BrainStorm Cell Therapeutics announced the presentation of positive survival data from its NurOwn® (debamestrocel) Expanded Access Program (EAP) at the 2024 Annual Northeastern Amyotrophic Lateral Sclerosis (ALS) Consortium (NEALS) Meeting. The data suggest that ALS patients may benefit from longer-term treatment with NurOwn. The company also presented the design of its planned Phase 3b NurOwn trial.
The EAP enrolled ten participants (6 debamestrocel, 4 placebo) from Brainstorm's prior Phase 3 clinical trial (BCT-002-US) in an open-label study. The EAP spanned two 28-week periods, with participants receiving an intrathecal dose of debamestrocel every 8 weeks, for a maximum of 6 doses over the 2 periods.
Survival Benefit
Baseline characteristics from the 10 EAP participants were matched against a comparable cohort from the PRO-ACT historical database using propensity score matching (PSM). Matching covariates for PSM included time since disease onset, pre-baseline ALSFRS-R slope, age, Slow/Forced Vital Capacity (SVC/FVC), and site of onset, with a 10:1 matching ratio. At the last available visit in the EAP, 9/10 participants were alive. The survival curves revealed a statistically significant difference in favor of debamestrocel (LRT, p= 0.0379) with a median survival time of 46.6 months for the debamestrocel group compared to 41.1 months for the matched control.
Biomarker Data
Among the six 'early-start' participants (those who had received Debamestrocel during the Phase 3 study), a continual reduction in NfL was observed. In contrast, for those who received placebo in the Phase 3, the group median NfL change was 37% by the end of phase 3, indicating worsening neurodegeneration. However, after these participants received debamestrocel in the EAP, the majority showed a stabilization in NfL levels.
"We were pleased to provide this important update from the NurOwn EAP with the ALS community at this year's NEALS meeting," said Bob Dagher, M.D., Executive VP and Chief Medical Officer at Brainstorm. "The encouraging findings suggest that among the 10 ALS participants who received NurOwn during the EAP, there was a long-term survival benefit when compared with the matched control group. As previously reported, we also observed reductions in neurofilament light (NfL) which is an important biomarker marker in ALS, measuring neurodegeneration and neural cell death. The consistent reductions in NfL observed both during the randomized Phase 3 trial and in the subsequent EAP periods, indicate that patients treated with NurOwn continued to see benefits from the extended treatment. These data align with our understanding of NurOwn's mechanism of action."
Phase 3b Trial Design
BrainStorm is planning a Phase 3b clinical trial of debamestrocel in ALS. The trial is expected to enroll approximately 200 participants with ALS who will receive 3 doses of either debamestrocel or placebo for 24 weeks (Part-A), followed by an open label period of receiving 3 doses debamestrocel for another 24 weeks (Part B). Participants in both treatment arms will be able to receive standard of care while on study. The key entry criteria will include: age 18 to 75 years old, ALS diagnosis defined by the revised El Escorial criteria as laboratory-supported probable, clinically probable, or definite, symptom onset within 24 months of screening, ≥2 points on each item of the ALSFRS-R, ALSFRS-R total score ≤45, and upright Slow Vital Capacity (SVC) ≥65% of predicted.
The primary efficacy endpoint will be a comparison of change in ALSFRS-R from baseline to week-24 (i.e. at the end of Part A) for debamestrocel vs. placebo. Other outcome assessments will include CAFS (Clinical Assessment of Function & Survival), SVC, HHD (Hand-Held Dynamometry) ALSAQ-40 questionnaire, the ZBI (Zarit Burden Interview), and survival. CSF and blood samples will be collected for analysis of biomarkers of neuroinflammation, neurodegeneration, and neuroprotection. A sample using an oral swab can be collected for DNA evaluation of ALS-related genes (optional).
Dr. Dagher added, "A key priority for BrainStorm is to confirm NurOwn's efficacy in the upcoming Phase 3b trial. Our goal is to conclusively demonstrate the treatment's benefits in early-stage ALS patients, hence, we have set the entry criteria to specifically target people living with ALS in the early stage of their disease. We have secured an agreement with the US FDA on a Special Protocol Assessment (SPA), thereby significantly derisking the regulatory aspects of this program. We have also aligned with the FDA on the Chemistry, Manufacturing, and Controls (CMC) aspects of the trial. We look forward to providing further updates as we advance our trial preparations."
