ONEn 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 followed study and bolstering the drug’s case for approval as early as January.
The positive result is welcome news for 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 led the disastrous rollout of Alzheimer’s treatment Aduhelm, the potential approval of lecanemab offers a rare second chance in a multibillion-dollar market.
The Lecanemab study is an “important milestone for Eisai in fulfilling our mission to meet the expectations of the Alzheimer̵[ads1]7;s disease community,” Eisai CEO Haruo Naito said in a statement.
In the study, which included approximately 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 the patients’ decline in 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 this type. Less than 3% of those patients had symptomatic cases, the companies said.
The study, called CLARITY-AD, was the largest to date to test the long-debated theory that removing toxic brain plaques, called amyloid, could 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 confirm the so-called amyloid hypothesis in a large phase 3 clinical trial after two decades of consistent failure and darker results 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 at the University of Southern California. Schneider cautioned that experts will have to look much more closely at the lecanemab data when it is 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 Tuesday evening, Ivan Cheung, chairman of Eisai’s US operations and global head of the Alzheimer’s unit, said lecanemab’s positive treatment effect emerged six months into the study and was greatest at the final 18-month point. Cheung called the benefit to patients “very clinically meaningful,” while acknowledging that opinions will vary.
The FDA is already considering lecanemab for a conditional approval, promising to make a decision by January 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 the filing, with the goal of winning full approval this summer and persuading Medicare to roll back a restrictive reimbursement policy set in the wake of Aduhelm.
CLARITY-AD may be enough to win over the FDA, but lecanemab’s future depends on whether doctors, payers and patients find the supporting data compelling. 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 from 0 to 18, with higher numbers indicating more severe dementia.
In the 18-month study, patients receiving lecanemab did 0.45 points better on the test than those receiving placebo, a result that met the threshold for statistical significance, meaning it is unlikely to be the result of random chance.
Aduhelm, in a comparable clinical study, slowed the decline by 22%, outperforming placebo by 0.39 points on the same measure. Another, identical study failed.
Lecanemab was administered as an intravenous infusion given twice per month. About 25% of the 1,800 participants in the CLARITY-AD trial were Hispanic and African American, 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, released a statement Tuesday night. “These are the most encouraging results in clinical trials addressing the underlying causes of Alzheimer’s to date,” the group said.
For lecanemab, statistical significance does not necessarily mean a life-changing drug. Alzheimer’s researchers have spent years debating what small changes in CDR-SB scores mean for patients with the disease. A fractional improvement on an 18-point scale may be imperceptible in real life. On the other hand, the metric is not an interval scale, meaning that its numerical differences are not proportional to each other. Going from a 1 to a 1.5 on the CDR-SB may mean that one can no longer drive independently, while going from a 14 to a 14.5 is likely to make little difference to a patient who is already in dementia.
For Michael Greicius, a neurologist at Stanford University who studies and treats Alzheimer’s, the degree of brain swelling in the lecanemab study can be confusing. When patients have the common side effect, called ARIA, everyone involved in the study can be pretty sure they’re getting the drug and not a placebo, exposing the study to bias. A true test of lecanemab’s benefits would be to look only at whether it helped the patients who did not test positive for ARIA, Greicius said.
“I think if anything this is going to be on the edge of what is 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 final decision 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 putting 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 almost 50% since Aduhelm’s approval in 2021, and Eisai has lost around 60% of its value.
“Today’s announcement gives patients and their families hope that lecanemab, if approved, could potentially slow the progression of Alzheimer’s disease and provide a clinically meaningful impact on cognition and function,” Michel Vounatsos, Biogen’s CEO, said in a statement.
Biogen’s share price rose 44% to $285 in premarket trading Wednesday, adding $13 billion to the company’s market capitalization. Eisai’s US-listed American depositary receipts had not yet opened for trading.
In a published research note, Brian Skorney, a biotech analyst at RW Baird and a longtime critic of Biogen and its Alzheimer’s drug programs, described the results of the lecanemab study as “pretty much a best-case scenario that should not only lead to approval and reimbursement but could challenging for competition (assuming any are successful) to match.” Skorney upgraded its Biogen rating to “outperform” from “neutral.”
The results kick off what will be a transformative 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 plaque. And in the first half of 2023, Eli Lilly expects to have results from a phase 3 study on donanemab, a similar treatment that met its goals in a small study last year.