FDA advisers were unmistakable in their assessment of BrainStorm Cell Therapeutics’ treatment for amyotrophic lateral sclerosis (ALS): there's just no evidence it works.
Members of the Cellular, Tissue, and Gene Therapies Advisory Committee voted 17 to 1, with one abstention, that there was not substantial evidence to show that the company’s cell therapy, NurOwn, is effective at stymying the progression of mild-to-moderate ALS. It’s a near-final blow for the company’s approval ambitions after two prior rejections from the agency.
The decision validates what the agency has conveyed for more than two years now, which is that NurOwn has failed to show any evidence of efficacy and that critical parts of the manufacturing process remain unclear.
The agency posted a rare regulatory update in March 2021 acknowledging the need for new ALS treatments while underscoring the lack of benefit in the company’s phase 3 trial. The FDA also flagged “a modest excess in deaths in those treated with NurOwn,” though the significance was unclear at the time. FDA said then that if BrainStorm had additional clinical studies planned, then it would continue to provide advice and guidance.
That didn’t happen and BrainStorm instead submitted an approval application in 2022 based on an exploratory analysis of the same phase 3 trial. The FDA refused to accept the application for a host of reasons that centered on a lack of demonstrated efficacy and insufficient manufacturing information.
The agency told the company to try again with more data but BrainStorm instead filed the application over protest in February—a rarely used Hail Mary drugmakers can leverage to force a public hearing on an application.
Just a few days ago, BrainStorm made a last-minute change to the application to trim the desired indication from patients with ALS to patients with mild-to-moderate ALS. The FDA held firm during the meeting that the data do not suggest that the treatment benefits patients in this newly selected subset, either.
At the meeting, BrainStorm emphasized two key points to try and make the case for efficacy: the first was that a subgroup of patients with a Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) of 35 or higher had a much better response to the treatment than placebo.
This scale ranges from 0 to 48 and measures the severity of the disease. A high score indicates more normal function, while lower scores suggest more severe progression.
The rate of response for patients with scores below 35, or more severe disease, was about the same as placebo, the company said.
But the statistical significance of the subgroup analysis was up for debate. FDA biostatistician Xue Lin, Ph.D., said that while the analysis may inform a new trial, these results should not be used to “rescue” the failed trial.
Another sticking point was that the phase 3 clinical trial had a “floor effect,” defined by the FDA as “insensitivity of an outcome measure to differences at the lower end of an assessment scale.”
BrainStorm argued this effect meant that scores plateaued over time because many patients enrolled in the trial had severe enough symptoms of ALS that it was difficult to measure further declines. The FDA and its reviewers disagreed.
ALS advocates and clinical trial participants fervently defended the treatment during the public hearing portion, including the founders and CEO of I AM ALS, an advocacy group that’s rallied support behind NurOwn for years. One speaker, Phillip Green, was a participant in the company’s phase 3 trial and said he experienced improved breathing and motor function, including in his hands and legs. Other trial participants said similarly.
But the advisers were wary of putting too much weight on anecdotal evidence even in the context of the devastation of the disease. Neumora Chief Medical Officer, Michael Gold, who was a non-voting industry representative, cautioned that the committee needed to stay focused on the data. Lisa Lee, Ph.D, a bioethicist on the panel, said that “providing false hope can be ethically problematic.”
“I hope as we move forward, we remember that is always the case in ethical gray areas, tensions between values, in this case, the value of hope, against the value of harm, that these are inevitable and definitive answers are often elusive," Lee said.
The panelists agreed that the company should conduct an additional study to validate some of the subgroup data amplified by the company.