FDA rejects BrainStorm's ALS data again, this time with a formal rejection - MedCity News

BrainStorm Cell Therapeutics received feedback from the FDA last year, noting clinical data flaws for its experimental amyotrophic lateral sclerosis therapy, suggesting a new trial may be needed. The company has not conducted that study and instead recently filed an application seeking regulatory approval. The FDA took another look and sent it back as incomplete.

BrainStorm revealed the FDA’s “refusal to submit” letter on Thursday. Such letters are short of drug refusal. Instead, they notify a company that a marketing application lacks enough information for a full review and more data is needed. In most cases, this means that the company must conduct another clinical trial.

Opt-out letters are considered confidential communication between the agency and the company. The recipients of these letters are usually tight-lipped about the details. Other than announcing the correspondence, New York-based BrainStorm is not disclosing what the FDA said, except that the company may request a meeting to discuss the matter. BrainStorm intends to do just that, CEO Chaim Lebowitz said in a prepared statement.

BrainStorm’s ALS treatment, NurOwn, is made by harvesting a patient’s own stem cells. In the laboratory, mesenchymal stem cells are isolated and propagated. Administered as an injection into the spine, these cells release proteins that stimulate growth. BrainStorm claims that these proteins can support neurons and improve neurological function lost due to the neuromuscular disorder.

NurOwn’s Phase 3 trial evaluated 189 ALS patients who were randomly assigned to receive the BrainStorm therapy or a placebo. The primary objective was to measure at week 28 the rate of decline according to a scale used to assess physical function in patients with ALS.

The filing denial letter comes nearly two years after BrainStorm announced preliminary results indicate that the therapy did not meet the primary objective of the clinical trial. Despite missing the clinical trial, the company pointed to what it said was a clinically meaningful response to the treatment in a subset of patients. Months later, BrainStorm said the FDA recommended the company generate additional clinical data to support a biologics license application. But according to BrainStorm, the FDA said its recommendation does not prevent the company from submitting an application.

In March 2021, the FDA took the unusual step of publicly commenting on a therapy that was not even under regulatory review at the time. The agency said NurOwn did not meet the study’s goals. Although the FDA did not mention the subgroup analysis highlighted by BrainStorm, the regulator said it would work with the company if it chose to conduct another clinical trial. Instead, BrainStorm continues to focus on the data in hand. The company has also made new analyzes of this data.

BrainStorm presented new biomarker assays last month during the annual research symposium organized by the ALS ONE organization. In the presentation, BrainStorm Chief Development Officer Stacey Lindborg noted that unlike pivotal trials for other ALS drugs, NurOwn’s Phase 3 trial included patients with more advanced disease. This makes it difficult to evaluate patients because of what the company describes as a “floor effect.”

The ALSFRS-R, the rating scale used to evaluate ALS patients, collects scores on 12 measures of function, each scored from 0 to 4. The lower the number, the less the patient’s ability to perform a certain function. Brainstorm noted that the average score of participants in the NurOwn study was five points lower than the average in the main study for Relyvrio, Amylyx Pharmaceutical’s recently approved ALS drug. The company said these lower scores make it difficult to assess NurOwn’s effect on patient decline because patient scores are already near the bottom of the scale, the bottom.

BrainStorm says its data shows NurOwn may have an effect on patients with less advanced disease. In support of this position, the company points to biological indicators in the cerebrospinal fluid associated with inflammation and degeneration, as well as protection. Analyzing these biomarkers was a secondary objective of the Phase 3 study. In its ALS ONE presentation, BrainStorm said its analysis showed that treatment with NurOwn for 20 weeks reduced neuroinflammation and neurodegeneration while increasing neuroprotection. The company added that these biomarkers are not affected by the floor effect.

The plan for statistical analysis of the biomarker was submitted to the FDA before the study was disclosed, BrainStorm said in the presentation. It’s not clear what the FDA thinks about this. When a clinical trial misses its primary goal, the agency usually frowns upon “data mining” to try to make a success of the failure. The FDA may also consider the biomarker data to be insufficient. In his Statement for 2021 regarding the NurOwn trial, he noted that the study failed to meet the secondary as well as the primary objectives. If BrainStorm wants the focus to be on biomarkers, the FDA could ask the company to generate more biomarker data from another clinical trial.

BrainStorm may offer more details next week. On November 14, the company is planned to report financial results for the third quarter of this year.

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