Biomarkers Boosted by NurOwn Regardless of Disease Severity: Data

Better neuroprotective and anti-inflammatory marker levels seen in Phase 3 trial

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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NurOwn, Brainstorm Cell Therapeutics’ investigational cell-based therapy, leads to meaningful disease-related biomarker changes regardless of amyotrophic lateral sclerosis (ALS) severity at the start of treatment, according to data from a Phase 3 trial.

Specifically, the therapy increased neuroprotection biomarker levels and anti-inflammatory molecules, and reduced those of neurodegeneration and pro-inflammatory molecules, when compared to a placebo.

While clinical responses to NurOwn, based on the ALS Functional Rating Scale-Revised (ALSFRS-R), were previously found to be stronger with less severe disease, these biomarkers were not subject to that limitation and showed similar changes in patients with more or less severe disease.

These findings “provide further evidence of NurOwn’s multifaceted mechanism of action and show consistent patterns in study participants regardless of the level of disease progression at baseline [study’s start],” Stacy Lindborg, PhD, Brainstorm’s chief development officer, said in a company press release.

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The results, shared by Lindborg in an oral presentation at the Annual ALS ONE Research Symposium, held virtually Oct 6–7, also further underscored ALSFRS-R’s limitations in detecting potential functional changes in more severe disease.

This “definitely contributed and may have led to NurOwn missing the trial’s primary [goal] and secondary endpoints” that were based on ALSFRS-R, Lindborg said in the presentation, “The Relationship between CSF Biomarkers and Efficacy of Treatment with NurOwn (MSC-NTF cells).”

NurOwn is a cell-based therapy wherein patients’ own mesenchymal stem cells — which have the capacity to transform into virtually any other cell type — are first isolated from bone marrow and then matured in the lab to produce large amounts of neurotrophic factors, which promote nerve cell growth and survival. Finally, they’re injected directly into the spinal canal, where they’re expected to promote nerve cell repair and slow disease progression.

Monitoring disease progression

The Phase 3 clinical trial (NCT03280056) involved 127 men and 62 women with fast-progressing ALS who were randomly assigned to receive three injections of either NurOwn or a placebo, every other month for 16 weeks (about four months). Patients were then followed for three months.

Disease progression was monitored with the ALSFRS-R, a measure of a person’s ability to perform daily activities. Ranging from 0 to 48, a lower score reflects worse functional abilities.

A positive response to treatment was regarded as a 1.25-point slower rate of decline in ALSFRS-R scores compared to the three months before the trial.

Top-line data showed that response rates were higher in the NurOwn group than in the placebo group (32.6% vs. 27.7%), but this difference failed to reach statistical significance, meaning the trial did not attain its main goal. ALSFRS-R-based secondary goals also were not met.

However, unlike other late-stage ALS trials, the NurOwn study included patients with more advanced disease, the company said in the release. Patients’ average baseline ALSFRS-R score was 31 in the NurOwn trial and 36 in Phase 3 testing of the most recently approved ALS treatment, Relyvrio (AMX0035).

Moreover, more than a third of patients in the NurOwn trial had scores of 0 for fine motor skills (42%) and gross motor skills (37%) at baseline.

This leads to a so-called “floor effect,” wherein clinical declines can no longer be meaningfully measured by ALSFRS-R in these patients, which limit comparisons of disease progression rates between treatment groups, Lindborg noted in the presentation.

Consistently, previous pre-specified analyses of patients with less advanced disease (ALSFRS-R scores of at least 35) showed NurOwn led to a twofold higher rate of responders relative to a placebo (34.6% vs 15.6%). Still, the finding did not reach statistical significance.

Slower declines with NurOwn

Subgroups of patients with ALSFRS-R scores of 27 through at least 35 did see a significantly and clinically meaningful slower score decline with NurOwn compared with a placebo — a finding revealed after an error in the original statistical analyses was corrected.

Cerebrospinal fluid, the fluid surrounding the brain and spinal cord, was also collected every two weeks throughout the study up to week 20 for biomarker analyses.

As previously reported, NurOwn reduced protein levels linked to neuroinflammation and neurodegeneration, and increased those of neuroprotective and anti-inflammatory molecules. Changes to some biomarkers were observed as soon as the first measurement after treatment.

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Newly presented data showed these biomarkers were not impacted by the floor effect the same way ALSFRS-R scores were.

Consistent patterns and significant changes across biomarkers were observed in participants with less advanced disease at baseline and those with baseline ALSFRS-R scores at or below 25, the most likely to be affected by the floor effect.

“This tells us that NurOwn is having similar [biological] effects on these participants, and that the reason we see differences in the clinical endpoints across subgroups is due to limitations of the [ALSFRS-R] caused by the floor effect,” Lindborg said in the presentation.

Also, a pre-specified statistical analysis identified three biomarkers that could predict clinical responses. These included baseline levels of the anti-inflammatory LAP molecule and of neurofilament light chain, a neurodegeneration biomarker, as well as mean changes in galectin-1 levels, a neuroprotective biomarker.

“The biomarker data and statistical analyses further our understanding of NurOwn’s mechanism of action and therapeutic potential,” Chaim Lebovits, Brainstorm’s CEO, said.

“Novel therapies that simultaneously target multiple pathways may offer great potential in the treatment of ALS and highlights the advantages that may come with NurOwn’s ability to simultaneously modulate multiple biological pathways,” Lindborg said.

The company announced plans this summer to ask the U.S. Food and Drug Administration to approve NurOwn for treating ALS. Whether this would include all ALS patients or a specific subgroup has not yet been determined.