Dismay as FDA declines to approve Biohaven's ataxia drug

Biohaven's troriluzole candidate for spinocerebellar ataxia (SCA) has been turned down by the FDA, causing shares in the company to lose more than 40% of their value in pre-market trading.

The news is also a crushing disappointment to patients with SCA, a rare, inherited, and life-threatening group of neurodegenerative diseases with no approved treatment options that affects around 150,000 people in the US.

Biohaven said that the FDA issued a complete response letter (CRL) for troriluzole – which has the proposed brand name of Vyglexia – due to concerns about bias and design limitations in a real-world study submitted in support of its marketing application.

It's the latest in a series of rejections by the FDA of drugs for rare diseases that have led to criticism of the regulator for moving goalposts at the final review stage, after agreeing to the studies proposed by sponsors in their filing during the consultation phase.

Those include a refusal to review uniQure's Huntington's disease gene therapy AMT-130, and earlier rejections of Replimmune's oncolytic virus RP1 for melanoma and Capricor Therapeutics' cell therapy deramiocel for Duchenne muscular dystrophy.

As with the AMT-130, the FDA's letter has highlighted the issues with relying on external, historical controls in studies, which could suggest a need to run a new, placebo-controlled trial. It has also expressed issues with "bias, design flaws, lack of pre-specification and unmeasured confounding factors."

Biohaven chief executive Vlad Coric said the company is "extremely disappointed on behalf of patients" by the decision, pointing out that Congress has called for "efficient, fair and flexible regulatory process" for therapies intended for rare diseases with high unmet need.

"There are a number of common-sense solutions and regulatory tools that the Office of Neuroscience could have applied, including a fair hearing of the drug's efficacy and safety risks at an advisory committee of experts and patients, post-marketing studies, labelling limitations or an accelerated approval pathway," he added.

In the real-world study, troriluzole was found to slow SCA disease progression by 50% to 70% compared to matched, untreated external controls.

Biohaven said the "statistical significance and clinical meaningfulness achieved on the primary endpoint and eight consecutive secondary endpoints…clearly met criteria of 'a large and robust treatment effect'."

The FDA's decision has also been roundly criticised by Jeremy Schmahmann, founding director of the ataxia Unit at Massachusetts General Hospital (MGH), who said the agency has chosen "not to listen to disease experts and respect the patient perspective."

That represents "a misstep in the due process, and a failure to deploy regulatory flexibility to evaluate benefit:risk of a medication that has proven to be safe and effective."

For Biohaven, which has been burning through its cash reserves in its effort to bring troriluzole to market, the CRL forces an immediate and difficult restructuring process, slashing staff and R&D projects to trim its annual spending by around 60%.

The company ended the second quarter with cash reserves of $408 million, down from $489 million at the start of the year.

It is now seeking a quick meeting with the FDA to determine whether there is a path forward for troriluzole in SCA, and focusing its other operations on degrader candidates for IgA nephropathy and Graves' disease, potassium ion channel activator opakalim for epilepsy and depression, and taldefgrobep alfa, a myostatin-activin pathway inhibitor for obesity and spinal muscular atrophy.