Eisai’s phase 3 clinical trial of Biogen-partnered Alzheimer’s disease candidate lecanemab has hit its primary and key secondary endpoints. The result, which analysts at Evercore ISI called a “major surprise,” gives a big boost to the partners as they head toward an accelerated approval decision in January.
The Clarity AD study randomized 1,795 people with early Alzheimer’s to receive lecanemab, an antibody designed to take out amyloid-beta aggregates, or placebo intravenously twice a month. After 18 months, the partners found lecanemab slowed cognitive decline by 27% compared to placebo, causing the trial to hit its primary endpoint with a p-value of 0.00005.
In an interview with Fierce Biotech earlier in the month, Ivan Cheung, Eisai's global Alzheimer's disease officer and CEO of the company's U.S. business, pointed out that the Japanese pharma had worked with centers around the country to ensure the trial's population mirrored the real-world situation, noting that 22.5% of participants were Hispanic and 4.5% were African American.
“We actually had pretty liberal inclusion-exclusion criteria that allowed people with a range of comorbidities and medications,” Michael Irizarry, M.D., deputy chief clinical officer of Alzheimer's disease and brain health at Eisai, told Fierce in the same interview. “So when we look at the baseline characteristics of people on the Clarity clinical trial, over 60% have hypertension or high cholesterol; about 20% of them have coronary artery disease, ischemic heart disease or diabetes.”
”We do feel that the clinical trial population really will generalize to the Medicare Alzheimer's disease population,” Irizarry added.
Eisai, the sponsor of the phase 3, used the global cognitive and functional scale, CDR-SB, to track clinical decline. Recipients of lecanemab performed 0.45 points better than their peers on placebo. In a similar trial, Biogen’s controversial Aduhelm slowed clinical decline by 22%, with a 0.39 point difference, versus placebo, although it also failed a second study.
Evercore ISI Umer Raffat analyst called the 27% benefit achieved by lecanemab “remarkably consistent” with the phase 2 data, adding that the 0.45-point improvement “appears to meet the threshold for ‘clinical significance’ that I was hearing.”
Eisai saw statistically significant improvements in CDR-SB from six months onward. With the phase 3 trial also meeting key secondary endpoints such as amyloid levels in the brain and other Alzheimer’s scales, Eisai looks to have the efficacy data to support approval of lecanemab. On the safety front, 12.5% of the recipients of lecanemab had amyloid-related imaging abnormalities-edema/effusion, an adverse event associated with such therapies, although only 2.8% of patients had symptoms.
The FDA is already reviewing other data on lecanemab as part of an accelerated approval application that has a decision date of Jan. 6. With Clarity AD set to serve as the confirmatory study, Eisai could pick up accelerated approval and then quickly convert it to a traditional authorization. Eisai is planning to file for approval in the U.S., Europe and Japan by the end of March.
The next big date in the calendar is Nov. 29, when Eisai is set to present the Clarity AD data at the Clinical Trials on Alzheimer’s Congress. The data will shed light on whether lecanemab can make a meaningful difference to the lives of patients.
Raffat flagged the question of whether lecanemab works in people with and without the risk factor of the APOE4 genotype as a key unknown on efficacy. Yet, as the analyst noted, given participants with the marker made up 30% of the relevant phase 2 population and 70% of the phase 3 population, Eisai may not have seen a p-value of 0.00005 “if there was a large disconnect on efficacy.”
Responsibility for convincing physicians and payers, including Medicare with its new, restrictive policy, of the merits of lecanemab will fall on Eisai, as Cheung explained to Fierce earlier in the month.
“All the interactions with the FDA, CMS, they're all done by Eisai,” he said. “And of course … should lecanemab be successful, the commercialization, access, pricing, strategy—all these matters will be led by Eisai.”
“Biogen plays a big role in the manufacturing of lecanemab,” added Cheung, as part of a deal where the two drugmakers will split the profits and losses evenly.
Biogen's shares had jumped 48% to $292 apiece in premarket trading Sept. 28.