The recommendation stems from recently published topline data which demonstrated a clinically meaningful treatment response compared to placebo but failed to meet statistical significance.
Following a review of the current clinical phase 3 (NCT03280056) data of BrainStorm Cell Therapeutic’s NurOwn (autologous mesenchymal stromal cells secreting neurotrophic factors [MSC-NTF] cells) amyotrophic lateral sclerosis (ALS) therapy, the FDA concluded that the current level of data does not cross the threshold of substantial evidence to support a biologics license application (BLA), according to an announcement from the company.1
The FDA did advise that this recommendation does not preclude BrainStorm from proceeding with a BLA submission.
In November 2020, the company announced topline results from its phase 3 trial, demonstrating that treatment with NurOwn was generally well tolerated in a population of rapidly progressing patients with ALS. While showing a numerical improvement in the treated group compared to placebo across the primary and key secondary end points, the trial did not reach statistically significant results.2
"BrainStorm will first consult with principal investigators, ALS experts, expert statisticians, regulatory advisors, and ALS advocacy groups to assess the benefit/risk of a BLA submission before making a final decision,” Chaim Lebovits, chief executive officer, BrainStorm Cell Therapeutics, said in a statement.1 “We will soon announce our next flagship product and program for other diseases with unmet needs.”
Using historical clinical trial data and NurOwn phase 2 data, investigators used improvement of 1.25 points per month in the post-treatment Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) slope as the primary efficacy end point, powered on assumed treatment response rates of 35% on NurOwn versus 15% on placebo.2
Following the conclusion of the trial, the primary end point was achieved in 34.7% of participants in the NurOwn group compared to 27.7% for placebo (P = .453), demonstrating that the NurOwn treatment met the expected 35%, but the high placebo response exceeded placebo responses observed in contemporary ALS trials.
"Many of us with longstanding experience in ALS therapy development agree that there was evidence of benefit from NurOwn cell therapy and hope that there will be an opportunity for further assessment of this modality in ALS,” Robert Brown, DPhil, MD, director, Program in NeuroTherapeutics, University of Massachusetts Medical School, said in a statement.1
The secondary efficacy end point measuring average change in ALSFRS-R total score from baseline to week 28 was –5.52 with NurOwn compared to –5.88 for placebo, a difference of 0.36 (P =.693).
Of note, in a subgroup of patients with early disease based on ALSFRS-R baseline score, the treatment demonstrated a clinically meaningful response across the primary and key secondary end points and remained consistent with pre-trial and data-derived assumptions. In this subgroup, 34.6% and 15.6% of responders met the primary end point definition on NurOwn and placebo, respectively (P =.288).
In January, BrainStorm announced that patients who completed the recently conducted phase 3 trial and met specific eligibility requirements can be admitted to the newly initiated Expanded Access Program (EAP). The company’s development of the EAP was in partnership with the FDA and will give patients less severely affected by ALS, as measured by the ALSFRS-R, highest priority to receive the treatment.3
"We learned a lot about the efficacy and safety of NurOwn in people with ALS in this well conducted trial. We also learned some of the challenges with the use of ALSFRS-R at the lower end of the scale. Additional discussions with the community and sharing all the data in a peer reviewed publication are critical next steps,” Merit Cudkowicz, MD, chief of neurology and director of the Healey & AMG Center for ALS, Massachusetts General Hospital, said in a statement.1
Cudkowicz, an investigator of the phase 3 trial, recently sat down to discuss the topline results with NeurologyLive. Watch below to find out more about the trial and what the clinical community should take away from these findings in light of the lack of statistical significance.