Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy Study of Oral Verdiperstat (BHV-3241) in Patients With Semantic Variant Primary Progressive Aphasia (svPPA) Due to TDP-43 Pathology

The purpose of the study is to test the safety and tolerability of twice daily Verdiperstat in patients with semantic variant primary progressive aphasia (svPPA) due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Three-fourths of the participants will receive Verdiperstat and one-fourth will receive Placebo during the 24-week treatment duration.

Start Date19 Apr 2022

Sponsor / Collaborator

The University of California, San Francisco

[+3]

NCT04616456 / CompletedEarly Phase 1IIT

Effect of Verdiperstat on Microglial Activation in Well-characterized MSA Patients

This study will comprise of two phases, an observational phase and a treatment phase.
In the observational phase the specific aims are: 1. To determine the presence and regional distribution of microglial activation, as assessed by 18F-PBR06 PET, in subjects with MSA as compared to healthy controls, at baseline and at 6-9 months' follow-up.
2. To assess the relationship between microglial activation and clinical progression at baseline and follow-up.
In the treatment phase the specific aims of the study are:
The specific aims of the study are:
To assess whether verdiperstat (BHV-3241) reduces 18F-PBR06 PET signal, and thus microglial activation and inflammation, in well-characterized MSA patients.
To assess the relationship between PET changes and clinical progression at baseline and follow-up in patients treated with verdiperstat.
To assess the relationship between PET changes and volumetric brain MRI at baseline and follow-up in patients treated with verdiperstat.
Currently there is no known disease modifying therapy for MSA. Recently, the drug verdiperstat (BHV-3241) has appeared in the investigational arena specifically for the indication of Multiple System Atrophy. Verdiperstat (BHV-3241) is currently being used in a phase 3 active drug trial at Massachusetts Hospital. Verdiperstat (BHV-3241) is known to target Myeloperoxidase, an enzyme implicated in neuroinflammation, a major driver in disease pathogenesis. Our previous study (IRB protocol #2016P002373) demonstrated that applying TSPO (translator protein) PET imaging enabled us to track changes in neuroinflammation and thus provide a viable biomarker for disease progression.
In this pilot study, the investigators aim to assess the effect of an investigational drug, verdiperstat (BHV-3241) on microglial activation in MSA patients using [F-18]PBR06 and to link it with clinical and morphometric MRI brain changes following treatment.

Start Date30 Dec 2020

Sponsor / Collaborator

The Brigham & Women's Hospital, Inc.

[+1]

NCT04436510 / CompletedPhase 2/3

HEALEY ALS Platform Trial - Regimen B Verdiperstat

The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS.
Regimen B will evaluate the safety and efficacy of a single study drug, verdiperstat, in participants with ALS.

Start Date28 Jul 2020

Sponsor / Collaborator

Biohaven Pharmaceuticals, Inc.

100 Clinical Results associated with Verdiperstat

100 Translational Medicine associated with Verdiperstat

100 Patents (Medical) associated with Verdiperstat

Literatures (Medical) associated with Verdiperstat

01 Feb 2023·Journal for immunotherapy of cancer

Inhibition of myeloperoxidase enhances immune checkpoint therapy for melanoma

Article

Author: Yang, Ping ; Piwnica-Worms, David ; Liu, Tracy W ; Wang, Jing ; Gammon, Seth T ; Ma, Wencai

Background:

The presence of a highly immunosuppressive tumor microenvironment has limited the success of immune checkpoint therapy (ICT). Immune suppressing myeloid cells with increased production of reactive oxygen species are critical drivers of this immunosuppressive tumor microenvironment. Strategies to limit these immune suppressing myeloid cells are needed to enhance response to ICT.

Methods:

To evaluate the contribution of myeloperoxidase (MPO), a myeloid lineage-restricted enzyme and a major source of reactive oxygen species, to mediating ICT response, we compared treatment outcome and immune composition in wild-type, MPO-deficient (MPO−/−), and MPO inhibitor-treated wild-type mice using established primary melanoma models.

Results:

Tumor growth and survival studies demonstrated that either host deficiency (MPO−/−) or pharmacological inhibition of MPO enhanced ICT response in two preclinical models of established primary melanoma in aged animals. The tumor microenvironment and systemic immune landscape underwent striking changes in infiltration of myeloid cells, T cells, B cells, and dendritic cells inMPO−/−mice; furthermore, a significant increase in myeloid cells was observed in ICT non-responders. The contribution of CD4+T cells and NK cells during ICT response also changed inMPO−/−mice. Interestingly, MPO enzymatic activity, but not protein, was increased in CD11b+Ly6G+myeloid cells isolated from marrow, spleen, and peritoneal cavities of mice bearing untreated melanoma, indicating systemic activation of innate immunity. Notably, repurposing MPO-specific inhibitors (verdiperstat, AZD5904) in combination with ICT pointedly enhanced response rates above ICT alone. Indeed, long-term survival was 100% in the YUMM3.3 melanoma model on treatment with verdiperstat plus ICT.

Conclusion:

MPO contributes to ICT resistance in established melanoma. Repurposing MPO-specific inhibitors may provide a promising therapeutic strategy to enhance ICT response.

01 Jun 2022·European journal of pharmacologyQ3 · MEDICINE

Verdiperstat attenuates acute lung injury by modulating MPO/μ-calpain/β-catenin signaling

Q3 · MEDICINE

Article

Author: Yu, Pengfei ; Jiang, Wanglin ; Ren, Rui ; Wang, Xin ; Xu, Zehui

Verdiperstat, a myeloperoxidase (MPO) inhibitor, is a well-known drug used for the treatment of multisystem atrophy. However, its therapeutic effect on acute lung injury (ALI) remains to be elucidated. In this study, the effect of verdiperstat on lipopolysaccharide (LPS)-induced two-hit rat ALI model was studied in vivo. Subsequently, to explore the anti-ALI mechanism of verdiperstat, an LPS-induced injury in human pulmonary microvascular endothelial cells (HMs) was studied in vitro. The continuous administration of verdiperstat at 120 mg/kg for 3 days exerted a protective effect on the LPS-induced two-hit rat ALI model, as reflected by the change in the lung coefficient and lung pathology scores from 0.72 to 0.61 and 6.08 to 4.37, respectively. Furthermore, the values of protective adhesion protein VE-cadherin and tight junction protein claudin 5 changed from 0.42 to 0.97 and 0.25 to 0.72, but MPO, the ratio of N-μ-calpain to μ-calpain, and the distribution of β-catenin in the nucleus changed from 3.04 to 2.17, 0.62 to 0.38 and 2.25 to 0.76, respectively. LPS-induced HMs in vitro also showed similar results, including lower MPO and the distribution of β-catenin in the nucleus, but higher VE-cadherin claudin 5 and N-μ-calpain. Moreover, MPO inhibition resulted in lower μ-calpain activation and lower β-catenin in the nucleus. Our cumulative results suggest that verdiperstat alleviates ALI by strengthening VE-cadherin and claudin 5 through the inhibition of MPO/μ-calpain/β-catenin activation.

01 Nov 2018·Journal of clinical pharmacologyQ3 · MEDICINE

Population Pharmacokinetic Modeling With Enterohepatic Circulation for AZD3241 in Healthy Subjects and Patients With Multiple System Atrophy

Q3 · MEDICINE

Article

Author: Tong, Xiao ; Mullen, Jamie A. ; Li, Jianguo ; Savage, Alicia ; Xu, Hongmei ; Li, Yan ; Al‐Huniti, Nidal ; Taylor, Wendy ; Zhou, Diansong

Abstract:

AZD3241 is a potent and selective myeloperoxidase inhibitor potentially for the treatment of a number of neurodegenerative disorders, including multiple system atrophy (MSA). The objectives of this work were to develop a population pharmacokinetic (PopPK) model for AZD3241 and to investigate the correlation between AZD3241 exposure and myeloperoxidase inhibition. The PopPK model was developed using AZD3241 data from one phase 1 study in healthy subjects and one phase 2 study in patients with MSA. A one‐compartment model incorporating a gallbladder compartment for enterohepatic circulation, sequential zero‐first order absorption, and first‐order elimination adequately described the AZD3241 concentration profiles. The apparent clearance and central volume of distribution were 63.1 L/h (interindividual variability: 34.8%) and 121.9 L (interindividual variability: 44.0%), respectively. The enterohepatic circulation model reasonably captured the second peak of AZD3241, and high‐fat food increased the absorption rate by 69%. A linear regression model was applied to describe the relationship between AZD3241 exposure and percentage change from baseline in myeloperoxidase‐specific activity. The developed PopPK model was consistent with known pharmacokinetic characteristics of AZD3241. This model can be used to estimate AZD3241 exposure in patients with MSA and could be applied to future pharmacokinetic‐pharmacodynamic analyses of AZD3241 in clinical development.

News (Medical) associated with Verdiperstat

12 May 2023

·www.prnewswire.com

Biohaven Reports First Quarter 2023 Financial Results and Reports Recent Business Developments

Acquired exclusive license for oral, brain-penetrant, dual TYK2/JAK1 inhibitor for immune-mediated brain disorders in March 2023 covering global rights (excluding China) Appointed Nick Kozauer, M.D. as SVP of Clinical Development and Regulatory Strategy following his tenure as Director of the Division of Neurology 2 in the Office of New Drugs of the U.S. Food and Drug Administration Taldefgrobep alfa granted Fast Track Designation in SMA Driving strong and consistent progress across six robust drug development platforms in 2023: in Kv7 activation, targeting Phase 2/3 study start in focal epilepsy and bipolar disorder in the second half of 2023; Phase 1 study initiation planned with potentially first-in-class TYK2/JAK1 brain-penetrant inhibitor in immune-mediated brain disorders; three Phase 3 studies gaining momentum with regulatory engagement and enrollment completion expected in programs spanning glutamate modulation in SCA and OCD, respectively, and enrollment ongoing in myostatin inhibition program in SMA; three IND submissions anticipated in 2023 spanning Kv7 activation, TRPM3 antagonism, and IgG degradation offer potential to drive long-term value creation beyond 2023 NEW HAVEN, Conn., May 12, 2023 /PRNewswire/ -- Biohaven Ltd. (NYSE: BHVN) ("Biohaven" or the "Company"), a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies for people with debilitating neurological and neuropsychiatric diseases, including ultra-rare disorders, today reported financial results for the first quarter ended March 31, 2023, and provided a review of recent accomplishments and anticipated upcoming milestones. Vlad Coric, M.D., Chairman and Chief Executive Officer of Biohaven, commented, "We have set forth ambitious goals for the balance of 2023, as we continue advancing what we believe is one of the most innovative and exciting neuroscience platform in development. We were energized by the preliminary safety, tolerability and pharmacokinetic data we reported from our SAD/MAD Phase 1 study of Kv7.2/Kv7.3 activator BHV-7000 earlier in the quarter, supported by the preponderance of preclinical efficacy data generated to date with BHV-7000 demonstrating potent anti-seizure efficacy, concentration-dependent hyperpolarization of the resting membrane potential, meaningful increases in action potential threshold, and encouragingly low GABAA activity. We also look forward to unlocking Kv7 platform expansion opportunities across a spectrum of indications with high unmet medical need." Dr Coric continued, "With our glutamate platform, we look to gain clarity on the regulatory path forward for SCA and expect to complete enrollment in our Phase 3 OCD program in 2023, which we believe are two critically important milestones given the dearth of approved therapies for these distinct patient populations. Regarding our myostatin platform, we continue to activate sites and drive enrollment in our ongoing Phase 3 SMA study. With our recently acquired TYK2/JAK1 platform, we remain focused on starting Phase 1 studies in 2023 and exploring BHV-8000's potential to address an array of immune-mediated brain disorders. And finally, we look forward to submitting IND applications across three separate programs, including BHV-7010, a next-gen Kv7 activator targeting epilepsy and mood disorders, BHV-2011, a TRPM3 inhibitor targeting chronic pain, and BHV-1300, our IgG degrader, following the report of robust preclinical data earlier in the year. We remain as committed as ever to driving data-driven, efficient results for patients and the shareholders who support our continued work, and look forward to executing and delivering continued value in the year ahead." First Quarter 2023 and Recent Business Highlights Acquired BHV-8000, a brain-penetrant inhibitor of TYK2/JAK1, from Highlightll - As previously reported, in March 2023, the Company acquired exclusive rights (excluding China) to a novel, oral, first-in-class, brain-penetrant, dual inhibitor of TYK2/JAK1 offering wide therapeutic index with TYK2 inhibition and high selectivity for JAK1 inhibition without the severely limiting adverse class effects of JAK2/JAK3 inhibitors. The Company expects to commence Phase 1 development in 2023, exploring its potential to address immune-mediated brain disorders. Delivered oral and poster presentations demonstrating preclinical efficacy and initial Phase 1 safety and tolerability of BHV-7000 on ASENT 2023 virtual platform - In March 2023, the Company presented data at the 2023 American Society for Experimental Neurotherapeutics Annual Meeting (ASENT 2023) demonstrating that activating Kv7.2/7.3 with BHV-7000, a structurally and pharmacologically distinct compound from ezogabine, produced concentration-dependent hyperpolarization of the resting membrane potential, potentiated meaningful increases in action potential threshold, exhibited significantly lower GABAA activity than ezogabine, and delivered potent anti-seizure efficacy in the maximal electroshock seizure (MES) model, without negatively impacting neurobehavior. The Company also presented data from the Phase 1 SAD/MAD clinical trial, demonstrating BHV-7000 was well-tolerated at single doses up to 100 mg and multiple doses up to 40 mg per day for 15 days. Most adverse events were mild and resolved spontaneously, and there were no serious or severe adverse events or dose-limiting toxicities reported. In BHV-7000 treated subjects in the MAD study, CNS-related adverse events typically associated with other anti-seizure medications were not reported. Taldefgrobep Alfa Granted Fast Track Designation and Orphan Drug Designation - As previously reported, Taldefgrobep alfa, an anti-myostatin adnectin in development for SMA, was granted Fast Track designation and Orphan Drug designation by the U.S. Food and Drug Administration (FDA) in February 2023, and December 2022, respectively. Phase 3 studies are ongoing; the Company expects to enroll approximately 180 patients in this randomized, double-blind, placebo-controlled global trial. Reported preclinical data with extracellular target degrader platform technology (MoDE™), a pan-IgG degrader - As previously reported, in January 2023, the Company evaluated the effect of a single dose of IgG degrader, BHV-1300, in cynomolgus monkeys. The Company reported 75% reduction of IgG levels from baseline and noted the observation occurred in three days; the data in this pre-clinical study compares favorably to standard of care therapy efgartigimod, where reduction of IgG levels with efgartigimod was observed to be 50% and had taken 5-7 days. The Company expects BHV-1300 will be ready for IND submission in the second half of 2023. Reported preclinical data with second MoDE in bispecific platform targeting IgA Nephropathy - As previously reported, in January 2023, the Company reported preclinical data with a second MoDE targeting galactose deficient IgA (Gd-IgA), which is believed to play a pathogenic role in IgA Nephropathy. Specific removal of pathogenic Gd-IgA with preservation of normal IgA potentially permits disease remission without incurring an infection risk. The Company 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. Leadership team expanded with key appointment - In April 2023, Biohaven announced the appointment of Nick Kozauer, M.D. as SVP of Clinical Development and Regulatory Strategy following his tenure as Director of the Division of Neurology 2 in the Office of New Drugs of the FDA. Dr. Kozauer had supervised and reviewed the approval of over 15 marketed drugs during his tenure at the FDA. Upcoming Expected Milestones: Biohaven is progressing its product candidates through clinical programs in a number of common and rare disorders. The Company expects to reach significant pipeline milestones in the coming periods. Biohaven expects to: Initiate EEG study with BHV-7000 in the first half of 2023: Following Phase 1 study completion, Biohaven expects to initiate pivotal trials in patients with epilepsy and patients with bipolar disorder in the second half of 2023. Submit IND with BHV-7010 in epilepsy and mood disorders: The Company expects to submit an IND with next-generation Kv7 activator BHV-7010 in epilepsy in the second half of 2023. Submit IND with BHV-2100 in chronic pain: The Company expects to submit an IND with BHV-2100, a TRPM3 antagonist in the Company's ion channel platform targeting a pain disorder in the second half of 2023. Submit IND with BHV-1300: The Company expects to submit an IND with pan-IgG degrader BHV-1300 in the second half of 2023. Commence Phase 1 studies with BHV-8000: The Company expects to commence Phase 1 studies with BHV-8000, an oral, brain-penetrant, dual TYK2/JAK1 inhibitor for immune-mediated brain disorders in 2023. Complete enrollment in Phase 3 study of troriluzole in OCD in 2023: Two Phase 3 randomized, double-blind, placebo-controlled studies are expected to enroll up to 700 patients (in each trial) across nearly 200 global study sites. The Company anticipates completing enrollment in year-end 2023. Provide an update on troriluzole in SCA: The Company intends to interact with the FDA and/or European Medicines Agency in the first half of 2023 on next steps. Continue advancing Phase 3 clinical studies of taldefgrobep alfa in SMA: The Company expects to enroll approximately 180 patients in the study through patient enrollment in up to 60 clinical sites. Continue advancements across multiple neuroscience and immunoscience indications: The Company's preclinical pipeline includes molecular degraders of extracellular proteins, CD38 targeting antibody recruiting molecules (ARMs), TRP channels, and other undisclosed targets, including those with disease-modifying potential. Capital Position: Cash, cash equivalents and marketable securities as of March 31, 2023 was $392.0 million, including $4.0 million of restricted cash, and excluding $61.5 million of cash payable to Biohaven Pharmaceutical Holding Company Ltd. (the "Former Parent"), compared to $467.9 million, including $2.5 million of restricted cash, and excluding $35.2 million of cash payable to the Former Parent, as of December 31, 20221. First Quarter 2023 Financial Highlights: Research and Development (R&D) Expenses: R&D expenses, including non-cash share-based compensation costs, were $63.5 million for the three months ended March 31, 2023, compared to $70.1 million for the three months ended March 31, 2022. The decrease of $6.6 million was primarily due to a decrease of $14.7 million in personnel-related costs including non-cash share-based compensation costs, and a decrease in expenses for verdiperstat, BHV-2100 and BHV-1200, partially offset by an increase in expenses for our clinical programs for Kv7 (BHV-7000 and 7010), troriluzole and BHV-2000. The decrease in personnel-related costs is due to non-cash share-based compensation expense for the first quarter of 2022 being allocated from the Former Parent equity plan based on equity awards with higher grant date fair values, which was partially offset by increased personnel costs related to an increase in headcount for our discovery operations. Non-cash share-based compensation expense was $2.2 million for the three months ended March 31, 2023, a decrease of $22.3 million as compared to the same period in 2022. General and Administrative (G&A) Expenses: G&A expenses, including non-cash share-based compensation costs, were $14.3 million for the three months ended March 31, 2023, compared to $19.7 million for the three months ended March 31, 2022. The decrease of $5.4 million was primarily due to decreased non-cash share-based compensation costs. This was partially offset by increased personnel costs in the first quarter of 2023 compared to the same period in 2022, due to a majority of the personnel costs in the first quarter of 2022 being allocated to the Former Parent. Non-cash share-based compensation expense was $1.5 million for the three months ended March 31, 2023, a decrease of $14.1 million as compared to the same period in 2022. The decrease in non-cash share-based compensation expense is due to the first quarter of 2022 expense being allocated from the Former Parent equity plan based on equity awards with higher grant date fair values. Other Income (Expense), Net: Other income (expense), net was a net income of $8.2 million for the three months ended March 31, 2023, compared to net expense of $4.0 thousand for the three months ended March 31, 2022. The increase of $8.2 million was primarily due to an increase in net investment income and an increase of $3.9 million in other income related to our transition services provided to our Former Parent, which is largely non-recurring. Net Loss: Biohaven reported a net loss for the three months ended March 31, 2023, of $70.5 million, or $1.03 per share, compared to $97.0 million, or $2.46 per share, for the same period in 2022. Non-GAAP adjusted net loss for the three months ended March 31, 2023 was $66.7 million, or $0.98 per share, compared to $56.9 million, or $1.45 per share for the same period in 2022. These non-GAAP adjusted net loss and non-GAAP adjusted net loss per share measures, more fully described below under "Non-GAAP Financial Measures," exclude non-cash share-based compensation charges. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the tables below. For periods prior to Biohaven's spin-off from the Former Parent on October 3, 2022 (the "Spin-Off"), net loss per share and non-GAAP adjusted net loss per share were calculated based on the 39,375,944 common shares of Biohaven distributed to the Former Parent shareholders at the time of the distribution, including common shares issued in connection with the Former Parent share options that were settled on October 3, 2022 and common shares issued in connection with the Former Parent restricted share units that vested on October 3, 2022. The same number of shares is being utilized for the calculation of basic and diluted earnings per share for all periods presented prior to the Spin-Off. Non-GAAP Financial Measures This press release includes financial results prepared in accordance with accounting principles generally accepted in the United States (GAAP), and also certain non-GAAP financial measures. In particular, Biohaven has provided non-GAAP adjusted net loss and adjusted net loss per share, which are adjusted to exclude non-cash share-based compensation, which is substantially dependent on changes in the market price of common shares. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. However, Biohaven believes the presentation of non-GAAP adjusted net loss and adjusted net loss per share, when viewed in conjunction with GAAP results, provides investors with a more meaningful understanding of ongoing operating performance and can assist investors in comparing Biohaven's performance between periods. In addition, these non-GAAP financial measures are among those indicators Biohaven uses as a basis for evaluating performance, and planning and forecasting future periods. These non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between these non-GAAP measures and the most directly comparable GAAP measures is provided later in this news release. About Biohaven Biohaven is a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies for people with debilitating neurological and neuropsychiatric diseases, including rare disorders. Biohaven's experienced management team brings with it a track record of delivering new drug approvals for products for diseases such as migraine, depression, bipolar and schizophrenia. The company is advancing a pipeline of therapies for diseases with little or no treatment options, leveraging its proven drug development capabilities and proprietary platforms, including Kv7 ion channel modulation for epilepsy and neuronal hyperexcitability, glutamate modulation for obsessive-compulsive disorder and spinocerebellar ataxia, myostatin inhibition for neuromuscular diseases, and brain-penetrant TYK2/JAK1 inhibition for immune-mediated brain disorders. Biohaven's portfolio of early- and late-stage product candidates also includes discovery research programs focused on TRPM3 channel activation for neuropathic pain, CD-38 antibody recruiting, bispecific molecules for multiple myeloma, antibody drug conjugates (ADCs), and extracellular target degrader platform technology (MoDE™) with potential application in neurological disorders, cancer, and autoimmune diseases. Forward-looking Statements This news release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The use of certain words, including "continue", "plan", "will", "believe", "may", "expect", "anticipate" and similar expressions, is intended to identify forward-looking statements. Investors are cautioned that any forward-looking statements, including statements regarding the future development, timing and potential marketing approval and commercialization of development candidates, are not guarantees of future performance or results and involve substantial risks and uncertainties. Actual results, developments and events may differ materially from those in the forward-looking statements as a result of various factors including: the expected timing, commencement and outcomes of Biohaven's planned and ongoing clinical trials; the timing of planned interactions and filings with the FDA; the timing and outcome of expected regulatory filings; complying with applicable U.S. regulatory requirements; the potential commercialization of Biohaven's product candidates; the potential for Biohaven's product candidates to be first in class therapies; and the effectiveness and safety of Biohaven's product candidates. Additional important factors to be considered in connection with forward-looking statements are described in Biohaven's filings with the Securities and Exchange Commission, including within the sections titled "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations". The forward-looking statements are made as of the date of this new release, and Biohaven does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. MoDEs is a trademark of Biohaven Therapeutics Ltd. Investor Contact: Jennifer Porcelli Vice President, Investor Relations [email protected] +1 (201) 248-0741 Media Contact: Mike Beyer Sam Brown Inc. [email protected] +1 (312) 961-2502 SOURCE Biohaven Ltd.

Phase 1Fast TrackExecutive Change

09 Nov 2022

·www.prnewswire.com

Biohaven Ltd. Reports Third Quarter 2022 Financial Results and Reports Recent Business Developments

Biohaven Ltd. launched post-closing of the Biohaven Pharmaceutical Holding Company Ltd. sale to Pfizer on October 4, 2022, and completed a public offering of 28,750,000 Biohaven Ltd. common shares at a price of $10.50 per share on October 25, 2022, with a total initial capitalization and net cash proceeds from offering of approximately $541 million, and no debt. Advancing multiple late-stage clinical programs including innovative drug candidates targeting Kv7 modulation for epilepsy and neuropsychiatric disorders, glutamate modulation in Obsessive-Compulsive Disorder (OCD) and spinocerebellar ataxia (SCA), and myostatin in spinal muscular atrophy (SMA). Key industry executives added to leadership team, including: Bruce Car, Ph.D. as Chief Scientific Officer; Irfan Qureshi, M.D. as Chief Medical Officer, and Tanya Fischer, M.D., Ph.D. as Chief Development Officer and Head of Translational Medicine. NEW HAVEN, Conn., Nov. 9, 2022 /PRNewswire/ -- Biohaven Ltd. (NYSE: BHVN) ("Biohaven" or the "Company"), a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies for people with debilitating neurological and neuropsychiatric diseases, including rare disorders, today reported financial results for the third quarter ended September 30, 2022, and provided a review of recent accomplishments and anticipated upcoming milestones. The reported financial results present, on a historical basis, the combined assets, liabilities, expenses and cash flows directly attributable to the Company, which have been prepared from Biohaven Pharmaceutical Holding Company Ltd., the former parent, consolidated financial statements and accounting records, and are presented on a stand-alone basis as if the operations had been conducted independently from the former parent. Vlad Coric, M.D., Chairman and Chief Executive Officer of Biohaven, commented, "Just weeks after launching in October as a new publicly traded company and separate independent entity as part of the merger agreement with Pfizer, we continued to advance our late stage clinical development programs and substantially enhanced our resources by raising gross proceeds of approximately $301.9 million in a public financing that drew support from a breadth of longstanding and new Biohaven investors. We are well positioned with an outstanding drug development team, a deep late-stage pipeline and a strong capital position to favorably position us to accelerate development across our portfolio." Dr. Coric continued, "Our Kv7 platform, with its vast potential to address epilepsy and neuropsychiatric indications, is being prioritized by the team with the goal of at least one Phase 2/3 study start in 2023. We also continue to make progress with our Phase 3 study evaluating taldefgrobep alfa in patients with spinal muscular atrophy, as well as with our Phase 3 study evaluating troriluzole in patients with OCD. Finally, our discovery efforts remain a key pillar of our pipeline formation strategy; with IND-enabling studies underway across several programs, we expect to provide updates on programs like TRPM3, a potential breakthrough, non-opioid treatment option for pain, and other earlier stage protein degrader programs in the coming months and years. Our unwavering commitment to patients continues propelling us forward and we cannot wait to deliver additional therapeutic breakthrough medicines to drive outcomes for patients, shareholders and employees." Third Quarter and Recent Business Highlights: Company launch - On October 3, 2022, Biohaven Ltd. began operating as a separate independent entity in connection with the merger agreement entered into with Pfizer Inc. in May 2022. As of October 4, 2022, Biohaven Ltd. commenced regular way trading under the symbol "BHVN" on the New York Stock Exchange as an independent, publicly traded company focused on delivering innovative life-changing treatments for neurological and neuropsychiatric diseases, including rare disorders, and leveraging its proven drug development capabilities and proprietary technology platforms to advance a pipeline of best-in-class therapies. The Company, led by Vlad Coric, M.D. as Chairman and Chief Executive Officer, launched with approximately $257.8 million in cash and no debt. Public offering - On October 25, 2022, the Company closed its previously announced underwritten public offering of 28,750,000 of its common shares, which includes the full exercise of the underwriters' option to purchase 3,750,000 additional shares, at the public offering price of $10.50 per share. The gross proceeds raised in the offering, before deducting underwriting discounts and estimated expenses of the offering payable by the Company, were approximately $301.9 million. As of November 7, 2022, we had 68,160,979 common shares, without par value per share, outstanding. Advanced Phase 1 studies for BHV-7000 - As previously reported, in the second quarter of 2022, the Company's Clinical Trial Application for BHV-7000 was approved by Health Canada, and the Company subsequently began clinical development. BHV-7000, the lead asset from the Kv7 platform, is an activator of Kv7.2/Kv7.3, a key ion channel involved in neuronal signaling and in regulating the hyperexcitable state in epilepsy. Advanced development of extracellular target degrader platform technology (MoDEs™) for therapies across a variety of diseases including neuroscience, immunology and oncology - In October, Biohaven announced advancements in the development of its MoDE extracellular target degrader platform technology licensed from Yale University for various disease indications, including, but not limited to, neurological disorders, cancer, infectious and autoimmune diseases. Biohaven made further innovations in this ground-breaking technology with new patent applications covering additional targets and functionality. Operationalized fully-equipped Biohaven Cambridge laboratory - In October, the Company expanded its footprint to include new laboratory space in Cambridge, Massachusetts. Commenced enrollment in Phase 3 SMA study - In July, the Company commenced enrollment in a Phase 3 clinical trial assessing the efficacy and safety of taldefgrobep alfa in SMA. Taldefgrobep targets myostatin, a natural protein that limits skeletal muscle growth, through two mechanisms: lowering myostatin directly and blocking key downstream signaling mechanisms. The Company expects to enroll approximately 180 patients in this randomized, double-blind, placebo-controlled global trial. Global Coalition for Adaptive Research (GCAR) commenced enrollment in Glioblastoma Adaptive Global Innovative Learning Environment (GBM Agile) Phase 2-3 adaptive platform trial for patients with glioblastoma - In July, GCAR announced the activation of Biohaven's troriluzole in GBM AGILE, a patient-centered, adaptive platform trial for registration that tests multiple therapies for patients with newly-diagnosed and recurrent glioblastoma (GBM). GBM AGILE is an international, innovative platform trial designed to more rapidly identify and confirm effective therapies for patients with glioblastoma through response adaptive randomization. The new interventions are opening first at Henry Ford Health Cancer in Detroit under Henry Ford site Principal Investigator Dr. Tom Mikkelsen and will subsequently open at more than 40 trial sites across the United States with additional global sites to follow. Upcoming Milestones: Biohaven is progressing its product candidates through clinical programs in a number of common and rare disorders. The Company expects to reach significant pipeline milestones in the coming periods. Biohaven expects to: Complete Phase 1 studies of BHV-7000 in the first half of 2023: If the Phase 1 studies are successfully completed, Biohaven expects to initiate at least one pivotal trial in patients with epilepsy in the second half of 2023. Complete enrollment in Phase 3 study of troriluzole in OCD in 2023: Two Phase 3 randomized, double-blind, placebo-controlled studies are expected to enroll approximately 1,300 patients across nearly 200 global study sites. The Company anticipates completing enrollment in 2023. Provide an update on troriluzole in SCA: The Company had previously reported top-line results from a Phase 3 clinical trial evaluating the efficacy and safety of its investigational therapy, troriluzole, in patients with SCA in May of 2022. While the primary endpoint, change from baseline to Week 48 on the modified functional Scale for the Assessment and Rating of Ataxia did not reach statistical significance in the overall SCA population, as there was less than expected disease progression over the course of the study, post hoc analysis of efficacy measures by genotype suggested a treatment effect in patients with the SCA Type 3 (SCA3) genotype, which represents the most common form of SCA and accounted for 41 percent of the study population. The Company intends to interact with the FDA and/or EMA in the first half of 2023. We have not yet decided on the format of such a regulatory interaction but we could seek advice through various formal or informal interactions with regulatory agencies or we could choose to submit a New Drug Application (NDA) if we believe that is warranted from the results of our ongoing post-hoc analyses. Continue advancing Phase 3 clinical studies of taldefgrobep alfa in SMA: The Company expects to enroll approximately 180 patients in the study. Continue advancing early discovery portfolio across multiple neuroscience and immunoscience indications: The Company's preclinical pipeline includes molecular degraders of extracellular proteins, CD38 targeting antibody recruiting molecules (ARMs), TRP channels, TDP-43 targeting small molecules, and other undisclosed targets, including those with disease-modifying potential. Continue pursuing formulation development work with BHVN-5500 for use in combination studies with Kv7 platform: The Company is developing BHV-5500 (lanicemine), a low-trapping NMDA receptor antagonist. One potential target indication includes Complex Regional Pain Syndrome. Other disorders of interest include post-herpetic neuralgia and diabetic peripheral neuralgia. Current work is focused on formulation development. Capital Position: Cash as of September 30, 2022 was $50.7 million, excluding $0.8 million of restricted cash, compared to $76.1 million as of December 31, 2021. On October 3, 2022, in connection with the closing of the acquisition of Biohaven Pharmaceutical Holding Company Ltd. by Pfizer, Biohaven Ltd. launched with a cash balance of approximately $257.8 million. On October 25, 2022, the Company closed its previously announced public offering, which resulted in net proceeds to the Company of approximately $282.8 million. Third Quarter 2022 Financial Highlights: Research and Development ("R&D") Expenses: R&D expenses, including non-cash share-based compensation costs, were $52.8 million for the three months ended September 30, 2022, compared to $47.0 million for the three months ended September 30, 2021. The increase of $5.9 million was primarily due to increased expenses relating to our clinical programs partially offset by decreases in our program expenses for verdiperstat. Non-cash share-based compensation expense was $9.7 million for the three months ended September 30, 2022, a decrease of $0.5 million as compared to the same period in 2021. General and Administrative ("G&A") Expenses: G&A expenses, including non-cash share-based compensation costs, were $14.8 million for the three months ended September 30, 2022, compared to $8.5 million for the three months ended September 30, 2021. The increase of $6.3 million was primarily due to increased expenses related to accounting, legal and other professional fees associated with the Pfizer acquisition and spin-off of Biohaven Ltd. as an independent, publicly traded company. Non-cash share-based compensation expense was $7.3 million for the three months ended September 30, 2022, an increase of $2.1 million as compared to the same period in 2021. Net Loss: Biohaven reported a net loss for the three months ended September 30, 2022, of $68.9 million, or $1.75 per share, compared to $54.4 million, or $1.38 per share, for the same period in 2021. Non-GAAP adjusted net loss for the three months ended September 30, 2022 was $49.2 million, or $1.25 per share, compared to $39.0 million, or $0.99 per share for the same period in 2021. These non-GAAP adjusted net loss and non-GAAP adjusted net loss per share measures, more fully described below under "Non-GAAP Financial Measures," exclude non-cash share-based compensation charges and gains or losses from equity method investment. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the tables below. Net loss per share and Non-GAAP adjusted net loss per share were calculated based on the 39,368,042 shares of Biohaven Ltd. common stock distributed to Biohaven Pharmaceutical Holding Company Ltd. shareholders at the time of the Distribution, including common shares issued in connection with Biohaven Pharmaceutical Holding Company Ltd. stock options that were exercised on October 3, 2022 and common shares issued in connection with Biohaven Pharmaceutical Holding Company Ltd. restricted stock units that vested on October 3, 2022. The same number of shares is being utilized for the calculation of basic and diluted earnings per share for all periods presented prior to the Spin-Off. Non-GAAP Financial Measures This press release includes financial results prepared in accordance with accounting principles generally accepted in the United States (GAAP), and also certain non-GAAP financial measures. In particular, Biohaven has provided non-GAAP adjusted net loss and adjusted net loss per share, adjusted to exclude the items below. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. However, Biohaven believes the presentation of non-GAAP adjusted net loss, when viewed in conjunction with GAAP results, provides investors with a more meaningful understanding of ongoing operating performance. These measures exclude (i) non-cash share-based compensation, which is substantially dependent on changes in the market price of common shares, (ii) gains or losses from equity method investment, which are non-cash and based on the financial results and valuation of another company that we did not manage or control, and (iii) transaction-related costs incurred relating to the Company's spin-off from Biohaven Pharmaceutical Holding Company Ltd., which are limited to a specific period of time and related to Biohaven Ltd. being established as a standalone public company. Biohaven believes the presentation of these non-GAAP financial measures provides useful information to management and investors regarding Biohaven's results of operations. When GAAP financial measures are viewed in conjunction with these non-GAAP financial measures, investors are provided with a more meaningful understanding of Biohaven's ongoing operating performance and are better able to compare Biohaven's performance between periods. In addition, these non-GAAP financial measures are among those indicators Biohaven uses as a basis for evaluating performance, and planning and forecasting future periods. These non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between these non-GAAP measures and the most directly comparable GAAP measures is provided later in this press release. About Biohaven Biohaven is a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies for people with debilitating neurological and neuropsychiatric diseases, including rare disorders. The company is advancing a pipeline of best-in-class therapies for diseases with little or no treatment options, leveraging its proven drug development capabilities and proprietary platforms, including Kv7 ion channel modulation for epilepsy and neuronal hyperexcitability; glutamate modulation for obsessive-compulsive disorder and spinocerebellar ataxia and myostatin inhibition for neuromuscular diseases. Biohaven's portfolio of early- and late-stage product candidates also includes discovery research programs focused on TRPM3 channel activation for neuropathic pain and CD-38 antibody recruiting, bispecific molecules for multiple myeloma. Forward-looking Statements This news release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The use of certain words, including "continue", "plan", "will", "believe", "may", "expect", "anticipate" and similar expressions, is intended to identify forward-looking statements. Investors are cautioned that any forward-looking statements, including statements regarding the future development, timing and potential marketing approval and commercialization of development candidates are not guarantees of future performance or results and involve substantial risks and uncertainties. Actual results, developments and events may differ materially from those in the forward-looking statements as a result of various factors including: the expected timing, commencement and outcomes of Biohaven's planned and ongoing clinical trials; the timing of planned interactions and filings with the Food and Drug Administration; the timing and outcome of expected regulatory filings; complying with applicable U.S. regulatory requirements; the potential commercialization of Biohaven's product candidates; the potential for Biohaven's product candidates to be first in class or best in class therapies; and the effectiveness and safety of Biohaven's product candidates. Additional important factors to be considered in connection with forward-looking statements are described in Biohaven's filings with the Securities and Exchange Commission, including within the sections titled "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations". The forward-looking statements are made as of the date of this new release, and Biohaven does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. MoDEs is a trademark of Biohaven Therapeutics Ltd. Investor Contact: Jennifer Porcelli Vice President, Investor Relations [email protected] +1 (201) 248-0741 Media Contact: Mike Beyer, Media Relations Counselor Sam Brown Inc. [email protected] +1 (312) 961-2502 SOURCE BIOHAVEN LTD

CollaborateFinancial StatementAntibodyInnovative DrugFirst in Class

17 Oct 2022

·www.fiercebiotech.com

Biogen's ALS ambitions on pause as FDA delays approval decision by 3 months

While the FDA reviews its amyotrophic lateral sclerosis drug, Biogen said it will continue its early access program for participants spanning over a dozen countries. The long and winding road Biogen’s tofersen has taken to FDA approval just got longer, with the agency delaying its decision on the amyotrophic lateral sclerosis (ALS) drug until April. Biogen’s tofersen plans were almost derailed a year ago by a phase 3 study that revealed the antisense medicine failed to improve the functional status of SOD1-ALS patients compared to placebo after six months, causing the 108-subject study to miss its primary endpoint. Undeterred, the Big Pharma used 12-month data from the phase 3 VALOR trial and an open-label extension to show that an earlier initiation of tofersen treatment slowed decline across measures of clinical and respiratory function, strength and quality of life. The FDA seemed convinced enough to consider the approval application and penciled in a decision date of Jan. 25, 2023. Now, the agency has pushed the date back to April 25, Biogen said in a release Monday morning. The FDA’s reasoning is that it considers responses submitted by Biogen as part of the ongoing review to be a “major amendment” to the application, requiring additional time to consider. The FDA first accepted the tofersen approval application back in July under the accelerated pathway and granted priority review. If approved, the Ionis Pharmaceuticals-partnered prospect would be the first drug to treat a genetic cause of ALS. While the FDA reviews the drug, Biogen said it will continue its early access program for participants spanning over a dozen countries. An open-label extension and the phase 3 ATLAS study in pre-symptomatic individuals with motor neurone disease and the SOD1 genetic mutation remain ongoing. Other potential ALS therapies have also had a tricky time with the regulator. In June, the FDA notified Amylyx Pharmaceuticals that it was extending its decision date for its drug AMX0035 to review additional data analyses. The therapy was previously voted down by an agency advisory committee in March in a tough vote that followed riveting patient testimony. Clinical trials have been even less forgiving, with Clene Nanomedicine seeing its shares slump after its ALS drug CNM-Au8 came up short in a phase 2 trial in October. A month earlier, Biohaven announced its ALS drug verdiperstat failed to improve disease progression.

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100 Deals associated with Verdiperstat

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D11684	-	-	DB12440

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple System Atrophy	Phase 3	US	Biohaven Pharmaceuticals, Inc.	29 Jul 2019
Multiple System Atrophy	Phase 3	AT	Biohaven Pharmaceuticals, Inc.	29 Jul 2019
Multiple System Atrophy	Phase 3	FR	Biohaven Pharmaceuticals, Inc.	29 Jul 2019
Multiple System Atrophy	Phase 3	DE	Biohaven Pharmaceuticals, Inc.	29 Jul 2019
Multiple System Atrophy	Phase 3	IT	Biohaven Pharmaceuticals, Inc.	29 Jul 2019
Multiple System Atrophy	Phase 3	GB	Biohaven Pharmaceuticals, Inc.	29 Jul 2019
Amyotrophic Lateral Sclerosis	Phase 3	US	Biohaven Pharmaceutical Holding Co. Ltd.	20 Jul 2019
Parkinson Disease	Phase 2	SE	AstraZeneca PLC	01 Apr 2012
Multiple System Atrophy (MSA) With Orthostatic Hypotension	Phase 1	US	Biohaven Pharmaceuticals, Inc.	30 Dec 2020
Multiple system atrophy, cerebellar variant	Phase 1	US	Biohaven Pharmaceuticals, Inc.	30 Dec 2020

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03952806 (CTgov)	Phase 3	Multiple System Atrophy	421	verdiperstat (Verdiperstat - Randomization Phase)	titccrehuf(wkntkwfyfg) = kggnklesde laudbeuxnl (rvebqogryy, avqunbglns - legsbgohuj) View more	-	29 Sep 2023
				placebo+verdiperstat (Placebo - Randomization Phase)	titccrehuf(wkntkwfyfg) = innvyuwpbb laudbeuxnl (rvebqogryy, edekhndtln - ozeyanrqwn) View more
NCT04436510 (CTgov)	Phase 2/3	Amyotrophic Lateral Sclerosis	167	Verdiperstat (Verdiperstat)	opnabmdnlr(epydbnwscb) = nmqjbxnqnp oqurcesqsx (sqjrnzqiwl, zmxlvuoncz - pevzybegfm) View more	-	12 Jun 2023
				Matching Placebo (Matching Placebo)	opnabmdnlr(epydbnwscb) = hqwuljhytv oqurcesqsx (sqjrnzqiwl, bzrmccylbl - dwtonjfgus) View more
NCT04436510 (HEALEY ALS, NEWS) Manual	Phase 2/3	Amyotrophic Lateral Sclerosis	-	Verdiperstat	rxitraqrip(xqgxzfacjq) = Verdiperstat did not statistically differentiate from placebo hdmmxqecln (dkxnrsvpdt )	Negative	29 Sep 2022
				Placebo
M-STAR (MDS2022)	Not Applicable	Multiple System Atrophy	-	Verdiperstat 600 mg	qbpawkqkbs(jlnjcgyipu): P-Value = 0.0005 View more	-	15 Sep 2022
				Placebo
NCT02388295 (CTgov)	Phase 2	Multiple System Atrophy	59	Placebo+AZD3241 (Placebo)	vhvclxswvk(rqyorfjyrv) = xwsfjxdanw anrtrfhrqs (pujyxoywui, lpmnqkgdzz - zcfjpzfhdr) View more	-	25 Sep 2017
				AZD3241 (AZD3241 300 mg)	vhvclxswvk(rqyorfjyrv) = vrcifzxyvl anrtrfhrqs (pujyxoywui, gzgprwcaee - cvlvchetwf) View more

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