When considering monoclonal antibodies for Alzheimer’s disease, ‘caution is key’

Key takeaways:

• A new Alzheimer’s disease drug has been shown to slow disease progression by 20% to 30%, translating to about 6 months delayed progression.
• The clinical relevance of recently approved treatments is uncertain.

SAN DIEGO — Two monoclonal antibodies are now available in the U.S. as disease-modifying therapies for early Alzheimer’s disease, but there are concerns about the drugs that physicians must be aware of before prescribing them, an expert said.

Amyloid has been the focus of Alzheimer’s disease treatment strategies for decades, Zaldy S. Tan, MD, MPH, FACP, Carmen & Louis Warschaw Endowed Professor of Neurology & Medicine and director of the Bernard & Maxine Lynn Family Memory & Aging Program at Cedars Sinai Medical Center/David Geffen School of Medicine at the University of California, Los Angeles, said during a presentation at the ACP Internal Medicine Meeting.

Researchers have investigated several monoclonal antibodies targeting amyloid, most of which have failed. Two, however, “have risen from the pack,” Tan said: Aduhelm (aducanumab, Biogen/Eisai) and Leqembi (lecanemab-irmb, Eisai).

Aducanumab

Aducanumab is the first disease-modifying therapy to be approved by the FDA for Alzheimer’s disease. It is delivered through a monthly IV infusion and clears deposited amyloid plaques in the brain, but there has been controversy surrounding the drug since its 2021 approval.

The safety and efficacy of aducanumab was tested in two “very large, very well done” randomized, double-blind controlled trials, EMERGE and ENGAGE, Tan said. Both trials were stopped prematurely due to a lack of efficacy. Upon further analyses, the manufacturer found that the EMERGE trial revealed a statistically significant improvement in cognitive function, Tan said. The ENGAGE trial, however, “remained a negative trial,” he noted.

“People were left wondering, ‘how come you have two great trials — one is positive and one is negative?’ And that is the question,” Tan said.

The manufacturer of aducanumab decided to submit the drug for FDA approval, “and the FDA surprisingly approved it under the accelerated pathway,” Tan said.

“Therein lies the controversy and all of the challenges with this medication and the press that came along with it,” he said.

The controversy has led to a congressional inquiry into how the drug was approved. In addition, CMS announced that it would only cover aducanumab for beneficiaries who are enrolled in clinical trials, limiting its access. As a result, most physicians do not prescribe it, and patients do not demand it., according to Tan.

Lecanemab

More recently, the FDA approved lecanemab, again under the accelerated pathway.

“This is not full FDA approval. This medication is still being reviewed by the FDA,” Tan said.

Lecanemab is administered intravenously twice per month and clears fibrillar and deposited amyloid.

According to Tan, a big difference between lecanemab and aducanumab is that the trial for the newer treatment was completed. After 18 months, lecanemab demonstrated a statistically significant slowing of cognitive and functional decline compared with placebo.

“The challenge is whether it’s clinically relevant because the effect size was quite modest,” Tan said. “Statistical significance does not mean clinical significance.”

Tan highlighted several prescribing considerations regarding lecanemab. The FDA approved it for patients with mild cognitive impairment and mild dementia with a Mini-Mental State Examination score of 22 to 30.

“So, not patients with moderate- or late-stage Alzheimer’s disease,” Tan said.

The drug is only indicated for patients with confirmed amyloid in their brain, which can be verified by amyloid PET scan or a cerebrospinal fluid study. Patients also need a recent MRI within the last year demonstrating four or fewer microhemorrhages.

In addition, for patients who are on anticoagulants, “you probably would want to have a really serious discussion about whether you want to prescribe this medication,” Tan said.

Genetic testing is also advised to identify carriers of the APOE e4 allele. In clinical trials for both monoclonal antibodies, Tan said these patients were more likely to develop cerebral edema or hemorrhage after treatment. Overall, about two in 10 patients who receive the medication develop amyloid-related imaging abnormalities and hemorrhages (ARIAs).

“This is why we approach these monoclonal antibodies with caution: the appearance of ARIAs,” he said.

He added that lecanemab “has also received some bad press” after some patients receiving the drug had died.

“The question is whether this is caused by lecanemab or something else,” he said. “Most of these people were on anticoagulants or received [tissue plasminogen activator] ... so that’s why it’s important to keep in mind that this is not a slam dunk in terms of therapy.”

Additional concerns

Although not as serious, about one in three patients who received monoclonal antibodies had an infusion reaction, “which can be troublesome for certain patients,” Tan said.

He also stressed that physicians should be aware that the efficacy of aducanumab and lecanemab remains uncertain, and patients should be advised that “the magnitude of the effect of this medication will be modest (at best).”

Although lecanemab has been shown to slow the rate of disease progression by 20% to 30%, “it really translates to about 6 months delay in progression after this bimonthly infusion for 18 months” Tan said.

“Put that in context,” he said. “There has to be a risk-benefit analysis and discussion that needs to happen with patients, especially those with risk factors.”

Other concerns are related to cost and resources. CMS does not cover lecanemab, “nor commercial insurance to my knowledge,” Tan said. It is unknown whether CMS will cover the drug if granted full FDA approval.

The medication costs about $25,000 per year, “but if you add in infusion costs, serial MRIs, PET amyloid scan, genetic testing, that could add up,” Tan said.

“There are a lot of unknowns about this medication. Caution is key,” he said.

Tan concluded that there are many other medications for Alzheimer’s disease in the clinical trial pipeline, “so hopefully soon we will have promising or even more promising treatments.”