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Will Lecanemab Win FDA Approval? The Stakes Are High as Phase 3 Results Show Efficacy

Article In Brief

The phase 3 trial of lecanemab, an anti-monoclonal antibody, showed promising results, and notwithstanding some safety concerns, dementia experts (at press time) were optimistic that the drug would be approved by the US Food and Drug Administration.

Dementia experts who were awaiting the results of a phase 3 trial of lecanemab were not disappointed. The anti-amyloid monoclonal antibody moderately slowed decline in patients with early Alzheimer's disease (AD) in randomized controlled Clarity AD trial, according to results published Nov. 29, 2022, in the New England Journal of Medicine.

The top-line results from the trial, presented at the at the Clinical Trials Against Alzheimer's Disease (CTAD) meeting simultaneously with the study publication, generated buzz, but so too did reports of adverse events among participants in the open-label phase of the trial that emerged two days before the meeting.

While the reports have tempered some enthusiasm around the drug—manufacturers Eisai and Biogen said in a statement that the events were not associated with the drug—leading clinicians and researchers were confident that the drug would likely win approval by the US Food and Drug Administration (FDA).

“It's really the first time in history that we have a therapy demonstrating an unequivocal slowing of decline in AD,” the study's lead author, Christopher Van Dyck, MD, professor of psychiatry, neurology, and neuroscience, director of the division of aging and geriatric psychiatry, and director of the Alzheimer's Disease Research Unit at Yale School of Medicine, told Neurology Today.

“It was a remarkable experience to be in that packed room at CTAD and experience the sheer amount of excitement among my fellow scientists,” said Liana Apostolova, MD, the Barbara and Peer Baekgaard Professor in Alzheimer's Disease Research and professor of neurology, radiology, medical and molecular genetics at Indiana University School of Medicine.

“It's been 20 years without any inkling of headway that we are moving in the right direction, a very disheartening two decades without a single drug that has some disease-modifying effects,” she said. “We haven't seen a drug with this kind of influence on disease course since Alzheimer first identified the disease. It's the first true disease-modifying therapy in AD. The effects are moderate, but significant, and it's our first big step toward curing this disease one day.”

Lecanemab—one of several drugs in the anti-amyloid class at various stages of the pipeline—selectively binds to neutralize and eliminate soluble, toxic amyloid-beta protofibrils that are thought to contribute to the AD neurodegenerative process.

Aducanumab, the only anti-amyloid monoclonal antibody on the market, was approved by the FDA in 2021 despite unclear evidence of its benefit in the EMERGE and ENGAGE clinical trials, which were halted early. Gantenerumab, another agent in the same drug class, showed disappointing top-line results in phase 3 Graduate I and II studies, released in mid-November 2022; it did not meet its primary endpoint of slowing clinical decline and the level of amyloid-beta removal was lower than expected.

The Clarity AD Trial

In the Clarity AD trial, however, lecanemab showed significant efficacy on its primary endpoint, a change from baseline at 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB). The change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (p=0.00005). The drug met all of its secondary endpoints as well, including the change from baseline at 18 months in amyloid burden on PET, the score on the Alzheimer's Disease Assessment Scale–Cognitive Subscale 14, the Alzheimer's Disease Composite Score, and the score on the Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

A total of 1,795 people with early AD were enrolled at 235 sites in North America, Europe, and Asia: 897 were randomized to receive placebo while 898 received 10-mg/kg IV biweekly lecanemab, and the randomization was stratified according to their clinical subgroup—MCI due to AD or mild AD—presence or absence of concomitant approved AD symptomatic medication at baseline (acetylcholinesterase inhibitors, memantine, or both), apolipoprotein E4 status, and geographical region.


“You can debate if it's ‘big enough,’ but the fact that the functional scores as well as the cognitive scores were significantly better than the placebo group, could mean going from noticing that someone occasionally has a memory lapse that's not always consistent to someone having consistent memory loss that's noticeable to anyone anytime they see the person for a few minutes.”—DR. DAVID M. HOLTZMAN


“We haven't seen a drug with this kind of influence on disease course since Alzheimer first identified the disease. It's the first true disease-modifying therapy in AD. The effects are moderate, but significant, and it's our first big step toward curing this disease one day.”—DR. LIANA APOSTOLOVA

The study also included a broader and more diverse population than previous anti-amyloid studies, with 4.5 percent Black and 22.5 percent Hispanic participants. It also allowed a range of comorbidities including hypertension, diabetes, heart disease, obesity, and renal disease.

What the Experts Say

“This appears to be an incredibly well carried out trial, done to the highest standards, and the data are convincing that there's an effect,” said David M. Holtzman, MD, FAAN, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology and associate director of the Alzheimer's Disease Research Center at the Hope Center for Neurological Disorders at Washington University in St. Louis School of Medicine.

“You can debate if it's ‘big enough,’ but the fact that the functional scores as well as the cognitive scores were significantly better than the placebo group, could mean going from noticing that someone occasionally has a memory lapse that's not always consistent to someone having consistent memory loss that's noticeable to anyone anytime they see the person for a few minutes,” he said. “There are other ways to look at it, but that's one example and to me it's important. And the fact that all the tests they did showed statistically significant differences in the rate of decline is quite convincing.”

A 698-participant sub-study of amyloid burden on PET found greater reductions in brain amyloid burden with lecanemab than with placebo (difference, −59.1 centiloids), Dr. Holtzman noted. He added that it took between six to nine months for most of the participants to clear the majority of the imaging-detectable amyloid. “Similarly, the cognitive measures in the placebo vs. the treatment group didn't start to show separation until after six months,” he said. “That's clearly showing an effect.”

Even more encouraging, said Dr. Apostolova, is the separation in the trajectories of decline. “This sort of effect is what we were hoping to see in the data: that the difference in rate of decline becomes larger over time. At the end of 18 months, we saw a half a point difference on the CDR-SB between the two groups, and in every secondary endpoint, all the global and functional scales, everything suggested disease modification, in which there is a sustained difference in the rate of decline and the two groups separate more and more over time. If this is a sustained effect, who knows what the effect could be at the end of 24 to 36 months?”

Whether or not that separation would continue and grow even larger over a longer period of time cannot be confirmed in a randomized clinical trial, as it would be unethical to randomize patients to a placebo arm against a drug with demonstrated efficacy.

Another way of looking at that half point difference on the CDR-SB is by considering it “time bought,” Dr. Apostolova said. “If you do statistical projections, the half point difference translates into about four to five months of time bought, meaning that when the people in the placebo group reach a certain endpoint in functional decline, the treatment group will get there four or five months later. If this difference continues to grow over time, that ‘time bought’ could be as much as a year. If there is a year when the person could still have their independence, drive their car, not need someone to help with their bills or medications, I think that's very meaningful.”

Risks of ARIA

Side effects from lecanemab were consistent with previous data from earlier trials and with the drug class as a whole. The most common adverse event in the lecanemab group compared with placebo was infusion reactions—26.4 percent versus 7.4 percent, respectively—but these effects were largely mild to moderate (96 percent were grade 1-2) and occurred on the first dose (75 percent).

Amyloid-related imaging abnormalities with hemorrhage (ARIA-H), involving the combined categories of cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis, occurred among 17.3 percent of the lecanemab group versus 9 percent of the placebo group, while ARIA-E (edema/effusion) was present in 12.6 percent of the lecanemab group and 1.7 percent of the placebo group. This incidence was lower than found in the EMERGE and ENGAGE trials that ultimately led to aducanumab's approval, in which 35.2 percent of aducanumab patients experienced ARIA-E and 33.8 percent experienced ARIA-H.

Most of the ARIA-related events in the Clarity AD trial were asymptomatic; the incidence of symptomatic ARIA-H was 0.7 percent in the lecanemab group and 0.2 percent in the placebo group, while 78 percent of those who had ARIA-E were asymptomatic and 91 percent had mild to moderate radiographic findings.

No deaths during the trial period were attributed to lecanemab; however, two deaths were reported after the completion of the trial during the open-label phase—one from a stroke and other from a brain hemorrhage—have been potentially linked to the drug. Both were taking anticoagulant therapy; patients in the trial who were on these agents were more likely to experience cerebral hemorrhages.

“There needs to be careful evaluation as to whether it is safe to treat patients on anticoagulant therapy with lecanemab,” said Stephen Salloway, MD, the founding director of the Memory and Aging Program at Butler Hospital in Providence, RI, and the Martin M. Zucker Professor of Psychiatry and Human Behavior and Professor of Neurology at the Warren Alpert Medical School of Brown University.

“It's encouraging that the rate of ARIA is lower than with some of the other studies, and it's usually mild, transient, and quite manageable, but there can be serious cases with all the anti-amyloid agents. When the drug is reviewed by the FDA, I hope that this question will be addressed in an appropriate-use recommendation. We want to avoid any disabling or fatal outcomes.”

These potential complications can be managed with appropriate guidance and training, said Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer's Association. “Side effects like ARIA are new to many people, but not to our field. We helped to lead a workgroup studying this phenomenon more than a decade ago, and proposed recommendations for the detection and monitoring of ARIA in ongoing AD clinical trials, as well as directions for future research. The FDA has incorporated our recommendations into guidance for study sponsors, and that is why more recent trials were able to continue safely and to completion.”

Prospects for Approval

The FDA granted priority review for lecanemab under its accelerated approval pathway in July of 2022, and the drug has a Prescription Drug User Fee Act action date of Jan. 6, 2023. Many experts expect that Eisai will submit an updated package to the agency seeking full approval, based on the Clarity AD results.

“With a trial this size and results this clear, it would make complete sense for them to go for a full regular approval,” said Dr. Holtzman.

If lecanemab is approved by the FDA, the next concern is whether Medicare will cover the drug. After the approval of aducanumab, the Centers for Medicare and Medicaid Services (CMS) in April of 2022 issued a final coverage policy not only addressing that drug, but also any future monoclonal antibodies directed against amyloid in treating Alzheimer's disease. The National Coverage Determination states that drugs not determined to have shown a clinical benefit (or that receive an accelerated FDA approval) will only be covered in patients participating in clinical trials approved by the FDA or National Institutes of Health.

That decision has, in part, resulted in extremely low levels of use of aducanumab. Drugs in this class that receive traditional FDA approval also will be covered using the coverage with evidence development (CED) process, but in this case, the required studies can be data collection through routine clinical practice or registries

With lecanemab, “we have a drug that has clear efficacy, meets its primary and secondary outcomes, shows biomarker effects in the proper direction, and has an acceptable safety profile,” said Dr. Salloway. “I think CMS should cover this.”

Dr. Salloway said the field is now setting up a registry network called ALZ-NET, with the Alzheimer's Association and the American College of Radiology taking the lead, which will collect longitudinal diagnostic and therapeutic clinical data, including measures of cognition, function and safety, from individuals treated with FDA-approved Alzheimer's therapies. “This additional post-marketing data to help guide clinical use is important, and hopefully CMS will take a reasonable position on lecanemab and not be overly restrictive,” he added.

[ALZ-NET also includes the American Society of Neuroradiology, the department of biostatistics at Brown University School of Public Health and the Critical Path Institute, along with international clinical, research, and imaging experts.]

Dr. Apostolova is even more blunt: “For this drug, CED has to go away,” she said. “Objectively measured levels of amyloids in blood, plasma, and CSF are agnostic of clinical presentation and cannot be in any way influenced by doctors or patients. These all move in the right direction, and in concert with the cognitive and functional scales. It all tells the story beautifully in an unprecedented way.”

The Alzheimer's Association has also called for lecanemab to receive full Medicare coverage. In a statement released Nov. 29, it said “...[t]he current CMS policy will prevent thousands and thousands of Medicare beneficiaries with a terminal, progressive disease from accessing this treatment within the limited span of time they will have to access it.

“If a patient decides with their health care provider that a treatment is right for them, Medicare must stand behind them as it does for beneficiaries with every other disease. CMS has pledged to move quickly to modify the NCD if warranted by new evidence. This evidence has now been delivered and CMS can begin its review immediately. The Alzheimer's Association calls on CMS to revise its policy with the utmost urgency.”

What do the Clarity AD findings suggest about aducanumab and other drugs in this category? “If gantenerumab had been clearly positive, that would have helped,” Dr. Salloway said. “I do think that the findings of clinical benefit with aducanumab are real, but unfortunately the studies were interrupted and we never got the full readout, so the results were conflicting.”

“I'm a little uncomfortable with treating amyloid as this unitary thing and suggesting that all agents that clear amyloid on a PET scan are doing the same thing,” said Dr. Van Dyck.

“Amyloid exists in multiple conformations, and there is substantial evidence that the most neurotoxic are the soluble aggregated species, which we can't measure well in our participants,” he added. “It isn't clear to me that if we just clear enough plaque, we're going to achieve something beneficial and safe. That's why I'm not sure we're ready for accelerated approval for these drugs based solely on biomarkers, because that presupposes something I'm not sure we know. For the time being I'm more comfortable with traditional approval, in which each drug needs to demonstrate clinical benefit.”

Preparing for Launch

Assuming FDA approval and CMS coverage, lecanemab will transform the treatment landscape for Alzheimer's disease. “We are at an inflection point in our field. It will require a paradigm shift in how we treat individuals moving forward if these agents are approved, with the need to create a new system of clinical readiness for a patient population that so needs and deserves treatments to help change their disease progression,” Dr. Edelmayer said.


“It's really the first time in history that we have a therapy demonstrating an unequivocal slowing of decline in AD.”—DR. CHRISTOPHER VAN DYCK

“The management of these patients is going to change dramatically,” Dr. Holtzman said. “If it's approved and paid for, literally millions of people will be eligible for treatment with this kind of agent just in the US alone. People will need to get infusions more frequently. Hospital systems are working on different ways to establish or adapt the infrastructure to get people to therapy, but that's going to be a big challenge. Still, it's a great challenge to have if we can delay the disease's progression.”

Imaging and other testing capacity, along with neuroradiology expertise, will also have to be expanded. “We will need to confirm the presence of amyloid pathology with amyloid PET, CSF or blood biomarker tests, and then monitor for ARIA with regular MRI scans,” said Dr. Salloway.

“APOE testing is going to be required for safe use of medicines like this, as those carriers of APOE4 have an increased risk of ARIA . Primary care providers will be essential to helping screen these patients. It's very exciting that new blood tests are looking good as biomarkers and can act as a pre-screener. They're almost ready to stand alone for screening, but at this point I would feel more comfortable if we confirmed with PET or CSF.”

Not all patients with MCI or moderate dementia will be eligible for the drug if approved. “Those with significant white matter changes, those with previous hemorrhages or amyloid angiopathy, and people with unstable medical issues will likely be contraindicated, and people with copies of the APOE4 gene would need to be counseled about their risk,” Dr. Apostolova said.

“But even with those limitations, so many AD patients will be eligible that the system could be overwhelmed. All institutions should be getting ready for launch, identifying infusion units where the therapies can get started as soon as the drug is on the market and covered, putting safety protocols in place, training radiologists in identifying ARIA, and engaging colleagues from stroke teams to develop rapid response protocols should someone develop significant bleeding in the brain.”

ALZ-NET is designed to help with these challenges, said Dr. Edelmayer. “It's meant to be to be an infrastructure to help us continue in a treatment-agnostic way to collect, analyze, and learn from additional real-world data generated in clinical practice. ALZ-NET will be a resource for gathering evidence, sharing information, and education across clinical and research communities, encouraging innovative, inclusive research and supporting opportunities to improve care.”

As clinicians gear up for the biggest thing to hit Alzheimer's treatment in the history of the disease, researchers are already mulling where to go next. “These results show that this drug will provide benefits to people with early symptomatic AD in the near term,” Dr. Van Dyck said. “But going forward, they also beg the question about moving [ahead] earlier.”

Lecanemab is already being studied in patients with preclinical Alzheimer's disease in a trial called the AHEAD 3-45, which launched in 2020 but is still not fully enrolled. “I'm hopeful that these results will stimulate enrollment in that trial and enable us to complete it,” he said. “The obvious idea is that if you can intervene before much brain damage is done and people are still cognitively normal, you may get much bigger effects than seen in early symptomatic AD. So in a way, as exciting as Clarity AD is, it also opens up the possibility for bigger things.”


Dr. Van Dyck is a paid consultant to Eisai and has received grant support from Eisai and Biogen for clinical trials. He is also a paid consultant to Ono and Cerevel. He and his institution, Yale, have received grant support from Eli Lilly, UCB, Janssen, Roche, Genentech, and Cerevel.

Dr. Salloway was a site principal investigator for the CLARITY study and provided consultation to Eisai. He has received consulting fees from Biogen, Lily, Roche, Genentech, Bolden, Amylyx, and Prothena. Dr. Edelmayer had no disclosures. Dr. Holtzman is a co-founder with equity in the company C2N Diagnostics, LLC. He consults for C2N Diagnostics, Genentech, Denali, and Alector.

Link Up for More Information

• Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease N Engl J Med 2022; Epub 2022 Nov 29.
• Salloway S, Chalkias S, Barkhof F, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease JAMA Neurol 2022:79(1):13–21.