Emboldened by lessons learned from an earlier endpoint-missing study, Biohaven Pharmaceutical Holding Co. Ltd. is reprising its investigation of troriluzole in the rare neurodegenerative disorder spinocerebellar ataxia (SCA) with a new phase III study that recently enrolled its first patient. The study features a higher dose, an extended treatment period and an FDA-blessed modified functional rating scale as a registrational endpoint. It's informed by an encouraging readout from a long-term extension study and a still-unmet need among thousands of patients with the debilitating genetic disorder.

The glutamate-modulating prodrug, formerly known as trigriluzole, failed to outperform a placebo at eight weeks in an earlier phase II/III trial. Reading out in late 2017, the study's outcome was measured on an eight-part Scale for the Assessment and Rating of Ataxia (SARA) and overwhelmed by a strong placebo effect. Still, determined to gain further insight into the drug's potential benefit it SCA, Biohaven researchers continued to study it in a preplanned year-long open-label extension study. Though lacking the rigor of a placebo control or randomization, the trial allowed investigators to compare the experience of troriluzole-treated patients to non-troriluzole-treated patients in a matched natural history cohort that surfaced evidence suggesting troriluzole attenuated disease progression at one year. Troriluzole-treated patients saw their SARA score decline by a mean 0.35 points while matched natural history patients saw their scores increase by a mean 1.07 points. Increasing scores indicate worsening disease status. (See BioWorld, Oct. 3, 2017.)

"Compared to the increase in diseases progression seen with the natural history cohort, we feel that's a clinically relevant difference, which gives us a tremendous amount of optimism with regard to going into the new study," Gil L'Italien, Biohaven's head of health economic outcomes research and epidemiology, told BioWorld.

With that optimism in hand, Biohaven's team now expects to enroll about 230 patients in its new randomized, double-blind, placebo-controlled trial. Investigators will evaluate the efficacy and safety of troriluzole over 48 weeks in patients with a diagnosis of SCA types 1, 2, 3, 6, 7, 8 and 10, but with the trial enriched primarily for types 1-3. The primary outcome measure will be the change in a patient's score on a modified version of the SARA scale.

Melissa Wolfe Beiner, Biohaven's director of R&D and medical lead for its ataxia development program, told BioWorld that the study's 48-week duration takes into account the relatively slow progression of SCA as well as the placebo effect seen in the company's earlier phase II/III study — an effect likely to be extinguished over the longer timeline, she said.

The study will also be enriched to more heavily enroll SCA1, SCA2 and SCA3 patients in light of the relatively more rapid progression of their disease and anecdotal information suggesting that SCA1 and SCA2 patients may have responded better to troriluzole in the earlier study, she said.

The modified SARA scale to be used as the trial's registrational endpoint, which will only measure the first four items of the scale — gait, stance, sitting and speech disturbance — is also new. "The first four items of the SARA really measure axial, or core body movement, while the second four items measure fine motor coordination or appendicular movement," Wolfe Beiner said. After talking to key opinion leaders in the field, "it's really apparent that the changes you're measuring with the axial items are really changes that are more reflective of something that would be clinically meaningful to a patient's ability to function in their daily life."

Finally, in light of post-hoc analyses indicating that a higher concentration of the drug appeared to fare better in the earlier eight-week study, the new study will employ a 200-mg dose of troriluzole vs. the original 140-mg dose used.

An oral medicine, troriluzole's primary mode of action is reducing synaptic levels of glutamate. It does so by augmenting the expression and function of excitatory amino acid transporters located on glial cells, thereby increasing glutamate uptake from the synapse.

Key competition Biohaven has identified for its SCA program includes the chemical chaperone trehalose, currently in development by Seelos Therapeutics Inc., and Steminent Biotherapeutics Inc.'s allogeneic adipose-derived mesenchymal stem cell therapy, among others.

But New Haven, Conn.-based Biohaven appears to just be getting started, seeing broad applications for troriluzole since glutamatergic dysfunction is implicated in the pathology of a broad range of disorders. The drug is also being tested in a phase III study as a potential treatment for generalized anxiety disorder and in ongoing trials for the treatment of obsessive compulsive disorder and Alzheimer's disease.

Company shares (NYSE:BHVN) closed about 1 percent higher on Thursday at $50.10, not far off a 52-week high.