The FDA's Slippery Slope, From Alzheimer's to ALS.

I have been a steadfast supporter of the FDA in recent years, as the people working there have a thankless job. However, I must express my concerns about some of the FDA's recent decisions, particularly their increased leniency in granting accelerated approvals.

Let's start with Ionis/Biogen's therapeutic, tofersen (BIIB067), for amyotrophic lateral sclerosis (ALS). In the Phase 3 VALOR study, tofersen, an antisense drug targeting SOD1 mRNA in superoxide dismutase 1 (SOD1) ALS, failed to meet its primary endpoint from baseline to week 28. It did not positively impact patients using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), despite trends seen across secondary and exploratory measures of biological activity and clinical function that suggest efficacy.

Tofersen did reduce SOD1 protein and neurofilament light chain (NfL), with the reduction in NfL being especially noteworthy as a potential biomarker for neurodegenerative diseases. Consequently, Ionis/Biogen engaged with regulators, the medical community, patient advocacy groups, and other stakeholders to determine potential next steps.

Their efforts were successful, as the FDA called an advisory committee (ADCOM) meeting to discuss whether tofersen should receive accelerated approval despite a negative Phase 3 trial and not meeting its primary endpoint. On March 22, 2023, the ADCOM committee voted 9 yes to 0 no that a reduction in plasma NfL concentration in tofersen-treated patients is reasonably likely to predict the benefit of tofersen for SOD1-ALS patients. However, they voted 3 yes to 5 no, with 1 abstention, on whether the clinical data provided substantial evidence of tofersen's effectiveness in treating SOD1-ALS patients. Despite this, the committee ultimately concluded that the benefit-risk profile of tofersen was favorable for SOD1-ALS patients.?

Doesn’t it feel the ADCOM committee is speaking out of both sides of their mouth here?

This outcome, and several before it, raises concerns about the FDA accelerated approval process. Clinical trials are conducted to establish a drug's efficacy, and the correlation of biomarkers with clinical efficacy is not always consistent. History has shown that a drug's impact on biomarkers does not guarantee its success in treating diseases, as demonstrated by numerous Alzheimer's drugs that reduced amyloid but failed in clinical trials.? Aducanumab, Biogen’s monoclonal antibody targeting B-amyloid, initially was approved based on two large randomized, controlled trials that showed it reduced the biomarker, B-amyloid plaque, DESPITE BOTH TRIALS BEING TERMINATED EARLY FOR FUTILITY.?

Not to be outdone Biogen’s recently approved lecanemab, which also reduced B-amyloid, was approved for Alzheimer’s disease despite objections from FDA biostatisticians that the study’s prespecified primary clinical end point wasn’t met and whether or not reducing B-amyloid predicts cognitive benefit.? The approval was amazingly made without formal consideration of the sponsor’s 18-month clinical trial involving 1795 patients showing a variably perceived 27% reduction in memory loss progression.

Correlation doesn’t equal causation.?

Intuition doesn’t equate to efficacy.

We have seen countless times in medicine, but especially in oncology, that drugs effectively inhibiting a pathway of interest can fail to have a beneficial clinical impact.?Accordingly, the approval of drugs based on biomarker improvements, rather than clinical metrics of efficacy, sets a dangerous precedent. It risks approving drugs without true clinical benefits, potentially causing significant medical, time, and financial toxicity.

To this end, the dire need for therapies should not result in the approval of drugs without meeting fundamental measures of clinical efficacy or primary clinical trial endpoints. Instead, it should manifest in lowering the hurdles for approval while still requiring proof of AT LEAST an incremental clinical benefit to justify approval.?Examples of this include the justifiable approvals of regorafenib and lonsurf in late-stage colorectal cancer.?Both drugs are complete garbage with median progression free survival benefits of LESS THAN 0.2 MONTHS,, but showed enough of an incremental benefit in overall survival (approximately 1 MONTH) in trial to garner approval in the setting of a malignancy where no other viable options were available. Even this is better than what we’re seeing now with drugs in ALS.

Case in point is the recent approval of Amylyx Pharmaceuticals' ALS drug, RELYVRIO.?The ADCOM committee that initially reviewed the drug voted 6-4 AGAINST approval of the drug in March 2022.?It was only because Amlyx was persistent and performed all sorts of pharmaceutical gymnastics, misdirection, and hand waving, that the committee reconvened in September 2022 to vote 7-2 in FAVOR of approving the drug.?The drug was FDA approved shortly thereafter.

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Amylyx’ RELYVRIO is 158,000/year and incredibly expensive, but it is a far cry from what Biogen/Ionis will charge for tofersen.?Unfortunately the Amylyx approval has now set the stage for Biogen’s tofersen to get approved under equally suspect circumstances.?

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The FDA's decision to call an ADCOM for tofersen based almost entirely on a neurofilament light chain biomarker, DESPITE FAILING IN CLINICAL TRIAL, is disconcerting.?It undoubtedly may lead to the accelerated approval of a costly drug that has NOT BEEN SHOWN to work and could propogate a slippery slope where companies use patient advocacy groups and biomarkers to facilitate approval of unproven therapeutics.

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The counterargument to this resides in the question, “what do we have to lose?”??In patients where there are no viable treatment options and willing to accept the risks of looking for hope in a world where there is none, why not allow them to receive drugs that fail in clinical trial??

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For starters, there are no free lunches when it comes to therapeutics.?No matter how innocuous a drug is en face it is still essentially an exogenous entity.?There are always going to be changes induced by therapeutics in the body, whether or not the drug causes overt side effects, and whether or not we fully elucidate them.?To this end, although we do the best we can, we never really know the long-term impact of experimental drugs tested in relatively short-term trials until patients.?Moreover, just as in the case of love where one cannot be with the right person if they are with the wrong one, one can’t be on the right trial if one is being treated with the wrong drug.?Approving drugs that have not been shown to work may preclude patients from enrolling in trials involving more effective therapeutics.?They may lose valuable time on an ineffective drug when they could be on a trial that may benefit them.?More minor issues to consider include the financial and time toxicity unproven drugs induce.?Patients often have to go through tremendous hoops to get such drugs and doing so can lead to profound financial difficulties for the patient and their loved ones, including bankruptcy; cancer is the second-leading cause of bankruptcy after divorce.?

Ultimately, adequate clinical efficacy must be demonstrated in trials BEFORE a drug is approved. ?If tofersen is believed to work based on its impact on biomarkers, then it should be proven in another clinical trial. I recognize that ALS is horrifying, but the truth is I can make a similar argument for numerous diseases, including many late-stage malignancies, numerous neurogenenerative conditions, etc.?Indeed, Numerous malignancies also require therapeutics, and the FDA has not approved expensive drugs in those settings when they failed their respective clinical trials. These decisions may have protected patients from unnecessary toxicity, including financial, associated with drugs that did not work.

WE HAVE TO STOP APPROVING DRUGS THAT FAIL THEIR PRIMARY CLINICAL TRIAL ENDPOINTS.?In failing to do so we now find ourselves on a very slippery slope the FDA irresponsibly created where companies don’t even have to truly show their drugs are effective before being approved.?Where does it stop??At what point do we forego clinical trials entirely and simply approve drugs based on intuition and preclinical data showing likely reductions in biomarkers??At what point does the FDA become a figurehead that bows down to the political machinations of companies employing patient advocacy drugs to get their drugs across the finish line??At what point does the FDA stop protecting patients from themselves, and allowing companies to prey on false hope??

In the case of tofersen, the FDA's decision to convene an ADCOM meeting based on biomarker data, despite the drug not meeting its primary endpoint, is concerning. If there is a strong belief that the drug may be effective based on biomarker data, it would be prudent to conduct further clinical trials to establish clinical efficacy before approving the drug.

As noted by Ross et. al. in the April 6, 2023, issue of the NEJM, Janet Woodcock, who was the director of the FDA's Center for Drug Evaluation and Research (CDER), stated in internal documents that the FDA should exercise "the greatest flexibility possible" when considering approval of etepliersen for Duchenee Muscular Dystrophy. In those same documents she wrote, "if Sarepta [the sponsor] did not receive accelerated approval for etepliersen, it would have insufficient funding to continue.". Similarly, Billy Dunn, the director of the FDA's Office of Neuroscience at the time, stated "[the FDA's] underlying legal authority is clear in not only allowing, but also endorsing and encouraging, the application of regulatory flexibility in the setting of serious and life-threatening diseases". The same logic was used in the approval of aducanumab (this approval was subsequently pulled by the FDA) when Patrizia Cavazzoni, the current CDER director, stated, "as we have learned from the fight against cancer, the accelerated approval pathway can bring therapies to patients faster while spurring more research and innovation."

I don't disagree with the aforementioned sentiments, but balance is key. We must not go to extremes, one way or the other. It's one thing to grant accelerated approval to a drug that has an incremental benefit and meets its PRIMARY CLINICAL TRIAL ENDPOINT, and an ENTIRELY DIFFERENT THING TO APPROVE A DRUG THAT FAILS IN CLINICAL TRIAL.

It is crucial for the FDA to maintain strict standards for clinical trial evidence, even when faced with pressure from stakeholders or the urgent need for new treatments.?THAT IS THE ENTIRE REASON THEY EXIST. While it's essential to provide patients with access to potentially beneficial treatments, it's also important to protect them from the risks associated with unproven therapies. The FDA has a responsibility to strike a balance between these considerations and ensure that any approved drugs have demonstrated clinical efficacy through rigorous trials. This will help maintain trust in the FDA and the integrity of the drug approval process.

Here's to hoping the FDA wakes up, LEARNS FROM THE ADUCANUMABS OF THE WORLD, and recognizes the slippery slope they’re on…