Trigriluzole

The FDA has turned down Biohaven’s drug for spinocerebellar ataxia, a neurodegenerative disease that leads to loss of coordination and balance, citing issues with using real-world evidence and natural history studies. As a result, Biohaven is cutting costs, pausing programs and may lay off staff. Known as troriluzole, it’s the latest rare disease drug to be rejected or face speed bumps under new FDA leadership. The challenges have come seemingly after companies and the agency had previously agreed on how a study would be conducted — eliciting frustration from drug developers. Others, like uniQure and Replimune , have also been turned away by the agency for using trials without a typical control arm that’s employed in randomized controlled trials. The lack of a control arm makes data more challenging to interpret, but rare disease drugmakers say there is no plausible way for them to run effective controlled trials given the small patient populations and lack of alternative treatment options, among other obstacles. It is difficult to know whether the agency has reversed its position on the use of these kinds of studies or whether there are real problems with the clinical data from these companies, particularly since the agency has been embroiled in drama under new leadership. But in this case, Biohaven is getting rejected after the agency declined to even review the company’s application in 2023 after a placebo-controlled trial failed. “This was a highly controversial application considering the use of RWD [real-world data] as the comparator,” TD Cowen analyst Tyler Van Buren wrote on Wednesday. “Thus, while disappointing, this outcome comes as unsurprising to many investors, especially in view of the ongoing tumult and lack of continuity at the FDA.” But to Biohaven CEO Vlad Coric, the agency’s recent actions against its drug and others represent an about-face, and will raise risk and reduce investment into the rare disease space. “You see an abrupt change in, not just our case, but numerous rare disease cases, with a lack of flexibility. How do you interpret it as anything other than a leadership issue?” he said. Biohaven is developing troriluzole — another form of a drug called riluzole used to treat the neurodegenerative disease ALS — for spinocerebellar ataxia. The company resubmitted its application using a real-world evidence study called Study 206-RWE, which showed the drug cut disease progression after three years compared to external controls. Biohaven said that in its rejection letter, the agency “cited issues that can be inherent to real-world evidence and external control studies, including potential bias, design flaws, lack of pre-specification and unmeasured confounding factors.” The regulator now releases these rejection letters, known as complete response letters, which will help provide more detailed information on Biohaven’s case. Biohaven’s shares $BHVN fell 40% Wednesday morning. The company said it plans to meet with the FDA to discuss next steps. In its press release on Wednesday, Biohaven attached a graphic laying out its regulatory interactions since 2017. Notably, the FDA in May delayed its decision on troriluzole by three months and required an advisory committee meeting to review the drug with outside experts. But then in August, the agency canceled the meeting. Coric said the agency did not provide any reason for the cancellation of the advisory committee meeting. “If you are going to reject an application like this that has a priority review and strong arguments why the data should be considered, that is exactly what would warrant an advisory committee. So why did they schedule it? And then after all these [doctors] and patients speak up, why do they cancel it?” he said. “You have policymakers saying all these great things, and divisions who are doing the opposite. And then you have the chaos of last weekend , right? You have leadership that has been absent, and that’s a problem. There’s numerous issues going on, and it’s not just our company,” Coric said. Biohaven said as a result of the rejection, it plans to prioritize three programs, including its degrader program for autoimmune diseases like IgA nephropathy and Graves’ disease, a focal epilepsy and depression drug, and a myostatin-activin blocker for obesity and SMA. That means the company is shelving six other programs outside of troriluzole currently listed on its pipeline page. The company said it plans to cut 60% of annual R&D costs, which it said would delay “non-priority” programs. When asked about layoffs, Coric said, “There will always be effects on some workforce, but it’ll mainly be program-level.”

Biohaven may pause or delay programs to extend its cash runway. \n The FDA has rejected Biohaven’s request for approval of a neurological disorder therapy, prompting the biopharma to reprioritize its pipeline in order to shrink its annual R&D spend by 60%.Biohaven first sought FDA approval for troriluzole in spinocerebellar ataxia on the strength of a phase 3 trial that missed its primary endpoint. The FDA refused to review that submission in 2023, but Biohaven continued to seek a path forward, leading to talks about the potential to use real-world evidence (RWE) to support a resubmission. Biohaven hailed positive three-year RWE findings in September 2024.After a three-month delay, the FDA has now rejected an approval request based on the RWE. According to Biohaven, the FDA’s complete response letter “cited issues that can be inherent to real-world evidence and external control studies including potential bias, design flaws, lack of pre-specification and unmeasured confounding factors.”Such issues were on the agenda when Biohaven met with the FDA to discuss the RWE study in 2024. The biopharma said it changed its RWE study protocol in response to the feedback, including by only using the U.S. natural history cohort as an external control for the primary analysis. Quoting official meeting minutes, Biohaven said the FDA’s view was that “a large and robust treatment effect would be needed to overcome the biases of an externally controlled trial, in order for it to be used as the primary basis for substantial evidence for effectiveness.” Biohaven executives believe their RWE study cleared that bar.Yet the FDA, which has undergone a change in leadership and direction since the 2024 meeting, ruled that the submission cannot support approval. The agency recommended Biohaven meet with its team to discuss the evidence it wants to see in a future filing for approval. Biohaven is in the process of formally requesting a meeting. In the wake of the news, Biohaven\'s stock dropped 44% to $7.76 in premarket trading Wednesday from a Tuesday closing price of $13.95.While Biohaven said it remains committed to finding a path forward for troriluzole, the FDA rejection has prompted the biopharma to prioritize other late-stage programs that management believes have the most potential for value generation. Biohaven’s priorities for the next year are the extracellular degraders BHV-1400 in IgA nephropathy and BHV-1300 in Graves’ disease, Kv7 ion channel activator opakalim in adult focal epilepsy and depression and myostatin-activin pathway inhibitor taldefgrobep alfa in obesity and spinal muscular atrophy.  The company may pause or delay other programs to extend its cash runway. Biohaven ended June with $408.2 million. The pipeline prioritization is intended to cut annual direct R&D spending, which excludes personnel costs, by 60%.The implications of the CRL could extend beyond Biohaven. The Division of Neurology I that handled the troriluzole review at the FDA has a record of regulatory flexibility dating back to its first big decision—the approval of Biogen and Eisai’s Aduhelm—but it was unclear whether that ethos had survived recent changes at the agency. Biohaven CEO Vlad Coric, M.D., shared a potential read-through from the rejection.“Real-world evidence is an important research approach to assessing and delivering new therapies for complex rare diseases but, despite FDA policy initiatives supporting such tools, the front-line review divisions are not yet embracing FDA policy for the use of real-world evidence or the application of regulatory flexibility for rare disease,” Coric said in a statement.