Days before the release of promising phase III trial data of lecanemab, an investigational anti-amyloid drug for early Alzheimer's disease, a death possibly linked to the treatment was reported.
An unpublished case report featured in suggested the death of a 65-year-old lecanemab trial participant with cerebral amyloid angiopathy may have resulted from the drug's possible interactions with tissue plasminogen activator (tPA), which was used to treat a stroke she experienced.
This is the second publicly discussed death of a lecanemab trial participant. In October, a man in his late 80s died of a brain hemorrhage that may have been linked to a possible interaction between lecanemab and the blood thinner apixaban (Eliquis), though lecanemab developer Eisai said the death was unrelated to the drug.
Lecanemab may be the most closely watched treatment in the Alzheimer's drug pipeline. In September, Eisai and its partner Biogen stating their of lecanemab met its primary endpoint, showing a statistically significant reduction in clinical decline in people with early Alzheimer's disease. The drug's profile of amyloid-related imaging abnormalities (ARIA) -- brain edema or small hemorrhages that may occur as amyloid is cleared -- was within expectations, the companies said.
Full data from the trial are this week at the annual conference.
"All eyes are on lecanemab because we have a press release that shows benefits of the drug compared to placebo across all primary and secondary endpoints," said Jason Karlawish, MD, of Penn Memory Center at the University of Pennsylvania in Philadelphia.
"Assuming those data all hold up to scrutiny, that's an effective treatment," Karlawish told 鶹ý. "But it's also a treatment that we knew, going into it, has risks -- ARIA risks. These case reports of patient deaths add to our knowledge of the risk of the drug."
If the drug proves to be effective in slowing cognitive decline and the FDA decides to move forward with approval, a risk evaluation and mitigation strategy () may be a solution, Karlawish noted. "A REMS could thread a number of difficult needles together," he said.
Even if the trial data are favorable, how the drug interacts with real-world patients remains a concern. "The move from clinical trials -- where participants are carefully screened and selected to exclude the presence of accompanying conditions that raise the risk of these side effects, to the more typical clinic population with multimorbidity -- will expose patients to higher risks of life-changing adverse effects, so that the risks and benefits of treatments will need to be very carefully considered by doctors, patients, and families," noted Robert Howard, MD, MRCPsych, of University College London in England.
"It's important that we analyze available clinical trial data comprehensively and make it publicly available to researchers so we can identify individuals who may be most at risk for serious and potentially life-threatening adverse events after exposure to lecanemab and other drugs in this class," added Madhav Thambisetty, MD, PhD, of the National Institute on Aging, who co-authored a with Howard and others outlining questions that still need to be addressed about anti-amyloid Alzheimer's therapies.
And it's not a forgone conclusion that the CLARITY trial results are meaningful clinically, observed Lon Schneider, MD, of the University of Southern California in Los Angeles.
"The issue here is whether there is clinically meaningful efficacy, not just a very low P value, which is not an effect size," Schneider told 鶹ý.
"We haven't seen the protocol-specified subset analyses -- who might have benefited to a meaningful extent, the dropouts, the likelihood of potential biases," Schneider said. "We need this to be able to weigh side effects."