FDA Review Skeptical of ALS Stem Cell Therapy Ahead of Panel Meeting

Kelli Whitlock Burton

September 26, 2023

The US Food and Drug Administration (FDA) review has raised concerns about the safety and efficacy of an experimental stem cell therapy for amyotrophic lateral sclerosis (ALS) scheduled for a public hearing by a federal advisory panel on Wednesday.

In documents released by the FDA on Monday, the review described the application from drugmaker BrainStorm Cell Therapeutics as "scientifically incomplete" and "grossly deficient."

The treatment, known as NurOwn, uses mesenchymal stem cells harvested from patients' own bone marrow that are engineered to secrete neurotrophic factors, proteins important for the survival and function of neurons. The manipulated stem cells are then injected into a patient's spine.

NurOwn was granted orphan status by the FDA in 2011 and fast-track status in 2014. A regulatory timeline from the FDA shows meetings with the manufacturer going back to 2016, with at least six meetings to discuss the agency's concerns about the company's trial design.

BrainStorm's application is based on data from four clinical studies, including a phase 3 randomized controlled trial of nearly 189 patients with ALS who received at least one treatment of NurOwn or a placebo.

After 28 weeks, there was no significant difference between groups in response rates (32.6% with NurOwn vs 27.7% with placebo; P = .45). Both groups also had similar changes in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, which reflects motor impairment and functional deterioration in ALS patients.

In a February 2021 meeting, the FDA warned BrainStorm that the study data did not demonstrate efficacy and expressed concern over the higher mortality in the treatment group. Of the 13 deaths during the study, 10 had received NurOwn, which the agency said indicated a lack of survival benefit that deserves further study.

The agency also cited concerns about product manufacturing, calling the Biologics License Application (BLA) "grossly deficient to ensure adequate product quality."

Details about how the company planned to ensure control of prefilled syringes and other materials, validation of methods, manufacturing consistency, and facilities' readiness for inspection were all missing from the application, which FDA officials outlined in a Refuse-to-File letter sent to the company in November 2022.

In addition to concerns about the high mortality rate in the phase 3 trial, the agency also noted an apparent higher incidence of respiratory failure, dysphagia, and pain in the treatment group.

"The available data do not meet the standard required for approval by either the traditional or the accelerated pathway," the agency reported following that meeting. "While the Applicant has the option of submitting a BLA (Biologics License Application) with the existing data, the Agency may refuse to file it."

BrainStorm chose to move forward with a BLA in September 2022, which was rejected by the FDA in November. In February 2023, the company requested that the application be filed over protest, leading to the public hearing with the FDA's Cellular, Tissue, and Gene Therapies Advisory Committee, scheduled for 10:00 AM (ET) Wednesday, September 27.

The FDA has already received more than 1900 public comments about NurOwn, many from patients or caregivers urging the agency to approve the drug. This follows a campaign from the ALS patient advocacy organization I AM ALS, which has been influential in raising public sentiment for speedier drug approval.

But not all ALS advocates support NurOwn. The ALS Association, which previously awarded BrainStorm $400,000 to develop NurOwn, has now raised concerns about the treatment in a statement on the organization's website.

"After BrainStorm shared that its Phase 3 trial of NurOwn did not meet its primary or secondary endpoints, we have consistently requested access to the full data package so we could try to better understand its effect on people living with ALS," the statement reads.

"The amazing testimonials we have seen online do not align with the data that BrainStorm has shared with us or has been published in peer-reviewed publications."

The FDA's final decision on the treatment is due later this year.

Kelli Whitlock Burton is a reporter for Medscape Medical News covering neurology and psychiatry.

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