Facing a familiar side effect problem, Eisai makes the case for its next Alzheimer's drug after patient deaths

Two potential treatment-related deaths have dimmed the initial glow surrounding Eisai and Biogen’s next Alzheimer’s disease therapy lecanemab. But the Japanese company believes it has more answers about the risks patients may need to accept—and the tough conversations doctors will need to have—before starting treatment.

With new data being released, lecanemab is beginning to be associated with side effects called amyloid-related imaging abnormalities, or ARIA, which are abnormalities that show up in MRI imaging and can signal bleeding in the brain or swelling. This is a known complication in the treatment class that has come into focus as multiple Alzheimer’s antibodies race toward the FDA finish line.

In datasets to be presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference and published in the New England Journal of Medicine this evening, Eisai will show that lecanemab is associated with “moderately less decline” in cognition and function compared with placebo. But the experimental drug also has been linked to adverse events. The trial investigators note that longer studies may be needed to determine the safety and efficacy of lecanemab in treating early Alzheimer’s disease.

Back in September, Eisai made waves with the announcement that lecanemab slowed cognitive decline in the phase 3 Clarity AD trial, meeting the main endpoint and providing the data needed to support a potential regulatory nod. The news sent a chorus of fresh hope through a drug development world long beset by failures and challenges to provide new therapies to address the devastating neurodegenerative disorder. But two potential treatment-related deaths in the study, one revealed by STAT in October and another in Science on Monday, have quieted the cheers.

In the Monday report from Science, the neuropathologist who conducted the autopsy on the second deceased patient said there's "zero doubt in my mind that this is a treatment-caused illness and death."

Pushing back, Eisai executives told Fierce Biotech in an interview that they don’t believe either death can be pinned on lecanemab.

Both were the result of brain hemorrhages. An autopsy report has shown that the first was cardiopulmonary related, according to Eisai. The second patient reportedly suffered a stroke.

In a company statement issued Tuesday, Eisai said that the rate of death from macrohemorrhage was 0.1% in both the placebo and lecanemab groups, or one patient taking placebo and two patients in the trial drug arm. The two deaths in the lecanemab arm occurred in the ongoing open-label extension study and both were associated with “significant comorbidities and risk factors” such as the use of blood thinners, the company said.

“Therefore, it is Eisai’s assessment that the deaths cannot be attributed to lecanemab,” the company said in the statement.

Brain bleeds, called cerebral macrohemorrhages, are an “adverse event of special interest,” according to Eisai’s Michael Irizarry, senior vice president of clinical research and deputy chief clinical officer for Alzheimer’s disease and brain health. In an interview, he said Eisai has been watching closely for these events throughout the clinical program for lecanemab.

Overall, 13 deaths have occurred in the Clarity AD study: seven in the placebo group and six in the lecanemab arm. The data does not breakdown the cause of these deaths but none "were considered by the investigators to be related to lecanemab or occurred with ARIA," according to the NEJM publication.

Irizarry says the rate of brain bleeds in the lecanemab arm was about 0.6% to 0.7%, compared with 0.2% in the placebo group. Only 2.8% of the reported bleeds were symptomatic. The study had 1,795 total participants, with half receiving the study drug and half getting placebo.

“Looking at these two rather complex cases, I think it's quite difficult to attribute these two deaths to lecanemab, although lecanemab of course, has the likelihood to increase the susceptibility of a brain bleed,” said Ivan Cheung, chairman and CEO of Eisai’s U.S. operations and global Alzheimer’s disease officer.

The study allowed patients taking blood thinners to participate, which could be a risk factor for brain bleeds. Irizarry said these patients had a slightly higher risk of bleeds, at 2.4% to 3.6%, than the general population taking lecanemab. But what’s not known is how often brain bleeds are associated with Alzheimer’s patients who take blood thinners to begin with, he noted.

“It does mean that individuals that are on both lecanemab and anticoagulation need to be informed about the risks of macrohemorrhage and the risk-benefit of treatment with lecanemab,” Irizarry said.

Eisai is hoping to present enough evidence to the FDA to convince regulators that the benefit of treatment with lecanemab outweighs the risks and avoid a warning on the drug’s potential label. Irizarry said the information will be included in the safety data on the future label, but could not say whether the FDA will require any more obvious warnings on the packaging. The company has already submitted a request for accelerated approval, which would allow the therapy to be marketed while follow up data confirming clinical benefit is prepared.

“Education is critical. Of course, awareness is critical. We fully support those important educational efforts,” Cheung said.

When releasing the initial data in September, Eisai said that the rate of ARIA was within expectations. Irizarry said he ultimately believes that after physicians are frank about the risks, patients will still be inclined to take lecanemab for a chance at reducing cognitive decline. Irizarry points to the less than 20% dropout rate among the bulk of patients who were enrolled during the height of the COVID pandemic when the Clarity AD study was conducted.

“I do think that there's a desire for effective treatments for Alzheimer's disease,” he said, adding that patients, caregivers and physicians will need to be aware of the main adverse event risks, which include infusion-related reactions, ARIA-E and rare macrohemorrhages, and participate in monitoring every two weeks.

Eisai also is not the only company dealing with ARIA concerns, as leading competitors Genentech and Eli Lilly have also previously reported some red flags for the safety signal.

“This is going to be something the community will have to understand that comes with these therapies,” Cheung said. “This is important, very important. You want to find the antibody that has the best safety profile, and lowest relative ARIA rates.”

He believes that lecanemab is that antibody, while analysts have similarly tipped the scale towards the Biogen-partnered candidate over Lilly's offering. Genentech will also be presenting an update on the failed phase 3 Graduate program at CTAD.  

As for efficacy, Eisai will present a deeper dive into the real-world promise of lecanemab at the conference. The analysis will include measures of quality of life and caregiver burden. Cheung said on those measures, patients will find a strong case to move forward with treatment. While the trial looked at a relatively short 18-month period, he said the data show that the therapy could provide more time at an earlier level of disease. That could mean multiple years added to patients’ lives.

“Those are not small, insignificant numbers for any family living with this horrific disease,” Cheung said.

The FDA has set a decision date of January 6, 2023, for Eisai's accelerated approval application. Eisai is in ongoing communication with the agency providing safety updates and adverse event reports, the company said. Cheung said he has no reason at this time to believe that the FDA will change that date based on the recently reported deaths or the cases of ARIA. If the accelerated approval is granted, Eisai plans to immediately submit data “within days” to flip that nod to a full approval.

This could be key, as lecanemab’s predecessor Aduhelm was plagued by a Centers for Medicare & Medicaid Services decision that limited coverage of the drug to only patients participating in approved clinical trials. The blanket determination as it stands now applies to all drugs in the class. Drugmakers, including peers Lilly and Genetech, have pushed back, and Eisai believes it has information in hand that could persuade the agency to be more lenient for the Aduhelm follow up.

“With all the evidence we've generated so far with lecanemab, it is our goal to lift the coverage determination or at least make the coverage determination much more amenable from an access perspective,” Cheung said.