FDA Advisory Committee Downvotes Mesenchymal Stem Cell Approach NurOwn as Potential ALS Therapy

The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee has voted that current data on NurOwn, BrainStorm Cell Therapeutics’ stromal cell therapy, is not sufficient in demonstrating efficacy as a treatment for patients with mild to moderate amyotrophic lateral sclerosis (ALS). The agency is expected to make a final decision on the treatment by its scheduled PDUFA date of December 8, 2023.¹

At the conclusion of the hearing, the committee voted 17-1-1 (17 No; 1 Yes; 1 Abstain) that the evidence presented did not adequately establish NurOwn as an effective treatment. Throughout the meeting, members of the committee raised concerns about the efficacy and manufacturing of the product, including its mechanisms of action. NurOwn, an investigational product, is a technology platform of autologous mesenchymal stromal cells secreting neurotrophic factors cells (MSC-NTF).¹

In the FDA’s presentation, 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 cannot 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.

Days before the meeting, briefing documents released by the FDA stated that the original biologics license application (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."² 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.³

BrainStorm elected to request that the BLA to be filed over protest, and subsequently provided further retrospective analyses and biomarker results. Overall, the MSC-NTF clinical development 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.²

Overall, treatment with NurOwn did not meet its primary end point of statistical significance, as 33% and 28% of those on MSC-NTF 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 of treatment. 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).^5,6

Earlier this year, BrainStorm announced additional post-hoc data from the phase 3 study highlighting NurOwn’s impact on markers of neuroprotection, neuroinflammation, and neurodegeneration. The analysis included 16 pro-inflammatory/anti-inflammatory, 8 neurodegeneration, and 9 neuroprotection biomarkers, and was considered one of the most robust biomarker analyses assessing an agent in ALS.

Over a 20-week period, in comparison with those on placebo, NurOwn-treated individuals showed a large, significant increase of 369% in vascular endothelial growth factor and an 11% decrease in neurofilament light (NfL), a marker of neuroaxonal damage. On stepwise variable regression model, findings revealed that NfL, a neurodegenerative marker, LAP/TGFß1, an anti-inflammatory biomarker, and change in galectin-1 at week 20, significantly contributed to the production of clinical outcomes with NurOwn treatment.⁷

The impact of NurOwn on NfL was notable considering the FDA’s decision earlier this year to approve tofersen (Qalsody; Biogen), the first marketed therapy for patients with SOD1 mutation-mediated ALS, based on reductions in the same biomarker. Tofersen was similar to NurOwn in that it failed to meet its primary end point of change in ALSFRS-R in its pivotal phase 3 study.⁸ Prior to its approval, a meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted unanimously that NfL may be used as a surrogate biomarker; however, the panel was split on whether data on tofersen’s effect on relevant biomarkers provided enough convincing evidence of the effectiveness of the agent.

In the AdComm hearing, the FDA addressed several concerns with the biomarker analyses, including the large amount of missing data for biomarker measurements at week 20 of the phase 3 trial. Additionally, they noted no clear association between the change of selected biomarkers and clinical benefit, as patients experiencing greater loss of function appeared to have more reduction of cerebrospinal fluid NfL. Furthermore, the agency brought up statistical concerns, noting that the analyses did not include multiplicity adjustment and that post-hoc analyses are highly susceptible to bias.

While presenting its case, BrainStorm noted that they plan to conduct another randomized, controlled phase 4 study with long-term open-label extension to assess the efficacy and safety of NurOwn. The trial was generated with insights from the phase 3 trial, along with scientific input from the patient and advisory board, and aims to enroll participants in the first half of 2024.¹

REFERENCES
1. FDA Cellular, Tissue, and Gene Therapies Advisory Committee Hearing. September 27, 2023. Accessed September, 27, 2023.
2. FDA Briefing Document BLA 125782. FDA. https://www.fda.gov/media/172403/download. Published September 27, 2023. Accessed September 29, 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 September 26, 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
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 September 26, 2023. https://ir.brainstorm-cell.com/2022-08-15-BrainStorm-Cell-Therapeutics-Announces-Second-Quarter-2022-Financial-Results-and-Provides-a-Corporate-Updat
6. Erratum. Muscle & Nerve. Published online August 12, 2022. doi:10.1002/mus.27697
7. 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.
8. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. News release. FDA. April 25, 2023. Accessed September 26, 2023. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene