Written by Dr. K. on 15 June 2021
- The FDA's approval of Biogen's Aduhelm, an Alzheimer's drug, has triggered a major controversy in dementia therapy.
- After the contentious Biogen drug approval, which may produce billions in sales, some high-profile FDA panel members resigned.
- Aducanumab comes with a hefty price tag of an estimated USD $56,000 per annum.
- Alzheimer's disease and other dementias affect more than 50 million people around the world, and there are nearly 10 million new cases every year.
Earlier this June, the FDA approved Aduhelm (Aducanumab) to treat Alzheimer's disease patients using the Accelerated Approval pathway. Aducanumab, to be marketed under the trade name Aduhelm, was approved to treat Alzheimer's disease patients, despite an FDA advisory committee's recommendation that there was insufficient evidence to support approval last year. The FDA has not approved a novel Alzheimer's disease therapy since 2003.
Dr. Patrizia Cavazzoni, Director of the FDA Center for Drug Evaluation and Research, remarked, “This approval is significant in many ways. Aduhelm is the first treatment targeted at the underlying pathophysiology of Alzheimer's disease, the presence of amyloid beta plaques in the brain”, she added.
According to the FDA, when a drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients, and there is some uncertainty about the drug's clinical benefit, the FDA approves it for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments.
A surrogate or intermediate clinical outcome is used to determine approval, in this case reduction of amyloid plaque in the brain. A surrogate endpoint is a marker that is considered to predict clinical benefit but is not itself a measure of clinical benefit, such as with a laboratory measurement, radiographic image, physical sign, or other indicator. The adoption of a surrogate endpoint may significantly reduce the time it takes to get FDA approval.
According to the FDA, the Aduhelm research studies were the first to indicate that a decrease in these plaques—a characteristic feature in Alzheimer's patients' brains—is predicted to lead to a reduction in the clinical decline of this severe form of dementia.
Since the approval, three members of the FDA panel overseeing research have resigned, including Dr. Aaron Kesselheim, a Harvard Medical School professor who said in a statement that the agency's decision on Biogen was “probably the worst drug approval decision in recent US history."
Last November, the panel voted 8-1 to reject Biogen's late-stage research, saying it didn't give “strong evidence" that Aducanumab effectively treated Alzheimer's; two other panellists said the data was “uncertain."
Dr. Paul Aisen, the director of the Alzheimer’s Therapeutic Research Institute at USC believes Aduhelm is an “effective treatment" for a disease that affects millions around the world, but he is concerned about the FDA's decision's implications for the plethora of other late-stage therapeutic options.
In a recent video chat with CNBC, Dr Aisen said “one urgent issue confronting other teams working on a wider Alzheimer's drug pipeline would be retaining existing trial participants, let alone attracting new ones. Many Alzheimer's patients would drop out of other drug trials to pursue treatment with the newly approved Aduhelm”, he added. Dr Aisen also stated that “their departure would make trial data for those alternative drugs less useful, even if the drugs in question could one day prove to be safer, more effective, or better suited to different stages of the disease's progression.”
How Does It Work?
Aducanumab is unique among presently available treatments in that it is the first of its kind to target amyloid beta plaques.
According to the manufacturer, this is the first antibody-directed Alzheimer's disease treatment that targets the major potential cause of the illness, which many believe is connected to the deposition and aggregation of a protein called amyloid beta. The antibody binds to amyloid protein aggregates and seems to selectively target amyloid plaques in the brain over those in the blood arteries.
Costs and Drug Administration
The majority of patients in the United States will be covered by Medicare, the government-run health insurance programme for those over 65, which Biogen expects to cover the “vast majority” of patients. According to some analysts, it may soon become US Medicare's largest expenditure for doctor-administered medications.
An estimated cost of USD $56,000 a year has been set in the US. The wholesale cost of Aducanumab treatment, which needs an infusion every four weeks, is roughly USD $4,312 per infusion, with an annual cost of roughly USD $56,000 for a high dosage, according to Biogen.
Despite this, the potential expenses extend well beyond the cost of the drug. The demands of administering it seem to be intended to challenge conventional healthcare delivery for those with dementia, necessitating the use of new types of staff and expensive technology not normally involved with dementia treatment.
According to Premier, an organisation that represents more than 4,000 US hospitals, the cost of the medicine's intravenous infusion, radiology, and imaging may add between USD $2,000 and USD $15,000, or perhaps more, to the drug's price tag.
“A lot of treatment for individuals with dementia in the United Kingdom is done from memory clinics, which are predominantly staffed by old-age psychiatrists,” says David Thomas, director of strategy at Alzheimer's Research UK. These clinicians, unlike neurologists, “often lack familiarity with the diagnostics and monitoring required to administer disease-modifying medications." Thomas also notes that “acquiring the necessary equipment is a major difficulty. Low-key cognitive tests are used to diagnose individuals suspected of having the condition, and no additional hardware is required.”
According to guidelines, to be eligible for Aducanumab, a patient must have a certain level of amyloids in their brain, which can build up in tissues or organs, as determined by a positron emission tomography (PET) scan or a lumbar tap, which involves removing fluid from the spine and is more invasive but typically less costly.
Eligible patients must then have an intravenous injection of Aducanumab once every four weeks and have routine MRI scans to check for serious side effects including brain swelling and bleeding.
According to Thomas, when Alzheimer's Research UK recently questioned psychiatrists in the UK, “the majority indicated it would take up to five years to be ready to administer a medication – only a third felt they could do it in a year."
Dr Sanjiv Sharma, founder of the Advanced Memory Institute of New Jersey recognises the challenges that lay ahead if the programme is to reach all people who may benefit. But he is certain that the United States must lead the way. “If we can't do it here, where can we do it?” he asks, referring to the United States as the world's most developed country.
Potential Side Effects
The prescribing information for Aducanumab warns about “amyloid related imaging abnormalities," or ARIA, which may be detected on magnetic resonance imaging (MRI) scans as brain swelling or incidents of brain haemorrhage. Aducanumab may also cause headaches, falls, diarrhoea, confusion, delirium and disorientation.
Dr. Lon Schneider, Della Martin Chair of Psychiatry and Neuroscience and director of the California Alzheimer's Disease Center at the University of Southern California said in an interview with CNN that “ARIA seems to occur early in treatment, around 12 to 16 weeks, and patients who have a variant of the apolipoprotein gene known as APOE4 — a risk factor for Alzheimer's disease — seemed to be at higher risk of such occurrences.”
According to the medication label in two studies, ARIA was seen in 41% of individuals treated with the recommended dose of Aducanumab compared to 10% of those who did not receive the treatment.
“At the end of the day, we followed our usual course of action when making regulatory decisions in situations when the data are not straightforward,” Dr. Cavazzoni said. The FDA added that they went through the clinical trial findings with great detail, received information from the Peripheral and Central Nervous System Drugs Advisory Committee, listened to patient perspectives, and reviewed all relevant data.
The FDA stated that “the 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.” The FDA ultimately decided to follow the Accelerated Approval pathway, which is designed to enable early access to potentially important medicines for patients with severe illnesses who have an unmet need but might expect clinical benefit despite some uncertainty about that benefit.
The FDA noted that in deciding whether the application fulfilled the criteria for Accelerated Approval, it determined that the advantages of Aduhelm for Alzheimer's disease patients outweighed the risks of the treatment.