The investigational cell-based therapy NurOwn may slow disease progression in people with amyotrophic lateral sclerosis (ALS) who have less severe disease, according to analyses from a Phase 3 trial.
Researchers’ analyses excluded patients with the lowest scores on the ALS Functional Rating Scale–Revised (ALSFRS-R) or in individual scale items to account for the possibility of a “floor effect.” This refers to patients whose continuing decline is not accurately detected with the scale because initial scores are already very low.
More people on NurOwn than a placebo were considered responders, with a slowing in disease progression as defined by a change of at least 1.25 points per month in ALSFRS-R scores. NurOwn also reduced the total decline in ALSFRS-R scores over the trial’s period, indicating treated patients experienced a lesser loss of function than did those on a placebo.
These findings were recently discussed at the 21st annual Northeast Amyotrophic Lateral Sclerosis (NEALS) meeting, held Nov. 1–3 in Florida and virtually.
Post-hoc analyses done in patients with less severe ALS to avoid ‘floor effect’ The poster, “Further Analysis of NurOwn Phase 3 Data Based on Baseline ALSFRS-R Status Clarifies Treatment Outcomes,” was presented by Stacy Lindborg, PhD, Brainstorm’s chief development officer, and Merit Cudkowicz, MD, chief of neurology and director of the Healey & AMG Center for ALS at Massachusetts General Hospital in Boston.
“We are pleased to be sharing this confirmatory evidence of NurOwn’s clinically-meaningful effects with the ALS community,” Lindborg said in a company press release. “Our confidence in NurOwn continues to grow as we conduct further analysis of the Phase 3 data.”
NurOwn is a cell-based therapy in which mesenchymal stem cells — cells with the capacity to transform into a variety of cell types — are isolated from the bone marrow and matured in the lab into cells that produce large amounts of neurotrophic factors that promote nerve cell growth and survival.
The matured cells are returned to the patient via injections into the spinal canal, where they are expected to protect nerve cells from damage and slow disease progression.
The completed Phase 3 trial (NCT03280056) investigated NurOwn in people with fast-progressing ALS, those whose ALSFRS-R scores dropped by at least 3 points over a run-in period of 18 weeks.
It enrolled 189 patients who were randomly assigned to three injections of either NurOwn or a placebo, given every other month for about four months. All were then followed for three more months, for a total 28 weeks of follow-up.
The trial’s main goal was to determine if more patients responded to NurOwn than a placebo, meaning whether NurOwn was more effective than placebo at slowing disease progression as seen in an ALSFRS-R score improvement of at least 1.25 points each month.
Top-line NurOwn trial data, announced in 2020, showed this goal was not met. More patients on NurOwn than a placebo were deemed responders (32.6% vs 27.7%), but the difference did not reach statistical significance.
Notably, the Phase 3 trial enrolled patients with more advanced disease than other late-stage ALS trials, with an average ALSFRS-R score of 30.9 at the study’s start (baseline measure). More than a third of its patients also had starting scores of 0 — the lowest possible score — in ALSFRS-R domains of fine motor skill and gross motor skill. In these cases, no further deterioration could be measured on these items.
According to the company, this likely introduced a floor effect, in which comparisons of disease progression between treatment groups using ALSFRS-R scores would be significantly limited.
ALSFRS-R score changes over trial favor NurOwn-treated patients And while a pre-specified analysis of patients with less severe disease — those with a baseline ALSFRS-R scores of at least 35 — did show a greater number of responders with NurOwn (34.6% vs. 15.6%), the findings still failed to reach statistical significance.
In the post-hoc analyses — those planned and conduced after the trial ended — outlined in the presentation, researchers aimed to further examine NurOwn’s potential clinical benefits after excluding patients most likely to be impacted by the floor effect. These people had a starting ALSFRS-R score of 25 or lower (23%, or 44 patients) or a score of 0 or 1 for at least five of the six questions relating to fine and gross motor function (16%, or 30 patients).
Findings were similar to those observed in the earlier pre-specified analysis, with non-significant improvements seen in the NurOwn group.
After removing patients with ALSFRS-R scores of 25 and lower, the response rate was 34.7% for NurOwn and 20.5% with the placebo. Likewise, removing those with scores of zero in most fine and gross motor function items yielded response rates of 35.4% (NurOwn group) and 22.5% (placebo group).
In both analyses, NurOwn-treated patients also showed less of a drop in their average ALSFRS-R scores over the 28 weeks, a secondary trial goal, suggesting that the treatment may slow function loss.
That finding is consistent with previously published post-hoc analyses demonstrating that this secondary trial goal was met, with significance, in all subgroups of patients with starting ALSFRS-R scores between 26 and 35.
Importantly, while the ALSFRS-R-based analyses suggest that the treatment may benefit patients with less severe disease, Brainstorm previously reported that NurOwn can also reduce markers of inflammation and neurodegeneration, and increase neuroprotective and anti-inflammatory molecules, in people with more severe disease.
“This suggests that NurOwn had similar biological activity on all participants in the trial, and that participants may also be benefiting from treatment clinically despite the inability of ALSFRS-R to accurately assess these benefits in certain participants due to a floor effect,” BrainStorm noted in its release.
“We have learned a lot about both the clinical and biological (biomarker) effects of NurOwn in people with ALS,” said Cudkowicz, who is also a professor of neurology at Harvard Medical School. “This presentation provides new insights into the NurOwn phase 3 trial demonstrating the consistency of treatment effect with NurOwn.”
