An investigational Alzheimer’s disease treatment from Biogen and Eisai slowed the rate of cognitive decline by 27% in a clinical trial, the companies said Tuesday, meeting the goals of a closely tracked study and strengthening the drug’s case for approval as early as January.
The positive result is welcome news for the millions of people living with Alzheimer’s and a big win for Eisai and Biogen, giving the companies a potential blockbuster product in the intravenous medicine, called lecanemab. For Biogen, which presided over the disastrous rollout of the Alzheimer’s treatment Aduhelm, the potential approval of lecanemab presents a rare second chance at a multibillion-dollar market.
The lecanemab study is an “important milestone for Eisai in fulfilling our mission to meet the expectations of the Alzheimer’s disease community,” said Eisai CEO Haruo Naito, in a statement.
In the study, which enrolled roughly 1,800 patients with early-stage Alzheimer’s, lecanemab outperformed placebo. The treatment also met its secondary goals of reducing toxic plaques in the brain and slowing patients’ decline on three other measures of memory and function.
About 21% of patients treated with lecanemab experienced brain swelling or brain bleeding visible on PET scans, a side effect associated with drugs of its type. Less than 3% of those patients had symptomatic cases, the companies said.
The study, called CLARITY-AD, was the largest conducted to date to test the long-debated theory that clearing toxic brain plaques, called amyloid, might slow the pace of Alzheimer’s by slowing the pace of memory loss or delaying the onset of dementia.
Lecanemab is the first treatment of its kind to affirm the so-called amyloid hypothesis in a large, Phase 3 clinical trial after two decades of consistent failure and murkier outcomes from similar, experimental drugs.
“This is a statistically robust and positive study but the treatment effect is small,” said Lon Schneider, a physician and Alzheimer’s expert at the Keck School of Medicine of the University of Southern California. Schneider cautioned that experts will need to take a much closer look at the lecanemab data when presented in more detail, but based on the results described in Eisai’s press release, he believes lecanemab is likely to win approval from the Food and Drug Administration. Schneider was not involved in the study.
In a telephone briefing for reporters on Tuesday night, Ivan Cheung, chairman of Eisai’s U.S. operations and global head of Alzheimer’s unit, said lecanemab’s positive treatment effect emerged six months into the study and was largest at the final, 18-month time point. Cheung called the benefit for patients “very clinically meaningful,” while also acknowledging that opinions will differ.
The FDA is already considering lecanemab for a conditional approval, promising to make a decision by Jan. 6 based on preliminary evidence from a smaller study showing the drug’s effect on amyloid in patients’ brains. Eisai now plans to add the more definitive results from the CLARITY-AD study to its application, aiming to win full approval in the summer and persuade Medicare to walk back a restrictive reimbursement policy set in the aftermath of Aduhelm.
CLARITY-AD might be sufficient to win over the FDA, but lecanemab’s future depends on whether physicians, payers, and patients find the supporting data convincing. The study used a metric called the Clinical Dementia Rating sum of boxes, or CDR-SB, which measures six cognitive domains including memory, problem solving, and personal care, and produces scores ranging from 0 to 18, with higher numbers indicating more severe dementia.
In the 18-month trial, patients who received lecanemab did .45 points better on the test than those receiving placebo, a result that hit the threshold of statistical significance, meaning it’s unlikely to be the result of random chance.
Aduhelm, in a comparable clinical trial, slowed decline by 22%, outperforming placebo by .39 points on the same measure. A second, identical study failed.
Lecanemab was administered as an intravenous infusion given twice per month. Approximately 25% of the 1,800 participants in the CLARITY-AD study were Hispanic and African-Americans, making it one of the more diverse populations ever enrolled in an Alzheimer’s clinical trial.
The Alzheimer’s Association, which has actively lobbied the FDA to approve new treatments, issued a statement Tuesday night. “These are the most encouraging results in clinical trials treating the underlying causes of Alzheimer’s to date,” the group said.
For lecanemab, statistical significance does not necessarily make for a life-changing medicine. Alzheimer’s researchers have spent years debating just what small changes in CDR-SB scores mean for patients with the disease. A fractional improvement on an 18-point scale could be imperceptible in real life. On the other hand, the metric is not an interval scale, meaning its numerical differences aren’t proportionate to one another. Going from a 1 to a 1.5 on the CDR-SB could mean no longer being able to drive on one’s own, while going from a 14 to a 14.5 would likely make little difference for a patient already in the throes of dementia.
To Michael Greicius, a neurologist at Stanford University who studies and treats Alzheimer’s, the rate of brain swelling in the lecanemab study could be confounding. Once patients present with the common side effect, called ARIA, everyone involved in the trial can be fairly certain they are receiving the drug and not placebo, exposing the study to bias. A true test of lecanemab’s benefits would be looking only at whether it helped the patients who didn’t test positive for ARIA, Greicius said.
“I think if anything this is going to be on the cusp of what’s considered minimally clinically significant, and it may be below that,” said Greicius, who was not involved in the study. “That’s where we need to see more data.”
Experts said any definitive ruling on lecanemab’s value would require more detailed results from CLARITY-AD, which Eisai has promised to present at a medical conference in November.
Wall Street had only moderate expectations for CLARITY-AD, with analysts setting a low probability of success and declaring that even a marginal benefit would count as a positive for Biogen and Eisai. Biogen’s share price has fallen by nearly 50% since Aduhelm’s 2021 approval, and Eisai has lost about 60% of its value.
“Today’s announcement gives patients and their families hope that lecanemab, if approved, can potentially slow the progression of Alzheimer’s disease, and provide a clinically meaningful impact on cognition and function,” said Michel Vounatsos, Biogen’s CEO, in a statement.
Biogen’s stock price rose 44% to $285 in Wednesday pre-market trading, adding $13 billion to the company’s market value. Eisai’s U.S.-listed American Depositary Receipts had not yet opened for trading.
In a published research note, Brian Skorney, biotech analyst at R.W. Baird and a long time critic of Biogen and its Alzheimer’s drug programs, described the lecanemab study results as “pretty much a best-case scenario that not only should lead to approval and reimbursement but could make it challenging for competition (assuming any are successful) to match.” Skorney upgraded his Biogen rating to “outperform” from “neutral.”
The results kick off what will be a transformational nine months for Alzheimer’s research. By the end of this year, Roche will have data from a pair of two-year studies on gantenerumab, another antibody that reduces brain plaques. And in the first half of 2023, Eli Lilly expects to have results from a Phase 3 trial on donanemab, a similar treatment that met its goals in a small study last year.