Machado-Joseph Disease

Takeda will not move forward with Wave Life Sciences on a Huntington’s disease drug, ending their collaboration that first started in 2018 with a $110 million upfront from the Japanese pharma. In an SEC filing Tuesday, Wave said Takeda “elected to terminate its option” for the huntingtin target, which is the only active portion left under the terms of the original deal. The biotech is now fully responsible for advancing the drug candidate, WVE-003, through clinical development for Huntington’s disease, as well as any other programs targeting the huntingtin protein. In June, Wave said the drug lowered levels of mutant huntingtin protein by 44% in a small Phase 1b/2a test in patients with Huntington’s disease. The biotech expects feedback from regulators on a potential accelerated approval pathway for WVE-003 by the end of the year. On Tuesday, the company said the drug still has a $5 billion “commercial opportunity,” adding the early data have drawn interest from other potential partners. The 2018 agreement saw Wave get $110 million upfront from Takeda alongside a share purchase worth $60 million in exchange for the option to co-develop and co-commercialize programs for Huntington’s, amyotrophic lateral sclerosis, frontotemporal dementia and spinocerebellar ataxia type 3. The deal featured $2 billion in potential milestones. If Takeda had stayed on board with the Huntington’s asset, it would have been able to opt-in to a split cost-sharing development plan. But Takeda had been pulling back from parts of its partnership with Wave for some time. The two companies revised their original pact in 2021, dropping joint discovery work, with Takeda paying Wave more than $22 million. Last year, Wave’s ALS drug failed to show clinical benefit versus placebo in an early-stage trial, leading to the termination of the asset. In May, Takeda said it would “rigorously prioritize its R&D pipeline” as part of a broader multiyear restructuring aimed at simplifying the business . Wave still has a cash runway through 2027 after a $230 million public offering that it completed earlier this month.

Biohaven, which spun out ​ of Biohaven Pharmaceuticals in 2022 when its parent company was acquired by Pfizer, has had a number of setbacks in the development of troriluzole –a prodrug of riluzole– including a phase 3 trial failure in 2022. However, the company continued development, as results of the failed phase 3 trial showed that patients with the most common kind of spinocerebellar ataxia, known as type 3, who made up 41% of the trial group, did appear to benefit from troriluzole. In 2023, Biohaven submitted a new drug application to the FDA for troriluzole in patients with type 3 spinocerebellar ataxia, but the regulator refused to file ​ the application based on the drugs earlier trial failure. The company then worked with the FDA to design a new, ‘real-world’ trial that compared 65 spinocerebellar ataxia patients (all types) given troriluzole to two sets of matched external controls in the US and Europe. The results ​ announced this week show troriluzole treated patients had a 50-70% slowing of disease progression compared with the external untreated controls over 3 years of follow up. Using the modified functional Scale for the Assessment and Rating of Ataxia (f-SARA) external controls were at least 4 times more likely to have a 2 point or greater worsening of their disease than patients treated with troriluzole. "SCA is a debilitating, relentlessly progressive disease that destroys quality of life, leaving patients unable to care for themselves, walk, or speak,” said Susan Perlman, director of the ataxia clinic and neurogenetics clinical trials at the David Geffen School of Medicine at UCLA, in a press statement about the trial. googletag.cmd.push(function () { googletag.display('text-ad1'); }); “Troriluzole is the very first treatment to show a delay in disease progression that can give patients additional years of independence, where they can walk without assistance, continue to work, play with their children, and participate in daily activities. This is an exciting and hopeful moment for the SCA community." Fighting for a treatment ​ Spinocerebellar ataxias are a group of rare progressive, inherited neurological diseases that affect movement and result in increasing disability over time. There are many types of spinocerebellar ataxias, defined by the genetic cause, and they are estimated to affect around 150,000 people in the US. Due to the heterogeneity of genetic mutations causing this condition the symptoms vary in severity but can be fatal. Most often, patients retain mental capacity, but gradually lose physical control of movement. No cure exists for spinocerebellar ataxia and limited treatments addressing the symptoms are available, with no FDA approved therapies specifically designed for treating spinocerebellar ataxia. Riluzole is approved to treat amyotrophic lateral sclerosis (ALS) and similar motor neuron diseases and has been shown to increase survival in some patients by several months. Troriluzole is a prodrug of riluzole and may have dosing advantages and better bioavailability than riluzole. Based on the new trial results, Biohaven now plans to resubmit troriluzole to the US Food and Drug Administration (FDA) for treatment of all SCA genotypes before the end of the year. Due to the lack of treatments and rare nature of the disease, troriluzole is eligible for priority review because it has FDA orphan drug and fast-track status.

Biohaven is on the cusp of a new drug application filing in a rare neurodegenerative disorder that currently has no approved therapies, a surprising development for a molecule with a long list of clinical trial and regulatory setbacks, including the FDA’s refusal to even review the pill more than a year ago. But Biohaven did not give up on the drug, and apparently, neither did the FDA. The agency is welcoming more real-world data to generate the evidence for its regulatory decisions. Based on a clinical trial design and endpoints that were blessed by the regulator, this approach for the Biohaven drug, troriluzole, led to more data, new analyses, and positive results in the treatment of the neurological disease spinocerebellar ataxia (SCA). Troriluzole is a prodrug, a compound that converts into an active drug inside the body. According to New Haven, Connecticut-based Biohaven, this once-daily pill treats diseases by reducing synaptic levels of glutamate, a neurotransmitter. While this brain chemical is key to brain function, excess glutamate is associated with a range of neurodegenerative disorders. However, Biohaven’s earlier work with the molecule in both anxiety and Alzheimer’s disease ended up failing in pivotal trials. A Phase 3 test is ongoing testing the molecule in obsessive compulsive disorder. presented by Sponsored Post The Promise of Value-Based Care and MedTech Innovation Monica Vajani, Executive Director for mHUB’s MedTech Accelerator, discusses how mHUB is helping innovators transition healthcare towards value-based care. By Monica Vajani - mHUB SCA is a group of inherited neurodegenerative disorders characterized by progressive loss of voluntary motor control and atrophy of the cerebellum, brainstem and spinal cord. The disease affects mobility, as patients fall frequently and eventually must use a wheelchair. The disease also causes speech impairment, swallowing difficulty, and premature death. SCA, which typically presents in early adulthood, affects an estimated 15,000 patients in the U.S. and 24,000 in Europe and the U.K., according to a Biohaven investor presentation. In 2022, Biohaven reported preliminary Phase 3 data showing troriluzole failed a Phase 3 study in SCA. Biohaven attributed this result to less-than-expected disease progression in the placebo arm over the course of the study. However, the company noted that a post-hoc analysis found a treatment effect in patients with SCA type 3, the most common of the more than 40 types of SCA. Last year, Biohaven submitted a new drug application seeking approval in adult SCA3 patients. This application did not even reach the point of an FDA review. The regulator sent Biohaven a refuse-to-file letter, noting that the drug failed to meet the main goal of its pivotal study. Discussions with the FDA led Biohaven to design a new protocol that used real-world evidence to assess troriluzole’s efficacy. Patients treated with the study drug were compared to two natural history external control groups matched for baseline characteristics, one cohort in the U.S. and the other in Europe. This analysis incorporates new data that were unavailable for the 2023 new drug application. Whereas the initial Phase 3 study spanned 48 weeks, the new real-world evidence study has data spanning three years. The main goal is measuring the change in score, from baseline, according to a scale used to assess SCA severity and progression. These are the results unveiled Monday. presented by Health Tech What’s Keeping Healthcare CIOs Up at Night: How to Improve Patient Satisfaction by Handling Calls More Efficiently Health systems have spent billions on portals while investments in modernizing the voice channel — the dominant preference of healthcare consumers — have taken a backseat. By Stephanie Baum According to Biohaven, preliminary results show the study achieved the primary endpoint by showing statistically significant and sustained benefit measured at years one, two, and three in all types of SCA compared to the natural history controls. The company added that data across multiple analyses demonstrate a robust and clinically meaningful 50% to 70% slower rate of decline compared to untreated patients. That translates to one-and-a-half to two-year delay in disease progression over the three-year study period. The study drug was safe and well tolerated by study participants. Based on these positive results, Biohaven executives say they now plan to seek FDA approval of troriluzole as a treatment for all SCA types. The company expects to submit a new drug application in the fourth quarter of this year. Last year, Biohaven submitted a marketing authorization application in Europe for troriluzole in SCA. That application is still under review. In a note sent to investors, William Blair analysts wrote that they are encouraged by the degree FDA guidance was incorporated into the troriluzole trial design. However, they also expect the regulator will convene an advisory committee meeting to discuss the differences between the failed Phase 3 study and the positive natural history-comparator study. Other potential discussion topics include differences in standard of care for subjects in the natural history studies that were initiated 15 to 20 years ago. “Overall, we are encouraged by the consistent signals of benefit across measures in the study in a population with extremely limited treatment options in a progressive disease,” the William Blair analysts said. Marc Goodman of Leerink Partners offered a more cautious take on the results. Though he acknowledged that the real-world evidence trial was based on input from the FDA, the drug carries “significant regulatory risk” in light of its Phase 2/3 and Phase 3 failures. Goodman also noted that the drug had received a refuse-to-file letter based on the subgroup analyses. He also expects an advisory committee meeting to discuss the mixed data package and the real-world evidence clinical trial design. Image: koto_feja, Getty Images