Biohaven’s Non-Migraine Portfolio Takes Another Hit As Verdiperstat Fails In ALS

Pfizer is buying Biohaven's migraine portfolio, but the rest of the pipeline is poised to be spun out and there have been two development setbacks. Despite verdiperstat's failure in ALS, the field had a same-day win with Amylyx's Relyvrio approval. 

While it came as a disappointment, the failure of Biohaven Pharmaceutical Holding Company Ltd.’s verdiperstat in amyotrophic lateral sclerosis (ALS) was not a big surprise, and it won't impact the planned sale of Biohaven to Pfizer Inc. since the deal was tied to the migraine drug portfolio.

Biohaven's non-migraine pipeline is poised to be spun out into a new company, and the developments on that front have not been encouraging. Biohaven has experienced two clinical trial failures outside of the migraine space since Pfizer’s $11.6bn acquisition of Biohaven was announced in May. (Also see "Pfizer To Put Big Marketing Muscle Behind Migraine With Biohaven Purchase" - Scrip, 10 May, 2022.)

One was for troriluzole in spinocerebellar ataxia, with the latest announced on 29 September for verdiperstat in a notoriously challenging area of drug development – ALS. However, the US Food and Drug Administration approved Amylyx Pharmaceuticals, Inc.'s Relyvrio (sodium phenylbutyrate and taurursodiol), also on 29 September. Relyvrio, also known as AMX0035, endured two advisory committee meetings before garnering enough support for FDA approval ahead of a confirmatory trial. (Also see "ICER Pushes ALS Drug Makers To Moderate Launch Price While Awaiting Confirmatory Data" - Scrip, 13 Sep, 2022.)

With verdiperstat, Biohaven said that an analysis of results from the Phase II/III HEALEY ALS Platform Trial showed the drug did not statistically differentiate from placebo on the primary outcome measure of disease progression measured by the ALS Functional Rating Scale-Revised and survival, or on key secondary endpoints during the 24-week study period.

HEALEY-ALS is an investigator-initiated study based at Massachusetts General Hospital, with 65 locations in total and designed to enroll 800 participants, according to ClinicalTrials.gov. The trial page lists five drugs including verdiperstat: UCB S.A.’s zilucoplan; Clene, Inc.’s CNM-AU8; Prilenia’s pridopidine; and Seelos Therapeutics, Inc.’s SLS-005 (trehalose).

The zilucoplan arm was stopped in March due to futility, while Clene announced data in July from another study, the company-sponsored Phase II RESCUE-ALS trial, that showed a survival benefit from CNM-AU8. Evaluation of the other two drugs in HEALEY ALS is ongoing.

Verdiperstat’s ALS Failure Not A Surprise

The failure of verdiperstat, a myeloperoxide enzyme inhibitor, in HEALEY ALS did not come as a surprise, given that ALS has generally proven a tough indication for drug development on top of being a devastating disease for those who have it.

“Although disappointing for patients and shareholders, this result does not surprise us given the lack of past clinical data for [verdiperstat], ALS being a ‘tough putt’ indication, and the relatively advanced patient population included in the study,” Cantor Fitzgerald analyst Charles Duncan said in a 29 September note.

HEALEY ALS is not the first study in which the drug has proven unsuccessful. Biohaven’s latest announcement came almost one year to the day after it said on 27 September 2021 that verdiperstat failed to differentiate from placebo on the primary and secondary endpoints of a Phase III trial in multiple system atrophy (MSA), an indication that like ALS is also high-risk. (Also see "Biohaven Faces Another Pipeline Upset, But Focus Remains On Migraine Portfolio" - Scrip, 27 Sep, 2021.)

Several drug makers have faced disappointing development in ALS. Most recently, AstraZeneca PLC said it would discontinue a Phase III trial of Ultomiris (ravulizumab), a complement C5 inhibitor, after an interim analysis showed a lack of efficacy. (Also see "AstraZeneca's Ultomiris Disappoints In ALS, Setting Back Rare Disease Ambitions" - Scrip, 20 Aug, 2021.)

On the other hand, the area of drug development has also attracted a lot of attention because of the high unmet need, and Amylyx's same-day Relyvrio approval stands out as a bright spot.

Migraine Remains The Target Of Pfizer

The failure of verdiperstat in MSA and now ALS will not impact Pfizer's plans to acquire Biohaven since that deal was focused on migraine drugs specifically. That centers on the calcitonin gene-related peptide (CGRP) inhibitor franchise, particularly the oral migraine drug Nurtec ODT (rimegepant) and zavegepant, a nasal spray currently undergoing US Food and Drug Administration review with a first quarter 2023 action date, along with five additional CGRP inhibitors. Other areas of Biohaven’s pipeline will be spun out into a new company.

Pfizer’s interest in acquiring Biohaven stemmed from a promise it made to investors to expand its late-stage and commercial portfolio with long-term growth drivers while also expanding its presence in migraine, where companies like AbbVie Inc. dominate. AbbVie markets two oral CGRP inhibitors, Ubrelvy (ubrogepant) for acute treatment and Qulipta (atogepant) for prevention of episodic migraine. (Also see "AbbVie Ready To Leverage Migraine Franchise In Crowded Market" - Scrip, 29 Sep, 2021.)

Given Pfizer’s focus primarily on Biohaven’s anti-CGRP franchise, Cantor Fitzgerald’s Duncan said it would take a “black swan” event to derail the acquisition, adding that verdiperstat’s failure in HEALEY ALS did not fall into that category, and the fundamentals of Nurtec ODT “remain strong.”

“Key is that Nurtec ODT appears to have a class-leading safety profile, which, in our view, renders the probability of a Black Swan adverse safety finding being very low,” Duncan said.

Nevertheless, Biohaven has stumbled outside of the anti-CGRP space, and not just with verdiperstat, even if that has not damaged its prospects with Pfizer.

In May, it said that a Phase III trial of troriluzole in spinocerebellar ataxia (SCA) did not meet its primary endpoint, though it continued to hold out hope that the FDA would endorse a path forward for the drug in a subgroup of patients, namely those with SCA type 3. However, expectations for troriluzole in SCA were not high. (Also see "Biohaven’s Life Without CGRP Inhibitors Gets Off To A Rocky Start" - Scrip, 23 May, 2022.)