BCLI: Awaiting Clarity on Regulatory Environment Before Deciding on Next Steps for NurOwn®…

By David Bautz, PhD

NASDAQ:BCLI

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Business Update

Awaiting Clarity on Regulatory Environment Before Moving Forward with NurOwn® in ALS

BrainStorm Cell Therapeutics, Inc. BCLI is developing NurOwn as a treatment for patients with amyotrophic lateral sclerosis (ALS). The company recently published results from the Phase 3 trial of NurOwn in Muscle and Nerve that showed while the trial did not reach statistical significance on the primary or secondary endpoints, there were a number of positive effects in less advanced patients (Cudkowicz et al., 2022). The regulatory fate for NurOwn has been uncertain since the Phase 3 trial results were announced as the company consulted with physicians, patients, and advocacy groups to get a better understanding of the best path forward.

Additional clarity on the path forward may be available soon as the FDA held an Advisory Committee meeting this week to discuss the new drug application (NDA) for AMX0035 as a treatment for ALS. AMX0035 is being developed by Amylyx Pharmaceuticals (AMLX) and the NDA was submitted based on a single Phase 2 study involving 137 ALS patients. The trial hit the primary endpoint as the mean rate of change in the ALSFRS-R score was -1.24 points per month for those treated with AMX0035 compared to -1.66 points per month for those treated with placebo (95% CI 0.03-0.81; P=0.03) (Paganoni et al., 2020).

While the primary endpoint was achieved, there are still a number of questions that were raised in regard to the trial. During the Advisory Committee meeting, a number of issues were discussed, including:

• The P value for the primary analysis was calculated assuming linearity of ALSFRS-R over time. However, linearity has never been established for the ALSFRS-R. The FDA utilized a statistical model with a quadratic term for time, which resulted in a P value for the primary outcome of P=0.1134.

• The analysis of the primary outcome was conducted by excluding two patients who died in the AMX0035 cohort but did not have post-baseline ALSFRS-R measurements.

• Approximately 17% of placebo patients and 18% of patients on AMX0035 did not have ALSFRS-R scores at Week 24.

• A much higher percentage of patients in the AMX0035 group initiated edaravone or riluzole post-baseline (15.7% vs 4.2%). In addition, a randomization error at the beginning of the study resulted in the first 18 patients (13% of the overall sample size) being assigned to the AMX0035 arm with the next 9 patients then assigned to the placebo arm.

• While not significant, the change in phosphorylated neurofilament heavy chain (pNF-H) favored the placebo group and actually increased in the AMX0035 group. pNF-H is a biomarker of neuronal axonal injury and neurodegeneration. Presumably, a treatment that shows a benefit in treating ALS would also decrease pNF-H levels.

On the question "Do the data from the single randomized, controlled trial and the open-label extension study establish a conclusion that sodium phenylbutyrate/taurursodiol is effective in the treatment of patients with amyotrophic lateral sclerosis?" the Advisory committee voted 4-yes and 6-no. While the FDA is not obligated to follow an Advisory Committee's recommendation, an analysis from a few years ago showed that from 2008-2015 the FDA followed the recommendation approximately 78% of the time (Milbank Memorial Fund, 2019). However, given how close the vote was and the fact that there is a pressing need for additional ALS treatments, it will be very interesting to see whether the FDA grants approval to AMX0035.

The approval decision for AMX0035 is not necessarily a make-or-break moment for BrainStorm, but if it is approved that would signal a more accommodating regulatory environment in which BrainStorm could push ahead with a BLA for NurOwn in the hopes to convince regulators to approve the drug based on the totality of the data, not just the Phase 3 results. For this reason, BrainStorm has essentially stayed quiet on what its plans are in regard to the path forward for NurOwn until there is more clarity on the fate of AMX0035. We believe once a decision has been made on AMX0035 we should have a better understanding of whether a BLA will be filed for NurOwn and the timeframe for it. The PDUFA date for AMX0035 is June 29, 2022.

Relationship Between UNC13A SNP and Clinical Outcomes in Phase 3 ALS Trial

On February 28, 2022, BrainStorm announced the acceptance of an abstract at the 2022 MDA (Muscular Dystrophy Association) Clinical and Scientific Conference. A copy of the company's oral presentation can be found here. The company genotyped 124 participants in the Phase 3 trial (63 NurOwn/61 placebo) to evaluate 31 ALS-related genes and 4 associated single nucleotide polymorphisms (SNPs). The focus of the company's presentation was on the UNC13A SNP. The C allele of this SNP is a risk variant for the development of both sporadic ALS and frontotemporal dementia (van Es et al., 2009). Almost all ALS patients have depletion of the RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord (Neumann et al., 2006). TDP-43 works as a repressor of cryptic exon inclusion (Ling et al., 2015). A recent study showed that loss of TDP-43 from the nucleus in human brain, neuronal cell lines, and motor neurons resulted in the inclusion of a cryptic exon in UNC13A mRNA, thus reducing UNC13A protein expression (Ma et al., 2022). These results tie the loss of TDP-43 in the nucleus with the presence of one of the strongest genetic risk factors for ALS.

In the NurOwn Phase 3 study, approximately 37%, 47%, and 15% of patients had the A/A, A/C, and C/C UNC13A alleles, respectively, which is very similar to the distribution seen in a much larger cohort (Tan et al., 2020). The following figure shows that patients with the A/C genotype responded better to NurOwn treatment, with 65% responders on NurOwn compared to 29% responders on placebo. This is in contrast to patients with the C/C or A/A alleles, in which the response rates between the NurOwn and placebo groups were very similar.

This is one of the first prospective pharmacogenomic studies in an ALS population and it is very encouraging to see such a strong association between response to NurOwn treatment and the presence of the A/C UNC13A genotype. Additional studies will need to be conducted to evaluate the mechanism of action of NurOwn as it relates to UNC13A genotypes.

Additional Dosing of NurOwn Authorized by FDA Under Expanded Access Program

In December 2022, BrainStorm announced that the FDA recommended that the company submit an expanded access protocol (EAP) amendment to provide additional doses of NurOwn to patients who had completed the EAP. Under the original EAP, patients from the Phase 3 NurOwn study were eligible to receive three additional doses. The amended EAP now allows for those patients to receive up to three additional doses on top of what have already been administered.

This is very encouraging news as it was the FDA that approached BrainStorm to request additional doses of NurOwn be made eligible for patients and the data collected under the original EAP is what led the FDA to make that move.

Financial Update

On March 28, 2022, BrainStorm announced financial results for 2021. As anticipated, the company did not report any revenues during 2021. Net R&D expenses for 2021 were $15.2 million compared to $22.3 million in 2020. The decrease was due to decreased costs associated with the Phase 3 and Phase 2 clinical trials, patents, payroll, and stock-based compensation. Excluding participation from the IIA and CIRM, R&D expenses decreased by $8.7 million from $24.6 million in 2020 to $15.9 million in 2021. G&A expenses were $9.3 million in 2021 compared to $9.4 million in 2020. The decrease was primarily due to decreased payroll cost, stock-based compensation, and consultant costs offset by an increase in rent and various other expenses.

The company exited 2021 with approximately $22.1 million in cash, cash equivalents, and short-term deposits. As of March 28, 2022, the company had approximately 36.5 million shares outstanding and, when factoring in stock options and warrants, a fully diluted share count of 40.1 million.

Conclusion

With the very close vote at the Advisory committee meeting for AMX0035 it is anyone's guess what the FDA is going to do. However, we will be keeping a very close eye on the situation as it could influence the direction that BrainStorm takes regarding the future of NurOwn in ALS. Thus far, the company has stayed relatively quiet about its plans, which in retrospect was a good plan given the fluidity of the regulatory environment. We look forward to the company's decision regarding NurOwn in ALS. In the meantime, we have not made any changes to our model and our valuation remains at $14 per share.

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