BrainStorm Reaches Accord With FDA on New Phase 3b Trial Design for ALS Cell Therapy NurOwn
The 2-part, multicenter BCT-006-US trial will seek to enroll patients who are in the earlier stages of ALS.
Chaim Lebovits
Under a special protocol agreement (SPA), BrainStorm Cell Therapeutics has received written agreement from the FDA regarding the protocol and statistical analysis for its planned phase 3b clinical trial (BCT-006-US; NCT identifier pending) to evaluate debamestrocel (NurOwn), an investigational autologous mesenchymal stem cell (MSC) neurotrophic factor–secreting cell therapy product that is intended to treat amyotrophic lateral sclerosis (ALS).1
BrainStorm pointed out that the written agreement indicates the company’s plans will be sufficient for supporting a biologics license application (BLA) for NurOwn in ALS, assuming the objectives of the trial are met. BrainStorm anticipates initiating the new phase 3b trial this year, following preliminary steps, including a review of the protocol with investigators, Institutional Review Board approvals of study sites, and engagement with the ALS patient community.
"We are pleased to have reached an agreement with the FDA on key elements of the phase 3b trial design that provides a potential path forward towards obtaining regulatory approval," Chaim Lebovits, the president and chief executive officer of BrainStorm, said in a statement.1 "We believe that having this SPA in place will help derisk certain regulatory aspects of the NurOwn clinical program. BrainStorm's ultimate goal is to provide a new treatment option that can help patients afflicted with ALS, and we believe that the SPA potentially brings us one step closer to this goal. We appreciate the Agency's engagement and guidance during the SPA process and look forward to moving forward with the study."
The 2-part, multicenter BCT-006-US trial will seek to enroll patients who are in the earlier stages of ALS, with the onset of symptoms having occurred within 24 months before enrollment. Furthermore, participants must have a score of at least 2 for all items on the Revised Amyotrophic Lateral Sclerosis Functional Rating (ALSFRS-R) and an upright slow vital capacity of at least 65% of what would be predicted for their gender, height, and age. BrainStorm additionally noted that participants will be able to be take concomitant treatment with standard of care options while participating in the study.
The first part of the study, which will have a 24 week duration, will randomly assign patients in a 1:1 ratio to receive either NurOwn or a placebo in a double-blind fashion. This part will include approximately 200 participants in total. Patients will undergo a single bone marrow aspiration procedure during a 6 to 9 week screening period in order to obtain MSCs for the manufacture of NurOwn. NurOwn and the placebo will be administered via 3 intrathecal injections spaced 8 weeks apart from one another. The second part of the study, which will also last 24 weeks, will similarly treat participants with 3 intrathecal injections of NurOwn spaced 8 weeks apart from one another, although this part of the study will be carried out in an open-label fashion without a placebo group. Eligible participants from the first part of the clinical trial may choose to roll over into the second part.
BCT-006-US's primary end point will be the change from baseline in ALSFRS-R score at 24 weeks posttreatment. BrainStorm noted that a p-value from the combined assessment of function and survival accounting for mortality seen in the study will be used for primary inference. Furthermore, analysis of biomarkers for neuroinflammation, neurodegeneration, and neuroprotection will be carried out with cerebrospinal fluid and blood samples.
"We have worked with leading neurologists, scientists, and members of the ALS community to create a robust study designed to evaluate the effectiveness and safety of NurOwn,” Stacy Lindborg, PhD, the co-CEO of BrainStorm Cell Therapeutics, added to the statement.1 “This trial builds on valuable insights from our earlier studies and will enroll people living with ALS who are earlier in the course of their disease. Based on the evidence generated on NurOwn to date, we have a trial that we're optimistic will be positive. Over the past year, we've assembled an excellent team in clinical development that is highly qualified to execute this trial with excellence. We've been parallel processing to enable us to deliver the first dose in the trial in 2024, and we're anxious to get started."
BCT-006-US will be BrainStorm’s second attempt at a registrational clinical trial for NurOwn.2 The cell therapy was previously evaluated in a pivotal phase 3 clinical trial (NCT03280056) that tested the treatment against a placebo in patients with ALS, but that trial did not meet any of its primary or key secondary end points. Despite the setbacks, BrainStorm still sought to make a case for NurOwn based on the trial data with posthoc sensitivity analyses intended to account for the floor effect. The company submitted a BLA, utilized a "File Over Protest" procedure to push forward the review after a refusal to file letter, and later argued for NurOwn at an FDA Cellular, Tissue, and Gene Therapies Advisory Committee meeting.2-4 Despite these efforts, the company ultimately pulled its original BLA for NurOwn in October 2023, before the FDA made a formal decision on the cell therapy.5
