Alzheimer's treatment aducanumab (Aduhelm) won controversial US Food and Drug Administration approval this week, writes MedicalBrief. With no eligibility restrictions imposed in the decision, practitioners will face enormous demand — and pressure — from families to prescribe the expensive but ambiguously effective treatment.
Biogen said that the US list price would be $56,000 a year.
Under the accelerated pathway, the agency approves a drug for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drug's clinical benefit.
"We are well-aware of the attention surrounding this approval," the FDA wrote in a statement explaining the decision. "At the end of the day, we followed our usual course of action when making regulatory decisions in situations where the data are not straightforward."
In November 2020, an FDA advisory committee voted overwhelmingly against the data presented about the Alzheimer's drug candidate, saying the positive results seen in one of the two trials could not be considered alone, but must be taken together with its twin, which clearly was negative.
Prescribing information for aducanumab includes a warning for amyloid-related imaging abnormalities (ARIA), which most commonly presents as temporary swelling in areas of the brain and often resolves over time. Another warning is for a risk of hypersensitivity reactions including angioedema and urticaria. The most common side effects of aducanumab were ARIA, headache, fall, diarrhea, and confusion/delirium/altered mental status/disorientation.
StatNews Today wrote that “as if the saga of aducanumab needed another twist, the FDA tossed in an extra curveball Monday as it approved the Alzheimer’s therapy by specifying who would be eligible for the treatment. Or rather, not specifying.”
Doctors had anticipated that if the FDA gave the green light it would endorse its use for patients like those who qualified for clinical trials: people in the earliest stages of Alzheimer’s disease, who also had the plaques of amyloid protein that the therapy aims to clear. Instead, the FDA approved the therapy broadly for Alzheimer’s disease. On Aduhelm’s label, there was no mention of limiting its indication to any subset of patients.
Many experts were left stunned by that decision. But on a press call, FDA officials argued that because Aduhelm helped clear amyloid plaques, it could provide benefits for people in any stage of the disease — at the same time as they acknowledged that any benefit from Aduhelm, even for patients in the early stages of the disease, was still unclear.
(Many experts also strongly push back against the claim that erasing amyloid plaques could help people in the late stages of the disease. Clinical trials of other amyloid-targeting therapies in moderate and severe Alzheimer’s have repeatedly failed to show a clinical benefit.)
“It’s important to recognise that Alzheimer’s really is a single disease but it exists across a continuum,” from asymptomatic to severe, said Peter Stein, the director of the FDA’s Office of New Drugs. But what unites them all is the fact that “amyloid pathology is a defining feature of Alzheimer’s disease. The expectation is that this drug would provide benefit across that spectrum.”
The broad approval from the FDA raises the stakes for some of the other players in the health care system, and could force some tough decisions. Insurers might now set tight limits on how they’ll cover the therapy, and clinicians could face even greater demand — and enormous pressure — from families to prescribe the treatment.
“A lot of people, in the absence of something they know is better, will want to try it,” said neurologist Victor Henderson of Stanford University, who has advised the Institute for Clinical and Economic Review, a nonprofit that estimates the value of new medicines.
Henderson said it could be hard for some physicians “to really hold back the flow of requests. If you’re a neurologist in private practice, there’s probably more incentive to try to satisfy the family demands, the patient demands,” he said.
One concern is that if insurers clamp down on who can receive the therapy, wealthy people will just pay for it on their own — even if they are unlikely to benefit from it. That could add a greater crunch at clinics like infusion centers, and potentially exacerbate access disparities in dementia care.
The Independent reports that Hilary Evans, chief executive at Alzheimer’s Research UK, said the FDA’s approval “marks a pivotal moment in the search for life-changing new treatments”, but said “renewed focus and investment” into researching the condition is needed across the world. According to the World Health Organisation, an estimated 30 million people globally suffer from Alzheimer's. In the UK, some 500,000 people are thought to be living with the disease.
Full FDA statement by Dr Patrizia Cavazzoni, Director, FDA Center for Drug Evaluation and Research:
Today FDA approved Aduhelm (aducanumab) to treat patients with Alzheimer’s disease using the Accelerated Approval pathway, under which the FDA approves a drug for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drug’s clinical benefit.
This approval is significant in many ways. Aduhelm is the first novel therapy approved for Alzheimer’s disease since 2003. Perhaps more significantly, Aduhelm is the first treatment directed at the underlying pathophysiology of Alzheimer’s disease, the presence of amyloid beta plaques in the brain. The clinical trials for Aduhelm were the first to show that a reduction in these plaques—a hallmark finding in the brain of patients with Alzheimer’s—is expected to lead to a reduction in the clinical decline of this devastating form of dementia.
We are well-aware of the attention surrounding this approval. We understand that Aduhelm has garnered the attention of the press, the Alzheimer’s patient community, our elected officials, and other interested stakeholders. With a treatment for a serious, life-threatening disease in the balance, it makes sense that so many people were following the outcome of this review. Further, the data included in the applicant’s submission were highly complex and left residual uncertainties regarding clinical benefit. There has been considerable public debate on whether Aduhelm should be approved. As is often the case when it comes to interpreting scientific data, the expert community has offered differing perspectives.
At the end of the day, we followed our usual course of action when making regulatory decisions in situations where the data are not straightforward. We examined the clinical trial findings with a fine-tooth comb, we solicited input from the Peripheral and Central Nervous System Drugs Advisory Committee, we listened to the perspectives of the patient community, and we reviewed all relevant data. We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit. In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy.
What the Data Show
The late-stage development program for Aduhelm consisted of two phase 3 clinical trials. One study met the primary endpoint, showing reduction in clinical decline. The second trial did not meet the primary endpoint. In all studies in which it was evaluated, however, Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion. It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.
We know that the Peripheral and Central Nervous System Drugs Advisory Committee, which convened in November 2020 to review the clinical trial data and discuss the evidence supporting the Aduhelm application, did not agree that it was reasonable to consider the clinical benefit of the one successful trial as the primary evidence supporting approval. The option of Accelerated Approval was not discussed by the Advisory Committee. As mentioned above, treatment with Aduhelm was clearly shown in all trials to substantially reduce amyloid beta plaques. This reduction in plaques is reasonably likely to result in clinical benefit. After the Advisory Committee provided its feedback, our review and deliberations continued, and we decided that the evidence presented in the Aduhelm application met the standard for Accelerated Approval. We thank the Advisory Committee for its independent review of the data and valuable advice.
The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need. Approval is based on a surrogate or intermediate clinical endpoint (in this case reduction of amyloid plaque in the brain). A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.
Drug companies are required to conduct post-approval studies to verify the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial does not verify the drug’s anticipated clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.
The Devastation of Alzheimer’s Disease
With all this said, we are extremely aware of the gradual and cumulative devastation that Alzheimer’s disease causes, as patients lose their memory and cognitive functioning over time. In late-stage disease, people can no longer hold a conversation or respond to their environment. On average, a person with Alzheimer’s disease lives four to eight years after diagnosis, but some patients can live up to 20 years with the disease.
The need for treatments is urgent: right now, more than 6 million Americans are living with Alzheimer’s disease and this number is expected to grow as the population ages. Alzheimer's is the sixth leading cause of death in the United States.
Although the Aduhelm data are complicated with respect to its clinical benefits, FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients. As a result of FDA’s approval of Aduhelm, patients with Alzheimer’s disease have an important and critical new treatment to help combat this disease.
FDA will continue to monitor Aduhelm as it reaches the market and ultimately the patient’s bedside. Additionally, FDA is requiring Biogen to conduct a post-approval clinical trial to verify the drug’s clinical benefit. If the drug does not work as intended, we can take steps to remove it from the market. But hopefully, we will see further evidence of benefit in the clinical trial and as greater numbers of people receive Aduhelm. As an agency, we will also continue to work to foster drug development for this catastrophic disease.
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