An experimental drug for Alzheimer's disease from Eisai and Biogen slowed cognitive decline in a closely watched trial, however, it may carry a risk of dangerous side-effects for certain patients, according to new data presented last week.
The drug, lecanemab, was associated with a type of brain swelling in 12.6 per cent of trial patients, a side-effect previously seen with similar drugs. Fourteen per cent of patients had microhemorrhages in the brain — a symptom linked to two recent deaths of people receiving lecanemab in a follow-on study — and five patients suffered macrohemorrhages.
The companies said in September that the 18-month trial, which enrolled nearly 1,800 participants with early-stage Alzheimer's, found that treatment with lecanemab reduced the rate of decline on a clinical dementia scale (CDR-SB) by 27 per cent compared to a placebo.
The results suggest lecanemab slowed the advance of Alzheimer's disease in its early stages by four to five months over the 18-month period of the study.
"All of these amyloid-lowering drugs carry a risk for increased brain hemorrhage," said Dr. Ronald Petersen, of the Mayo Clinic in Rochester, Minnesota. "I think the primary outcomes, the secondary outcomes, the amyloid-lowering is pretty impressive."
The Alzheimer's Association said the data confirms the drug "can meaningfully change the course of the disease for people in the earliest stages of Alzheimer's disease," and called on U.S. regulators to approve the company's application for accelerated approval.
Examples of abilities people could retain if there's a slowing of the progression of Alzheimer's include being able to manage their own finances or drive to the local supermarket.
Little benefit for patients with genetic variants
The trial showed no benefit on the CDR-SB measure for some patients with a genetic risk of developing the mind-robbing disease.
About 16 per cent of participants had two copies (homozygous) of the APOE4 gene variant known to raise the risk of developing Alzheimer's, 53 per cent had one copy of the gene (heterozygous) and 31 per cent were non-carriers.
"For that small group of homozygous patients, when it comes to CDR-SB, we don't see a signal favouring lecanemab," said Ivan Cheung, Eisai's U.S. chairman, in an interview. He suggested that could be because homozygous study patients who were given a placebo fared better than expected.
The APOE4 carriers did show improvement on the trial's secondary goals, including other measures of cognition and daily function. Overall, lecanemab patients benefited by 23 per cent to 37 per cent compared with a placebo on these secondary trial goals.
I believe it's an important benefit that will justify full approval. But of course, we want a bigger benefit," said Dr. Paul Aisen, director of the University of Southern California Alzheimer's Therapeutic Research Institute and a co-author of the study published in the New England Journal of Medicine. He said lecanemab is likely to provide greater benefit if given earlier in the disease, "before you've accumulated enough irreversible damage to be causing symptoms."
Detailed data from the study were presented at the Clinical Trials on Alzheimer's Disease meeting in San Francisco.
Eisai, based in Tokyo, believes the trial results prove a longstanding theory that removal of sticky deposits of a protein called amyloid beta from the brains of people with early Alzheimer's can delay its advance.
At 18 months, 68 per cent of trial participants treated with lecanemab had amyloid clearance, Eisai said.
Two deaths — both from brain hemorrhages — have been reported among participants in a trial extension. They involved a 65-year-old woman who received a type of medicine known as a tissue plasminogen activator to clear blood clots after suffering a stroke and an 87-year-old who was on the blood thinner Eliquis.
Eisai said it believes the two deaths "cannot be attributed to lecanemab."
Regulatory push in the coming months
Cheung said Eisai has protocols in place for monitoring brain swelling and sees no need for restrictions on which patients might be eligible for lecanemab treatment.
Dr. Howard Fillit, chief science officer at the Alzheimer's Drug Discovery Foundation, said doctors always balance the benefits and risks of therapies. "Currently, I would hesitate to give this drug to someone on blood thinners," he said.
The U.S. Food and Drug Administration is slated to decide by Jan. 6, 2023 whether to approve lecanemab under its "accelerated" review program, which requires proof that a drug can impact a biomarker associated with a disease, such as reduction of amyloid beta in the brain.
Regardless of that decision, Cheung said Eisai plans to soon file for standard FDA approval of the drug and will also seek approval in Europe and Japan. They plan to submit lecanemab to European and Japanese regulators by March 2023. They haven't announced a timeline for seeking approval in Canada or given a price.
In a contentious move last year, the FDA approved the first amyloid-targeting drug, aducanumab (Aduhelm) from Massachusetts-based Biogen, despite lack of evidence of better patient outcomes. Insurers and many doctors have hesitated to prescribe the expensive drug — another reason experts have anxiously awaited word of how well the newer lecanemab may work.
If the FDA approves lecanemab, patients and their families will need a voice in deciding whether it's worth the hassle of IV infusions and the risk of side-effects for the chance of at least some delay in progression, Petersen said.
"I don't think we're going to stop the disease in its tracks" with just amyloid-targeting drugs, he added, saying it will take a combination of medications that target additional Alzheimer's culprits.
Researchers are preparing to test lecanemab with other experimental drugs, and how it works in high-risk people before they show the first signs of memory problems.