BrainStorm Cell Therapeutics said Tuesday that aPhase III studyinvestigating the cell therapy NurOwn as a treatment for patients with amyotrophic lateral sclerosis (ALS) failed to meet significance for the primary efficacy endpoint, sending shares down as much as 68%. The company added that while NurOwn showed a numerical improvement for the main goal, as well as on key secondary efficacy endpoints, none of these were significant versus placebo.
The study involved 189 "rapid progressor" ALS patients, defined as those with at least a three-point decrease on the Revised ALS Functional Rating Scale (ALSFRS-R) during the 18-week run-in period. Subjects were randomised to undergo a total of three intrathecal transplantations with NurOwn, spaced eight weeks apart, or placebo, and followed for 28 weeks. The experimental therapy uses mesenchymal stem cells (MSCs) isolated from a patient's bone marrow, and induces them to secrete high levels of neurotrophic factors (NTFs) to convert them to MSC-NTF cells.
Higher-than-expected placebo response
The trial's primary endpoint was a responder analysis of the rate of decline in ALSFRS-R score, where response was defined as an improvement of 1.25 points/month in the post-treatment versus pre-treatment slope in ALSFRS-R at 28 weeks after the first treatment. Meanwhile, secondary goals included the percentage of patients with disease progression halted or improved, ALSFRS-R change from baseline, combined analysis of function and survival, slow vital capacity, tracheostomy-free survival, overall survival and cerebrospinal fluid (CSF) biomarker measurements.
According to BrainStorm, the efficacy goal was powered on assumed treatment response rates of 35% for NurOwn compared to 15% for placebo, with both based on historical clinical trial data and mid-stage results for the experimental therapy. The company said the main goal was achieved in 34.7% of NurOwn participants, but the placebo group outperformed expectations at 24.7%, a result that "exceeded placebo responses observed in contemporary ALS trials." The secondary efficacy endpoint measuring average change in ALSFRS-R total score from baseline to week 28 also failed to reach significance, at -5.52 with NurOwn versus -5.88 for placebo.
Clinically meaningful response in sub-group
However, the company noted that in a pre-specified subgroup of patients with early disease based on an ALSFRS-R baseline score of at least 35, NurOwn demonstrated a clinically meaningful treatment response across the primary and key secondary endpoints. In this subgroup, 34.6% of participants responded to treatment with NurOwn, compared to 15.6% for placebo, while the average change from baseline to week 28 in ALSFRS-R total score was -1.77 and -3.78, respectively, reflecting an improvement of 2.01 points favouring NurOwn. BrainStorm also highlighted CSF biomarker analyses indicating that NurOwn led to a significant increase of NTFs as well as a reduction in neurodegenerative and neuroinflammatory biomarkers. Based on statistical modelling, BrainStorm suggests "NurOwn treatment outcomes could be predicted by baseline ALS function as well as key CSF neurodegenerative and neuroinflammatory biomarkers."
Looking for a path forward
Stacy Lindborg, who heads global clinical research at the company, said "the placebo response observed in this trial is unprecedented and the ability to show treatment benefit in this context provides evidence of the clinical value of NurOwn." She noted that changes in CSF biomarkers of neurodegeneration, including NfL and MCP-1, "allows identification of likely responders prior to treatment [and] is encouraging." Lindborg added that detailed analyses will be shared at upcoming scientific conferences and in subsequent publications.
Meanwhile, CEO Chaim Lebovits stated "we are in active discussions with the FDA who have expressed their eagerness to review the data and have committed to prioritise review of this data," adding that the agency will "see if there is a path forward to support approval."
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