Week 48.

Scores range from 0-3 on each item, with higher scores indicating higher functioning.

The study is neither restricted nor limited to patients based on ambulatory status or classification of SMA and is designed to randomize approximately 180 patients in this randomized, double-blind, placebo-controlled global trial.

We expect to report topline data from our Phase 3 study in the second half of 2024.

The study was neither restricted nor limited to patients based on ambulatory status or classification of SMA and was designed to randomize approximately 180 patients in this randomized, double-blind, placebo-controlled global trial.

In November 2024, we announced that taldefgrobep alfa showed clinically meaningful improvements in motor function at all timepoints on the MFM-32, but the treatment arm did not statistically separate on the primary outcome at Week 48 compared to the placebo+standard of care ("SOC") group.

Efficacy signals were observed in clinically relevant and biomarker-defined subgroups including those related to age, ambulatory status, background therapy, and baseline myostatin level.

Analyses of prespecified subgroups by race and ethnicity demonstrated that the largest study population (87% Caucasian;

n=180) showed clinically meaningful improvements on the MFM-32 at all timepoints, including Week 48, compared to the corresponding placebo+SOC group (p < 0.05).

Additional analyses of these subjects (n=123) who had measurable baseline myostatin (the pharmacological target of taldefgrobep) showed an improved efficacy signal within this myostatin-positive population (p=0.02).

Prespecified outcome measures in the overall study population analyzing the change from baseline in body composition at Week 48 demonstrated a greater reduction in the percent change in total body fat mass in the taldefgrobep arm compared to the placebo+SOC arm (p=0.008) as measured by dual energy x-ray absorptiometry ("DXA").

The taldefgrobep arm also showed numerically larger increases in lean muscle mass and bone density compared to the placebo+SOC arm.

Biohaven plans to engage the FDA in the first half of 2025 to discuss the potential registrational path forward and will present the study data at an upcoming conference.

The optional long-term extension phase of the trial will remain ongoing pending further data analysis as well as regulatory discussions.

In February 2023, we received Fast Track designation from the FDA for taldefgrobep alfa for the treatment of SMA.

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In December 2022, we received orphan drug designation from the FDA for taldefgrobep in the treatment of SMA and from the European Commission in July 2023.

In April 2024, we announced that the FDA granted "rare pediatric disease" designation for taldefgrobep alfa.

The designation provides for the potential for taldefgrobep to receive a priority review voucher (“PRV”) if ultimately approved for the indication of SMA prior to September 30, 2026.

The rare pediatric disease PRV program began to sunset in December 2024 and will not apply for approvals after September 30, 2026.

Taldefgrobep Alfa’s Role in Spinal Muscular Atrophy

In the past three years, significant advancements were made to address the underlying cause of disease in SMA with the up-regulation of SMN1 and SMN2 expression which positions taldefgrobep as a potential combination therapy to enhance muscle performance.

Data from both an SMA animal model study that shows advantages of combination SMN therapy with taldefgrobep and the extensive clinical data in DMD support the advancement of taldefgrobep into a SMA Phase 3 study.

Other indications in muscle wasting diseases may be a fast follow-on for taldefgrobep along with other life-cycle opportunities.

In the past few years, significant advancements were made to address the underlying cause of disease in SMA with the up-regulation of SMN1 and SMN2 expression which positions taldefgrobep as a potential combination therapy to enhance muscle performance.

Data from an SMA animal model study that shows advantages of combination SMN therapy with taldefgrobep and the extensive clinical data in DMD support the advancement of taldefgrobep into a SMA

Phase 3 study.

Other indications in muscle wasting diseases may be a follow-on for taldefgrobep along with other life-cycle opportunities.

Metabolic Disorders

Obesity is a disease of excess and/or abnormal deposits of adipose tissue and a current global public health crisis.

By 2030, it is expected that nearly one billion people will be living with obesity, including 50% of the adult and 25% of the adolescent US population.

By 2030, it is expected that nearly one billion people will be living with obesity, including 50% of the adult and 25% of the adolescent U.S.

The primary driver of obesity-related morbidity and mortality is metabolically active visceral adipose tissue and associated deposits of adipose tissue in and around organs such as the heart, liver, kidneys, and muscle.

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In a Phase 1 MAD study conducted by BMS in normal healthy volunteers, the cohort using the projected therapeutic 45mg dose of taldefgrobep demonstrated a continued improvement in lean mass and a reduction in fat mass during the 29 day dosing period that continued to increase through the observation period at 4 weeks post dosing (see figure below).

We plan to initiate a Phase 2 clinical trial of taldefgrobep in the management of metabolic disease in the second quarter of 2024.

The study will evaluate the ability of taldefgrobep to maintain lean mass muscle as an adjunctive to standard of care GLP-1 therapy in adults living with overweight and obesity (see figure below for anticipated trial design).

In May 2024, we announced preclinical data from a diet induced obesity mouse model, which showed treatment with taldefgrobep alfa together with a glucagon-like peptide-1 ("GLP-1") agonist produced greater reductions in body weight and fat mass, and a larger increase in lean muscle mass, compared to treatment with GLP-1 alone (see figure below).

We plan to initiate a Phase 2 clinical trial of taldefgrobep in the management of metabolic disease in the first half of 2025.

We are evaluating and have not yet finalized potential clinical trial designs, including size and primary and secondary endpoints.

Ion Channel Platform

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EEG spectral power is a measure derived from quantitative analysis of EEG signals that assesses the amount of rhythmic activity in different frequency bands, including delta [1-3.5 Hz], theta [3.5-7.5 Hz], alpha [7.5-13 Hz], beta [13-30 Hz], and gamma [30-100 Hz].

Changes in spectral power have been used to evaluate the risk, onset and progression of seizures, assess cognitive and behavioral impairments, and characterize the effects of anti-seizure medications ("ASMs");

and, they may also have utility in refining dose selection in clinical trials of ASMs.

Spectral analysis was performed by Epilog (Ghent, Belgium), a global leader in EEG analytics.

Spectral analysis was performed by Clouds of Care (Ghent, Belgium), a global leader in EEG analytics.

Interim data from the Phase 1 EEG study were presented in December 2023 at the American Epilepsy Society meeting in Orlando, Florida.

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The preliminary EEG study results confirm the CNS activity of BHV-7000 at projected therapeutic concentrations, dose-dependent and time-dependent changes in EEG spectral power, and are consistent with the quantitative EEG effects observed with other ASMs approved for the treatment of epilepsy.

Based on the results from the EEG study and the safety profile in SAD/MAD trials, along with PK data from a new once-daily extended-release (“ER”) formulation, Biohaven plans on exploring three oral doses of BHV-7000 (once daily 25 mg ER, once daily 50 mg ER, and once daily 75 mg ER) in the Phase 2/3 clinical trials in epilepsy and mood disorders.

dosing approach with a Kv7 activator will allow for assessment of distinct target concentrations over a wide range, above and below projected efficacious EC50 drug concentrations (Figure 3), not previously feasible with drugs in this class.

Based on the results from the EEG study and the safety profile in SAD/MAD trials, along with PK data from a new once-daily extended-release (“ER”) formulation, Biohaven is exploring three oral doses of BHV-7000 (once daily 25 mg ER, once daily 50 mg ER, and once daily 75 mg ER) in the Phase 2/3 clinical trials in epilepsy and mood disorders.

approach with a Kv7 activator will allow for assessment of distinct target concentrations over a wide range, above and below projected efficacious EC50 drug concentrations (Figure 3), not previously feasible with drugs in this class.

Predicted PK profile of BHV-7000 ER, mean predicted concentration vs.

time profiles for 25 mg ER, 50 mg ER and 75 mg ER once-daily dosing at steady state relative to EC20 and EC50 (EC values from preclinical MES models).

In December 2024, t the American Epilepsy Society meeting, we presented additional safety data with the BHV-7000 once-daily extended-release formulation, which further demonstrated tolerability.

Epilepsy affects approximately 3.5 million Americans, or more than 1.2% of adults and 0.6% of children in the U.S., and more than 50 million patients worldwide, according to the World Health Organization (“WHO”).

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While the use of anti-seizure medications is often accompanied by dose-limiting side effects, our clinical candidate BHV-7000 is specifically designed to target subtypes of Kv7 potassium channels without engagement of GABA A receptors.

The lack of GABA A -R activity potentially gives BHV-7000 a wide therapeutic window and is expected to result in an improved side effect profile, limiting the somnolence and fatigue often seen in patients receiving anti-seizure medications.

This preclinical profile is supported by safety data from our Phase 1 SAD/MAD trial of BHV-7000 in healthy volunteers, which showed a favorable CNS tolerability profile.

The lack of GABA A -R activity potentially gives BHV-7000 a wide therapeutic window which we expect to result in an improved side effect profile, limiting the somnolence and fatigue often seen in patients receiving anti-seizure medications.

We aim to bring this potassium channel modulator as a potential solution to patients with epilepsy who remain uncontrolled on their current regimens.

In January 2024, we completed our End-of-Phase 2 meeting with the FDA to advance to Phase 3 trials and announced that more than 110 global clinical sites have been selected in the first of two focal epilepsy trials, with enrollment commencing in the first quarter of 2024.

The two pivotal studies evaluating the efficacy of BHV-7000 in refractory focal epilepsy are planned as randomized, double-blind, placebo-controlled, 8- and 12-week trials with a primary endpoint of change from baseline in 28-day average seizure frequency in adults and adolescents with focal epilepsy.

One of the focal epilepsy studies will evaluate 25 mg and 50 mg doses of BHV-7000 and the second study will evaluate 50 mg and 75 mg doses of BHV-7000 (see figure below).

In addition to the focal epilepsy program, we anticipate initiating a Phase 2/3 study of BHV-7000 in idiopathic generalized epilepsy ("IGE") in the second quarter of 2024.

Our Clinical Trials for BHV-7000 in Epilepsy

Focal Epilepsy

Enrollment in our Phase 2/3 program commenced in the first quarter of 2024.

One of the focal epilepsy studies will evaluate 25 mg and 50 mg doses of BHV-7000 and the second study will evaluate 50 mg and

75 mg doses of BHV-7000 (see figures below).

We expect to report topline results from the first study in the first half of 2026.

Idiopathic Generalized Epilepsy

In addition to the focal epilepsy program, we initiated a Phase 2/3 study of BHV-7000 in idiopathic generalized epilepsy ("IGE") in the second quarter of 2024.

The pivotal study evaluating the efficacy of BHV-7000 with IGE is planned as a randomized, double-blind, placebo-controlled 24-week time-to-event trial with a primary endpoint of time to second generalized seizure in adults and adolescents with IGE (see figure below).

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are living with neuropsychiatric illnesses that are associated with inadequate treatment, poor quality of life, disability, and considerable direct and indirect costs.

There is significant unmet need for

novel and effective therapeutic options that are not limited by long latency periods to clinical effects, low response rates, and significant risks and side effects.

There is significant unmet need for novel and effective therapeutic options that are not limited by long latency periods to clinical effects, low response rates, and significant risks and side effects.

Increasing evidence from animal models and clinical trials now suggests that Kv7.2/7.3 targeting drugs offer the potential to treat a spectrum of these neuropsychiatric diseases including, but not limited to, mood disorders such as major depressive disorder, bipolar disorder and anxiety.

Major Depressive Disorder

Major depressive disorder is a leading cause of morbidity.

Prevalence estimates for MDD episodes in the U.S.

Major depressive disorder ("MDD") is a leading cause of morbidity.

Approximately 8.3% of adults in the U.S.

have had at least one major depressive episode;

accordingly, there is an urgent need for more effective treatments.

Within the current armamentarium of treatments nearly one third of patients fail to respond.

Kv7 activation has emerged as a novel strategy to treat and prevent depressive episodes and holds significant potential as a novel treatment for patients with MDD.

Kv7 activation has emerged as a novel strategy to treat and prevent depressive episodes and holds significant potential as a novel treatment for patients with

The therapeutic role for Kv7 activation in MDD is supported by a broad range of epigenetic, mechanistic, preclinical, and clinical evidence.

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Together, these data, coupled with the favorable clinical safety and tolerability profile exhibited by BHV 7000 to date, provide a compelling rationale for the evaluation of Kv7 activation with BHV-7000 in MDD.

We plan to initiate a Phase 2 clinical trial with BHV-7000 for the treatment of MDD in the first half of 2024.

We anticipate the study will be a 6 week, randomized, double-blind, placebo-controlled trial in approximately 300 subjects, with a primary endpoint of measurement on the Montgomery-Asberg Depression Rating Scale ("MADRS").

See below for expected trial design detail.

Our Clinical Trial for BHV-7000 in Major Depressive Disorder

We initiated a Phase 2 clinical trial with BHV-7000 for the treatment of MDD in the second quarter of 2024.

The study is a 6 week, randomized, double-blind, placebo-controlled trial in approximately 300 subjects, with a primary endpoint of measurement on the Montgomery-Asberg Depression Rating Scale ("MADRS").

See figure below for trial design.

We expect to report topline results from the study in the second half of 2025.

Bipolar disorder

Bipolar disorder affects approximately 7 to 11 million Americans, with an estimated 4.4% of U.S.

adults having bipolar disorder over their lifetime.

Bipolar disorder affects an estimated 4.4% of U.S.

adults over their lifetime.

Bipolar disorder is associated with significant morbidity, decreased quality of life and economic burden.

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Preclinical and pilot clinical data similarly suggest a potential therapeutic role for Kv7 activation in bipolar disorder, which is expected to result in an improved side effect profile compared to other anti-seizure medications.

We are advancing BHV-7000 as a potential treatment for patients with bipolar disorder and intend to start a Phase 2/3 clinical trial targeting this indication in the first half of 2024.

We expect the study to be a 3 week, randomized, double-

blind, placebo-controlled trial in approximately 256 subjects, with a primary endpoint of measurement on the Young Mania Rating Scale ("YMRS").

See below for expected trial design detail.

Our Clinical Trial for BHV-7000 in Bipolar Disorder

We initiated a Phase 2/3 clinical trial with BHV-7000 for the treatment of bipolar disorder in the second quarter of 2024.

The study was a 3 week, randomized, double-blind, placebo-controlled trial in approximately 256 subjects, with a primary endpoint of measurement on the Young Mania Rating Scale ("YMRS").

See below for trial design detail.

In March 2025, the Company completed a focused topline analysis of treatment with BHV-7000 in the acute treatment of manic episodes associated with bipolar disorder in a 3-week trial.

BHV-7000 did not statistically differentiate from the comparator arm on the primary efficacy endpoint of improvement from Baseline to Day 21 on the YMRS.

Additional analyses are ongoing, and complete study results will be presented at an upcoming scientific meeting.

BHV-7000 75 mg once daily, the highest dose of BHV-7000 being evaluated in Phase 2/3 trials, was safe and well-tolerated in this study.

No adverse trends in vital signs, ECGs, or labs were noted.

There were no treatment emergent serious adverse events.

Most adverse events were mostly mild in intensity and resolved spontaneously.

This offers a highly favorable and differentiated profile compared to other antiseizure medicines and is consistent with lack of GABA effects.

Developmental Epileptic Encephalopathies

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In the United States, over 30 million adults are estimated to be living with neuropathic pain.

Pharmacological treatments for neuropathic pain vary according to patient needs, although recommendations such as the WHO analgesic ladder, United States Centers for Disease Control (“CDC”), and FDA guidelines are in use.

Initial or first line treatment for neuropathic pain includes non-opioid analgesics, in particular, antidepressants, anticonvulsants, steroids, and anxiolytics.

Second line treatment of persistent, severe pain may require escalation to opiates, often less potent ones at first, followed by more potent opiates for intense refractory pain.

Thus, an urgent need exists for effective, non-addictive pain therapies.

Second line treatment of persistent,

severe pain may require escalation to opiates, often less potent ones at first, followed by more potent opiates for intense refractory pain.

Accordingly, an urgent need exists for effective, non-addictive pain therapies.

Flupirtine, a non-selective Kv7 activator, was previously approved in several European countries and indicated for the treatment of pain.

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We are currently evaluating the activity of various compounds from our proprietary series of selective Kv7.2/7.3 activators in multiple preclinical models of neuropathic pain.

The Company recently initiated a sponsored research agreement with Yale to evaluate the activity of BHV-7000 in an iPSC model of inherited erythromelalgia, a severe rare genetic neuropathy.

The Company has also initiated a sponsored research agreement with Yale to evaluate the activity of BHV-7000 in an iPSC model of inherited erythromelalgia, a severe rare genetic neuropathy.

We are currently exploring BHV-7000 as a potential treatment for migraine.

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Under the KU Leuven Agreement, we receive exclusive global rights to develop, manufacture and commercialize KU Leuven's portfolio of small-molecule TRPM3 antagonists.

The portfolio includes the lead candidate, BHV-2100, which we are evaluating in several preclinical pain models and advancing towards the clinic in 2023.

The portfolio includes the lead candidate, BHV-2100.

We are continuing to support further basic and translational research on the role of TRPM3 in pain and other disorders through our collaboration with professors in Transient Receptor Potential ("TRP") biology at KU Leuven.

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Initially, there was much excitement and investment in TRPV1 antagonists due to promising preclinical efficacy and some evidence of clinical pain reduction.

However, trials of most TRPV1 antagonists were terminated after the class consistently caused clinically-significant hyperthermia in study participants.

However, trials of most TRPV1 antagonists were terminated after the class consistently caused clinically-significant

hyperthermia in study participants.

Several companies then made efforts to progress antagonists of TRPA1, the receptor for mustard oil.

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Additionally, people with TRPM3 gain-of-function mutations experience altered pain sensation (de Sainte Agathe 2020, Dyment 2019, Van Hoeymissen 2020).

Knocking out or antagonizing TRPM3 in animal models attenuates the development of various pain states, including those associated with nerve injury, chemotherapy, and diabetic peripheral neuropathy, further indicating that TRPM3 is a promising target

for neuropathic pain.

Lastly, preclinical evidence suggests that antagonizing TRPM3 may avoid the on-target body temperature effects and TRPV1 antagonist-induced malignant hyperthermia.

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Our Phase 1 Study with BHV-2100

We have an ongoing Phase 1 study of BHV-2100 in Canada.

The Phase 1 study is a randomized, double-blind, placebo-controlled, SAD/MAD study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of BHV-2100.

Single ascending dose cohorts are ongoing (including subjects randomized to placebo) with ascending dose levels.

Each dose cohort will be initiated with sentinel dosing.

Dose levels for subsequent cohorts are determined based on available PK, PD, safety and tolerability from previous cohort(s).

Up to approximately 88 subjects are planned to be evaluated.

Our Development of BHV-2100 for the Treatment of Migraines

We completed a Phase 1 study of BHV-2100 in Canada.

The Phase 1 study was a randomized, double-blind, placebo-controlled, SAD/MAD study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of BHV-2100.

In May 2024, we reported positive pharmacokinetic and safety data from the completed Phase 1 study with BHV-2100.

The results demonstrated rapid absorption with therapeutic concentrations achieved by 20 minutes.

The favorable tolerability profile at single doses up to 500 mg exceeds the anticipated therapeutic dose and is well above the EC90 concentration.

Based on these findings, we initiated a Phase 2 study of BHV-2100 in the acute treatment of migraine and a proof-of-concept study in pain in the fourth quarter of 2024.

Our Clinical Trial for BHV-2100 in Migraine

Nearly 40 million people in the U.S.

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There is a significant unmet need for new treatments as more than 90 percent of migraine sufferers are unable to work or function normally during an attack.

We expect to initiate a BHV-2100 Phase 2 study in acute migraine in the second half of 2024.

We are evaluating and have not yet finalized clinical trial design, including trial size, and primary and secondary endpoints for the anticipated clinical trial.

In September 2024, we announced that we have initiated a Phase 2 study evaluating BH-2100 in the acute treatment of migraine.

The study is a 45-day, randomized, double-blind, placebo-controlled trial in approximately 575 subjects, with primary endpoints of freedom from pain at two hours post-dose and freedom from most bothersome symptom at two hours post-dose.

See figure below for trial design.

Data from the proof-of-concept migraine study are expected in the first half of 2025.

Our Development of BHV-2100 for the Treatment of Neuropathic Pain

BHV-2100 is also being developed as a potential non-opioid treatment for neuropathic pain.

We are evaluating the ability of BHV-2100 to reduce pain behaviors across several preclinical models of neuropathic pain, including chemotherapy induced neuropathy, diabetic neuropathy, and nerve injury.The Company expects to conduct a proof of concept study for neuropathic pain in the second half of 2024.

We are evaluating the ability of BHV-2100 to reduce pain behaviors across several preclinical models of neuropathic pain, including chemotherapy induced neuropathy, diabetic neuropathy, and nerve injury.We initiated a conduct a proof-of-concept study for neuropathic pain in the fourth quarter of 2024.

The study is a Phase-1b, randomized, double-blind, placebo and active reference controlled, crossover trial to assess the anti-nociceptive and anti-hyperalgesic effects of single oral doses of BHV-2100 (25 mg, 75 mg, and 150 mg) vs.

placebo, in a cohort of approximately 24 healthy male volunteer participants, utilizing a laser-evoked potential experimental pain paradigm.

Preliminary data from the laser-evoked hyperalgesia study demonstrated that BHV-2100 reduced laser heat-induced pain and brain evoked potentials in healthy volunteers.

Preliminary data demonstrated that BHV-2100 reduced laser heat-induced pain and brain evoked potentials in healthy volunteers.

Complete data from the laser-evoked potential study are expected in the first half of 2025.

Additional research on TRPM3-mediated disorders

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There are currently no brain penetrant, selective, dual TYK2/JAK1 inhibitors approved for brain disorders.

Target indications for BHV-8000 include Parkinson's disease, Alzheimer's disease, prevention of amyloid-related imaging abnormalities ("ARIA"), and multiple sclerosis ("MS").

Biohaven completed interactions with FDA enabling registrational programs for Parkinson's disease and the prevention of ARIA.

Our Phase 1 Study with BHV-8000

In May 2023, we began dosing with BHV-8000 (previously TLL-041), in a phase 1 study in normal healthy volunteers.

The planned phase 1 study is a randomized, double-blind, placebo-controlled, sequential parallel group, single ascending dose / multiple ascending dose study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of BHV-8000 following oral administration.

In this study, single ascending dose cohorts are planned and ongoing (including subjects randomized to placebo) with up to 6 dose levels.

Each dose cohort will be initiated with sentinel dosing, e.g., one active and placebo patient will be dosed simultaneously.

Doses for subsequent cohorts are determined based on available PK, PD, safety and tolerability from previous cohort(s).

Up to 40 subjects are planned to be evaluated with approximately 30 subjects randomized to receive active drug and approximately 10 subjects randomized to receive placebo in a double-blind fashion.

In July 2023, we reported that we had successfully dosed three dose cohorts with single ascending doses of BHV-8000 in the ongoing Phase 1 study.

Based on the preliminary data that are available, BHV-8000 achieved projected therapeutic concentrations and was well tolerated with only mild adverse events reported.

We anticipate beginning clinical trials with BHV-8000 in the second half of 2024 targeting neuroinflammatory conditions, potentially including Parkinson's disease, Amyloid-Related Imaging Abnormalities ("ARIA") in Alzheimer’s disease, Alzheimer's disease, and multiple sclerosis.

We are evaluating and have not yet finalized clinical trial designs, including trial size, and primary and secondary endpoints for these anticipated clinical trials.

MoDE Degraders

Bispecific Molecular Degraders of Extracellular Proteins

Molecular Degraders of Extracellular Proteins (“MoDEs”) are bispecific molecules that target pathologic circulating proteins and direct them to the liver (or other organ systems) for degradation by the endosomal/lysosomal pathway.

Our MoDE platform is being explored for use in a wide range of therapeutic areas, including indications in immune-mediated diseases, cancer and other diseases.

We are planning for MoDEs to be administered as intravenous or subcutaneous formulations.

We expect to initiate a total of 4 INDs for the degrader program in 2024.

Antibody-based Galactose-deficient IgA (“Gd-IgA”) MoDEs

IgA nephropathy (“IgAN”) is the most common primary glomerulonephritis that can progress to renal failure and is characterized by immunoglobulin deposits in the renal mesangium comprised exclusively of the IgA1 subclass.

Patients with IgAN have increased serum levels of IgA1 with a hinge region containing truncated galactose-deficient O-linked saccharides (“Gd-IgA”) and can present with a range of symptoms, from hematuria or proteinuria to severe hypertension owing to renal damage.

The clinical progression varies, with 30–40% of patients reaching end-stage renal disease 20–30 years after the first clinical presentation.

Patients are managed by therapeutic immunosuppression, with the aim of controlling blood pressure and maintaining renal function.

Lai, Nat Rev Dis Primers (2016)

We are leveraging our MoDE platform to develop novel bispecific molecules for the treatment of IgA nephropathy (“IgAN”) that remove potentially disease-causing Gd-IgA and associated immune complexes in patients and thereby prevent harmful kidney deposits.

We have taken a published rodent format IgG antibody that recognizes Gd-IgA and converted it into a partially-humanized antibody, then subsequently completed the molecule liver-targeted degrader MoDE.

This compound potently binds Gd-IgA and causes its endocytosis in human liver cells through its ASGPR binding motif.

Nonclinical development work is ongoing to progress this as a potential IgAN treatment.

BHV-1400 is a MoDE which is being developed to target Gd-IgA for the treatment of IgA Nephropathy.

Specific removal of pathogenic Gd-IgA and associated circulating immune complexes with preservation of normal IgA potentially permits disease remission without incurring an infection risk.

We shared preliminary data demonstrating the chimeric antibody-ASGPR ligand conjugate specifically mediated endocytosis of Gd-IgA, as opposed to normal IgA, in an endocytosis assay with HepG2 cells, and that MoDE degraders successfully internalize and degrade these immune-complexes.

We expect to initiate Phase 1 studies of BHV-1400 in the second half of 2024.

In May 2024, we reported positive results from the Phase 1 single and multiple ascending dose study, including evidence of target engagement along with a safe and well tolerated profile.

Phase 1 study data also confirmed cerebrospinal fluid ("CSF") exposures of BHV-8000.

We expect to initiate a pivotal trial in Parkinson's in the first half of 2025 and advance Alzheimer's, MS and ARIA programs in 2025.

We are evaluating and have not yet finalized potential clinical trial designs, including size and primary and secondary endpoints.

Therapeutic pan-IgG depletion

Analogous to the depletion of pan-IgA or dg-IgA with molecular degraders, hepatic asialoglycoprotein receptor ("ASGPR") ligand degraders are able to recognize potentially pathogenic isoforms of immunoglobulin ("IgG") and represent a novel, competitive platform with differentiated and improved profile relative to FcRN inhibitors.

These molecules are specifically designed to spare the IgG3 subclass, to promote better host defense.

FcRN inhibitors such as efgartigimod (Vyvgart) and nipocalimab also deplete IgG, but are not selective and deplete all IgG subclasses.

Specifically, high circulating levels of antibodies (monoclonal or polyclonal gammopathy) drive conditions such as myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, pemphigus vulgaris and many other diseases.

It is hypothesized that rapid and sustained lowering of pathogenic antibody titers in blood will significantly reduce disease symptoms.

As this has been shown with FcRN inhibitors for myasthenia gravis (Vyvgart), therapeutic pan-IgG depletion using Biohaven’s proprietary MoDE platform technology is expected to have significant potential benefit for multiple diseases including but not limited to the conditions outlined above.

Drug candidates utilizing this technology are in nonclinical development, approaching IND.

BHV-1300 is an IgG1, IgG2 and IgG4 bispecific degrader which we are initially developing for the treatment of rheumatoid arthritis ("RA").

MoDE and TRAP Degraders

Molecular Degraders of Extracellular Proteins

The Molecular Degraders of Extracellular Proteins (“MoDEs”) platform harnesses selectivity, rapidity, and patient-friendly self-administration to remove disease-causing proteins from the body to potentially treat a range of diseases.

Each MoDE degrader is a novel bispecific molecule that targets a specific form of circulating protein and directs it to the liver for degradation by the endosomal/lysosomal pathway.

Four INDs have been accepted by the FDA for MoDE degrader molecules in 2024 and multiple other investigational agents are in development.

Three assets have been dosed in Phase 1 trials, with the fourth anticipated to be dosed in the first half of 2025.

The first-of-its-kind molecule, BHV-1300 has demonstrated deep lowering of IgG1, 2 and 4 in Phase 1 clinical trials and is being developed as a proprietary subcutaneous formulation in conjunction with an autoinjector for easy-to-use self-administration.

BHV-1400 and BHV-1600, currently in Phase 1 clinical trials, Biohaven's first Targeted Removal of Aberrant Protein ("TRAP"™) molecules, represent next generation MoDEs targeting very specific pathogenic antibodies, while sparing healthy immunoglobulin to preserve immune function.

Data from the first, and lowest, dose cohort of BHV-1400 demonstrated clear differentiation from competitors in the IgA nephropathy space, with rapid lowering of Gd-IgA1 within hours and preservation of host immunoglobulins including IgG, IgA, IgE, and IgM.

Multiple new and novel investigational MoDE and

TRAP molecules are in development for potential treatment of diseases, such as membranous nephropathy, Graves' disease, diabetes, and IgG4-mediated diseases.

The first-of-its-kind molecule BHV-1300 has demonstrated deep lowering of IgG1, 2 and 4 in Phase 1 clinical trials and is being developed as a proprietary subcutaneous formulation in conjunction with an autoinjector for easy-to-use self-administration.

BHV-1300 was rationally designed to spare IgG3, potentially allowing for preservation host defense.

BHV-1300 is being developed for the treatment of common immune mediated-diseases, such as Graves' Disease and Rheumatoid Arthritis ("RA").

Graves' Disease is a disease in which IgG1 autoantibodies stimulate the thyroid to produce excess thyroid hormone.

Targeted removal of disease-causing IgG has the potential to eliminate the pathogenic thyroid-stimulating antibody and modify the disease.

Graves' Disease is estimated to impact 1% of the population globally.

RA is a chronic autoimmune disease estimated to affect 1 to 2% of the global population.

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The length of significant exposure to BHV-1300 is approximately one day within the dosage interval compared to continuous exposure required of the FcRn inhibitors.

Mechanism related liabilities of FcRn inhibitors seen in animals and man, including

hypoalbuminemia and hypercholeresterolema, are not expected and do not occur with BHV-1300 in cynomolgus.

Mechanism-related liabilities of FcRn inhibitors seen in animals and humans, including

hypoalbuminemia and hypercholeresterolemia, are not expected and do not occur with BHV-1300 in cynomolgus.

See figures below comparing the speed and depth of lowering to FcRn inhibitors.

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* Adapted from BLA 761154, IND 116471, Study no.

The Phase 1 SAD study examining BHV-1300 in healthy subjects was initiated in the first quarter of 2024 and we expect preliminary results late in the first quarter or early in the second quarter of 2024.

The FDA indicated that the MAD assessment of BHV-1300 should be performed in a relevant patient population.

Upon completion of the SAD study, we are planning the MAD portion of the study in a relevant patient population with the possibility of benefit from BHV-1300.

The Phase 1 study is a randomized, open-label, placebo-controlled, SAD study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of BHV-1300.

Each dose cohort will be initiated with sentinel dosing.

Dose levels for subsequent cohorts will be determined based on available PK, PD, safety and tolerability from previous cohort(s).

Up to approximately 32 subjects are planned to be evaluated.

Phase 2 studies of BHV-1300 are anticipated to initiate in 2024.

We are evaluating and have not yet finalized potential clinical trial designs, including size and primary and secondary endpoints.

BHV-1310 is a next generation bispecific IgG degrader with the same specificity as BHV-1300 for IgG1, IgG2 and IgG4 which is initially being developed for the treatment of generalized myasthenia gravis ("gMG") and potentially other acute conditions or conditions with acute exacerbations or flares.

MG is a chronic autoimmune disorder of the musculoskeletal system that is estimated to affect approximately 36,000 to 60,000 people in the United States.

Our Phase 1 Study with BHV-1300

The Phase 1 SAD study examining BHV-1300 in healthy subjects was initiated in the first quarter of 2024 and remains ongoing.

In May 2024, we reported preliminary results from our Phase 1 study of BHV-1300.

These results in healthy subjects demonstrated that BHV-1300 rapidly and selectively lowers IgG in a dose-dependent manner in the first 4 cohorts completed to date (see figure below).

Preliminary IgG lowering data is consistent with modeling, with dose- and time-dependent IgG lowering observed even in initial low-dose cohorts.

Some subjects experienced IgG reductions as low as 50 to 70% of baseline.

BHV-1300 demonstrated reduction of IgG without significantly impacting LFTs, albumin, LDL cholesterol or other serum labs.

BHV-1300 has been safe and well tolerated to date, with no serious or severe adverse events.

Most AEs were mild, deemed unrelated to study drug and resolved spontaneously.

As expected from the selectivity of the molecule for IgG, when compared to placebo, there were no meaningful reductions in average IgA, IgM or IgE levels during the week after dosing.

No adverse trends have been observed in vital signs or ECGs.

Modeling suggests additional

cohorts in the Phase 1 study will achieve greater than 70% lowering of IgG utilizing doses compatible with subcutaneous administration.

The Phase 1 study has also compared intravenous and subcutaneous administration of BHV-1300.

Subcutaneous administration of BHV-1300 demonstrated an average of approximately 44% higher than expected exposure compared to the dose-equivalent intravenous formulation without injection site reactions.

This new human data confirms the feasibility of our plan for convenient dosing of BHV-1300 with a patient self-administered subcutaneous autoinjector.

In the fourth quarter of 2024 we provided an update to our Phase 1 study of BHV-1300, reporting that subcutaneously administered BHV-1300 achieved deep lowering of targeted IgG (IgG1, IgG2, IgG4, over IgG3), with reductions over 60% in the lowest subcutaneous dose tested in the ongoing MAD study.

Subcutaneous BHV-1300 achieved progressive reduction in IgG within hours of each weekly dose administration in the MAD, and pharmacodynamic effects were sustained relative to baseline over the four-week study period.

BHV-1300 has been safe and well-tolerated across the Phase 1 study.

There were no clinically significant effects on albumin or liver function, and no increases in cholesterol were noted.

Further enhancing the competitive safety profile and as intentionally designed, plasma IgG3 levels were preserved through the end of study week 4 to allow for healthy immune effector functioning.

All AEs were mild, any drug-related AE resolved, and there were no discontinuations due to study drug related AEs.

The optimized subcutaneous formulation in the MAD also showed substantially less inter-patient variability compared to previously reported intravenous BHV-1300.

In addition, we announced that we entered into an agreement with Ypsomed to develop and manufacture BHV-1300 in an easy-to-use, autoinjector for self-administration intended for commercialization.

In March 2025, we provided further updates to our ongoing Phase 1 study of BHV-1300.

In the four-week Phase 1 study, subcutaneously administered BHV-1300 at a dose of 1000 mg weekly achieved rapid, deep and sustained reductions

in total IgG of up to 84%, with a median reduction of 80% (see Figure 1 below).

Reductions occurred within hours of each dose, were progressive, and were sustained compared to baseline over the four-week period.

BHV-1300 was safe and well-tolerated in subcutaneous doses up to 2000 mg with no clinically significant increases in ALT, AST, or bilirubin, no clinically significant reductions in albumin, and no clinically significant increases in cholesterol over the four-week dosing period compared to placebo.

There were no clinically significant reductions in IgG3, IgA, IgE, or IgM compared to baseline.

Most AEs were mild and self-resolving, there were no discontinuations due to AEs related to study drug, and there were no serious or severe AEs.

The Phase 1 study is ongoing with plans to continue to escalate multiple doses to explore deeper reductions to characterize the potential range of IgG lowering possible with MoDE technology, allowing for customization of speed and depth of IgG lowering and decreased frequency of administration across different disease indications.

We plan to initiate a Phase 2 study of BHV-1300 in Graves’ disease in mid-2025.

Additional follow-on studies in other autoimmune diseases will be pursued.

BHV-1310 is a next generation bispecific IgG degrader with specificity for IgG1, IgG2 and IgG4, which is initially being developed for the treatment of rare disorders including conditions like generalized myasthenia gravis ("gMG") and potentially other acute or chronic conditions, or chronic conditions with acute exacerbations or flares.

MG is a neuromuscular disorder that is estimated to affect approximately 36,000 to 60,000 people in the United States.

Patients with gMG develop antibodies that attack critical signaling receptor proteins at the junction between nerve and muscle cells, inhibiting communication between nerves and muscle and resulting in weakness of the skeletal muscles.

GMG affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat and limbs.

In January 2024, we demonstrated optimization of degrader technology with BHV-1310 which allows for deeper reductions in IgG after single dose (see figure below).

The deep and rapid reductions observed suggest that BHV-1310 could have potential application in acute settings.

We expect to initiate Phase 1 studies of BHV-1310 in the second half of 2024.

We are evaluating and have not yet finalized potential clinical trial designs, including size and primary and secondary endpoints.

BHV-1600 is a selective MoDE designed to remove circulating agonistic antibodies of all isotypes and subclasses directed against myocardial beta-1 adrenergic receptor ("β-1 AR") through hepatic ASGPR binding and hepatocellular degradation.

This molecule was created using a peptide that mimics the antigenic epitope common to most patients with autoantibodies directed to β-1 AR.

This peptide is sufficiently similar to the native sequence such that circulating antibodies are efficiently trapped and subsequently removed by hepatic endocytosis through the ASGPR receptor.

As these agonistic antibodies will be markedly depleted, the rapid cessation of inappropriate agonism of the myocardial β-1 AR receptors should result in rapid reversal of symptoms, as precedented with plasmapheresis.

We are developing BHV-1600 for the treatment of dilated cardiomyopathy.

Dilated cardiomyopathy is a condition where the cardiac muscle contracts less effectively, the chambers of the heart are enlarged and thinning of cardiac walls results.

This can lead to cardiac valvular incompetency, arrhythmias, thrombosis, and heart failure.

We expect to initiate Phase 1 studies of BHV-1600 in the second half of 2024.

We are evaluating and have not yet finalized potential clinical trial designs, including size and primary and secondary endpoints.

BHV-1310 is completing preclinical testing prior to initiation of a Phase 1 study in the first half 2025.

BHV-1400 is the first TRAP degrader introduced by Biohaven, a selective MoDE which is being developed to target Gd-IgA1, an aberrant immunoglobulin that drives IgA Nephropathy (see figure below).

Specific removal of pathogenic Gd-IgA1 and associated circulating immune complexes with preservation of normal IgA potentially permits disease remission without incurring an infection risk.

We shared preliminary data demonstrating the chimeric antibody-ASGPR ligand conjugate specifically mediated endocytosis of Gd-IgA1, as opposed to normal IgA1 and IgA2, in an endocytosis assay with ASGPR-expressing cell lines, and that TRAP degraders successfully internalize and degrade these immune-complexes.

In mice, after deposition of Gd-IgA1 in the glomerular mesangial matrix followed by administration of BHV-1400, Gd-IgA1 is progressively removed and no longer detected by six hours.

Our Phase 1 Study with BHV-1400

We initiated Phase 1 studies of BHV-1400 in the fourth quarter of 2024.

The first-in-human ("FIH") trial is a randomized, open-label, placebo-controlled, single and multiple ascending dose study to evaluate the safety, tolerability, PK, and PD of BHV-1400 in healthy volunteers.

In the first quarter of 2025, Biohaven announced deep and selective lowering of Gd-IgA1 with the first dose cohort tested in the SAD.

Subjects achieved median Gd-IgA1 lowering of 60% within 4 hours of dose administration without clinically significant lowering of healthy immunoglobulins IgA, IgE, IgM, or IgG (see figure below).

As a next generation TRAP degrader, BHV-1400 is a potential therapeutic for the treatment of IgA nephropathy, and highlights the precision of MoDE platform molecules in their ability to selectively remove a pathogenic disease-causing protein without suppressing the healthy immune system.

BHV-1600 is a selective TRAP designed to remove agonistic antibodies directed against myocardial beta-1 adrenergic receptor ("β-1 AR").

β-1 AR autoantibodies have been identified in serum individuals with dilated cardiomyopathies, such as peripartum cardiomyopathy, and have been shown to cause chronic stimulation and dilation of the myocardium.

Peripartum cardiomyopathy is a life-threatening condition affecting mothers within the months following delivery of a child.

Through elimination of the agonistic β-1 AR autoantibodies, BHV-1600 is designed to potentially treat the underlying autoimmune etiology of this disease with no approved therapy, and prevent irreversible cardiac pump dysfunction.

We initiated Phase 1 studies of BHV-1600 in the fourth quarter of 2024.

The FIH trial is a randomized, open-label, placebo-controlled, single and multiple ascending dose study to evaluate the safety, tolerability, PK, and PD of BHV-1600.

Early results from the first two dose cohorts indicate that BHV-1600 was safe and well tolerated, with no SAEs, and without clinically relevant changes in innate or adaptive immunity, including white blood cells and immunoglobulins IgG, IgA, IgE, and IgM.

There were no clinically significant reductions in albumin, liver function test abnormalities, or increases in cholesterol compared to baseline.

Additional Degraders

We are currently developing additional MoDE degraders advancing towards candidate nomination.

These include an IgG4 specific degrader, a phospholipase A2 receptor ("PLA2R") autoantibody degrader for membranous nephropathy, a pro-insulin autoantibody degrader for type 1 diabetes, and a Thyroid Stimulating Hormone ("TSH") receptor autoantibody degrader as a selective follow-on asset for Graves' Disease.

Oncology Platform

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Antibody Recruiting Molecules (“ARMs”) are bispecific molecules that recruit endogenous antibodies to target cancer, virally infected cells, and disease-causing microorganisms for immune-mediated clearance.

These molecules are

engineered as modular components that are readily interchangeable, giving the platform tremendous flexibility for a variety of indications and therapy areas.

These molecules are engineered as modular components that are readily interchangeable, giving the platform tremendous flexibility for a variety of indications and therapy areas.

By recruiting antibodies to coat the disease cell target, ARMs mark it for removal by the body’s innate antibody-mediated immune mechanisms (antibody dependent cellular cytotoxicity and antibody dependent cellular phagocytosis).

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ARM™ NK Combination Therapy

ARMs provide target specificity to Natural Killer (“NK”) cell therapies without needing to design chimeric antigen receptors (“CARs”) or other methods of genetic manipulation.

NK cells are a type of immune effector cell that can recognize and destroy non-self targets and certain diseased cells.

NK cells do not target specific protein epitopes like T cells of the adaptive immune system.

Our ARMs are being used to provide antigen target specificity to NK cell therapies (both allogeneic and autologous) with the goal of enhancing efficacy and safety.

ARM NK combination therapy directs NK cells to a disease target of interest.

Our Clinical Trial for BHV-1100 in Newly Diagnosed Multiple Myeloma Patients

We have initiated dosing in a Phase 1a/1b trial in recovering, post-myeloablative multiple myeloma patients.

Our ARM, BHV-1100, in combination with autologous cytokine induced memory-like (“CIML”) NK cells and immune globulin (“Ig”), is expected to target and kill multiple myeloma cells expressing the cell surface protein CD38.

The trial is supported by compelling preclinical data showing that BHV-1100 enhanced recruitment of autologous CIML NK cells increases killing of multiple myeloma cells.

This open-label single center Phase 1a/1b study assesses the safety and tolerability as well as exploratory efficacy endpoints in newly diagnosed multiple myeloma patients who have tested positive for minimal residual disease (“MRD+”) in first remission prior to autologous stem cell transplant (“ASCT”).

We expect to enroll 30 newly diagnosed multiple myeloma patients.

The primary outcome measures are dose limiting toxicities following combination product administration (time frame:

100 days post-combination product administration) and incidence and severity of side effects related to the combination product (time frame:

90 to 100 days post-combination product administration).

BHV-1100 Binds CD38 and lg to Create a Targeting Therapy to Kill Multiple Myeloma Cells

BHV-1100 Enhances Recruitment of NK Cells and Increases Killing of Multiple Myeloma Cells

The BHV-1100 program is a CD-38 targeting NK ARM engager intended for use as a combination therapy in the treatment of multiple myeloma.

Due to strategic re-prioritization within both our oncology-specific and non-oncology programs, and multiple changes in the treatment landscape for multiple myeloma since the inception of the open-label single center Phase 1a/b trial of BHV-1100 and such changes negatively impacting trial enrollment, the multiple myeloma trial is planned to end shortly.

Alternative trial designs in multiple myeloma and additional indications for our ARM(TM) platform are being considered for possible development.

Antibody Drug Conjugates

We are using the MATE conjugation technology to generate site-specific antibody drug conjugates (“ADC”s) from native IgG1 proteins and have shown show superior stability in comparison with those using current industry-standard cysteine maleimide and click conjugation methodologies.

Our expectation is that the enhanced in vivo stability and expected superior physicochemical properties of these ADCs will lead to increased therapeutic indices in patients (more cytotoxic payload reaching cancer cells and less reaching normal tissues, as has been shown in vitro, in mice and cynomolgus).

Several site-specific ADCs, including BHV-1500, using the well validated valine-citrulline monomethyl auristatin E ("vcMMAE") payload linker system have been prepared and are undergoing biological testing in comparison with industry standard maleimide conjugated ADCs.

We are using next-generation ADC conjugation technologies, including our MATE® platform, to generate site-specific antibody drug conjugates (“ADC”s) which have shown show superior preclinical stability in comparison with those using current industry-standard methodologies.

Our expectation is that the enhanced in vivo stability and expected superior physicochemical properties of these ADCs will lead to increased therapeutic indices in patients (more cytotoxic payload reaching cancer cells and less free payload that can lead to off-target toxicities in normal tissues), consistent with early in vitro and in vivo (rodent and cynomolgus monkey) studies.

In January 2024, we acquired BHV-1510 through our acquisition of Pyramid Biosciences, Inc.

BHV-1510 is a next-generation Trophoblast Cell Surface Antigen 2 ("TROP-2") directed ADC employing an optimized next-generation construct with novel linker-payload and enzymatic, site-specific conjugation, targeting TROP2-expressing carcinomas.

Carcinoma refers to a malignant neoplasm of epithelial origin.

BHV-1510 is a next-generation Trophoblast Cell Surface Antigen 2 ("TROP-2") directed ADC.

BHV-1510 utilizes a next-generation, highly stable site-specific conjugation, resulting in a favorable preclinical PK, toxicity and manufacturability profile.

The ADC targets TROP2-expressing carcinomas, which are malignant neoplasms of epithelial origin.

Carcinomas account for 80 to 90 percent of all cancer cases and several examples have been successfully treated with ADCs.

Abundant TROP-2 expression has been described for many carcinoma subtypes.

In preclinical TROP-2 expressing tumor models, BHV-1510 has shown improved antitumor activity versus other TROP-2 directed ADCs, in addition to improved plasma stability, more potent in vitro cytotoxicity, superior bystander effect, and greater immunogenic cell death with the novel TopoIx payload.

Improved and differentiated safety has been seen in cynomolgus monkey GLP toxicology studies, suggesting a wife therapeutic index.

BHV-1510 has similar favorable characteristics to our proprietary MATE conjugation technology, which should allow highly stable site-specific conjugation, resulting in a favorable PK, toxicity and manufacturability profile.

Preclinically, BHV-1510 has shown high plasma stability, enhanced cellular cytotoxicity, bystander killing, and immunogenic cell death with a novel topoisomerase 1 inhibitor ("TopoIx") payload, resulting in improved efficacy as monotherapy, and synergistic efficacy in combination with anti-programmed cell death protein-1 ("anti-PD1") immune checkpoint inhibitor therapy.

In IND-enabling GLP toxicology studies in cynomolgus monkeys, BHV-1510 showed a differentiated safety profile that suggests a wider therapeutic margin relative to more advanced TROP-2 ADCs, including a lack of lung toxicity, that may translate to an improved clinical efficacy and safety profile.

Our Phase 1/2 Study with BHV-1510

The IND for BHV-1510 was approved by the FDA in January 2024.

The First-in Human trial evaluating BHV-1510 in patients with advanced solid tumors is expected to start in the second quarter of 2024.

The First-in Human, Phase 1/2 trial evaluating BHV-1510 in patients with advanced solid tumors commenced in the second quarter of 2024.

This trial consists of two parts;

Phase 1 dose escalation and Phase 2 dose expansion, in patients with advanced incurable cancer that have progressed on or are intolerant to standard therapy.

The primary objective of Phase 1 is safety, to identify a recommended dose for expansion ("RDE") or maximum tolerated dose.

The trial will also evaluate BHV-1510 in combination with the anti-PD1 monoclonal antibody Libtayo® (cemiplimab-rwlc).

In May 2024, we announced that we entered into a clinical supply agreement with Regeneron Pharmaceuticals, Inc.

("Regeneron") under which we will sponsor and fund the planned combination Phase 1/2 clinical trial, and Regeneron will provide Libtayo®.

The primary objective of Phase 1 is to characterize the safety profile of BHV-1510 as monotherapy and in combinations with cemiplimab, and to identify a recommended dose for expansion ("RDE") or maximum tolerated dose.

Phase 1 dose escalation will be implemented based on a Bayesian optimal interval design, with the lowest dose initiated as a single patient cohort.

Patients are expected to be dosed in escalating cohorts, with dosing regimens administered intravenously every three weeks.

Patients are expected to be dosed in escalating cohorts, with dosing regimens administered intravenously every two or three weeks.

The Phase 2 dose expansion part of the study will consist of non-randomized efficacy finding expansion cohorts, defined by specific tumor types that will be treated at the RDE to estimate the anti-tumor activity of BHV-1510.

Up to approximately 220 subjects are planned to be evaluated.

BHV-1500 is a next-generation CD30-directed ADC employing a Biohaven proprietary site-specific conjugation (MATE reagent), targeting CD30-expressing tumors such as Hodgkin's and other lymphoma and the MMAE payload.

Hodgkin's lymphoma, also referred to as Hodgkin's Disease, is a malignant neoplasm of mesothelial origin.

Approximately 9,000 new Hodgkin's disease cases are diagnosed each year.

Hodgkin's disease and other CD30-expressing lymphoma are characterized by the uncontrolled growth of malignant lymphocytes or lymphoblasts.

Adcetris has demonstrated effectiveness in the treatment of Hodgkin's Lymphoma.

In preclinical CD30 expressing murine tumor models, BHV-1500 has shown improved antitumor activity versus Adcetris (brentuximab vedotin), and substantially improved safety, plasma stability and pharmacokinetics in monkeys.

We expect to submit an IND for BHV-1500 in 2024.

In the first quarter of 2025, we announced preliminary data from the initial Phase 1 monotherapy dose escalation cohorts of BHV-1510, which demonstrated early evidence of clinical activity, including tumor shrinkage, with a safety profile of the TopoIx payload supporting further development.

Clinical activity was seen in various monotherapy dose cohorts tested to date, including the lowest dose tested of 2mg/kg once every three weeks.

Early PK data demonstrate a stable ADC with low serum concentrations of free payload.

Preliminary safety data showed a lack of payload-associated interstitial lung disease, gastrointestinal toxicities, or significant hematological toxicities observed in early cohorts.

The main toxicity observed thus far in the study has been stomatitis, an expected on-target Trop2 class toxicity.

The Phase 1/2 study of BHV-1510 is progressing, with robust enrollment in dose escalation and optimization, both as monotherapy and in combination with the anti-PD1 monoclonal antibody Libtayo® (cemiplimab-rwlc).

Based on these early results, we have entered into an expanded collaboration agreement with GeneQuantum Healthcare Co.

("GeneQuantum"), which provides broad target exclusivity for up to 18 ADC targets incorporating the TopoIx payload.

The next ADC incorporating the TopoIx payload that we plan to move into clinical development is BHV-1530.

BHV-1530 is a fibroblast growth factor receptor 3 ("FGFR3")-directed ADC with potential indications in cancers driven by FGFR3 alterations and/or upregulated FGFR3 protein expression, including urothelial cancers and other solid tumors.

FGFR3 is a clinically validated target in oncology, with one small molecule inhibitor (Balversa(R), erdafitinib) approved;

however, to our knowledge there are currently no FGFR3-directed ADCs in clinical development.

Biohaven retains global rights for BHV-1530 under an exclusive license with GeneQuantum (the "FGFR3 Agreement").

IND for BHV-1530 was opened in the second half of 2024, and a FIH study for solid tumors is planned to initiate in the first half of 2025.

Our Phase 1 Study with BHV-1530

The Phase 1 study will evaluate BHV-1530 in patients with advanced solid tumors, including patients whose cancers have progressed on or are intolerant to standard therapy.

The primary objective of Phase 1 is to characterize the safety profile of BHV-1530, and to identify a recommended dose or maximum tolerated dose.

Patients are expected to be dosed in escalating cohorts, with dosing regimens administered intravenously every three weeks.

Up to approximately 95 subjects are planned to be evaluated.

BHV-1500 is a next-generation CD30-directed ADC generated using Biohaven's proprietary MATE(R) technology, targeting CD30-expressing tumors such as Hodgkin and non-Hodgkin lymphomas.

Hodgkin lymphoma ("HL") is a malignant neoplasm of B-cells.

Approximately 9,000 new HL cases are diagnosed each year.

HL and other CD30-expressing lymphoma are characterized by the uncontrolled growth of malignant lymphocytes or lymphoblasts.

A first-generation CD30 directed ADC, Adcetris (brentuximab vedotin), has demonstrated effectiveness in the treatment of Hodgkin's Lymphoma.

In preclinical CD30 expressing murine tumor models, BHV-1500 has shown improved antitumor activity versus Adcetris, and in preliminary cynomolgus monkey studies, BHV-1500 has shown substantially improved safety, plasma stability and pharmacokinetics.

A regulatory interaction with the FDA to discuss the development plans for BHV-1500 is planned for the first half of 2025.

Merus Agreement

In January 2025, Biohaven announced a research collaboration and license agreement with Merus N.V.

("Merus") to co-develop three novel dual-targeting ADCs, leveraging Merus’ Biclonics® technology platform, and Biohaven’s next-generation ADC conjugation and payload platform technologies (the "Merus Agreement").

Pursuant to the Merus Agreement, Merus will receive an upfront payment and license fee at ADC candidate nomination of the first program, with Merus to assume the preclinical bispecific antibody generation cost, and Biohaven to assume the preclinical ADC generation cost.

Thereafter, upon mutual agreement to advance each program, the parties plan to share further development and commercialization costs.

Clinical-Stage Milestones

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

Smaller or early-stage companies may also prove to be significant

competitors, particularly through collaborative arrangements with large and established companies.

Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

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Commercialization

We intend to develop and, if approved by the FDA, commercialize our product candidates in the United States, and we may enter into distribution or licensing arrangements for commercialization rights for other regions.

With respect to our product candidates, we currently intend to build a neurological specialty sales force to manage commercialization for these product candidates, potentially in combination with a larger

pharmaceutical partner, to maximize patient coverage in the United States and to support global expansion.

Members of our management team and board of directors have deep experience leading neuroscience research and have been involved in the development and commercialization of drugs such as Abilify, Opdivo and, most recently, Nurtec ODT and Zavzpret.

We intend to develop and, if approved by the FDA, commercialize our product candidates in the United States, and we may commercialize or enter into distribution or licensing arrangements for commercialization rights for other regions.

With respect to troriluzole, if approved for the treatment of adult patients with SCA, we currently intend to build a neurological specialty sales force to manage commercialization, potentially in combination with a larger pharmaceutical partner, to maximize patient coverage in the United States and to support global expansion.

Members of our management team and board of directors have deep experience leading immunology, neuroscience, and oncology research, and have been involved in the development and commercialization of drugs such as Abilify, Opdivo, Nurtec ODT and Zavzpret.

Our Chief Executive Officer, Vlad Coric, M.D.

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Patents provide the innovator with the right to exclude others from practicing an invention related to the medicine.

Patents may cover, among other things, the active ingredient(s),

various uses of a drug product, discovery tools, pharmaceutical formulations, drug delivery mechanisms and processes for (or intermediates useful in) the manufacture of products.

Patents may cover, among other things, the active ingredient(s), various uses of a drug product, discovery tools, pharmaceutical formulations, drug delivery mechanisms and processes for (or intermediates useful in) the manufacture of products.

Protection for individual products extends for varying periods in accordance with the expiration dates of patents in the various countries.

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Patent 10,851,067 (the “‘067 Patent”), issued December 1, 2020, specifically claims BHV-7000 and will expire in March 2039, not including possible patent term extensions.

counterparts to the ‘067 patent have been granted in Australia and Mexico, and patent applications to the ‘067 patent are pending in Brazil, Canada, China, European Union, United Kingdom, Hong Kong, Israel, India, Japan, Republic of Korea, New Zealand, Singapore and South Africa.

counterparts to the ‘067 patent have been granted in Australia, Israel, Korea, Mexico and New Zealand and patent applications to the ‘067 patent are pending in Brazil, Canada, China, European Union, United Kingdom, Hong Kong, Israel, India, Japan, Republic of Korea, New Zealand, Singapore and South Africa.

patents, and patent applications, if granted, will expire in March 2039, not including possible patent term extensions in countries where such extensions are available.

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Patent 9,481,653 (the “‘653 patent”), issued November 1, 2016, claims a class of compounds including BHV-7000 and will expire in September 2035, not including possible patent term extensions.

Ex-US counterparts to the ‘653 patent are granted in Belgium, Switzerland, Germany,

Denmark, Spain, Finland, France, United Kingdom, Ireland, Iceland, Italy, Netherlands, Norway and Sweden.

counterparts to the ‘653 patent are granted in Belgium, Switzerland, Germany, Denmark, Spain, Finland, France, United Kingdom, Ireland, Iceland, Italy, Netherlands, Norway and Sweden.

patents will expire in September 2035, not including possible patent term extensions in countries where such extensions are available.

In addition, PCT/US23/10295, PCT/US23/63111, PCT/US23/63113 and PCT/US23/63115 directed to various Kv7 activator chemotypes were filed in January and February 2023.

These applications are pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.

These applications are pending in the United States and major market countries.

The patent applications, if granted, will expire in January/February 2043, not including possible patent term extensions in countries where such extensions are available.

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This patent expires in February 2036, not including possible patent term extensions.

Ex-US counterparts to the ‘791 patent have been granted in Albania, Armenia, Austria, Australia, Azerbaijan, Belgium, Brazil, Bulgaria, Belarus, Canada, Switzerland, China, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Hong Kong, Croatia, Hungary, India, Ireland, Israel, Italy, Japan, Kyrgyzstan, Kazakhstan, Lithuania, Luxembourg, Latvia, Monaco, North Macedonia, Macao, Malta, Mexico, Netherlands, Norway, Philippines, Poland, Portugal, Republic of Korea, Romania, Serbia, Russia, Sweden, Slovenia, Slovakia, Tajikistan, Turkmenistan, Turkey and South Africa, and a patent application is pending in Singapore.

The ex-US patents and patent applications will expire in February 2036, not including possible patent term extensions in countries where such extensions are available.

counterparts to the ‘791 patent have been granted in Albania, Armenia, Austria, Australia, Azerbaijan, Belgium, Brazil, Bulgaria, Belarus, Canada, Switzerland, China, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Hong Kong, Croatia, Hungary, India, Ireland, Israel, Italy, Japan, Kyrgyzstan, Kazakhstan, Lithuania, Luxembourg, Latvia, Monaco, North Macedonia, Macao, Malta, Mexico, Netherlands, Norway, Philippines, Poland, Portugal, Republic of Korea, Romania, Serbia, Russia, Singapore, Sweden, Slovenia, Slovakia, Tajikistan, Turkmenistan, Turkey and South Africa.

patents and patent applications will expire in February 2036, not including possible patent term extensions in countries where such extensions are available.

In addition, the use of these compounds for treating OCD, ALS, SCA, depression, Alzheimer’s Disease and other diseases are described and claimed in these patents and patent applications.

These patent applications are subject to an agreement with ALS Biopharma and FCCDC.

In addition, we have filed patent applications relating to drug product formulations containing troriluzole and methods of using the formulations to treat various diseases, including, for example, the use of troriluzole with immunotherapies to treat cancer, including among others U.S.

11,400,155, issued August 2, 2022, which expires in May 2037, not including possible patent term extensions.

Ex-US counterparts to the ‘155 patent have been granted in Albania, Austria, Australia, Belgium, Bulgaria, Switzerland, China, Cyprus, Czechia, Germany, Denmark, Estonia, Spain, Finland, France, United Kingdom, Greece, Hong Kong, Croatia, Hungary, Israel, Ireland, Italy, Japan, Republic of Korea, Lithuania, Luxembourg, Latvia, Mexico, Monaco, North Macedonia, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Sweden, Slovenia, Slovakia and South Africa and patent applications are pending in Brazil, Canada, India, Philippines and Singapore.

The ex-US patents and patent applications will expire in May 2037, not including possible patent term extensions in countries where such extensions are available.

In addition, a patent application directed to the use of troriluzole for treating various SCA genotypes was filed in November 2018 (PCT/US18/60232) and national applications are pending in major jurisdictions with patents granted in Japan and Mexico.

Another patent application directed to the treatment of SCA3 (PCT/US23/67326) was filed in May 2023 and is pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.

These patents, if granted, will expire in 2038 through 2043, not including possible patent term extensions in countries where such extensions are available.

Patent 12,102,618, issued October 1, 2024, which expires in November 2038, not including possible patent term extensions.

patents and patent applications corresponding to the '618 patent will expire in November 2038, not including possible patent term extensions in countries where such extensions are available.

In addition, another patent applications directed to the treatment of SCA3 (PCT/US23/67326) was filed in May 2023 and is pending in the United States and other major market countries.

These patents, if granted, will expire in May 2043, not including possible patent term extensions in countries where such extensions are available.

Also, a patent application directed to the use of troriluzole for treating OCD was filed in June 2021 (PCT/US21/38789) and national applications are pending in major jurisdictions.

These patents, if granted, will expire in 2041, not including possible patent term extensions in countries where such extensions are available.

Another patent application directed to the treatment of glioblastoma (PCT/US23/69038) was filed June 26, 2023 and is pending in the United States Receiving Office of the Patent Cooperation Treaty and all PCT countries were designated for filing.

MoDEs Platform, ARMs, MATEs

In January 2021, we entered into a worldwide, exclusive license agreement with Yale University for the development and commercialization of a novel Molecular Degrader of Extracellular Protein (MoDEs) platform.

The platform pertains to the clearance of disease-causing protein and other biomolecules by targeting them for lysosomal degradation using multi-functional molecules.

Another patent application directed to the treatment of glioblastoma (PCT/US23/69038) was filed June 26, 2023 and is pending in the United States and other major market countries.

MoDE Platform, ARM Technology, MATE Conjugation Technology

In January 2021, we entered into a worldwide, exclusive license agreement with Yale University for the development and commercialization of a novel MoDEs platform.

The platform pertains to the clearance of disease-causing protein and

other biomolecules by targeting them for lysosomal degradation using multi-functional molecules.

The platform is differentiated from existing approaches in that it does not rely on ubiquitin ligases, and it allows for a broad range of targets to be degraded.

The patent portfolio is directed to the composition of matter of bifunctional degraders and their use in degrading circulating proteins and treating diseases.

11,767,301, issued September 26, 2023, and U.S.

12,083,181, issued September 10, 2024, relate to bifunctional molecules to degrade circulating proteins, including BHV-1300.

counterparts to the '301 patent and '181 patent are pending in the European Union, Canada, China and Hong Kong, and, if granted, will expire in April 2039, not including possible patent term extensions in countries where such extensions are available.

17/046221, filed October 8, 2020, relates to bifunctional small molecules to target selective degradation of circulating proteins.

Ex-US counterparts to the '221 application have been filed in China, European Union and Hong Kong and, if granted, will expire in April 2039, not including possible patent term extensions in countries where such

extensions are available.

counterparts to the '221 application have been filed in China, European Union and Hong Kong and, if granted, will expire in April 2039, not including possible patent term extensions in countries where such extensions are available.

17/768166, filed April 11, 2022, relates to bifunctional compounds as degraders of autoantibodies.

Ex-US counterparts to the '166 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, European Union, Israel, Japan, Republic of Korea, Mexico, Philippines, Saudi Arabia, Singapore, and South Africa and, if granted, will expire in October 2040, not including possible patent term extensions in countries where such extensions are available.

17/046192, filed October 8, 2020 and issued as U.S.

11,767,301 on September 26, 2023, relates to bifunctional molecules to degrade circulating proteins.

Ex-US counterparts to the '192 application have been filed in the European Union and Hong Kong, and, if granted, will expire in April 2039, not including possible patent term extensions in countries where such extensions are available.

counterparts to the '166 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, European Union, Israel, Japan, Republic of Korea, Mexico, Philippines, Saudi Arabia, Singapore, and South Africa and, if granted, will expire in October 2040, not including possible patent term extensions in countries where such extensions are available.

17/768145, filed April 11, 2022 relates to engineered antibodies as molecular degraders through cellular receptors.

Ex-US counterparts to the '145 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa and Singapore and, if granted, will expire in October 2040, not including possible patent term extensions in countries where such extensions are available.

counterparts to the '145 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa and Singapore and, if granted, will expire in October 2040, not including possible patent term extensions in countries where such extensions are available.

PCT/US2022/017319, which relates to targeted bifunctional degraders, was filed February 22, 2022, and national applications are pending in the United States and major jurisdictions worldwide.

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The patent applications, if granted, will expire in March 2042, not including possible patent term extensions in countries where such extensions are available.

PCT/US2022/075527 and PCT/US2022/075535, filed August 26, 2022, which relate to difunctional degraders of pathogenic anti-β1ECII (the second extracellular loop of the β1 adrenergic receptor) autoantibodies, are pending in the United States Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.

PCT/US2024/026709, filed April 28, 2024, which relates to degraders of immunoglobulin G, including BHV-1310, is pending in the United States PCT Receiving Office designating all PCT countries.

PCT/US2024/026733, filed April 29, 2024, which relates to bifunctional degraders of galactose deficient immunoglobulins, including BHV-1400, is pending in the United States PCT Receiving Office designating all PCT countries.

We also acquired Kleo Pharmaceuticals, Inc.

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This acquisition included Kleo’s proprietary technology platforms which are modular in design and enable rapid generation of novel immunotherapies that can be optimized against specified biological targets and combined with existing cell- or antibody-based therapies.

These include ARMs and MATEs, which complement the MoDEs technology licensed from Yale.

These include ARM technology and MATE conjugation technology, which complement the MoDE technology licensed from Yale.

17/769924, filed April 18, 2022, relates to directed conjugation technologies.

Ex-US counterparts to the '924 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent

Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa and Singapore and, if granted, will expire in November 2040, not including possible patent term extensions in countries where such extensions are available.

counterparts to the '924 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa and Singapore and, if granted, will expire in November 2040, not including possible patent term extensions in countries where such extensions are available.

17/912563, filed September 19, 2022, relates to technologies for treating COVID infections.

Ex-US counterparts to the '563 application have been filed in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa and Singapore and, if granted, will expire in March 2041, not including possible patent term extensions in countries where such extensions are available.

PCT/US2022/015390, which relates to technologies for preventing or treating infections, was filed February 6, 2022 and national applications are pending in the United States and major jurisdictions worldwide.

The patent applications, if granted, will expire in February 2042, not including possible patent term extensions in countries where such extensions are available.

counterparts to the '563 application are pending in major market countries.

PCT/US2022/015390, which relates to technologies for preventing or treating infections, was filed February 6, 2022 and is pending in the United States.

PCT/US2022/029533, which relates to compositions including conjugated therapy enhancers, was filed May 17, 2022 and national applications are pending in the United States and major jurisdictions worldwide.

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The patent applications, if granted, will expire in May 2042, not including possible patent term extensions in countries where such extensions are available.

PCT/US2022/030070, which relates to antibody drug conjugates using MATE technology for delivering cytotoxic agents, was filed May 19, 2022 and national applications are pending in the United States and major jurisdictions worldwide.

PCT/US2022/030070, which relates to antibody drug conjugates using MATE technology for delivering cytotoxic agents, including BHV-1500, was filed May 19, 2022 and national applications are pending in the United States and major jurisdictions worldwide.

The patent applications, if granted, will expire in May 2042, not including possible patent term extensions in countries where such extensions are available.

PCT/US2024/025746, filed April 23, 2024 relates to BHV-1500 and national applications are pending in the United States and major jurisdictions worldwide.

The patent applications, if granted, will expire in April 2044, not including possible patent term extensions in countries where such extensions are available.

In January 2022, we entered into an exclusive global license and research agreement to develop and commercialize TRPM3 antagonists to address the growing proportion of people worldwide living with chronic pain disorders.

The TRPM3 antagonist platform was discovered at the Centre for Drug Design and Discovery (“CD3”) and the Laboratory of Ion Channel Research (“LICR”) at Katholieke Universiteit Leuven (KU Leuven).

PCT/EP2021/082853, which relates to aryl derivatives for treating TRPM3 mediated disorders, was filed November 24, 2021 and national applications are pending in the United Arab Emirates, Australia, Brazil, Canada, China, countries of the Eurasian Patent Organization, European Union, Israel, India, Japan,

Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, South Africa, Singapore, Taiwan and the U.S.

The TRPM3 antagonist platform was discovered at the Centre for Drug Design and Discovery (“CD3”) and the Laboratory of Ion

Channel Research (“LICR”) at Katholieke Universiteit Leuven (KU Leuven).

The patent applications, if granted, will expire in November 2041, not including possible patent term extensions in countries where such extensions are available.

PCT/EP2021/082865, which relates to heterocycle derivatives for treating TRPM3 mediated disorders, was filed November 24, 2021 and national applications are pending in the United Arab Emirates, Australia, Brazil, Canada, China, Eurasia, European Union, Israel, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, Singapore, Taiwan, South Africa and the U.S.

PCT/EP2021/082865, which relates to heterocycle derivatives for treating TRPM3 mediated disorders, including BHV-2100, was filed November 24, 2021 and national applications are pending in the United Arab Emirates, Australia, Brazil, Canada, China, Eurasia, European Union, Israel, Japan, Republic of Korea, Mexico, New Zealand, Philippines, Saudi Arabia, Singapore, Taiwan, South Africa and the U.S.

The patent applications, if granted, will expire in November 2041, not including possible patent term extensions in countries where such extensions are available.

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patents expire in September 2033, not including possible patent term extensions.

Ex-US counterparts to the U.S.

patents have been granted in Argentina, Austria, Australia, Belgium, Bulgaria, Brazil, Canada, Switzerland, Chile, China, Colombia, Czechia, Germany, Denmark, Algeria, Egypt, Spain, Finland, France, United Kingdom, Greece, Hong Kong, Croatia, Hungary, Indonesia, Ireland, Israel, India, Italy, Japan, Republic of Korea, Lithuania, Morocco, Macao, Mexico, Malaysia, Netherlands, Norway, New Zealand, Peru, Philippines, Poland, Portugal, Romania, Serbia, Russia, Sweden, Singapore, Slovenia, Slovakia,

Thailand, Tunisia, Turkey, Taiwan, Uruguay, Venezuela, Vietnam and South Africa.

The ex-US patents will expire in September 2033, not including possible patent term extensions in countries where such extensions are available.

counterparts to the U.S.

patents will expire in September 2033, not including possible patent term extensions in countries where such extensions are available.

16/607688, filed May 3, 2018, relates to stable formulations fibronectin based scaffold domain proteins that bind to myostatin.

Ex-US counterparts to the '688 application have been granted in Japan and are pending in Australia, Canada, China, European Union, Hong Kong, Israel, Republic of Korea, Mexico, Singapore and Taiwan.

The ex-US patents and patent applications, if granted, will expire in May 2038, not including possible patent term extensions in countries where such extensions are available.

counterparts to the '688 application have been granted in Israel, Japan, Korea and are pending in Australia, Canada, China, European Union, Hong Kong, Mexico, Singapore and Taiwan.

patents and patent applications, if granted, will expire in May 2038, not including possible patent term extensions in countries where such extensions are available.

In March 2023, we entered into an exclusive, worldwide (excluding People’s Republic of China and its territories and possessions) license agreement with Highlightll pursuant to which we obtained the right to research, develop, manufacture and commercialize Highlightll’s brain penetrant dual TYK2/JAK1 inhibitor program.

Patent RE49834 (the “‘834 Patent”), having an issue date of February 13, 2024, is directed to BHV-8000 and will expire in September 2037, not including possible patent term extensions.

counterparts to the ‘834 patent have been granted in Australia, European Union, Israel, Japan, Mexico, and New Zealand, and patent applications to the ‘834 patent are pending in Brazil, Canada, Eurasia, India, and Republic of Korea.

counterparts to the ‘834 patent have been granted in Australia, European Union, Israel, India, Japan, Mexico, and New Zealand, and patent applications to the ‘834 patent are pending in Brazil, Canada, Eurasia, and Republic of Korea.

patents and patent applications, if granted, will expire in September 2037, not including possible patent term extensions in countries where such extensions are available.

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The patent applications, if granted, will expire in August 2042, not including possible patent term extensions in countries where such extensions are available.

In January 2024, the Company acquired Pyramid Biosciences, Inc.

(“Pyramid”), pursuant to an Agreement and Plan of Merger, dated January 7, 2024 ("the Pyramid Agreement").

As a result of the merger, the Company acquired rights under certain patents exclusively licensed to Pyramid from GeneQuantum Healthcare (Suzhou) Co.

The licensed patents include the following, among others:

PCT/CN2023/107444, filed July 14, 2023, which relates to anti-TROP2 antibodies and conjugates, including BHV-1510, is pending in the CNIPA Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.

PCT/CN2024/087405, filed April 12, 2024, which relates to combinations of antibody-drug conjugates and anti-PD-1 antibodies, is pending in the CNIPA Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.

PCT/CN2025/071669, filed January 10, 2025, which relates to pharmaceutical compositions of antibody-drug conjugates, is pending in the CNIPA Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.

In December 2024, the Company entered into a Development and License Agreement with GeneQuantum Healthcare (Suzhou) Co.

and Aimed Bio, Inc.

relating to certain Fibroblast Growth Factor Receptor ADCs.

The licensed patents include the following, among others:

WO2024002154A1, published January 4, 2024, which relates to anti-FGFR3 antibody conjugates and medical uses thereof is pending in the CNIPA Receiving Office of the Patent Cooperation Treaty and all countries were designated for filing.

WO2022149837, published July 14, 2022, which relates to anti-FGFR3 antibodies and uses thereof, is pending in Australia, Canada, China, the European Patent Office, Japan, Korea and the United States.

WO2023088235, published May 25, 2023, which relates to exatecan derivatives, linker-payloads and conjugates thereof, is pending in Australia, Canada, China, the European Patent Office, Japan, Korea, Mexico and the United States.

WO2022160156, published August 4, 2022, which relates to ligase fusion proteins and applications thereof, is pending in Australia, China, the European Patent Office, Japan, Korea and the United States.

Licensing and Other Agreements

In addition to our independent efforts to develop and market products, we enter into agreements such as licensing agreements, option-to-license agreements and strategic collaborations.

In addition to our independent efforts to develop and market products, we from time to time enter into agreements such as licensing agreements, option-to-license agreements and strategic collaborations.

The licensing and other agreements typically include, among other terms and conditions, non-refundable upfront license fees, option fees and option exercise payments, milestone payments and royalties.

See Note 11, "License Agreements," to the Consolidated Financial Statements included in this report for additional information regarding our licenses and other agreements.

See Note 10, "License, Acquisitions and Other Agreements," to the Consolidated Financial Statements included in this report for additional information regarding our licenses and other agreements.

Government Regulation

In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act

("FDCA") and its implementing regulations.

In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (the "FDCA") and its implementing regulations.

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

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The steps required before a drug may be approved for marketing in the United States generally include:

• nonclinical laboratory tests and animal tests conducted under Good Laboratory Practices ("GLP");

• preclinical laboratory tests and animal tests conducted under Good Laboratory Practices ("GLP");

• the submission to the FDA of an IND application for human clinical testing, which must become effective before human clinical trials commence;

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The testing and approval process requires substantial time, effort and financial resources, and the receipt and timing of any approval is uncertain.

The FDA may suspend clinical trials at any time on various

grounds, including a finding that the subjects or patients are being exposed to an unacceptable health risk.

Nonclinical and Human Clinical Trials in Support of an NDA

Nonclinical studies include laboratory evaluations of the product candidate, as well as in vitro and animal studies to gather information on the safety and efficacy of the product candidate.

The conduct of nonclinical trials is subject to federal regulations and requirements including GLP regulations.

The results of the nonclinical studies, together with manufacturing information and analytical data, among other things, are submitted to the FDA as part of the IND, which must become effective before clinical trials may be commenced.

The FDA may suspend clinical trials at any time on various grounds, including a finding that the subjects or patients are being exposed to an unacceptable health risk.

Preclinical and Human Clinical Trials in Support of an NDA

Preclinical studies include laboratory evaluations of the product candidate, as well as in vitro and animal studies to gather information on the safety and efficacy of the product candidate.

The conduct of preclinical trials is subject to federal regulations and requirements including GLP regulations.

The results of the preclinical studies, together with manufacturing information and analytical data, among other things, are submitted to the FDA as part of the IND, which must become effective before clinical trials may be commenced.

The IND will become effective automatically 30 days after receipt by the FDA, unless the FDA raises concerns or questions about the conduct of the trials as outlined in the IND prior to that time.

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Submission and Review of an NDA

The results of nonclinical studies and clinical trials, together with detailed information on the product's manufacture, composition, quality, controls and proposed labeling, among other things, are submitted to the FDA in the form of an NDA, requesting approval to market the product.

The results of preclinical studies and clinical trials, together with detailed information on the product's manufacture, composition, quality, controls and proposed labeling, among other things, are submitted to the FDA in the form of an NDA, requesting approval to market the product.

The application must be accompanied by a significant user fee payment, which typically increases annually, although waivers may be granted in limited cases.

The FDA has substantial discretion in the approval process and may refuse to accept an application if they determine that the data are insufficient for approval and require additional nonclinical, clinical or other studies.

Once an NDA has been accepted for filing, which occurs, if at all, 60 days after submission, the FDA sets a user fee goal date that informs the applicant of the specific date by which the FDA intends to complete its review.

A standard review typically takes 10 months from the date that the application is accepted for filing by the FDA and a priority review typically takes 6 months from the date that the application is accepted by the FDA for filing.

The review process can be extended by FDA requests for additional information or clarification.

The FDA reviews NDAs to determine, among other things, whether the proposed product is safe and effective for its intended use, and whether the product is being manufactured in accordance with cGMPs to assure and preserve the product's identity, strength, quality and purity.

The FDA reviews NDAs to

determine, among other things, whether the proposed product is safe and effective for its intended use, and whether the product is being manufactured in accordance with cGMPs to assure and preserve the product's identity, strength, quality and purity.

Before approving an NDA, the FDA typically will inspect the facilities at which the product is manufactured and will not approve the product unless the manufacturing facilities comply with cGMPs.

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For example, the FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance programs to further assess and monitor the product's safety and effectiveness after commercialization.

The FDA may also require a REMS, which could involve requirements for, among other things, medication

guides, special trainings for prescribers and dispensers, patient registries, and elements to assure safe use.

The FDA may also require a REMS, which could involve requirements for, among other things, medication guides, special trainings for prescribers and dispensers, patient registries, and elements to assure safe use.

In addition, entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies, and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements.

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Drugs may be promoted only for the approved indications 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, and a company that is found to have improperly promoted off-

label uses may be subject to significant liability, including investigation by federal and state authorities.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including investigation by federal and state authorities.

Section 505(b)(2) NDAs

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A competitor seeking to launch a generic substitute of small molecule drug in the U.S.

must file an Abbreviated New Drug Application ("ANDA") with the

must file an Abbreviated New Drug Application ("ANDA") with the FDA.

In the ANDA, the generic manufacturer needs to demonstrate only “bioequivalence” between the generic substitute and the approved NDA drug.

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An innovative chemical pharmaceutical product is entitled to five years of RDP in the U.S., during which the FDA cannot approve generic substitutes.

If an innovator’s patent is challenged, as described above, a generic manufacturer may file its ANDA after the fourth year of the five-year RDP period.

If an innovator’s patent is challenged, as described above, a generic manufacturer may file

its ANDA after the fourth year of the five-year RDP period.

A pharmaceutical drug product that contains an active ingredient that has been previously approved in an NDA, but is approved in a new formulation, but not for the drug itself, or for a new indication on the basis of new clinical studies, may receive three years of RDP for that formulation or indication.

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After an innovator has marketed its product for four years, any manufacturer may file an application for approval of a “biosimilar” version of the innovator product.

However, although an application for approval of a biosimilar version may be

filed four years after approval of the innovator product, qualified innovative biological products will receive 12 years of regulatory exclusivity, meaning that the FDA may not approve a biosimilar version until 12 years after the innovative biological product was first approved by the FDA.

However, although an application for approval of a biosimilar version may be filed four years after approval of the innovator product, qualified innovative biological products will receive 12 years of regulatory exclusivity, meaning that the FDA may not approve a biosimilar version until 12 years after the innovative biological product was first approved by the FDA.

The law also provides a mechanism for innovators to enforce the patents that protect innovative biological products and for biosimilar applicants to challenge the patents.

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After the EMA evaluates the MAA, it provides a recommendation to the European Commission ("EC") and the EC then approves or denies the MAA.

Regulatory approval via the centralized procedure results in a marketing authorization for the innovative pharmaceutical product

in each EU member state.

Regulatory approval via the centralized procedure results in a marketing authorization for the innovative pharmaceutical product in each EU member state.

It is also possible for new chemical products to obtain marketing authorization in the EU through a “mutual recognition procedure,” in which an application is made to a single member state, and if the member state approves the pharmaceutical product under a national procedure, then the applicant may submit that approval to the mutual recognition procedure of some or all other member states.

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In contrast to the U.S., patents in the EU are not listed with regulatory authorities.

Generic versions of pharmaceutical products can be approved after data protection expires, regardless of whether the innovator holds patents covering its drug.

Generic versions of pharmaceutical products can be approved after data protection expires, regardless of whether the

innovator holds patents covering its drug.

Thus, it is possible that an innovator may be seeking to enforce its patents against a generic competitor that is already marketing its product.

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In addition to the relevant legislation and annexes related to biologic medicinal products, the EMA has issued guidelines that outline the additional information to be provided for biosimilar products, also known as generic biologics, in order to review an application for marketing approval.

To obtain marketing authorization of pharmaceutical products in Japan, an NDA must be submitted to the Pharmaceutical and Medical Devices Agency (“PMDA”) once safety and efficacy has been established.

In Japan, medicines of new chemical entities are generally afforded eight years of data exclusivity for approved indications and dosage.

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As in the U.S., patents in Japan may be extended to compensate for the patent term lost during the regulatory review process.

general, Japanese law treats chemically-synthesized and biologically-derived drugs the same with respect to intellectual property and market exclusivity.

In general, Japanese law treats chemically-synthesized and biologically-derived drugs the same with respect to intellectual property and market exclusivity.

To obtain marketing authorization of pharmaceutical products in China, an NDA must be submitted to the National Medical Products Administration ("NMPA") once safety and efficacy has been established in Chinese patients.

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Challenges exist that pertain to the coverage and reimbursement status of any products for which regulatory approval is sought.

In the United States and

foreign markets, sales of any products that receive regulatory approval for commercial sale will depend, in part, on the availability of coverage and the adequacy of reimbursement from third-party payors.

In the United States and foreign markets, sales of any products that receive regulatory approval for commercial sale will depend, in part, on the availability of coverage and the adequacy of reimbursement from third-party payors.

Third-party payors include government authorities, such as Medicare and Medicaid, and private entities, such as managed care organizations, private health insurers and other organizations.

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The latter is often informed by entities such as the Institute for Clinical and Economic Review ("ICER") which provides a reimbursement rate based on a multifactorial value assessment.

Admittedly, ICER value assessments are more pertinent to the U.S.

Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not include all of the FDA-approved products for a particular indication.

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For example, the payor's reimbursement payment rate may not be adequate or may require patient co-payments that patients find unacceptably high.

Additionally, coverage and reimbursement for products can differ significantly from one payor system to the next.

Additionally, coverage and

reimbursement for products can differ significantly from one payor system to the next.

Private payor systems set reimbursement policy in accordance with their particular model.

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If third-party payors do not consider a product to be cost-effective compared to other available therapies, they may not cover the product after approval as a benefit under their plans or, they may deem a subpopulation of eligible patients based on greater unmet need as eligible for reimbursement.

Thus, obtaining and maintaining

reimbursement status can be time-consuming and costly.

Thus, obtaining and maintaining reimbursement status can be time-consuming and costly.

However, drug developers accept these requirements as a condition of reimbursement, analogous to their acceptance of the level of evidence needed to obtain regulatory approval.

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Department of Health and Human Services ("HHS") moved 41% of Medicare fee-for-service payments to alternative payment models ("APMs") tied to the quality or value of services by the end of 2018.

HHS had set a goal of moving 50% of such Medicare payments into these alternative payment models by the end of 2018, but in 2019, this performance goal was discontinued and replaced it with a new developmental goal to increase the percentage of Medicare health care dollars tied to APMs incorporating downside risk, with a target of 40% for fiscal year 2021.

HHS has a developmental goal to increase the percentage of Medicare health care dollars tied to APMs incorporating downside risk, with a target of 55% for fiscal year 2024 and 60% for fiscal year 2025.

These constitute significant challenges, which are analogous to the regulatory hurdles in many aspects and drug developers acknowledge these challenges as the path to providing safe and effective therapies to the patients that require them.

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In the European Union, pricing and reimbursement requirements can vary widely from country to country.

Some countries link market authorization to reimbursement decisions.

Others may require the completion of additional studies that assess the cost-effectiveness or comparative effectiveness of novel approved drugs relative to standard of care.

These are compiled as health technology assessments ("HTAs"), that constitute a requisite for reimbursement or pricing approval.

These may range from ICER-like value assessments (e.g.

NICE in the U.K.

and SMC in Scotland) that include cost-effectiveness parameters to criteria that are based solely on a novel therapy’s incremental effectiveness (efficacy, safety) relative to approved standards of care.

These latter criteria may require additional studies.

All of these are compiled as country-specific health technology assessments ("HTAs"), that constitute a requisite for reimbursement or pricing approval.

For example, the European Union provides options for its member states to restrict the range of drug products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

European Union member states may approve a specific price for a drug product or may instead adopt a system of access restrictions that typically target sub populations with high unmet need.

Sponsors are expected to demonstrate incremental value including effectiveness in these subpopulations via additional analyses.

Healthcare Laws and Regulations

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• The federal Health Insurance Portability and Accountability Act of 1996 ("HIPAA") which imposes criminal liability for executing or attempting to execute a scheme to defraud any healthcare benefit program and creates federal criminal laws that prohibit knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services;

• HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act ("HITECH") enacted as part of the American Recovery and Reinvestment Act of 2009 and its implementing regulations, which imposes certain obligations, including mandatory contractual terms, on entities subject to the law, such as healthcare providers, health plans, and healthcare clearinghouses and their respective business associates to safeguard the privacy, security and transmission of individually identifiable

health information from any unauthorized use or disclosures;

• The federal transparency requirements under the Physician Payments Sunshine Act, created under the ACA, which requires certain manufacturers of drugs, devices, biologics and medical supplies reimbursed under Medicare, Medicaid, and other programs such as CHIP to report to HHS information related to payments and other transfers of value provided to physicians and teaching hospitals and physician ownership and investment interests;

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and state health information privacy and data breach notification laws, which govern the collection, use, disclosure, and protection of health-related and other personal information, many of which differ from each other in significant ways and some of which are not pre-empted by HIPAA, thus complicating compliance efforts.

We will be required to spend substantial time and money to ensure that our business arrangements with third parties comply with applicable healthcare laws and regulations.

We are required to spend substantial time and money to ensure that our business arrangements with third parties comply with applicable healthcare laws and regulations.

Healthcare reform legislation has strengthened these federal and state healthcare laws.

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Violations of these laws can subject us to criminal, civil and administrative sanctions including monetary penalties, damages, fines, disgorgement, individual imprisonment, and exclusion from participation in government funded healthcare programs, such as Medicare and Medicaid, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, and reputational harm, we may be required to curtail or restructure our operations.

Moreover, we expect that

there will continue to be federal and state laws and regulations, proposed and implemented, that could impact our future operations and business.

Moreover, we expect that there will continue to be federal and state laws and regulations, proposed and implemented, that could impact our future operations and business.

Healthcare Reform

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• extension of a manufacturer’s Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;

• expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with

income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;

• expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;

• expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program;

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Some of the provisions of the ACA have yet to be implemented, and there have been judicial and Congressional challenges to certain aspects of the ACA.

In January of 2021, an Executive Order entitled “Executive Order on Strengthening Medicaid and the Affordable Care Act” repealed two previous Executive Orders delaying the implementation of certain provisions of the ACA.

In January 2021, an Executive Order entitled “Executive Order on Strengthening Medicaid and the Affordable Care Act” repealed two previous Executive Orders delaying the implementation of certain provisions of the ACA.

Concurrently, Congress has considered legislation that amend all or part of the ACA.

In addition, other federal health reform measures have been proposed and adopted in the United States since the ACA was enacted.

These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year pursuant to the Budget Control Act of 2011 (known as Medicare sequestration) and subsequent extensions, which began in 2013 and will remain in effect through 2030 (with the exception of a temporary suspension from May 1, 2020 through March 31, 2022, with a subsequent one quarter phase-in of 1%) unless additional Congressional action is taken.

These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year pursuant to the Budget Control Act of 2011 (known as Medicare sequestration) and subsequent extensions, which began in 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2032 unless additional Congressional action is taken.

Further, the American Taxpayer Relief Act of 2012 reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments from providers from three to five years.

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Further, there have been several Congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.

At the federal level, the costs of prescription pharmaceuticals in the United States has also been the subject of considerable discussion.

The previous administration released a "Blueprint" to lower drug prices and reduce out-of-pocket costs of drugs.

HHS solicited feedback on some

of these measures and, concurrently, implemented others under its existing authority.

President Biden continues to push for reforms that would address the high cost of drugs.

In response to an Executive Order from President Biden, the Secretary of HHS issued a comprehensive plan for addressing high drug prices that describes a number of legislative approaches and identifies administrative tools to address the high cost of drugs.

Democrats included drug pricing reform provisions reflecting elements of the plan in a broader spending package in late 2021—such as capping Medicare Part D patients’ out-of-pocket costs, establishing penalties for drug prices that increase faster than inflation in Medicare, and authorizing the federal government to negotiate prices on certain select, high-cost drugs under Medicare Parts B and D.

While a number of these and other proposed measures would require authorization through additional legislation to become effective, Congress has indicated that it will continue to seek new legislative and/or administrative measures to control drug costs.

In August 2022, Congress passed the Inflation Reduction Act of 2022, which included, among other things, a provision allowing Medicare to negotiate drug prices directly with pharmaceutical manufacturers.

At the federal level, the cost of prescription pharmaceuticals in the United States has also been the subject of considerable discussion.

In August 2022, Congress passed the Inflation Reduction Act of 2022 (the "IRA"), which, among other things, requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap; imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023); and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025).

Subsequently, certain pharmaceutical companies and other entities filed lawsuits in various courts against HHS and CMS asserting that, among other things, the IRA’s Drug Price Negotiation Program for Medicare constitutes an uncompensated taking in violation of the Fifth Amendment of the Constitution.

While some of these cases are on appeal, HHS has generally won the substantive disputes in these cases, and various federal district court judges expressed skepticism regarding the merits of the legal arguments being pursued by the pharmaceutical industry.

Litigation involving these and other provisions of the IRA will continue with unpredictable and uncertain results.

In addition, recent administrations have released various executive orders with provisions aimed at, among other things, prescription drug pricing, lowering drug costs for Medicare and Medicaid beneficiaries and setting forth various potential policies or actions that Congress or administrative agencies could pursue.

We expect that additional U.S.

federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that the U.S.

federal government will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.

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

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The Nominating and Governance Committee of the Board has oversight of strategy and risk management related to Environmental, Social and Governance (“ESG”).

Applying NYSE’s listing standards for independence, six of our eight directors are independent.

At the management level, we have implemented a cross-functional Sustainability Working Group, which meets on a regular basis and reports to the Board of Directors periodically.

We also maintain a Chief Talent & Sustainability Officer position who works closely with the working group and coordinate efforts related to the advancement of ESG capabilities across the organization.

Six of our eight directors are independent under the NYSE’s listing standards for independence.

Business Ethics

We are committed to creating an environment where we are able to excel in our business while maintaining the highest standards of conduct and ethics.

Our Code of Business Conduct and Ethics (the “Code of Conduct”) will reflect the business practices and principles of behavior that support this commitment, including our policies on bribery, corruption, conflicts of interest and our whistleblower program.

Our Code of Business Conduct and Ethics (the “Code of Conduct”) reflects the business practices and principles of behavior that support this commitment, including our policies on bribery, corruption, conflicts of interest and our whistleblower program.

We expect every director, officer, and employee to read, understand and comply with the Code of Conduct and its application to the performance of his or her business responsibilities.

We encourage employees to come to us with observations and complaints, ensuring we understand the severity and frequency of an event in order to escalate and assess accordingly.

We encourage employees to come to us with observations and complaints, and we strive to understand the severity and frequency of an event in order to escalate and assess accordingly.

Our Chief Compliance Officer strives to ensure accountability, objectivity, and compliance with our Code of Conduct.

If a complaint is financial in nature, the Audit Committee Chair is notified concurrently, which triggers an investigation, action and report.

All incidents are reported up to the Board of Directors on a quarterly basis.

Incidents are reported up to the Board of Directors on a quarterly basis.

Environmental Commitment

We are committed to protecting the environment and attempt to mitigate any negative impact of our operations.

We monitor resource use, improve efficiency, and at the same time reduce our emissions and waste.

We are committed to protecting the environment and attempt to mitigate negative impacts of our operations.

We monitor resource use, and aim to improve efficiency, and at the same time reduce our emissions and waste.

Externally, we strive to reduce the overall impact of our product on the environment by taking steps to enhance the sustainability of our manufacturing processes for our drug substances.

In collaboration with our contract research organization partners, we apply various green chemistry methodologies to our commercial and development

In collaboration with our contract research organization partners, we apply various green chemistry methodologies to our commercial and development pipeline.

We have especially focused on using biocatalysis, a technology that makes use of enzymes instead of chemicals to accomplish specific chemical reactions used to construct organic small molecules such as Active Pharmaceutical Ingredients.

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This green technology relies on the use of micelles to enable such reactions to occur in water where they would normally not occur due in part to the very poor solubility of most organic compounds in water.

These greener processes not only create less waste, but the waste that is produced is much less hazardous, therefore reducing the environmental impact of the manufacturing process.

These greener processes create less waste and reduce the environmental impact of the manufacturing process.

Social Responsibility

For third-party vendor selection and oversight, we have adopted standard operating procedures that apply to employees and subcontractors who on our behalf, oversee and conduct research regulated by the FDA.

We retain ultimate authority and responsibility for the conduct of regulated research, manufacturing, and testing and we must ensure that contracted services are conducted in accordance with Good Practice Guidelines and all applicable regulations.

We retain ultimate

authority and responsibility for the conduct of regulated research, manufacturing, and testing and we must ensure that contracted services are conducted in accordance with Good Practice Guidelines and all applicable regulations.

Human Capital Management

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We strive to provide an inclusive workplace to foster growth and innovation.

Our efforts to achieve gender diversity in the workforce are evidenced by a workforce that is approximately 57% female and includes a robust group of female leaders in the scientific and associated fields.

Biohaven engages in forward-thinking people policies to allow for our employees to thrive in our workforce.

Regular attendance at an office is only required of our lab professionals, allowing over 50% of

our workforce to work remotely full-time.

Regular attendance at an office is only required of our lab professionals, allowing over 50% of our workforce to work remotely full-time.

Our vacation policy is unlimited and is aimed at giving employees the ability to achieve work/life balance in a way that is bespoke to their circumstances.

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

What changed 10-K

Item 1. Business