BrainStorm’s ALS Drug Flops Phase III Study

 

A Phase III trial of NurOwn® (MSC-NTF cells), BrainStorm Cell Therapeutics’ investigational therapy for amyotrophic lateral sclerosis (ALS), did not find a statistically significant difference between the therapy and placebo for improving scores on a revised ALS functional rating scale (ALSFRS-R), a measure of ALS severity.

But the New York-based company is not giving up on NurOwn just yet – their late-stage trial did demonstrate a clinically meaningful treatment response compared with placebo, at least in a pre-specified subgroup. Additionally, NurOwn led to significant increases in neurotrophic factors as well as a reduction in both neuroinflammatory and neurodegenerative biomarkers.

The findings from this trial follow the publication of Phase IIa preclinical data in August, which the company said supported the proposed mechanism of the therapy in ALS.

BranStorm’s multicenter Phase III trial enrolled 189 patients with ALS to study the safety and efficacy of NurOwn. Patients who were “rapid progressors,” or those with at least a three-point reduction in the ALSFRS-R score during the run-in period, were randomly assigned to either three intrathecal injections of NurOwn or placebo.

During a follow-up period of 28 weeks, the investigators assessed safety as well as the rate of decline in the ALSFRS-R score. Participants who had a 1.25-points/month improvement in the post-treatment ALSFRS-R slope were considered to have met the primary endpoint. Additional secondary endpoints were the percentage of patients with halted disease progression, combined analysis of function and survival, slow vital capacity, tracheostomy-free survival and overall survival, among others.

In spite of the main findings, the clinical trial did show a clinically meaningful treatment response across the primary and key secondary endpoints in a pre-specified subgroup of patients with early disease. Approximately 34.6% of responders in this subgroup met the primary endpoint definition on NurOwn versus 15.6% of patients who received placebo, but again the differences were not statistically significant (p=0.288).

The mean change from baseline to week 28 in the ALSFRS-R total score was -1.77 and -3.78 with NurOwn and placebo, respectively (p=0.198). The investigators noted this represented an improvement of 2.01 ALSFRS-R points, ultimately favoring NurOwn.

“A change in pre- to post- treatment slope of 1.25 or more is substantial and clinically important,” said Principal investigators of the trial, Dsr. Merit Cudkowicz and Julianne Dorn, Harvard Medical School, Healey Center for ALS and Mass General Hospital, in a statement. “Given the heterogeneity of ALS, it is not surprising that measurement of treatment effect may be influenced by disease severity including the behavior of disease progression rates at the lower end of the scale. It is important to fully explore this finding.”

The researchers added that NurOwn had “clear intended biological effects with important changes in the pre-specified disease and drug related biomarkers.”

Chaim Lebovits, Chief Executive Officer of BrainStorm, noted the clinical trial enrolled a population of patients with severe ALS, which may have potentially contributed to the findings. Otherwise, the finding of a superior treatment response in the subgroup of patients with less advanced disease was promising.

“We are in active discussions with the FDA who have expressed their eagerness to review the data and have committed to prioritize review of this data,” Lebovits said. “The FDA will review the data to see if there is a path forward to support approval.”

Ralph Kern MD MHSc, President and CMO of Brainstorm, said in a statement that biosamples from the trial will be shared through the NEALS biorepository to support additional scientific discovery efforts. Additionally, Stacy Lindborg Ph.D., EVP and Head of Global Clinical Research, said that additional granular analyses will be shared at upcoming scientific meetings and publications, indicating that the company will likely continue using data from the trial to support additional key discoveries in ALS management.

In late October, BrainStorm announced a partnership with Catalent to assist in the manufacturing process of the former company’s NurOwn. Additionally, BrainStorm linked with Rapid Reshore & Development to accelerate site selection and design services for a manufacturing facility for NurOwn in the U.S. Currently, there has been no news to suggest these partnerships has been impacted by the findings from the Phase III trial.