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FDA Refuses to File BrainStorm’s BLA for NurOwn Mesenchymal ALS Therapy

NurOwn, otherwise known as autologous mesenchymal stromal cells secreting neurotrophic factors cells, has demonstrated significant effects on disease progression in less severe forms of ALS.

Months after the company claimed it was planning on submitting a biologics license application (BLA) for its NurOwn technology platform for the treatment of patients with amyotrophic lateral sclerosis (ALS), BrainStorm Cell Therapeutics announced that it received a refusal to file letter from the FDA. The FDA indicated that the company can request a Type A meeting to discuss the content of the refusal to file letter.1

"While we are disappointed that the FDA has not accepted our BLA for NurOwn in ALS, we remain committed to NurOwn's advancement as a treatment for this devastating disease. The company intends to request a Type A meeting and looks forward to continued discussions with the FDA," Chaim Lebovits, chief executive officer, BrainStorm, said in a statement.1 "We continue to believe that NurOwn's Phase 3 trial represents a significant contribution to ALS therapy and will continue to work tirelessly to address the needs of people living with ALS by advancing science and partnering with researchers around the world."

In March 2021, following a review of the pivotal phase 3 trial (NCT03280056) of NurOwn (autologous mesenchymal stromal cells secreting neurotrophic factors [MSC-NTF] cells), the agency concluded that the current level of data did not cross the threshold of substantial evidence to support a BLA. Original results showed that NurOwn did not meet its primary end point of statistical significance, as 33% and 28% of those on MSC-NTF and placebo, respectively, showed a change in disease progression of at least 1.25 points on ALS Functional Rating Scale (ALSFRS-R) after 28 weeks of treatment.2

More than a year later, in August 2022, BrainStorm announced new clinical analyses that strengthened the findings of NurOwn. The erratum included several changes, which prompted the company to submit the BLA, a decision that came more than a year after the FDA recommended against it.3

Although it did not reach statistical significance in its primary end point, several analyses have shown that the agent may have more of an effect in less severe ALS populations. In a prespecified analysis of participants with baseline ALSFRS-R scores of at least 35 showed that 35% of those on MSC-NTF had clinical response vs 16% of those on placebo (odds ratio [OR], 2.6; P = .29). On secondary end points, the newly added results indicated that MSC-NTF participants progressed on average 2 points less on the ALSFRS-R compared with placebo (P = .05), while for participants with more advanced disease, the change from baseline to week 28 was similar between treatment groups (P = .97).

In post hoc analyses, it was originally reported that the least square (LS) mean for placebo (range, –4.32 to –5.81) exhibited far less spread in the LS mean change than those in the MSC-NFT group (range, –1.58 to –4.61). These LS means were corrected for both the MSC-NTF (range, –1.39 to –4.82) and placebo (range, –4.24 to –5.98), but still indicated that placebo-treated patients lost 4 to 5 points on average in 28 weeks across baseline thresholds while those on active treatment lost less function at higher compared with lower baseline levels.4

Most recently, at the 2022 Annual Northeast Amyotrophic Lateral Sclerosis (NEALS) Meeting, November 1-3, in Clearwater Beach, Florida, sensitivity findings from the phase 3 trial further confirmed NurOwn’s benefit in those with less severe ALS. The post hoc sensitivity analyses focused on minimizing the ALSFRS-R floor effect by identifying and excluding those at highest risk of being impacted by a floor effect. To do so, investigators applied the Total Score Threshold (TST), which removed 23% (n = 44) of the cohort who had ALSFRS-R scores less than 25, and Item Level Threshold (ITL), which removed those with a baseline score of 0 or 1 in at least 5 of 6 of the ALSFRS-R’s Fine and Gross Motor scale items, or 16% (n = 30) of the trial cohort.5

The primary end point was a responder analysis defined as the percentage of participants with at least a 1.25 points/month improvement on ALSFRS-R after treatment with NurOwn. When applying the TST and ILT, 34.7% and 35.4% of NurOwn-treated patients, respectively, achieved the primary end point, compared with 20.5% and 22.5% of those on placebo (= .053 and = .035). The secondary end point—average change from baseline to week 28 in ALSFRS-R—also continued to favor active treatment. After utilizing TST and ILT, patients showed average changes of –4.82 and –4.6, respectively, compared with changes of –5.98 and –6.08 for those on placebo (= .250 and = .125).

Robert Brown, MD; Merit Cudkowicz, MD, MSc; and Tony Windebank, MD, the 3 co-principal investigators of the phase 3 study, said in a joint statement that, "While the pre-specified primary outcome measure was not met, there were participants with beneficial clinical effects and overall changes in relevant biomarkers of drug effect. Understanding whether there are people with ALS who might respond better to NurOwn is important given the unmet therapeutic need. As the three co-PIs of the Phase 3 study of NurOwn, we support continued discussions with the FDA on the best path forward."1

REFERENCES
1. BrainStorm Cell Therapeutics receives refusal to file letter from FDA for its new biologics license application for NurOwn for the treatment of ALS. News release. November 10, 2022. Accessed November 10, 2022. https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-receives-refusal-to-file-letter-from-fda-for-its-new-biologics-license-application-for-nurown-for-the-treatment-of-als-301673753.html
2. Cudkowicz ME, Lindborg SR, Goyal NA, et al. A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis. Muscle & Nerve. Published online December 10, 2021. doi:10.1002/mus.27472
3. BrainStorm Cell Therapeutics announces second quarter 2022 financial results and provides a corporate update. News release. BrainStorm Cell Therapeutics. August 15, 2022. Accessed August 16, 2022. https://ir.brainstorm-cell.com/2022-08-15-BrainStorm-Cell-Therapeutics-Announces-Second-Quarter-2022-Financial-Results-and-Provides-a-Corporate-Update
4. Erratum. Muscle & Nerve. Published online August 12, 2022. doi:10.1002/mus.2769
5. Cudkowicz ME, Lindborg SR, Goyal NA, et al. Further analysis of NurOwn phase 3 data based on baseline ALSFRS-R status clarifies treatment outcomes. Presented at: 2022 Annual NEALS Meeting; November 1-3; Clearwater Beach, FL. Abstract 107