According to a new announcement, the FDA has granted BrainStorm Cell Therapeutics a meeting to discuss NurOwn, the company’s investigational stromal cell therapy, and its regulatory path forward as a treatment for patients with mild to moderate amyotrophic lateral sclerosis (ALS). The meeting is set to take place on December 6, 2023, and the company stated that it plans to discuss a Special Protocol Assessment (SPA) with the agency for the overall protocol design of a potential confirmatory phase 3 trial.1
"We are pleased that the FDA has granted this expedited in-person meeting to discuss the best path forward for NurOwn for ALS. Our proposed plan is to conduct a confirmatory phase 3b trial and it is important that we are aligned with the agency on the expected requirements for resubmitting a biologics license application (BLA),” Chaim Lebovits, president and chief executive officer of BrainStorm Cell Therapeutics, said in a statement.1 “We believe that reaching an agreement through a SPA on the overall protocol design and the adequacy to address the requirements for marketing approval will be a key step to position the company for success and to potentially derisk the program. We are grateful for the FDA's support and quick response in granting this meeting as we remain committed to our goal of making NurOwn available to the ALS community."
Clinical Takeaways
- BrainStorm Cell Therapeutics secures an FDA meeting on December 6, 2023, to discuss NurOwn's regulatory path for ALS, aiming for alignment on protocol design for a confirmatory phase 3b trial.
- The company plans SPA discussions with the FDA during the meeting, highlighting the need for alignment on BLA resubmission requirements and expressing gratitude for the FDA's prompt support.
- BrainStorm considers the SPA agreement crucial to program success, potentially minimizing risk, and maintains a commitment to providing NurOwn for the ALS community.
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. NurOwn, a technology platform of autologous mesenchymal stromal cells secreting neurotrophic factors cells (MSC-NTF), was supported by several clinical studies.2
In the AdComm hearing, the agency concluded that MSC-NTF showed no efficacy compared with placebo on primary and all key secondary end points in the main phase 3 study used, and that exploratory and post-hoc subgroup analyses could not provide substantial evidence of effectiveness. In one part of their response, the agency claimed that BrainStorm tried to “rescue” the failed study by exploring various subgroups. Above all, the subgroup analyses could not be considered reliable because of factors such as high risk of obtaining false positive results, lack of control for multiple hypothesis testing, and breaking randomization.
Prior to the meeting, briefing documents released by the FDA stated that the original BLA submission of NurOwn was "scientifically incomplete to demonstrate substantial evidence of effectiveness, and that the manufacturing information was grossly deficient to ensure adequate product quality."3 This led the agency to return a refusal to file letter to the company in November 2022, noting that a Type A meeting was needed to discuss the contents of the letter.4
READ MORE: Machine Learning Model Using Speech Acoustics Identifies Neurodegenerative Diseases With High Accuracy
BrainStorm elected to request that the BLA to be filed over protest, and subsequently provided further retrospective analyses and biomarker results. Overall, the clinical development of NurOwn consisted of 4 studies: 2 single-arm early-phase studies (MSC-NTF-001-IL and MSC-NTF-002-IL); 1 phase 2 randomized, double-blind, placebo-controlled study (BCT-001-US); and 1 phase 3, double-blind, randomized, placebo-controlled study (BCT-002-US), in which individuals received a total of 3 intrathecal injections of either NurOwn or placebo. The phase 3 study was the only such controlled study to test administration of NurOwn using both the intended route and dose interval.3
Overall, 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, showed a change in disease progression of at least 1.25 points on ALS Functional Rating Scale-Revised (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.5
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).6,7
In July 2023, additional post-hoc data from the phase 3 study highlighted NurOwn’s impact on markers of neuroprotection, neuroinflammation, and neurodegeneration. The analysis included 16 pro-inflammatory/anti-inflammatory, 8 neurodegeneration, and 9 neuroprotection biomarkers. Over a 20-week period, NurOwn-treated individuals showed a large, significant increase of 369% in vascular endothelial growth factor and an 11% decrease in neurofilament light (NfL) compared with placebo. On stepwise variable regression model, findings revealed that NfL, LAP/TGFß1, and change in galectin-1 at week 20, significantly contributed to the production of clinical outcomes with NurOwn treatment.8
REFERENCES
1. BrainStorm Cell Therapeutics Announces In-Person Meeting with the FDA to Discuss Confirmatory Phase 3 Trial for NurOwn® in ALS. News Release. BrainStorm Cell Therapeutics. Published November 20, 2023. Accessed November 21, 2023. https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-announces-in-person-meeting-with-the-fda-to-discuss-confirmatory-phase-3-trial-for-nurown-in-als-301993513.html
2. FDA Cellular, Tissue, and Gene Therapies Advisory Committee Hearing. September 27, 2023. Accessed November 21, 2023.
3. FDA Briefing Document BLA 125782. FDA. https://www.fda.gov/media/172403/download. Published September 27, 2023. Accessed November 21, 2023.
4. 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 November 21, 2023. 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
5. 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
6. BrainStorm Cell Therapeutics announces second quarter 2022 financial results and provides a corporate update. News release. BrainStorm Cell Therapeutics. August 15, 2022. Accessed November 21, 2023. https://ir.brainstorm-cell.com/2022-08-15-BrainStorm-Cell-Therapeutics-Announces-Second-Quarter-2022-Financial-Results-and-Provides-a-Corporate-Updat
7. Erratum. Muscle & Nerve. Published online August 12, 2022. doi:10.1002/mus.27697
8. Lindborg S, Goyal N, Berry J, et al. CSF biomarkers identified as predictive of clinical outcomes in ALS participants following NurOwn treatment in a phase 3 clinical trial: reductions in NfL associated with less ALSFRS-R decline. Presented at: 2023 ALS and Related Motor Neuron Diseases Gordon Research Conference.
