The US Food & Drug Administration (FDA) surprised the Alzheimer’s community by approving Biogen’s aducanumab (now Aduhelm). The FDA found this monoclonal antibody to be the first to show a reduction in amyloid plaques in the brains of Alzheimer’s patients. Previous medications have slowed but not reduced the progression of these aberrant protein clumps, a hallmark of Alzheimer’s disease.
The government granted “expedited approval” to allow earlier access to potentially valuable therapies for serious diseases where there is an unmet need and “where clinical benefit is expected despite some residual uncertainty,” noted Center for Drug Director Patrizia Cavazzoni Evaluation and Research of the FDA.
This uncertainty is partly due to the fact that the two Phase 3 clinical trials for the drug were discontinued in 2019 when an interim analysis showed no clinical benefit. Later, when more data was processed, one group of patients in one of the studies showed improvement. This review of the data and the post-hoc analysis failed to impress an independent advisory body at the end of last year. At least three members of this body resigned in protest against the approval decision.
I expected them to request more data or get conditional approval
The FDA found that amyloid plaques were reduced in all studies and concluded that there is some likelihood of this leading to a clinical benefit. But only one study showed clinical benefits. The reactions of Alzheimer’s researchers have been very different. “I expected them to request more data or get conditional approval,” says John Hardy of University College London, UK.
“They had a positive process and an absolutely inconclusive process,” adds Hardy. “It was approved after reaching its secondary endpoints” [amyloid reduction] which is really rather unusual. ‘ He predicts that if amyloid plaque removal is used as a surrogate for Alzheimer’s drugs, just as cholesterol lowering is a marker for heart medications, there will be significant resistance from many researchers.
Some of the comments Hardy saw among colleagues went something like this: “I didn’t think that amyloid in the brain was the disease. I thought dementia was the disease. ‘ However, opinions are divided. ‘To be honest, calling a surrogate mother is a strange thing [amyloid plaque] because it is the cause of the patient’s memory failure, “says neurologist Dennis Selkoe of Brigham and Women’s Hospital and Harvard Medical School in Boston, USA, who welcomed the FDA’s decision.
Neuroscientist Thomas Wisniewski of New York University in the US says he supported the approval but was surprised by the decision. He welcomes amyloid reduction as a surrogate marker, “because it increases the possibility that other active substances will also be approved.” However, he admits skepticism as to whether targeted treatment of plaques is a viable therapeutic approach even for patients with symptoms.
Wisniewski immediately told his patients that while Aduhelm is a milestone, it does not cure Alzheimer’s and there remains uncertainty about its clinical benefit. Approval has not been limited to early disease and it remains to be seen how patients will be selected for treatment, which requires an intravenous infusion every four weeks.
Aduhelm targets the early stages of Alzheimer’s disease. But scans to detect early amyloid plaques typically cost $ 5,000 in the US, and most US health insurers don’t cover them, Wisniewski says. “It is difficult to find patients with mild illnesses,” agrees Hardy, “and it is also difficult to tell patients that the disease is too late for this drug to work.” He notes that there are half a million Alzheimer’s patients in the UK alone. The drug is unlikely to be effective for them and could bankrupt the country, he adds. If the UK regulators follow suit, the National Institute for Health and Care Excellence would also do a cost-benefit analysis before offering it to patients.
Patient groups like the Alzheimer’s Association have campaigned for approval and welcomed the FDA’s decision. The pressure from patients will now be immense. Wisniewski says he has already received “tons of calls and messages,” so much to be done for treatment. But in many patients the disease will be too advanced. The FDA should only have been approved for patients with mild or very mild cognitive impairment, says Selkoe. “According to the label, anyone with Alzheimer’s could get it” [drug] , ‘he adds. “And that makes it more difficult for us practitioners.”
He is not alone in this view. “I’m surprised that the approval seems so high,” says Hardy. “One would hope that the reason the FDA is so positive is because they have data that we haven’t seen from people who continued to receive the drug.” Selkoe believes the “FDA may have been influenced by the three other antibody compounds that are currently in clinical trials.” [from Eisai, Eli Lilly and Roche] some of which have published positive results. ‘
It is difficult to find patients with mild symptoms, and it is also difficult to tell patients that the disease is too late for this drug to work.
“As a healthcare professional, I’m concerned about the consequences of this approval,” says Harvard University neuroscientist Rudolph Tanzi, because removing amyloid from the brain won’t improve cognition. “As a scientist, I’m excited.” This is because the FDA has now opened the door to clinical trials of amyloid removal drugs that are safer, cheaper, and therefore could allow people to be treated years before they show any symptoms of the disease, he explains.
“We thought about how we could get amyloid drugs into trials if the FDA wants them to improve cognition, and they won’t,” says Tanzi. He believes Aduhelm is best for those who can afford scans before they have any symptoms and then afford the drug as a preventative medicine to remove amyloid before it causes neuroinflammation and brain cell death.
Biogen found that the safety profile of Aduhelm is “well characterized” in over 3,000 patients who received at least one dose. However, Wisniewski says frequent surveillance scans are needed to make sure there are no serious complications from the drug, such as “amyloid-related imaging abnormalities,” which could indicate brain swelling or bleeding.
FDA’s Cavazzoni wrote that the agency will continue to monitor Aduhelm when it reaches patients and a post-approval clinical trial is required. Selkoe expects a placebo-controlled study in countries where Aduhelm is not approved. This could lead to the drug being withdrawn from the market if it doesn’t prove effective. The drug is being reviewed by regulatory agencies in Japan, Europe, and Brazil.