BCLI: Biomarkers Predict Response in ALS Phase 3 Trial…

By David Bautz, PhD

NASDAQ:BCLI

READ THE FULL BCLI RESEARCH REPORT

Business Update

New Biomarker Data from Phase 3 ALS Trial

On October 6, 2021, BrainStorm Cell Therapeutics, Inc. BCLI announced the presentation of an abstract containing new data from the Phase 3 trial in amyotrophic lateral sclerosis (ALS) showing that changes in specific biomarkers were correlated with the primary clinical outcome using an unbiased stepwise logistic regression. The abstract, titled "CSF biomarker correlations with primary outcome in NurOwn Phase 3 clinical trial", was presented at the fully digital 2021 Northeast Amyotrophic Lateral Sclerosis Consortium^® (NEALS) conference. A copy of the poster can be found here.

The following graphs show the change in three separate biomarkers in patients administered NurOwn (blue line) or placebo (red line). The biomarkers shown are from the central nervous system (CNS) 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.

The three biomarkers shown above were part of a larger set of pre-specified biomarkers that were examined during the trial. The changes in these biomarkers were analyzed both separately and as a group to construct a stepwise regression model that would accurately predict the primary clinical response endpoint in the Phase 3 ALS trial. The final model showed 82.5% accuracy in predicting those patients that responded to NurOwn treatment, which is assisting in understanding who the responders were during the trial and potentially why. The company is planning to publish the full analysis of this data set in a separate peer-reviewed manuscript.

Determining the Best Path Forward for NurOwn® in ALS

BrainStorm has completed a Phase 3 clinical trial for NurOwn as a treatment for ALS and in November 2020 announced topline results showing that the trial did not reach statistical significance for the primary endpoint, a responder analysis examining the percentage of participants that experienced a 1.25 point per month improvement in the post-treatment Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R) slope. However, an analysis of a pre-specified subgroup of patients with ALSFRS-R scores ≥ 35, of which approximately 30% of trial participants were included, showed a clinically meaningful treatment response with NurOwn with 34.6% of responders compared to 15.6% of responders in placebo-treated participants (P=0.288).

In February 2021, BrainStorm announced feedback from the FDA following a meeting with senior leadership in which the agency concluded from their initial review of the Phase 3 data that it does not provide the threshold of substantial evidence that the FDA is seeking to support a Biologics License Application (BLA). The FDA also advised that the recommendation does not preclude BrainStorm from proceeding with a BLA submission.

The company has submitted a manuscript on the Phase 3 ALS results to a peer-reviewed journal and it is currently in the review process. The company is continuing to meet with regulatory consultants, ALS advocacy groups, physicians, and potential strategic partners to determine the best path forward, which may include an FDA BLA submission, a regulatory submission in other geographies, and/or other regulatory and business options. We anticipate publication of the manuscript of the Phase 3 results before an announcement on what path the company plans to take to advance NurOwn in ALS.

Positive Proof-of-Concept Data for NurOwn in Progressive MS

In March 2021, BrainStorm announced positive proof-of-concept data for NurOwn in patients with progressive multiple sclerosis (MS). The trial achieved the primary endpoint of safety and encouraging results were seen in multiple secondary, functional endpoints.

The Phase 2 trial was a multicenter, open label trial that enrolled 20 patients, with 18 treated and 16 completing the study. Two of the enrolled patients decided against continuing in the trial before dosing began, with one patient withdrawing following dosing due to non-specific symptoms and another due to back/leg pain. Following a 10-week run-in period, patients were dosed with 1-1.25 x 10⁶ MSC-NTF cells three times at 2-month intervals. Patients were followed for 28 weeks following the first treatment. The secondary functional endpoints examined included:

• Timed 25-Foot Walking Speed (T25FW): Scoring is the average of two trials. A patient is directed to walk 25 feet quickly and as safely as possible from one marked end to the other. The patient then walks back the same distance.

• 9-Hole Peg Test (9-HPT): This test is administered by patients taking pegs from a container, one by one, and placing them in holes as quickly as possible. The patient then removes the pegs one by one and puts them back in the container. Both dominant and non-dominant hands are tested.

• Low Contrast Letter Acuity (LCLA): This is similar to a standard eye chart test but instead of black letters on a white background (100% contrast), low contrast levels are used and the number of letters identified is scored.

• Symbol Digit Modality Test (SDMT): Using a reference key, a test subject has 90 seconds to pair specific numbers with given geometric figures. It is a simple substitution task that normal adults can easily perform and can be utilized to detect changes in cognitive functioning over time.

• 12-item Multiple Sclerosis Walking Scale (MSWS-12): This is a self-reported measure of the impact of MS on a patient's walking ability.

Baseline characteristics for study participants showed that the mean age was 47, 56% were female, and the mean baseline Expanded Disability Status Scale (EDSS) score was 5.4. The results of the trial were compared to a matched clinical cohort of 48 patients from the Comprehensive Longitudinal Investigations in MS at the Brigham & Woman's Hospital (CLIMB Study) (Gauthier et al., 2006).

Highlights from the topline results of secondary functional outcomes include:

• 14% and 13% of NurOwn-treated patients showed a 25% improvement in T25FW and 9-HPT, respectively, compared to 0% from the matched cohort from the CLIMB registry.

• 38% of NurOwn-treated patients showed a ≥10-point improvement in the MSWS-12 (CLIMB cohort not analyzed for this outcome).

• 47% of NurOwn-treated patients showed a ≥8-letter improvement in the LCLA (CLIMB cohort not analyzed for this outcome).

• 67% of NurOwn-treated patients showed a ≥3-point improvement in the SDMT (BrainStorm is waiting on the results for SDMT for the CLIMB cohort).

• On average, there was a 10% improvement in T25FW and a 4.8% improvement on the 9-HPT for NurOwn-treated patients, compared to a 1.8% and 1.4% worsening, respectively, in the matched control group from the CLIMB registry.

Previous trials of MS drugs have noted an association between loss of vision, as measured by the LCLA, and diminished quality of life (Chahin et al., 2015), thus the improvements in vision seen in almost half the patients treated with NurOwn are particularly noteworthy.

The company recently presented data from the Phase 2 progressive MS trial at two scientific meetings and a manuscript summarizing the results has been submitted to a peer reviewed journal. In addition, BrainStorm continues work on a development plan and is currently holding discussions with MS experts while seeking guidance from the FDA to determine next steps for the MS program.

Financial Update

On November 15, 2021, BrainStorm announced financial results for the third quarter of 2021. As anticipated, the company did not report any revenues during the third quarter of 2021. Net R&D expenses for the third quarter of 2021 were $3.6 million, compared to $1.9 million during the third quarter of 2020. The increase was primarily due to decreased participation of the Israel Innovation Authority (IIA) and the California Institute for Regenerative Medicine (CIRM), and increased preclinical expenses. Excluding participation from the Israeli Innovation Authority (IIA) and other grants, R&D expenses were $3.6 million in the third quarter of 2021 compared to $4.1 million in the third quarter of 2020. G&A expenses for the third quarter of 2021 were $1.7 million compared to $2.6 million for the third quarter of 2020. The decrease was primarily due to decreased payroll and stock-based compensation.

The company exited the third quarter of 2021 with approximately $28 million in cash, cash equivalents, and short-term deposits. As of August 15, 2021, BrainStorm had approximately 36.3 million common shares outstanding and, when factoring in stock options and warrants, a fully diluted share count of approximately 41.0 million.

Conclusion

The biomarker data presented by BrainStorm is intriguing, particularly since it may lead to a better understanding of which patients respond to NurOwn and potentially why and we look forward to the publication of the full data set. While we wait to hear what decision the company has made regarding the regulatory path for NurOwn in ALS, we anticipate the publication of the Phase 3 trial results in ALS along with the Phase 2 progressive MS results in peer reviewed journals. With no changes to our model our valuation remains at $11.

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