FDA Agrees to New Specialized Protocol for Phase 3b Study of ALS Agent NurOwn

Chaim Lebovits

According to a new announcement, the FDA has agreed on a new design for a phase 3b trial of BrainStorm Cell Therapeutics agent NurOwn in patients with amyotrophic lateral sclerosis (ALS) using a special protocol assessment (SPA). The phase 3b trial, a 2-part, multicenter study, is expected to commence in 2024 and address objectives that support a future biologics license application (BLA) in ALS.¹

NurOwn, an investigational product, is a technology platform of autologous mesenchymal stromal cells secreting neurotrophic factors cells (MSC-NTF). Under the SPA agreement, the FDA validated the clinical trial protocol and statistical analysis of the planned phase 3b study. Also known as Study BCT-006-US, the trial will enroll 200 participants earlier in the course of their disease, having the onset of ALS symptoms, including limb weakness, within the prior 24 months.

"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, president and chief executive officer at BrainStorm, said in a statement.¹ "We believe that having this SPA in place will help de-risk 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."

In late 2023, the FDA granted BrainStorm a meeting to discuss NurOwn and the SPA for the phase 3b trial, which would serve as a confirmatory study. Months prior to the meeting, in September 2023, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted 17-1-1 (17 No; 1 Yes; 1 Abstain) that the current data on NurOwn was not sufficient in demonstrating efficacy as a treatment for patients with mild to moderate ALS. Throughout the meeting, members of the committee raised concerns about the efficacy and manufacturing of the product, including its mechanisms of action.²

The newly announced trial will randomly assigned patients 1:1 to either NurOwn or placebo for a 24-week treatment period, with changes on the ALS Functional Rating Scale-Revised (ALSFRS-R) score as the primary efficacy end point. Prior to receiving treatment, there will be a screening period lasting 6-9 weeks where participants will undergo a single bone marrow aspiration procedure to procure the mesenchymal stem cells that will be used to manufacture each participant’s NurOwn treatment for the duration of the trial. Following randomization, each group will receive three repeated intrathecal injections, once every 8 weeks, of their own respective treatment.

In the study, participants will be allowed to receive concomitant treatment of an approved standard of care. For the primary end point, primary inference from the trial will be based on a p-value from the combined assessment of function and survival (CAFS) to account for morbidity observed in the trial. In addition, cerebrospinal fluid and blood samples will be collected for analysis of biomarkers of neuroinflammation, neurodegeneration, and neuroprotection.

READ MORE: FDA Removes Partial Clinical Hold on Phase 1 Trial for MAP4K Inhibitor Prosetin in ALS

"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. 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," Stacy Lindborg, co-chief executive officer at BrainStorm, said in a statement.¹ "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."

BrainStorm’s original attempt to submit an application for NurOwn was met with a refusal to file letter in November 2022, noting that a Type A meeting was needed to discuss the contents of the letter. The company elected to request that the BLA to be filed over protest, and subsequently provided further retrospective analyses and biomarker results. The clinical development of NurOwn consisted of 4 studies, with the phase 3 BCT-002-US trial as the only such controlled study to test administration of NurOwn using both the intended route and dose interval.³

In that study, treatment with NurOwn did not meet its primary end point of statistical significance, as 33% and 28% of those on active treatment and placebo, respectively, demonstrated a chance in disease progression of at least 1.25 points on ALSFRS-R after 28 weeks. The study also failed to demonstrate efficacy on key secondary end points of survival and change in slow vital capacity. Survival in the phase 3 study was worse at study completion for treated individuals as well, as 10 deaths (10 of 95) occurred during the post-treatment follow-up (28 weeks) in the MSC-NTF group vs 3 (3 of 94) in placebo.⁴

The BLA was submitted with clinical data from retrospective analyses of the phase 3 study, specifically a subgroup of patients with less severe forms of ALS, defined as scores of less than 35 on ALSFRS-R. Overall, the updated findings showed that 35% of those on NurOwn had clinical response vs 16% of those on placebo (OR, 2.6; P = .29). Additionally, these participants progressed on average 2 points less on the ALSFRS-R compared with placebo (P = .05), while for participants with more advanced disease, the change from baseline to week 28 was similar between treatment groups (P = .97).⁵

REFERENCES
1. BrainStorm Cell Therapeutics announces agreement with FDA on a special protocol assessment (SPA) for phase 3b trial in ALS. News release. BrainStorm Cell Therapeutics. April 9, 2024. Accessed April 9, 2024. https://ir.brainstorm-cell.com/2024-04-09-BrainStorm-Cell-Therapeutics-Announces-Agreement-with-FDA-on-a-Special-Protocol-Assessment-SPA-for-Phase-3b-Trial-in-ALS
2. FDA Cellular, Tissue, and Gene Therapies Advisory Committee Hearing. September 27, 2023. Accessed November 21, 2023.
3. BrainStorm Cell Therapeutics receives refusal to file letter from FDA for its new biologics license application for NurOwn for the treatment of ALS. News release. November 10, 2022. Accessed April 9, 2024. https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-receives-refusal-to-file-letter-from-fda-for-its-new-biologics-license-application-for-nurown-for-the-treatment-of-als-301673753.html
4. Cudkowicz ME, Lindborg SR, Goyal NA, et al. A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis. Muscle & Nerve. Published online December 10, 2021. doi:10.1002/mus.27472
5. BrainStorm Cell Therapeutics announces second quarter 2022 financial results and provides a corporate update. News release. BrainStorm Cell Therapeutics. August 15, 2022. Accessed April 9, 2024. https://ir.brainstorm-cell.com/2022-08-15-BrainStorm-Cell-Therapeutics-Announces-Second-Quarter-2022-Financial-Results-and-Provides-a-Corporate-Updat