FDA Rejects ALS Stem Cell Therapy for the Third Time

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FDA Rejects ALS Stem Cell Therapy for the Third Time

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FDA Rejects ALS Stem Cell Therapy for the Third Time. 10 Years of Development Ends in Futility?

In the waning days of 2021, President Joe Biden signed a bill aimed at expediting access to crucial treatments for Amyotrophic Lateral Sclerosis (ALS).

The ALS community, fervently seeking any potential therapy, anxiously awaited the FDA’s decisions, as the agency strived to balance its responsibility with patients’ urgent needs.

Over the past year, the FDA exhibited flexibility in its approach to ALS therapies. For instance, when Relyvrio sought initial market approval, the FDA initially wanted Amylyx to conduct a larger-scale trial.

However, under mounting pressure, the FDA agreed to review the drug concurrently with the trial. Additionally, another ALS drug, Qalsody, intended for a specific population, was granted approval based on “biomarker” data, despite failing crucial clinical trials.

Amid these regulatory oscillations, BrainStorm optimistically aimed to replicate the successes of Relyvrio and Qalsody with its stem cell therapy, NurOwn, and sought FDA’s approval through three attempts.

In early 2021, the FDA informally declined BrainStorm’s application, citing insufficient data.

BrainStorm, however, believed there were statistical errors in evaluating secondary endpoints that obscured the “truth.” They resubmitted their Biologics License Application (BLA) in September 2022, but the FDA officially rejected it in November of the same year.

Refusing to concede, BrainStorm lodged a formal protest with the FDA in March of this year, a rarely successful procedure.

Recent documents released by the FDA aggressively rebutted the materials submitted by BrainStorm for approval and called for a panel meeting to vote on whether BrainStorm’s clinical trial data met the FDA’s “substantial evidence of effectiveness” standard.

With the recent announcement of the expert committee’s vote, it is nearly certain that NurOwn, or this biotech firm, may not have a future in the ALS field.

“Gambling on FDA’s Flexibility”

Before formally reviewing a drug, the FDA typically conducts a “filing review” to assess whether the drug’s data is complete enough for substantive evaluation. If the application is incomplete, the FDA refuses to accept it and notifies the applicant of the deficiencies.

The benefit of this approach is to reduce the FDA’s resource allocation on incomplete applications, allowing applicants to address issues early, often related to drug quality, safety, and efficacy. After receiving a refusal letter, applicants have the right to “protest” and request a comprehensive review of their original submissions.

However, according to a study analyzing refusal-to-file letters issued by the FDA from 2008 to 2017, only four NDAs filed protests during that decade, and none of them resulted in a successful full review – none of the drugs were approved.

BrainStorm’s decision to pursue this uncommon route was not only in pursuit of the official claim of “getting results as quickly as possible” but also hinged on their gamble that the regulatory agency might show leniency in ALS treatments.

In the past year, the FDA initiated a five-year plan primarily focused on accelerating the development of drugs for rare neurological diseases, including ALS. Furthermore, the ALS legislation called for FDA funding assistance to public and private entities. In practice, the FDA has indeed exhibited considerable flexibility when approving ALS medications.

Relyvrio from Amylyx became the first ALS drug to receive approval in nearly five years. In a pivotal Phase II study involving 137 patients, researchers found that, at the end of a 6-month study, patients treated with Relyvrio experienced a 40% reduction in disease progression, which was statistically significant. Moreover, a 3-year follow-up of all subjects showed a 44% reduced risk of death and an extended median survival time of 6.5 months compared to the initial placebo group.

The FDA initially stated that larger studies were needed to confirm the observed benefits in the Phase II trial. However, for a disease with a lifespan of only 3 to 5 years, a few months of extended life is akin to a lifeline.

Regardless of whether it was voluntary or driven by public opinion, after five months of back-and-forth, the FDA eventually changed its stance, stating that it would consider smaller-scale studies. In the meantime, Amylyx initiated a Phase III study involving approximately 600 patients, expected to conclude in late 2023 or early 2024.

In March 2022, the FDA convened an expert advisory panel vote, which narrowly opposed Relyvrio’s approval. When Amylyx submitted new analyses, the FDA took the highly unusual step of reconvening the advisory vote. Ultimately, Relyvrio was granted approval in September 2022 based on Phase II clinical data. However, if the Phase III trial fails to demonstrate its benefits, Relyvrio’s fate may be withdrawal from the market.

In contrast, another ALS drug, Qalsody, missed its primary clinical endpoints during a pivotal trial.

However, research revealed that Qalsody reduced a biomarker known as neurofilament light chain by 55% (the placebo group saw a 12% increase). When nerve cells are damaged, the levels of neurofilament light chain increase in the blood and cerebrospinal fluid around the brain and spinal cord, especially in ALS patients.

Post hoc exploratory analyses indicated a clear improvement in Qalsody’s efficacy over time. Based on the predictive clinical benefits derived from this “biomarker,” in April, the FDA granted Qalsody accelerated approval, setting a precedent in the history of ALS drug approvals, generating a sensation similar to Aduhelm’s accelerated approval in previous years.

As per the FDA’s request, Biogen is conducting additional trials on patients carrying SOD1 mutations but not yet displaying symptoms, with results expected in 2027.

Looking back at the approval journeys of Relyvrio and Qalsody, it is evident that the FDA has shown flexibility. The fervent desire of ALS patients for new therapies has made them a significant player in negotiation; the FDA considers their opinions and supports the approval of all potential therapies. Based on this, BrainStorm believed it had an advantage.

The Fragile ‘Truth’

Through this rare protest action, BrainStorm effectively compelled the FDA to make a decision. When ALS advocates submitted a petition with 30,000 signatures to the FDA, seeking recognition for NurOwn, the FDA scheduled a panel meeting to discuss whether BrainStorm’s existing data constituted substantial evidence of effectiveness.

As expected, BrainStorm did not succeed. On September 27, the expert panel voted 17 to 1, with one committee member abstaining, to deem NurOwn ineffective. In documents released on September 25, the FDA provided a detailed explanation of their concerns regarding this stem cell therapy.

1. Scientific Shortcomings:

In the completed Phase III clinical study, NurOwn failed to meet both primary and secondary endpoints. Moreover, the FDA found that at the end of the study, the NurOwn-treated group had more deaths and a higher rate of serious adverse events compared to the placebo group. After discussions with researchers, BrainStorm attributed this to a higher number of advanced-stage patients in the trial, leading to biased results. However, in additional analyses, BrainStorm believed that there were errors in the statistical methods used to evaluate one of the secondary endpoints, which would show better treatment outcomes when corrected.

In January 2023, both parties met, and BrainStorm submitted a post-h

oc analysis report. According to their report, in the subgroup with a baseline score of ALS Functional Rating Scale-Revised (ALSFRS-R) of ≥35, NurOwn’s response rate was higher than the placebo (34.6% vs. 15.6%).

However, the FDA pointed out that this report carried a high risk of false-positive conclusions. Such subgroup analyses might provide hypotheses for future trials, but they evidently could not “overturn” the negative findings in the earlier Phase III clinical trial.

2. Lack of Biomarker Data:

Fifty years ago, neurotrophic factors (NTFs) were first discovered, and these proteins play a fundamental role in the development of the nervous system. They were widely considered a promising potential therapy for treating neurodegenerative diseases. NurOwn operated by increasing NTF levels in cerebrospinal fluid. BrainStorm evaluated 45 biomarkers, but the FDA found that at week 20, nearly 50% of all biomarker data was missing. Consequently, BrainStorm’s analysis contained numerous data estimations, and the models used were post hoc and could selectively produce more favorable results for NurOwn.

Unlike Qalsody, the biomarker data for NTFs did not support NurOwn as an alternative endpoint for accelerated approval.

3. Insufficient Manufacturing Data:

As a cell-based therapy using autologous mesenchymal stem cells collected from patients’ bone marrow and processed with growth factors to promote nerve growth, NurOwn’s manufacturing process requires a higher level of quality control compared to other biologics. The FDA noted that BrainStorm’s BLA lacked critical information in the Chemistry, Manufacturing, and Controls (CMC) section, making it difficult to assess product quality based on the available information. Additionally, the FDA pointed out that BrainStorm lacked data to demonstrate manufacturing consistency and had insufficient production and testing methods. The FDA expressed uncertainty about this biotech company’s ability to produce reliable, quality cellular products.

Year-End: A Harsh Reality

In reality, BrainStorm’s options appear limited. Since the failure of the Phase III clinical trial, BrainStorm’s stock has continuously declined, plummeting by 90% by the end of last year, with a share price of only 39 cents. This biotech firm seems to rely solely on support from ALS advocates.

With the FDA’s panel meeting, BrainStorm proposed a plan for an additional comparative trial. This plan involves three phases and is expected to take approximately two years.

However, it is an uphill battle that BrainStorm is unlikely to sustain by itself. According to its half-year report at the end of June this year, it had only $750,000 in cash, cash equivalents, and short-term deposits. The ALS advocates whom BrainStorm relies on have limited capacity, and the market behind the stock no longer holds faith in it.

The FDA will make its final decision on December 8 this year. Perhaps, the regulatory agency might make some compromises, approving NurOwn for certain patients while awaiting clearer results, similar to what Qalsody experienced. However, based on the current trend, this possibility appears slim.

People hope for a perfect drug, but unfortunately, that’s not always attainable. Faced with a disease that is a race against time, the FDA’s flexibility in granting approval to drugs with weaker evidence than traditional standards may provide hope for patients. Nevertheless, this “leniency” based on weaker evidence inevitably carries the risk of compromising drug development quality.

Throughout U.S. history, hundreds of ineffective and expensive drugs were on the market. It was not until 1962 that the Kefauver-Harris Amendments fundamentally changed the FDA’s review standards. Therefore, even in the case of ALS therapies in high demand, there will always be a point where “the gate” is closed.

Regulatory agencies don’t want to miss out on potential ALS treatments, but they also don’t want to provide false hope and lead to more severe consequences—further delaying the already limited time for treatment.

FDA Rejects ALS Stem Cell Therapy for the Third Time

References:

1. FDA staff hold ‘major concerns’ with Brainstorm ALS therapy, documents show；biopharma dive

(source:internetmBvb4O1P0IMINCBui49uLA, reference only)

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