Alzheimer’s Drug Safety Hinges on Doctors Heeding FDA Warning

How safe Eisai Co. and Biogen Inc.’s Alzheimer’s drug is for patients will depend on whether physicians adequately heed the FDA’s warnings of potential brain swelling and bleeding, clinicians and researchers say.

The Food and Drug Administration granted on July 6 full traditional approval of Leqembi for the treatment of mild cognitive impairment or early dementia caused by Alzheimer’s disease. Traditional approval indicates late-stage studies confirmed the drug’s clinical benefit to slow progression of the disease. Alzheimer’s patients and their caretakers see it as a pivotal milestone in the research and treatment of the memory-loss disease.

The drug’s approved label included a black box warning—the highest level of safety guidance issued by the FDA—alerting patients and prescribers about the danger of swelling and bleeding in the brain called ARIA. Leqembi’s prescribing information recommends health-care providers use “caution” when considering whether to prescribe Leqembi to patients taking anticoagulants or with other risk factors for intracerebral hemorrhage.

Research dating back several years has shown that many prescribers and patients don’t always read prescription drug warning labels carefully. Analysts and clinicians say they aren’t sure FDA’s instructions will have any true impact on minimizing risks associated with Leqembi.

They argue that physicians will need to use care and robust judgment in determining whether Leqembi is beneficial for a particular patient, especially until the Medicare agency’s patient registry provides the medical community with a clearer understanding of the prevalence of some of the serious risks associated with the therapy.

“We should all hope that physicians will take all these warnings seriously and spend time with their patients to make sure they understand what is known and not known about the risks as well as the benefits of this new drug,” said Diana Zuckerman, president of the nonprofit think tank the National Center for Health Research.

The Centers for Medicare & Medicaid Services expanded coverage of Leqembi, or lecanemab, the same day FDA granted traditional approval, but patients must have a physician who participates in a registry in order to submit data on the drug’s safety and benefit in the real world, as well as a clinical team providing follow-up care. The medicine, which costs $26,500 a year, had previously been covered by Medicare only for patients enrolled in clinical trials.

Prescribing Practices

To limit risks of brain swelling and hemorrhaging, Leqembi’s boxed warning states that patients should undergo APOE4 gene testing to assess the risk of developing ARIA—amyloid related imaging abnormalities. Clinical trials on Leqembi found that patients who carry two copies of the APOE4 gene, a genetic variant linked to Alzheimer’s risk, experienced severe symptoms like brain swelling and bleeding.

This, along with the caution of use among patients taking anticoagulants, followed concerns from some members of an independent panel of advisers to the FDA last month about complications that showed up with certain patients.

These risks “are not things that should be brushed aside,” said Christian Camargo, a neurologist at the University of Miami Health System who treats patients with Alzheimer’s disease.

“This is something that a physician sits down with the patients and explains what the risks are with individuals, chances of having a higher incidence of these episodes, and making that individual determination of whether or not to move forward,” said Camargo, also an assistant professor of clinical neurology.

But the warnings “are all suggestive and not requirements for clinicians to consider,” said Reshma Ramachandran, a Yale School of Medicine family physician and chair of the Doctors for America’s FDA Task Force.

Formal research on how well health-care providers read and comprehend prescription drug labels is limited. But one 2012 study showed that while “some FDA drug risk communications had immediate and strong impacts, many had either delayed or had no impact on health care utilization or health behaviors.”

And a lack of understanding on drug labels is among the leading causes for medication errors, according to one 2014 study from the Mayo Foundation for Medical Education and Research.

Ramachandran said that, for Leqembi, the FDA could have considered using a Risk Evaluation and Mitigation Strategy (REMS)—a safety program the agency puts in place for some drugs to ensure the benefits outweigh the risks. The abortion pill mifepristone has a REMS program requiring that physicians and pharmacies be certified to prescribe and dispense the drug, respectively.

A REMS program for Leqembi “would help collect additional data that me and my colleagues are wanting so that we can make a more informed decision when prescribing these treatments and also help alleviate our worries that prescribing this drug could result in harm,” Ramachandran said.

The FDA can add a REMS following a product’s approval if the agency “becomes aware of new safety information that suggests a REMS is necessary to ensure that the benefits of the drug or biological product outweigh the risks,” according to the FDA’s website.

Patient Registry

Patient advocacy groups have called on the CMS to expand coverage for Leqembi beyond patients in the registry. But clinicians and policy analysts say a registry can help monitor the very risks that the FDA warns of in Leqembi’s label.

The registry requires providers to submit information on a patient’s clinical diagnosis, results from amyloid tests, and evidence of adverse events such as brain swelling or hemorrhage. Eisai has estimated that roughly 1,200 neurologists are ready to prescribe Leqembi, and health providers at more than 700 infusion centers have been trained to administer it.

Continuing to monitor these areas will be especially important to understand how the treatment works among Black and other minority populations, Zuckerman said. Black Americans made up just 2.3% of the study population in Leqembi’s phase 3 clinical trial, despite the fact that the Alzheimer’s Association says they are twice as likely as White Americans to have Alzheimer’s or another dementia condition.

Camargo, who says most of his patients come from historically underrepresented communities, believes “having the registry would be useful, as long as it’s not a barrier.”

“These therapeutics, when it comes to clinical trials and registries, don’t often make it to these traditionally underrepresented populations, so we’re really looking forward to the opportunity to be able to provide it to these populations,” he said.