Eisai’s expanded Alzheimer’s data leave open questions about safety and clinical benefit

Researchers still have key questions about Eisai’s investigational Alzheimer’s drug lecanemab following the publication of more Phase III data in the New England Journal of Medicine Tuesday night.

In the paper, which was released in conjunction with presentations at an Alzheimer’s conference, trial investigators write that a definition of clinical meaningfulness “has not been established.” And the relative lack of new information, following topline data unveiled in September, left experts asking for more — setting up a potential showdown to precisely define how big a difference the drug makes in patients’ lives.

Lon Schneider

Lon Schneider, director of the USC State of California Alzheimer’s Disease Center, emphasized to Endpoints News in an email that the outcomes were “remarkably similar” to one of the trials supporting Aduhelm’s controversial approval last year. Eisai developed Aduhelm, or aducanumab, with its partner Biogen, which also collaborated on lecanemab.

“The same controversy about clinical meaning and clinically important differences with aducanumab are in play with lecanemab,” Schneider wrote. “You can see the battle lines being drawn in the paper, ancillary publications in press offering new takes on defining clinically important differences for the [primary endpoint].”

Tuesday’s presentation comes after Eisai said two months ago the CLARITY AD trial showed a 27% reduction in cognitive decline compared to placebo, based on a 0.45 difference on an 18-point scale measuring memory, judgment, problem solving and other life essentials impeded by the disease. The 0.45 difference contrasts with scientific literature describing at least a 1-point difference as constituting clinical meaningfulness, experts said.

Madhav Thambisetty

“The reported difference between lecanemab and placebo is well below what is considered to be a clinically meaningful treatment effect,” Madhav Thambisetty, an investigator within the NIH’s National Institute on Aging, told Endpoints via email, adding, “It is unlikely that the small difference reported in this trial will be noticeable by individual patients.”

Constantine George Lyketsos

Meanwhile, Constantine George Lyketsos, a psychiatry and behavioral sciences professor at Johns Hopkins, said outright that Eisai “skirted the issue” of clinically meaningful effects, declining entirely to reference earlier research in its NEJM paper, saying he’s “surprised the reviewers didn’t push them.” Lyketsos said at this point, he would not prescribe lecanemab to his patients.

Not all the reviews were negative, however. Robert Vassar, an Alzheimer’s researcher at Northwestern University who helped identify the beta secretase enzyme inhibitors, or BACE1, called the results “pretty remarkable.” Even with a “modest clinical benefit,” the trial confirms the amyloid hypothesis, he said in a phone interview.

The FDA will decide by Jan. 6, 2023 whether to grant accelerated approval to lecanemab.

Eisai researchers measured lecanemab in nearly 1,800 mild Alzheimer’s patients, randomizing them 1-to-1 to receive either the drug or placebo. The 18-point scale, known as the Clinical Dementia Rating-Sum of Boxes or CDR-SB, and its variations are used frequently in Alzheimer’s drug trials.

Aducanumab and Roche’s gantenerumab, which failed a Phase III study earlier this month, also used CDR-SB, while Eli Lilly’s donanemab is using CDR-GS (Global Score) in its pivotal trials currently underway.

Safety will be top of mind, especially in an elderly population with Eisai’s trial comprising patients 50 to 90 years of age. Eisai previously reported amyloid-related imaging abnormalities, or ARIA-E and ARIA-H, rates of 12.5% and 17.0%, respectively, in the drug arm compared to 1.7% and 8.7% in the placebo group. Final results presented Tuesday did not differ much: 12.6% and 17.3% among those taking lecanemab, compared to 1.7% and 9.0% on placebo.

Michael Irizarry

The drug was found to lead to higher ARIA rates in this study than in a Phase IIb trial, Eisai’s deputy chief clinical officer for Alzheimer’s and brain health Michael Irizarry told Endpoints. Irizarry said that may have resulted from a greater portion of patients who carried the ApoE ε4 gene, which is associated with higher vascular amyloid burden, in the later-stage study.

Reports of two deaths potentially related to lecanemab have also put a magnifying glass on its safety profile in recent weeks. The two deaths were part of the trial’s open-label portion, and Eisai said in a statement that its assessment determined “the deaths cannot be attributed to lecanemab.”

Going further in the NEJM paper, investigators deemed none of the six deaths in the 898-patient treatment arm were related to the study drug. There were seven deaths in the 897-patient placebo cohort. Eisai did not specify in the paper when the deaths occurred.

Irizarry reiterated that the deaths weren’t treatment-related. In one of the cases, a 64-year-old woman in Chicago who died after a severe brain bleed and stroke, the Eisai SVP said they “can’t rule out that lecanemab might have increased risk some,” but that particular case is confounded by blood thinner use.

Vassar said the deaths, including one patient at his own institution, need to be “thoroughly investigated” and does “send up some red flags about lecanemab together with blood thinners.”

Ivan Cheung

Irizarry and Ivan Cheung, Eisai’s US leader and global Alzheimer’s chief, also touted analyses that found the drug was favored over placebo across multiple comorbidities, like hypertension, diabetes, heart disease and others. Patients with comorbidities saw greater numerical improvements than the overall patient population.

Additionally, infusion-related reactions were the most commonly reported adverse events, with 26.4% in the lecanemab group and 7.4% in the placebo arm. Michael Greicius, a Stanford University neurology professor, told Endpoints via email that he thinks “there is a reasonable likelihood” patients and clinicians may have been able to unblind themselves using the infusion reactions.

Michael Greicius

“The data seem fairly consistent across outcome measures, but I remain concerned that the small effect size might be smaller still with adequate correction for potential unblinding,” he said.

With the curtain now revealed on the Phase III data, clinicians, researchers and competing drug developers are left to sort out how an approval might affect Medicare and other payers and insurers, given Aduhelm’s disastrous rollout. A near-moratorium on Medicare coverage of anti-amyloid monoclonal antibodies would also apply to lecanemab, should it win accelerated approval.

Cheung said the ultimate goal has never been an accelerated nod, so within days after a potential quick OK, the biotech plans to ask for full approval. The Medicare restriction — essentially limiting coverage to patients in clinical trials — was instituted in April 2022.

Discussions are underway with Centers for Medicare & Medicaid Services, Irizarry and Cheung said, and the company thinks the CLARITY AD data will help convince the agency to rescind the narrow coverage scope for lecanemab. A price has yet to be set, Cheung said. Eisai will lead those conversations instead of Biogen, which took control of the Aduhelm strategy. The original Aduhelm price, set at $56,000 per year, caused an outcry from critics and Biogen slashed the price in half five months later.

Both drugs go after a leading hypothesis in the field around how the buildup of amyloid plaques can contribute to Alzheimer’s progression typically seen in older adults. If a drug were to attack those plaques and shuttle them away, the theory goes, then fewer memories would be erased and cognitive function wouldn’t wither at the same rate.

Clinical failures abounded as compound after compound and company after company hit a brick wall. But then Biogen and Eisai took another look at two Phase III studies of aducanumab and, after a thumbs-down vote from FDA’s outside experts, the agency cleared it in June 2021. A litany of pushback ensued from government agencies, politicians, clinicians, hospitals, payers and others.

Robert Vassar

The amyloid hypothesis is getting put to the test again by a trio of high-profile drugs late in the clinical development stages: lecanemab, donanemab and gantenerumab. Eisai and Biogen were the first to uncloak late-stage data with the September topline results, reinvigorating the amyloid hypothesis.

“This has been a much-repeated experiment with multiple failures until now. In itself, this is a significant advance in the field,” Thambisetty said. “However, a successful experiment does not always guarantee translation into safe, effective, and meaningful treatments.”

Weeks later, Roche reported its subcutanenous drug gantenerumab failed. Lilly, meanwhile, will put out some six-month data on a trial comparing donanemab to Aduhelm on Wednesday in amyloid removal, also at the 15th Clinical Trials on Alzheimer’s Disease conference in San Francisco.

Cheung and some researchers cheered the promptness of the data’s publication in NEJM, but questions still remain about data and analyses not included in the paper. Thambisetty highlighted changes in brain volume, measured by MRI and documented in an earlier Phase II trial of lecanemab, as one example.

Researchers also want to know more about blood and spinal fluid levels of the protein neurofilament light-chain, or NfL. It has garnered interest in other neurodegenerative conditions like ALS, and Biogen has filed its New Drug Application for its ALS drug tofersen aiming to win the first approval using NfL as a surrogate biomarker.

“A full and timely analysis of these data is essential to understand whether the drug may worsen neurodegeneration,” Thambisetty said.

Vassar, the Northwestern professor, said he thought it “was a little weird” that there wasn’t a reduction in the NfL biomarker. Nevertheless, the study contributes key bricks to the R&D foundation in a space that has long befuddled drug developers and researchers.

Andrew Saykin

“This is an important inflection point for the field. Future trials will build on this foundation and will likely include combination therapies and lifestyle modification,” said Andrew Saykin, director of the Indiana Alzheimer’s Disease Research Center at the University of Indiana, in an email. “We have seen similar progress in oncology and HIV therapeutics where the initial modest successes were followed by increasingly better agents and regimens.”

The drug developers “still have work to do” on other fronts as well, Irizarry said, when asked about diversity in the trial. In the US portion of the North America, Europe and Asia study, a mere 4.5% of patients were Black/African American, which the NEJM paper called “an underrepresentation” of the real-world population. There was an “overrepresentation of Hispanic” patients, at 22.5% of the US enrollees, the authors wrote.

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