Donanemab, a new therapy for Alzheimer’s disease developed by drug maker Eli Lilly, has received unanimous support from independent scientists advising the United States Food and Drug Administration (USFDA), bringing it a step closer to clinical use. “The potential risks of donanemab, appropriately managed as instructed in labeling, are outweighed by the demonstrated benefits on the clinical endpoints in those with AD (Alzheimer’s disease),” the FDA advisory committee said in a briefing document. With two predecessors with a similar mechanism of action having been approved by the regulator, the convening of the advisory committee in March had come as a surprise to many, including the company. In a statement, the company had said at the time: “It was unexpected to learn the FDA will convene an advisory committee at this stage in the review process.” How do the benefits of the drug stack up against its risks? The drug is meant only for those in the early stages of Alzheimer’s disease — those who have mild cognitive impairment or mild dementia. The drug shows significant clinically meaningful slowing of the disease — meaning a person on the drug retains their functions for a longer time. Most ARIA events — amyloid-related imaging abnormalities such as brain bleeds and seizures — were found to be non-serious, and resolved or stabilised after discontinuation of therapy, according to the FDA document weighing the risks and benefits. “The key risks can be mitigated through appropriate labeling and clinical monitoring, and further characterized through post-authorization studies… Overall, given the seriousness of AD and the limited options for disease-modifying treatments, donanemab provides a clinically meaningful treatment benefit for patients with AD,” the document said. What is donanemab, and how does it work? Like the two other Alzheimer’s drugs approved over the past three years, donanemab is a monoclonal antibody that targets depositions of amyloid beta proteins in the brain, one of the defining features of Alzheimer’s disease. The phase 3 study shows that donanemab slows down cognitive decline in early Alzheimer’s patients by 35.1% at 76 weeks. The result was based on a study with 1,736 patients, of whom 860 received the infusion every four weeks till the amyloid beta plaque cleared. The main adverse effect of the drug is swelling or bleeding in the brain, most of which is asymptomatic. The study showed that 24% participants given donanemab had brain swelling and 19.7% had brain bleeds. Three treatment related deaths were reported in the study. Why is a breakthrough of this kind important? Dr M V Padma Srivastava, Chairperson of Neurology at Paras Health, Gurugram, and former head of the department of neurology at AIIMS, Delhi said: “The world is getting older and the burden of diseases such as Alzheimer’s is on the rise. Most countries around the world need drugs such as this. In developing countries with huge populations, the burden [of Alzheimer’s] is likely to be higher.” An estimated 5.3 million people are currently living with dementia in India. Alzheimer’s is one of the most common forms of dementia. This prevalence is likely to increase to 14 million by 2050. Dr Srivastava, however, said that these “horrendously” expensive drugs need to be evaluated against the benefits that they bring. “While the treatment can give a few more good years to a person, should they sell their home to get the treatment? These things have to be decided,” she said. She agreed, however, that “it is a much-needed innovation and could pave the way for something better.” Why was the approval for the drug delayed? Earlier this year, Eli Lilly was informed that the US regulator wanted to understand further the data relating to the therapy, including implications of the limited dosing protocol that was used. During the trial, the therapy was stopped in patients who achieved a certain level of clearing of amyloid beta plaques, a deposition of the amyloid beta protein in the brain that is a hallmark of Alzheimer’s. This limited dosing is one of the features that sets donanemab apart from the two other therapies approved in the category. The additional scrutiny of the drug also came after a US congressional committee examined the approval process for the first drug, aducanumab, developed by Japanese and American companies Eisai and Biogen, and found it to be “rife with irregularities”. The committee found an unusually close collaboration with the drugmaker; and that approval was given even after the clinical trial was cancelled by the company after an independent report indicated that the drug was unlikely to effectively slow cognitive decline and functional impairment, and despite an expert panel’s recommendation against it. The second drug, lecanemab, also developed by Biogen, was greeted with cautious optimism by doctors. This is because it indeed demonstrated a slowing of cognitive decline with fewer side effects for a disease that does not have any effective treatment yet.
