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Biohaven acknowledges its experimental drug for spinocerebellar ataxia failed in a pivotal study, but the biotech hoped results showing benefit in a subgroup would be enough to secure approval for those patients given that this rare, inherited neuromuscular disorder has no approved therapies. The FDA disagrees. On Thursday, Biohaven said the FDA refused to review the application for the drug, troriluzole. Refuse to file letters are not public documents. According to Biohaven, the agency said the study’s failure to meet the primary endpoint “would not permit a substantive review.” The New Haven, Connecticut-based company said it plans to request a meeting to discuss the FDA’s concerns. Spinocerebellar ataxia (SCA) affects the cerebellum, the part of the brain that governs muscle control. The worsening of muscle control from SCA eventually leads to patients requiring wheelchairs. More than 40 types of this disease have been identified, many of them linked to a particular genetic mutation. Troriluzole doesn’t address the genetic mutation. Rather, it is intended to reduce levels of glutamate, a neurotransmitter whose dysfunction is associated with many neurological disorders, including SCA. Biohaven’s Phase 3 test of troriluzole evaluated the drug in all types of SCA. Last year, the company reported the drug failed to meet the main goal of showing, at week 48, a significant change in score according to a scale used to assess muscle control and movement. However, the company pointed to a post hoc analysis of the data showing a treatment effect in patients with SCA type 3, or SCA3. This type is the most common form of the disease and it represented 41% of the study population. The analysis showed SCA3 patients had fewer falls compared to those given a placebo, results the company said demonstrate clinically meaningful improvement. In May, Biohaven submitted a new drug application seeking approval of troriluzole for patients with SCA3. In a note sent to investors Thursday, William Blair analyst said the FDA’s decision to decline review of troriluzole was disappointing in light of other recent favorable regulatory decisions for rare disease drugs. As examples, he pointed to the approvals of Reata Pharmaceuticals drug Skyclarys for ultra rare disease Friedreich’s ataxia and Acadia Pharmaceuticals drug Daybue for Rett syndrome. Both drugs are the first approved treatments for their respective disease indications. Lugo said troriluzole may still have a path forward, but it is unlikely the FDA will change its decision without additional clinical data. That could mean Biohaven needs to conduct another Phase 3 study enrolling only SCA3 patients. Biohaven believes troriluzole’s mechanism of action has potential applications in other neurological diseases, but clinical trial results have been disappointing so far. In 2020, the drug failed a Phase 3 test in generalized anxiety disorder. In 2021, it failed a Phase 2/3 test in Alzheimer’s disease. Biohaven stands by the data produced for troriluzole in SCA. In a prepared statement, CEO Vlad Coric said that about 200 patients have been treated with the drug for up to three years and these patients have remained stable compared to the untreated natural history cohorts who showed disease progression over a similar time period. In addition to delaying disease progression, Coric said the troriluzole data also show a reduction in falls. “The risk-benefit profile for troriluzole warranted careful consideration by the FDA for this ultra-rare disorder,” Coric said. “SCA is clearly a severely debilitating, life-threatening disease with substantial unmet need. The approximately 6,000 patients in North America at least deserved a thorough review of the data package submitted.” Public domain image by Flickr user SciTechTrend

Despite the agency's refusal to review the application, Biohaven "is committed to working closely with the FDA to bring troriluzole to people with SCA3 as quickly as possible." Biohaven’s attempts to redefine itself as a post-migraine company are continuing to encounter headaches, with the company expressing “deep disappointment” at the FDA’s refusal to review the brain disorder drug troriluzole. Even according to Biohaven’s description, the FDA’s reasoning is straightforward—as the drug has previously failed a phase 3 trial in spinocerebellar ataxia, the regulator “would not permit a substantive review.” In the phase 3 study readout in May 2022, an unexpected lack of disease progression among trial participants over the nearly one-year follow-up period hindered the impact of the drug. Despite failing the trial, CEO Vlad Coric, M.D., said at the time that the company looked forward to sharing genotype data with regulators and “working with the FDA to address the high unmet need in this patient population.” Coric wasn’t the only one who remained upbeat on the drug’s chances, with Mizuho Securities analysts also pointing out last year that there are no treatment options for the disease. If Biohaven was able to find positive results for the subgroup as it planned to do, the analysts noted at the time, troriluzole could still find a niche market. It was with this mindset that Biohaven submitted troriluzole for approval to the FDA last month. The new drug application was specifically for patients with the genotype SCA3, who the company said had demonstrated “consistent treatment benefits.” This group represents the most common form of SCA and accounted for 41% of the population of the failed phase 3 trial. Despite the agency's refusal to review the application, Biohaven “is committed to working closely with the FDA to bring troriluzole to people with SCA3 as quickly as possible given no therapy is currently approved for this ultra-rare genetic disorder.” The company was given the option to request a Type A meeting with the regulator within 30 days, and Biohaven said it will take up this offer to “comprehensively address FDA's concerns cited in the refusal to file letter.” These letters are issued when the agency determines that an application has significant deficiencies. “As a physician, I am deeply disappointed by the FDA's decision not to review the submitted NDA, and not to give complete consideration of all available data that we believe show disease-modifying effects for this genetic disorder that has no approved treatments,” Coric said in this morning’s release. “We believe the NDA package is compelling and shows that treatment with troriluzole leads to clinically meaningful treatment benefits, including significantly delaying disease progression and reduction in falls,” the CEO added. “We stand by these data and analyses.” Luckily, Biohaven’s fortunes don’t rest on troriluzole. The company has been making efforts to flesh out its neuroscience pipeline since relaunching after the sale of its migraine program to Pfizer for more than $11 billion in 2022. Most recently, that has meant licensing a neuroinflammation drug from China’s Highlightll Pharmaceuticals. The company also tried to soften the blow of the FDA’s decision this morning by highlighting positive interim data from its lead investigational epilepsy candidate BHV-7000 in healthy volunteers. Biohaven’s shares were down 16% to $20 in pre-market trading Thursday from a Wednesday closing price $23.80. Still, it marks a relatively small dent in an overall positive year for Biohaven’s stock, which entered 2023 at just $13.50.

Submitted a new drug application (NDA) for troriluzole in Spinocerebellar Ataxia Type 3 (SCA3) to U.S. FDA in 2Q2023, marking the team's fourth NDA in approximately 3 years Released additional data from Kv7 platform, including Phase 1 safety data by dose groups for BHV-7000 that further validates differentiated profile Projected Phase 3 Spinal Muscular Atrophy trial to complete enrollment in 2023 Initiated Phase 1 study of brain penetrant TYK2/JAK1 inhibitor, BHV-8000, and anticipate beginning Phase 2 trial in Parkinson's disease next year Highlighted robust pipeline with multiple INDs planned to be filed within the next year, including pan IgG degrader for multiple immune-mediated diseases in 2023 NEW HAVEN, Conn., May 31, 2023 /PRNewswire/ -- Biohaven Ltd. (NYSE: BHVN) ("Biohaven"), a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies for people with debilitating diseases, including ultra-rare disorders, will provide an overview of clinical progress, regulatory updates, and pipeline developments at an in-person R&D Day today, concurrently with the Yale Ventures' Innovation Summit 2023 taking place on May 31-June 1. Members of Biohaven's senior management team and key opinion leaders will meet with investors and research analysts. The clinical progress, regulatory updates, and pipeline developments to include: Troriluzole in SCA: Submitted New Drug Application (NDA) to the U.S. FDA for troriluzole for the treatment of spinocerebellar ataxia type 3 (SCA3), an ultra-rare, genetically-defined, neurodegenerative disease associated with progressive disability, frequent falls, loss of ambulation, speech and swallowing impairment, and premature death that is the most common SCA genotype worldwide. NDA supported by consistent treatment benefits observed in patients with genotype SCA3 in Study BHV4157-206 across multiple outcome measures including the change from baseline f-SARA at Week 48, CGI-I total score at Week 48, and a robust reduction in fall risk over the study period. A rigorous analysis by genotype was possible as patients were randomized by genotype strata at baseline prior to randomization in the pivotal Phase 3 48-week, double-blind, placebo-controlled phase of Study BHV4157-206. SCA3 represented 41% of study participants, consistent with being the most common subtype. SCA3 affects approximately 10,600 people in North America and in the EU and Japan. NDA further supported by a composite scale development (SCACOMS) and analysis of Study BHV4157-206, and confirmatory evidence of efficacy provided by data from the 3-year, long-term open-label (OLE) extension phase of two studies (BHV4157-206 and BHV4157-201) using a Matching Adjusted Indirect Comparison (MAIC) to an external control group. Biohaven has previously received Fast-Track and Orphan drug designation (ODD) from the FDA, and ODD from the European Medicines Agency, for troriluzole in SCA. Kv7 Platform: Highlighted progress and broad potential of Kv7 platform, including ongoing and planned development of BHV-7000 (Kv7.2/3 activator): Phase 1 EEG study with BHV-7000 in 1H2023. Pivotal studies with BHV-7000 in focal epilepsy and bipolar disorder planned to initiate in 2H2023. Burgeoning evidence for therapeutic benefits of targeting Kv7 in diverse, high unmet need indications. Bispecific Platform: Provided updates regarding planned INDs for targeted extracellular protein degradation franchise (including IgG, IgA, and autoantibody-specific degrader programs) and next-generation antibody-drug conjugate (ADC) technologies; IND application for novel IgG degrader, BHV-1300, on track for submission in 2023. TYK2/JAK1 Inhibition in Immune-Mediated Brain Disorders: Began dosing with BHV-8000 (an oral, brain-penetrant, dual TYK2/JAK1 inhibitor) in a ­­­Phase 1 study in normal healthy volunteers. Taldefgrobep Alfa: In Spinal Muscular Atrophy: Enrollment of approximately 225 patients in global Phase 3 trial now anticipated to complete in 2023. In Metabolic Disorders: Planned Phase 2 trial initiation in 2H2023. Vlad Coric M.D., CEO and Chairman of Biohaven, commented, "Today's R&D Day review of our robust pipeline highlights Biohaven's continued dedication to advance novel therapeutics for brain disorders and builds upon our team's successes with the prior approvals of Nurtec® ODT and Zavzpret™ that have changed the treatment paradigm in migraine." "The NDA we submitted for troriluzole for SCA3 represents approximately seven years of effort by the Biohaven team to bring forward a potentially new treatment for this ultra-rare disease. Advancing a new investigational drug for a rare disease that has no current therapy is a multi-year process that is the culmination of not only our own internal efforts but also close coordination with patient advocacy groups including the National Ataxia Foundation (NAF), leading academic researchers and regulatory agencies. Rare brain diseases are particularly challenging to research given relatively small populations of patients to run / participate in clinical trials, the need to rely on real-world data and often a lack of standardized ratings scales or biomarkers. We could not have advanced the SCA program this far without the leadership from the National Ataxia Foundation that has supported basic science research as well as the development of natural history cohorts in SCA that serve as an external control for longitudinal studies. The Biohaven clinical trials in SCA were a first of its kind in this area and utilized a newly developed rating scale (the functional SARA or f-SARA) that was developed in close consultation with the FDA using standard regulatory pathways to elucidate this new scale. We look forward to interactions with the US FDA, EMA and other regulatory agencies across the globe as our submissions advance in the review process," Dr. Coric added. "We are pleased that our decades-long investment in ataxia research and understanding of disease progression has accelerated treatment development for SCA," said Andrew Rosen, Executive Director of the National Ataxia Foundation. "Thank you to all NAF members who participated in these important trials." Bruce Car PhD, Biohaven's CSO, stated, "Given the lack of efficacious therapies for many brain disorders, we must urgently evaluate new mechanisms and approaches to change the treatment paradigm in this therapeutic area. Our R&D Day today demonstrates the commitment that we have given to this effort with exciting new approaches ranging from our submission of a glutamate modulator in SCA to immune modulation using small molecule degraders to ion channels targeting agents for epilepsy and mood disorders, as well as a biologic treatment to enhance muscle growth in SMA. Our scientific and clinical team is poised to file multiple new INDs from our deep pipeline and complete late-stage clinical trials in the next couple of years. It is an exciting time at Biohaven for our passionate employees, patients and investors as we advance these novel investigational drugs in our pipeline." The Research & Development Day presentations will be made available following the conclusion of the program on . 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 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 disorder 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 targeted extracellular protein degrader platform technology (MoDE™) with potential application in neurological disorders, cancer, and autoimmune diseases. For more information, visit . 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 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.