NEW YORK – BrainStorm Cell Therapeutics is hoping the adage "third time's the charm" will prove true for a controversial amyotrophic lateral sclerosis (ALS) drug that it has already put before the US Food and Drug Administration twice without success.
New York City-based BrainStorm late last month said it was seeking feedback from the FDA on a new registrational trial for NurOwn (debamestrocel) in ALS, just four months after it had withdrawn a biologics license application (BLA) on the heels of feedback it received from the US regulator and an advisory committee of independent experts. BrainStorm has specifically submitted a special protocol assessment (SPA) request with the FDA, which, if granted, would allow the company to get the agency's input on its proposed design for a Phase IIIb trial.
"As a company, we're confident in the importance of this trial," said BrainStorm co-CEO Stacy Lindborg, who was promoted from executive VP and chief development officer in early 2023.
ALS, a rare and fatal neurodegenerative illness better known as Lou Gehrig's disease, has been at the center of multiple complicated FDA decisions, as the agency has been forced to balance the need for evidence against pressure from the ALS patient community to approve medications for a disease that has few treatments and no cures.
Earlier this month, Amylyx Pharmaceuticals announced that it would pause promoting Relyvrio (sodium phenylbutyrate and taurursodiol) as a treatment to slow progression of ALS. The drug had been approved by the FDA in 2022 on the basis of a single Phase II study despite questions of its effectiveness, but in a larger Phase III trial, the top-line results from which were published this month, the drug failed to meet primary or secondary endpoints. Biogen's Qalsody (tofersen) was granted accelerated approval last year to treat a genetic form of ALS based on its ability to reduce the biomarker neurofilament light, despite failing to meet a primary endpoint of improving patients' physical functions.
Lindborg said BrainStorm is committed to continuing to develop NurOwn in ALS and that the company views the stem cell therapy as essential to its business strategy. The company is working to raise capital to conduct that Phase IIIb trial and hopes to begin enrolling ALS patients into the new trial as early as this year.
NurOwn, which BrainStorm envisions as a platform for developing treatments for multiple neurodegenerative diseases, is based on multipotent stem cells derived from a patient's own bone marrow, which are induced to secrete high levels of neurotrophic factors. By supporting neuronal growth and survival, BrainStorm believes those neurotrophic factors will slow disease progression for patients with various diseases, beginning with mild-to-moderate ALS.
For BrainStorm, launching the Phase IIIb trial of NurOwn in ALS is a top priority, Lindborg said, as it will pave the way for potential marketing approval. BrainStorm intends to get NurOwn initially approved in ALS and, from there, the company expects to "move quickly" to apply the stem cell therapy technique to other indications. The firm has completed a Phase II trial of NurOwn in patients with progressive multiple sclerosis, and has also conducted preclinical work in Parkinson's and Huntington's diseases.
The new Phase IIIb trial in ALS will incorporate lessons from the initial Phase III trial, Lindborg said, including "targeting participants that are less advanced and earlier in their disease course."
NurOwn has faced a rocky road at the FDA. BrainStorm originally submitted a BLA to the regulator in 2022, which the agency refused to accept on the basis that the data did not demonstrate substantial evidence that NurOwn slowed disease progression. BrainStorm proceeded to submit a request for the FDA to accept the BLA in spite of that decision and provided additional retrospective and biomarker analyses. The FDA resumed its review of the application in February 2023.
BrainStorm argued that the Phase III trial had failed because it is difficult to measure disease progression in patients who have already progressed to advanced disease. This led the firm to conduct its own retrospective analyses on unblinded Phase III data, through which it homed in on improvements seen in patients with mild or moderate ALS. However, those analyses didn't assuage the FDA's worries, and agency reviewers expressed "major concerns" over the retrospective analyses, which they said could be spurious and provided "little confidence on which to base regulatory decisions." An advisory committee for the FDA agreed, voting 17-to-1 that the firm hadn't provided enough evidence of efficacy for the experimental treatment.
In the new Phase IIIb trial, BrainStorm is hoping to prove the efficacy of NurOwn specifically in patients with mild-to-moderate ALS.
"We go into this knowing we've learned a lot from our Phase III trial," Lindborg said. "We have a lot of evidence that we believe really speaks, already, to the effect of NurOwn."
Lindborg declined to disclose expected costs associated with the new Phase IIIb trial; however, she said the company is "actively working" to raise the needed capital.
BrainStorm had $1.5 million in assets as of Sept. 30, the company reported in a disclosure about its Q3 2023 financial results. The company's quarterly net loss was about $1.2 million, or $.03 per share, compared to a net loss of about $6.9 million, or $.19 per share, the year prior. "We're committed to our goal of making NurOwn available to the ALS community," BrainStorm President and co-CEO Chaim Lebovits said on a call with investment analysts to discuss the results in November. "Our priority now is to work with the FDA and do everything in our power to align on a path forward."
"In parallel with these regulatory activities, our management team and board are giving serious thought on how to finance the company and ensure we have the resources to fund the planned Phase III trial and position ourselves for success in the future," he added. "We're actively exploring various options to raise capital, including non-dilutive grants, as well as capitalizing on certain non-core assets, such as our exosome technology."
He said BrainStorm likely will raise funds in "stages," rather than waiting to start a trial until it's raised the entire amount needed. Lebovits added that BrainStorm is also open to partnering with other biopharmaceutical companies.
As part of an effort to "realign" resources and corral funding for the planned Phase IIIb study, BrainStorm in October said it would lay off about 30 percent of its workforce and reduce resource consumption by about 50 percent. On the Q3 call with investment analysts, Lebovits said that all of senior management took a 30 percent cut in wages as part of the cost-cutting effort, and that he had taken a 90 percent cut in wages.
Lindborg said BrainStorm's goal is to dose the first patient in the Phase IIIb trial this year, but that the company won't finalize details of the trial until it receives feedback from the FDA.
"We feel, as a company, that an agreement with FDA on the design, size, and goals conveys a lot of confidence," Lindborg said.
So far, BrainStorm has said it is proposing a new pivotal registrational Phase IIIb trial in which it expects to enroll up to 200 patients with early or mild-to-moderate ALS, who will also be allowed to continue to receive other approved ALS treatments. Investigators will evaluate efficacy of three intrathecal injections of NurOwn or a placebo once every eight weeks based on the widely used Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), the same scale used in its original Phase III trial.
BrainStorm will track patients for 24 weeks in the clinical trial, followed by a 24-week open-label extension study. In addition to the ALSFRS-R, BrainStorm plans to monitor other outcomes, including respiratory function, muscle strength, and caregiver burden, and will collect optional cerebrospinal fluid and blood samples to analyze biomarkers related to neuroinflammation, neurodegeneration, and neuroprotection.
The firm hasn't determined whether it expects to pursue traditional or accelerated approval from the FDA, Lindborg said, and the decision will be informed by the agency's input on study endpoints. While the company is interested in pursuing regulatory clearances for NurOwn in ALS internationally, it is currently focusing its efforts and trial enrollment in the US before expanding.
"It's critical to us that we are successful," Lindborg said. "This is our flagship indication."