FDA questions NurOwn’s efficacy, quality ahead of today’s hearing

Advisory panel to consider if data support stem cell therapy's approval for ALS

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The U.S. Food and Drug Administration (FDA) has shared its major concerns with data available for NurOwn, BrainStorm Cell Therapeutics‘ experimental stem cell therapy for amyotrophic lateral sclerosis (ALS).

According to a new briefing document put out by the FDA, the agency believes that currently available clinical data do not provide substantial evidence to support NurOwn’s effectiveness in people with ALS. It also raised concerns about whether BrainStorm can reliably manufacture the therapy.

The document was released in advance of an FDA advisory committee meeting on NurOwn’s efficacy, set to take place today, Sept. 27.

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BrainStorm: ‘Floor effect’ reason for NurOwn failure in Phase 3 ALS trial

NurOwn treatment involves harvesting mesenchymal stem cells (MSCs) from a patient’s bone marrow. The stem cells are engineered in a laboratory so that they secrete high levels of signaling molecules that promote nerve cell growth. Then, the cells are returned to the patient through injections into the spinal canal.

Late last year, the FDA refused to consider BrainStorm’s application seeking approval of NurOwn as a treatment for ALS.

The company then used the FDA’s “file over protest” procedure to ask the agency to review the application anyway, and a final agency decision on NurOwn is expected in December.

At the advisory committee meeting, a panel of experts will review available data on NurOwn and offer a recommendation to the FDA. The panel has two questions to address: Do data submitted in support of NurOwn amount to “substantial evidence of effectiveness meeting the approval standard”? If not, discuss “potential designs” needed in a future trial to produce such evidence.

The FDA isn’t bound to abide by advisory committee opinions, but it usually follows them.

In its briefing document, the FDA reiterated a major concern it had voiced when it originally refused to consider BrainStorm’s application for NurOwn: Currently available clinical trial data don’t show the therapy works to slow ALS progression as intended.

BrainStorm sponsored a Phase 3 clinical trial (NCT03280056) that compared NurOwn against a placebo in 189 people with rapidly progressing ALS.

The trial hoped to show that NurOwn slowed disease progression, as measured by changes over time in a measure of disease severity called the ALS Functional Rating Scale-Revised (ALSFRS-R).

However, the study failed to show a significant difference between patients given NurOwn or a placebo. Other measures of disease progression also generally did not show differences between the two groups.

BrainStorm has argued that the trial’s negative results might be explained by a “floor effect” associated with the ALSFRS-R scale. Some patients with more advanced disease, it argued, may have had ALSFRS-R scores so low that they couldn’t meaningfully get lower, so statistical analyses were unable to accurately capture disease progression in these patients.

The company conducted post hoc analyses — statistical tests designed and run after the trial ends and all data have been collected — where researchers either excluded patients with the potential for a floor effect or included only those with less advanced disease. These analyses were generally positive, suggesting that NurOwn slowed disease progression compared with a placebo.

FDA questions ‘floor effect’ and other findings meant to show NurOwn efficacy

According to the FDA, however, these analyses aren’t enough to show the therapy is effective. For one thing, the agency notes that post hoc analyses like these “in general have high risk of finding false positive results,” because the tests are being done on data that are already available.

“Such exploratory analyses provide little confidence on which to base regulatory decisions, and though they may serve to generate hypotheses for testing in future trials, cannot compensate for negative results in a well-controlled study,” the FDA wrote.

Moreover, the agency says that in its analysis of the data, it did not find evidence of a “floor effect.” If such an effect were present, it would be expected that ALSFRS-R scores would plateau when they couldn’t get lower.

In the FDA’s analysis, these scores tended to continuously change over the course of the trial, even for patients who BrainStorm flagged as having a “floor effect.” In fact, data suggest that ALSFRS-R scores tended to worsen slightly more quickly for patients given NurOwn than a placebo, and the overall change in scores was comparable between the two groups.

Collectively, these data show “the lack of efficacy of [NurOwn] over placebo cannot be explained by a floor effect,” the FDA document states.

The agency also noted that, over the course of the six-month trial, 10 patients given NurOwn died, as compared with three given a placebo. While the trial was not designed to assess survival, the agency said this finding “suggests the lack of efficacy of [NurOwn] on survival of patients with ALS.”

FDA concerns about manufacturing consistency and quality for NurOwn

In addition to concerns about NurOwn’s efficacy, the FDA also raised concerns about BrainStorm’s ability to consistently manufacture the therapy. According to the FDA, BrainStorm has failed to demonstrate that it can consistently produce the modified stem cells used for NurOwn, noting that the number of cells produced, as well as the amount of signaling molecules the cells make, has varied across lots for reasons that aren’t clear.

“FDA has concerns about the consistency of the manufacturing process and potential sources of product variability,” the agency wrote.

The briefing document notes that an evaluation of BrainStorm’s manufacturing and quality control data still is ongoing, and the upcoming advisory committee meeting will focus mainly on questions about the therapy’s demonstrated efficacy in clinical trials.

“FDA recognizes the urgent unmet need for additional effective treatments for ALS. At the same time, the critical statutory requirements for approval of drugs and biologics include substantial evidence of effectiveness and evidence of safety, and demonstration of adequate product quality,” it writes.

“At this advisory committee meeting FDA is seeking to obtain input from the committee as to whether the available data can be considered to constitute substantial evidence of effectiveness to support regulatory approval of [NurOwn] for treatment of ALS.”