Alzheimer’s disease is the most common form of dementia – which currently affects more than 55 million people globally – making up 60% to 70% of cases. It is a complex disease, encompassing multiple interrelated and progressive destructive processes in the brain, resulting in neuron damage that extends to parts of the brain that enable basic bodily functions. Ultimately, the disease is fatal.
Until recently, there had not been a newly approved medication for Alzheimer’s in almost two decades. But, as neuroscientists began to better understand the process of the disease, 2021 saw the accelerated approval by the U.S. Food and Drug Administration (FDA) of Aduhelm, which became the first Alzheimer’s treatment to address a defining pathology of the disease – the accumulation of amyloid beta plaques in the brain.
As it turned out, the new drug also came with a catch, subsequently becoming subject to the first big Alzheimer’s drug controversy of the decade.
In this article, we explore several controversies and scandals in Alzheimer’s drug trials in the last couple of years, each one shining a negative spotlight on the Alzheimer’s drug industry as a whole.
Aduhelm: the first big Alzheimer’s drug controversy of the decade
In 2021, Aduhelm – developed by Biogen and Eisai – was granted accelerated approval by the FDA based on data from clinical trials demonstrating the effect of the drug on reducing amyloid beta plaques. The FDA’s accelerated approval pathway allows for the approval of a drug to be solely based on a “surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.” In this case, the fact that Aduhelm reduced amyloid beta plaques was enough for the FDA to regard it as “a biomarker that is reasonably likely to predict clinical benefit” and, thus, reduce clinical decline.
The European Medicines Agency (EMA), on the other hand, took a very different tone, and outright refused a marketing authorization in the EU for the drug in December 2021: “The European Medicines Agency noted that although Aduhelm reduces amyloid beta in the brain, the link between this effect and clinical improvement had not been established. Results from the main studies were conflicting and did not show overall that Aduhelm was effective at treating adults with early stage Alzheimer’s disease…In addition, the studies did not show that the medicine was sufficiently safe as images from brain scans of some patients showed abnormalities suggestive of swelling or bleeding, which could potentially cause harm. Furthermore, it is not clear that the abnormalities can be properly monitored and managed in clinical practice.”
In fact, despite the FDA nod, it turned out there was also a lot of doubt about Adulhem’s overall efficacy in treating Alzheimer’s at the time of the approval in the U.S., so much so that two U.S. congressional committees launched an 18-month investigation into the FDA’s process for approving the drug. The report concluded that the FDA’s “atypical collaboration” to approve Adulhem was “rife with irregularities”.
Rewind a couple of years to 2019, and Biogen and Eisai – the latter of which subsequently exited its supporting role in developing the drug – actually had to halt two phase 3 trials of Aduhelm in patients with early stage Alzheimer’s after an independent data monitoring committee found that the drug probably would not slow the cognitive and functional impairment related to Alzheimer’s. But, later that year, in June, the FDA and Biogen started a “working group” to see whether the development effort could be saved. This also signaled the initiation of a very close working relationship that would continue over the next couple of years.
The congressional investigation found that the FDA and Biogen were involved in at least 115 meetings, calls, and email discussions from July 2019 to July 2020, including 40 meetings to guide Aduhelm’s potential approval. In fact, there might have been even more meetings between the two, but the committees said the FDA failed to follow its own documentation protocol.
The FDA then collaborated with Biogen to draft a document, which was used to brief an independent advisory panel that met in November 2020. At that meeting, none of the panel members voted to say the Aduhelm studies presented strong and convincing evidence of the drug’s efficacy. And yet, despite the panel’s recommendations, the FDA granted accelerated approval to Aduhelm anyway. According to the report, the committee members said senior FDA leadership told them that the shift in how the drug would be approved came after an FDA expert council meeting in April 2021, provided “unfavorable feedback” for the traditional approval process.
On top of the controversy surrounding the clinical efficacy of Aduhelm, the report also noted that Biogen set an “unjustifiably high price” for the Alzheimer’s drug, purely so that they could “make history”, thinking of it as an “unprecedented financial opportunity.” This came after Biogen initially priced Aduhelm at $56,000 per year – several times higher than experts had previously estimated – despite insufficient evidence of the drug’s benefits.
Furthermore, the investigation found that Biogen had planned to spend several billion dollars on aggressive marketing to counter an expected “pushback” over whether Aduhelm was worth its price, targeting doctors, patients, advocacy groups, insurers, policymakers, as well as communities of color, who were underrepresented in its clinical trials of the drug.
Despite all the controversies surrounding Biogen’s Alzheimer’s drug, its approval remains intact, and the company is now undertaking a post-approval confirmatory study. This phase 4 trial, ENVISION, should reach primary completion after 4 years, so it will still be some time before we know whether aducanumab actually has significant clinical benefit.
Biogen and Eisai strike again: the accelerated approval of Leqembi
In another major, but more recent, Alzheimer’s drug controversy, which involved the same players as the Aduhelm scandal – Eisai and Biogen – Leqembi received accelerated approval from the FDA at the beginning of this year, before eventually receiving full FDA approval in July. This came after the drug was shown to slow cognitive decline in early Alzheimer’s patients by 27%, and made it the first amyloid beta-directed antibody to be converted from an accelerated approval to a traditional approval for the treatment of Alzheimer’s disease.
So, why was this decision controversial?
Well, after the fast track approval of Leqembi, there was concern among health experts that the FDA was once again cutting corners in evaluating Alzheimer’s drugs, as they urged the agency to convene an expert panel to review safety concerns around Leqembi.
According to a report from Science in December 2022, a third patient death potentially tied to Leqembi was reported in a phase 3 extension study, attributed to brain swelling and bleeding, as well as seizures. The two previous patients who died had suffered cerebral hemorrhages after receiving the infusions. They had been administered blood thinner medications. Meanwhile, the third patient had an underlying condition called cerebral amyloid angiopathy, whereby the blood vessels in the brain are weak.
There are also possible efficacy issues with the drug. Some Alzheimer’s experts have said it is unclear from the trial evidence whether Leqembi’s ability to delay the erosion of memory and cognition is enough to be noticeable or meaningful for patients and their families.
The independent advocacy group, Doctors for America, said in a statement. “…Critical questions remain as to whether the benefits outweigh the risks reported of brain swelling, brain bleeding, and death among patients who received this drug.”
Leqembi is still on the market. But, as a way to address the risks it could potentially present to patients, the FDA added a black-box warning – the most urgent level – on the drug’s label after it received full approval, alerting people to the fact that in rare cases, the drug can cause “serious and life-threatening events,” including brain bleeding.
Cassava Sciences accused of scientific misconduct in latest Alzheimer’s drug controversy
Just this month, Cassava Sciences was the latest company to come under fire for its experimental Alzheimer’s drug, simufilam.
The drug had already been heavily criticized. Its woes began in 2021, when shareholder rights law firm, Labaton Sucharow, filed a citizen’s petition with the FDA, in which they described “grave concerns about the quality and integrity” of the research that supported simufilam’s purported efficacy. It is also the subject of ongoing federal probes regarding allegations that Cassava falsified data to support simufilam.
And, now, another investigation by the City University of New York (CUNY) has accused neuroscientist, CUNY faculty member, and longtime Cassava collaborator, Hoau-Yan Wang, of scientific misconduct involving 20 research papers. Wang frequently collaborated with Lindsay Burns, Cassava’s senior vice president for neuroscience, on studies that outside experts and journals have called into question.
The committee convened by CUNY found numerous signs that images were improperly manipulated, such as in a 2012 paper in The Journal of Neuroscience that suggested simufilam can blunt the pathological effects of beta-amyloid.
The report also concluded that Burns bears primary or partial responsibility for some of the possible misconduct or scientific errors. But, its criticism was primarily reserved for Wang, saying that its finding of wrongdoing was based on “long-standing and egregious misconduct in data management and record-keeping by Dr. Wang.”
However, it is worth noting that the committee could not entirely prove its suspicions, due to the fact that Wang did not produce the original raw data.
Since the investigation was released, Cassava has come out to defend itself, saying that CUNY did not have a legitimate basis for its accusations of long-standing and egregious misconduct in how the biotech company managed data and kept records. The company’s CEO, Remi Barbier, said that the company remains confident in the underlying science for simufilan, and that its phase 3 clinical program will continue.
BMJ investigative report questions FDA fast-track approval of brexpiprazole for Alzheimer’s agitation
Although not intended to slow down the progression of Alzheimer’s, when the FDA granted fast track approval to Rexulti in May this year, experts heralded it as a breakthrough; it became the first drug approved specifically for treating agitation in Alzheimer’s patients, which involves episodes of aggression, irritability, and disinhibition.
However, once again, it became an Alzheimer’s drug shrouded in controversy, as a troubling British Medical Journal (BMJ) investigation suggested that the drug failed to show a meaningful benefit to patients, and also raised the risk of death.
In clinical trials, Rexulti failed to deliver meaningful improvements in agitation symptoms compared to placebo. On a 174-point symptom scale, the maximum difference was only 5.3 points – well below the 17-point threshold experts generally agree signals a real-world change, according to the BMJ investigation. It was also found that the drug increased the chances of death four-fold compared to placebo over 16 weeks.
And, if you were wondering why the FDA decided to approve the Alzheimer’s agitation drug; the report suggested that the drug got the green light because the FDA has lowered its standards compared to past antipsychotic approvals.
Looking forward: still grounds for optimism for Alzheimer’s treatments
While it is true that there has been an overwhelming amount of Alzheimer’s drug controversies in the last two years, the future is still looking fairly bright when it comes to potentially finding a treatment for Alzheimer’s disease.
In an article for Medical News Today (MNT), Emer MacSweeney, chief executive officer (CEO) and consultant neuroradiologist at Re:Cognition Health, said: “Currently, there are over 120 different potential new medications for Alzheimer’s disease in clinical trials…This impressive pipeline of new medications targets the many different biological processes, which result in Alzheimer’s disease and its symptoms.”
And, in the same article, The Alzheimer’s Association concluded: “There is an increasingly robust treatment landscape for Alzheimer’s disease. The progress we’ve seen in not only this class of treatments, but also in the diversification of targets over the past few years, is exciting and provides hope to those impacted by this devastating disease.”
Finding a treatment for Alzheimer’s disease has arguably been one of the most challenging tasks facing the biotech industry over the past two decades. But with so many companies devoting their time and resources to trying to better the lives of people living with this debilitating disease, we can surely hope for the best in the coming decade.