BCLI: Phase 3 ALS Results Published in Muscle and Nerve…

By David Bautz, PhD

NASDAQ:BCLI

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Phase 3 ALS Data Published in Muscle and Nerve

On December 13, 2021, BrainStorm Cell Therapeutics, Inc. BCLI announced the publication of results from the Phase 3 clinical trial of NurOwn in patients with amyotrophic lateral sclerosis (ALS). The publication, entitled "A Randomized Placebo-Controlled Phase 3 Study of Mesenchymal Stem Cells Induced to Secrete High Levels of Neurotrophic Factors in Amyotrophic Lateral Sclerosis" was published in Muscle and Nerve and can be found here. The trial enrolled a total of 189 ALS patients and consisted of an 18-week run-in period in which those who were "rapid progressors" (defined as patients with at least a 3-point decrease in ALSFRS-R score during the run-in period) were randomized 1:1 to receive three intrathecal injections of NurOwn or placebo at Weeks 0, 8, and 16. Participants were followed for 28 weeks following the first treatment.

The published data includes the previously disclosed results showing that the trial did not reach statistical significance on the primary or secondary endpoints along with pre-specified and post-hoc analyses that show a NurOwn-specific treatment effect in patients with less advanced disease. To summarize the findings in the paper:

• Participants enrolled in the study had more advanced disease than is typically seen in other ALS Phase 3 trials (23% of participants had ALSFRS-R scores ≤ 25).

• The inclusion of participants with more advanced disease may have had a dilutive effect that reduced the ability to show a treatment effect. This is exemplified by the fact that some participants had a score of 0 for certain subscales of the ALSFRS-R, thus preventing the ability to show disease progression (the ALSFRS-R subscale scores do not go below 0).

• For the study population as a whole, the NurOwn-treated group had a higher percentage of responders compared to the placebo-treated group, however this difference was not statistically significant (32.6% vs. 27.7%; P=0.45).

• A pre-specified subgroup analysis of participants with ALSFRS-R scores ≥ 35 showed that 34.6% responded in the NurOwn group compared to 15.6% in the placebo group (P=0.29).

• When the baseline mean ALSFRS-R score was utilized (ALSFRS-R ≥ 31), NurOwn-treated participants achieved 35.4% response compared to 15.4% for placebo-treated participants (P=0.043).

• NurOwn was generally safe and well tolerated with no clinically significant differences between NurOwn-treated and placebo-treated participants.

The baseline characteristics for participants in the trial were similar for treated and control groups. The average ALSFRS-R score was 31 and included a number of participants with advanced disease (ALSFRS-R ≤ 25). The following table shows that some participants had a value of zero on ALSFRS-R individual items, thus it wasn't possible to show disease progression on those items.

NurOwn treatment was generally well tolerated and almost all participants experienced mild-to-moderate treatment emergent adverse events (TEAEs). The following table shows the incidence of TEAEs, with most being associated with pain having to do with the treatment administration lumbar puncture procedure. Only one participant in each treatment group had a related serious AE (SAE) and there were more withdrawals due to TEAEs in the placebo group. Importantly, there were no clinically significant differences between the treatment groups nor in clinical laboratory values, vital signs, physical examination findings, and ECG results. Sixteen participants died following randomization to treatment, however no deaths were related to study treatment by the investigator.

As previously disclosed by BrainStorm, the trial did not meet the primary endpoint, which was a responder analysis in which a patient was defined as a responder if their change in disease progression post-treatment compared to pre-treatment was ≥1.25 points/month, which would reflect slowing of decline or improvement of function. The percentages of participants that were deemed responders at 28 weeks was 33% for NurOwn and 28% for placebo (OR=1.33, P=0.45). In a pre-specified subgroup of participants with ALSFRS-R scores ≥35, treated participants achieved 35% response compared to 16% for placebo, which was not statistically significant. The following table shows efficacy analyses across ALSFRS-R baseline scores, thus exhibiting the consistent response rate seen for NurOwn-treated participants while the placebo response rate was inconsistent across baseline thresholds. When the baseline mean ALSFRS-R score was utilized (ALSFRS-R ≥31), NurOwn-treated participants achieved 35.4% response compared to 15.4% for placebo-treated participants (P<0.043).

When examining changes in ALSFRS-R subscales, changes in each subscale favored NurOwn treatment except for the respiratory scale, as shown in the following image (A). The largest differences favoring NurOwn treatment were seen in the Fine Motor subscale and the Gross & Fine Motor subscale combined. In addition, the differences favored NurOwn more in participants with less severe disease at baseline (B and C).

The following graphs show the change in three separate biomarkers in participants administered NurOwn (blue line) or placebo (red line). The biomarkers shown are from the cerebrospinal fluid (CSF) and represent those associated with neurodegeneration (NFL), neuroinflammation (MCP-1), and neuroprotection (VEGF-A). At Week 20, there was a two-fold increase in VEGF-A in patients treated with NurOwn while VEGF-A in patients treated with placebo remain unchanged. MCP-1 was 74% of placebo values in NurOwn-treated patients at Week 20. NFL was 84% of placebo values in NurOwn-treated patients at Week 20.

Conclusion

We are excited to see the full data set from the Phase 3 trial of NurOwn in ALS has been published, and having reviewed all the data we believe there is ample evidence that NurOwn is having a positive treatment effect, particularly in patients with less severe disease. Now that the full dataset has been published, we anticipate the company meeting with regulators to discuss the totality of the data and a potential regulatory path forward. We are uncertain about the time frame for when the company will announce next steps for NurOwn, but are confident that there is a path forward for NurOwn in ALS. We have raised our probability of approval for NurOwn in ALS to 30%, which has increased our valuation to $14 per share, and we eagerly await the company's update on next steps.

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