BLA Application to Be Submitted for ALS Agent NurOwn Following Phase 3 Statistical Corrections

Chaim Lebovits

In a company update, BrainStorm Cell Therapeutics announced new clinical analyses that strengthened the phase 3 findings of its NurOwn technology platform for patients with amyotrophic lateral sclerosis (ALS). The erratum will prompt the company to submit a biologics license application (BLA) for the therapeutic, a decision that comes more than a year after the FDA recommended against it.¹

In March 2021, following a review of the current clinical phase 3 (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 MSC-NTF 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

Despite this, a prespecified analysis of participants with baseline ALSFRS-R scores of at least 35 showed a 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).

"The continued analysis and the feedback received from the many scientific presentations of NurOwn'sphase 3 data have uncovered key insights that furthered our understanding of the product mechanism of action and therapeutic potential and strengthened the conclusions of NurOwn's efficacy," Chaim Lebovits, chief executive officer, BrainStorm, said in a statement.¹ "After carefully considering these learnings, the totality of the evidence from NurOwn's clinical studies, and the feedback received from key opinion leaders and the broader ALS community, we will submit a biologics license application to the FDA. We intend to provide additional updates upon learning whether the FDA files our BLA submission."

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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.³

In the same section, newly updated results showed that MSC-NTF-treated participants lost, on average, 2 points of function less compared with placebo, which was maintained or increased through the prespecified threshold of ALSFRS-R scores of 35, a difference which was nominally statistically significant (P <.05) for all thresholds greater than 26 up to 35 and an exact P value of 0.050 for the threshold of 35 and above. Changes in ALSFRS-R over time showed how quickly the MSC-NTF diverged from placebo, across baseline thresholds, using the prespecified MMRM model and the post hoc sensitivity analysis that accounted for death and missing data.

In the discussion section, the original results showed a 2.39-point treatment difference in the difference between MSC-NTF and placebo using the observed baseline study mean (ALSFRS-R ≥ 31). After correction, the data showed a 2.48-point treatment difference after 28 weeks, with a nominally significant P value (P = .020).

Editor's note: An earlier version of this story included unintended confusing language about the timing of this application submission. This language has since been updated.

REFERENCE
1. 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
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. Erratum. Muscle & Nerve. Published online August 12, 2022. doi:10.1002/mus.27697