The FDA shocked many life sciences observers by greenlighting Biogen’s treatment candidate for Alzheimer’s last week. Yet, for much of the Alzheimer’s disease community on both sides of the Atlantic, the decision also brings cautious hope.
Controversy recently erupted when the FDA conditionally granted accelerated approval to Biogen’s aducanumab, making it the first approved treatment for Alzheimer’s disease (AD) in almost two decades. The drug, which is backed by only shaky clinical evidence that it can slow the progression of the disease, will be sold in the US under the brand name Aduhelm. The EMA is currently conducting a separate review of the same drug.
Aducanumab is an antibody that reduces the amount of amyloid beta proteins in the brain. The treatment is based on a popular hypothesis formulated back in the 1990s — though as of yet unproven — that a pathological buildup of this protein causes AD. No drugs that have been approved for the treatment of AD to date can cure the disease, with most limited to tackling the symptoms.
“Aduhelm is the first treatment directed at the underlying pathophysiology of Alzheimer’s disease, the presence of amyloid beta plaques in the brain,” the FDA stated in its announcement.
The FDA based its decision on two phase III trials of aducanumab, which showed the drug can reduce the amyloid plaque load in the brain. Both trials were discontinued in 2019 when a planned futility analysis deemed them unlikely to meet their primary endpoint of reducing cognitive decline. Later that year, however, Biogen made a shock turnaround by claiming the initial futility analysis was incorrect and that the primary endpoint was, in fact, met in one trial.
In spite of the drug’s inconsistent clinical performance, the FDA saw aducanumab as worthy of an accelerated approval — a mechanism based on whether a drug can tackle a disease endpoint that might predict clinical benefits, in this case amyloid plaques. The agency conditioned its approval on the successful completion of a further clinical trial.
Biogen and others working in the field say that the approval is expected to stimulate further research and investor interest in AD after a decade of disappointments.
“We believe the approval of aducanumab will be a catalyst for further critical scientific progress in addressing Alzheimer’s, which is a complex disease,” a Biogen spokesperson told me.
“Many drugs approved under the FDA’s accelerated approval program have paved the way for tremendous innovation, especially in oncology. The first multiple sclerosis therapy was also an accelerated approval in 1993.”
According to Chris Lynch, the acting CEO of the charity Alzheimer’s Disease International, the landmark decision could even produce a subtler but powerful shift in the attitude towards Alzheimer’s and other neurodegenerative disorders within the medical profession and beyond.
“Stigma around dementia continues to be high, including amongst healthcare practitioners, but we are hopeful that a prescribed, modifying treatment will begin to help tackle some of that stigma,” Lynch said.
“Likewise, we are reassured that this news will translate into further research and investment, with further treatments coming to the market over the next decade, broadening out from early-stage Alzheimer’s disease treatments, to other stages and other types of dementia.”
The backlash, however, was swift. Three members of an 11-person external neurology panel advising the FDA resigned last week following the decision to fast-track approval of Biogen’s aducanumab, which ignored the panel’s unanimous recommendation not to approve it. Additionally, polls show that the biotech community at large is hostile to the move, with many saying that it can set a dangerous precedent for basing approvals on questionable statistics.
A thorny issue is that numerous attempts to resolve symptoms by targeting the amyloid beta plaques have failed in recent years: so much so that many researchers have started to question the amyloid beta hypothesis altogether or at least to seek alternate disease pathways to target with novel treatments.
In fast-tracking aducanumab’s approval but conditioning it on a further clinical trial, the FDA is clearly walking a tightrope. Fairness is a major concern: industry observers have criticized not only the shaky science behind the approval, but also the hefty price tag of the therapy, at around €48,000 ($56,000) per patient per year in the US. According to a report by the Boston-based non-profit Institute for Clinical and Economic Review, a fairer price for the therapy given the remaining uncertainties would be up to €6,800 ($8,300) per person per year.
On the other hand, the decision allows patients access to a badly needed therapy that has shown certain promise and incentivizes further AD research. Others working on AD therapies—there are over a hundred candidates in the pipeline all over the world—say it is a welcome respite after years of bad news.
“Along with inspiring hope for patients, families and caregivers, the FDA’s decision demonstrates that there is progress being made in the AD field to wider audiences, including scientists and drug developers working on novel therapeutics and also investors who contribute to these efforts,” said Ulrich Dauer, CEO of the German biotech Vivoryon Therapeutics.
Vivoryon is working on its own small molecule therapy, which aims to block the buildup of toxic amyloid beta proteins, but also covers additional likely disease pathways. One potential path to the market for the company is seeking an accelerated approval from the FDA as Biogen did. This decision would be based on whether two phase II trials, one of which is underway in Europe and the other one about to start in the USA, return positive results.
Vivoryon and other European AD players such as BioArctic and AlzeCure have seen stock price jumps of up to 40% since Biogen’s landmark approval, though these stocks are beginning to drop again.
Fears of moral hazards and unexpected consequences linger, but overall, reactions within the AD community appear cautiously optimistic.
“On the one hand, I am concerned about the potential impact that the approval of an Alzheimer’s medicine may have on the recruitment and retention of participants for new and ongoing clinical trials,” said Jean Georges, Executive Director of the non-governmental organization Alzheimer Europe.
“On the other, I hope that the positive news will incentivize more and new companies and organizations to invest in Alzheimer’s research exploring different types of therapeutic approaches across the whole disease spectrum.”
This article was updated on 21/06/2021 to clarify Vivoryon’s plans regarding reaching the market.
Cover image from Elena Resko. Body text image from Shutterstock