“Scientifically incomplete.” “Grossly deficient.” “Lacking scientific rigor.” These are just a few of the ways the FDA has described BrainStorm Cell Therapeutics’ application for the amyotrophic lateral sclerosis treatment NurOwn—a therapy that has already been rejected twice and is now getting its day before an agency advisory committee after being filed over protest.
The FDA’s briefing docs, published two days ahead of the committee meeting, detail the agency’s doubts about the safety and efficacy of NurOwn at length. The Cellular, Tissue, and Gene Therapies Advisory Committee has been asked to discuss two questions: Is there substantial evidence of effectiveness meeting the approval standard based on available evidence? And if this bar has not been met, how could a new trial be designed to show substantial evidence of effectiveness in ALS?
The FDA
If you ask the FDA, the answer to the first question is a hard no. NurOwn failed a phase 3 study on the primary and all secondary efficacy endpoints in November 2020. The agency rejected an application from BrainStorm twice, only for the biotech to file the application over protest, which led to the meeting.
BrainStorm's shares had tumbled 39% to 49 cents by noon on Monday, from 81 cents at the previous close.
NurOwn is a mesenchymal stem cell-secreting neurotrophic factors therapy generated from bone marrow. Its proposed mechanism of action is unknown and BrainStorm’s description of how it works “is unclear and inconsistent across the BLA,” according to the FDA.
The late-stage trial showed no statistically significant difference on the primary endpoint measuring the rate of responders to the medicine, with 32.6% on the study drug meeting the criteria compared to 27.7% in the placebo arm. The p-value was 0.45.
Ten patients who received NurOwn died during follow up compared to three in the placebo arm, meaning survival was worse for those who took the study drug.
“This outcome suggests the lack of efficacy of [NurOwn] on survival of patients with ALS,” the FDA concluded.
BrainStorm attributed the deaths in the study to disease progression, “which seems reasonable based on available information,” the FDA noted. But since autopsy reports were not submitted, the agency could not make a determination as to whether NurOwn also played a role in the deaths.
The early change in overall survival in patients taking the therapy compared to the placebo arm “is of serious concern,” according to the FDA's documents.
BrainStorm then conducted post-hoc exploratory subgroup analyses in an attempt to find a positive from the study. The FDA noted that these analysis can be helpful to find a trend that can be studied in a new trial, but “such subgroup analyses following overall nonsignificant tests in the overall population must always be interpreted with caution.”
The company asserted that a floor effect impacted the overall results, which “refers to insensitivity of an outcome measure to differences at the lower end of an assessment scale,” according to the FDA. BrainStorm claimed that the floor effect resulted in a plateauing on the ALS Functional Rating Scale‒Revised (ALSFRS-R) over time so further deterioration could not be measured. This scale measures the severity of ALS based on motor impairment and functional deterioration. Those patients supposedly impacted by the floor effect were excluded from the post hoc analysis.
“However, no floor effect was demonstrated in the analyses. In addition, floor effect would not be expected in the assessment of survival or biomarkers,” the FDA said.
In fact, the agency explained that when patients were assessed by change in their total ALSFRS-R score from baseline to week 28, those who received NurOwn had a deeper decline than placebo patients.
“This result indicates continued deterioration of function and suggests lack of treatment benefit for [NurOwn] subjects,” the FDA said.
BrainStorm also analyzed cerebrospinal fluid for certain biomarkers associated with ALS, including neurofilament light chain, or NfL, which is released by damaged or degenerating axons, which is a hallmark of ALS. As a patient’s condition worsens, NfL levels rise. To demonstrate efficacy, a treatment should demonstrate a clear reduction in this biomarker and then show less decline on the ALSFRS-R.
NurOwn was associated with a reduction in NfL of about 8.9% at week 20 when compared with placebo. But these patients also had a greater loss of function and the FDA noted that data was missing from the analysis. The agency said this is “the opposite of what would be expected” and could be because half the week 20 data was missing.
And then there’s the manufacturing of NurOwn. The FDA “has substantial concerns” about how the therapy is manufactured and BrainStorm has yet to resolve the issues. The agency's concerns surround the comparability of product quality across different clinical studies, control of product variability for the phase 3 study, lack of process validation, failure to manufacture the full dose for all patients and the intended commercial manufacturing process.
Since evaluation of the manufacturing data is still ongoing, the FDA is focusing on the clinical, statistical and biomarker analyses but noted that manufacturing and testing facilities must be licensed for a drug sponsor to receive a biologics license application for a new treatment.
Safety is also not the focus of the advisory committee’s review, but the FDA noted seven life-threatening serious adverse events and 15 events that required hospitalization, in addition to the deaths. Respiratory failure and dysphagia, or difficulty swallowing, were the most common serious treatment-emergent adverse events.
The company
BrainStorm presented the benefit-risk profile for NurOwn as positive, asserting that the totality of the evidence shows the treatment “has a consistent and clinically meaningful treatment effect across a broad range of patients with ALS, which is further supported by significant results across multiple biomarkers.”
The company calls for regulatory flexibility in the devastating disease, which has a median survival of just two to five years from onset. BrainStorm quoted several patients in its documents, noting the potential harm of waiting to approve a potentially efficacious treatment “is not hypothetical.”
NurOwn treats ALS by modulating neuroprotective and neuroinflammatory pathways to reduce neurodegeneration and cell death, according to BrainStorm.
To explain the failure on the phase 3 endpoints, the biotech noted that the trial enrolled a high number of very advanced patients compared to similar studies. The company specifically noted two recently approved therapies, Biogen and Ionis’ Qalsody and Amylyx’s Relyvrio, which had patients with less advanced ALS in the studies. Both received FDA approval anyway—although both have proven controversial. Qalsody also did not meet the goals of a phase 3 trial.
BrainStorm asserts that the floor effect was in fact in play, “due to the inability of a scale to capture progression in participants with the lowest scores on individual items.” This was particularly apparent in the patients who entered the study with low baseline ALSFRS-R scores, which impacted the overall results.
“Importantly, in the majority of participants where ongoing decline could be measured, a consistent and meaningful effect was observed across endpoints, including a nominally significant treatment effect in a pre-specified subgroup (p = 0.05) and across several post-hoc sensitivity analyses,” BrainStorm said.
On biomarkers of neuroinflammation, neurodegeneration and neuroprotection, NurOwn showed significant improvements, the company said. This benefit was even seen in patients who had more advanced disease.
BrainStorm also disagreed with the FDA on the NfL biomarker, asserting that there was a strong relationship between the reduction in the biomarker and preservation of function.
“Overall, the biomarker data demonstrated a consistent biological effect with NurOwn in an analysis of all trial participants across multiple biomarkers,” BrainStorm said.
Speaking to the deaths in the study, BrainStorm said the events were “consistent with progression of ALS.” The company noted 16 that happened during the phase 3 study, but none were related to the treatment by the investigator or sponsor.
“There was no statistical difference in survival between groups,” BrainStorm said. The biotech attributed 12 of the deaths to disease progression—eight in the NurOwn group and four in placebo—and most of those who died had more advanced disease at the start of the study, according to the company.
BrainStorm also noted some patient-reported changes in daily activity, such as being able to walk without a walker, swallowing more dense foods like fried chicken or sushi, speaking more clearly without needing a caregiver to translate, using a cell phone and breathing stronger as shown by a forced vital capacity test.
As for manufacturing, BrainStorm calls its process “innovative” but did not go into details on the FDA’s concerns.
No matter how the committee votes on the two questions, the meeting is sure to be emotional, as 60-minutes have been set aside for the public during the afternoon. At a similar meeting last March for Amylyx’s AMX0035—a combination of sodium phenylbutyrate and taurursodiol—an advisory panel said the evidence from one study wasn’t strong enough to warrant approval. However, many of the committee members expressed how difficult the decision was, regardless of how they voted.
Patients, advocates and caregivers also begged for access to the treatment with emotional testimony that gave several of the committee's members pause. Kenneth Fischbeck, M.D., said approving AMX0035 would be a “disservice” to the ALS patient community given the “problematic study,” because the therapy might ultimately prove to be ineffective. But he noted the moving testimony of the patients and their advocates during the hearing.