RUTHFULLY YOURS

The Food and Drug Administration on July 6 granted full approval to the first therapy for Alzheimer’s that slows the cognitive decline associated with the disease. That “first” is good news, because it validates a therapeutic approach that has long been in doubt, but more important, it benefits patients afflicted with a terrible disease.

The approval is hardly a breakthrough, however: The benefits of the drug, Leqembi (lecanemab) are meager; it does not restore lost function; it is expensive and administered intravenously every two weeks; and there are occasionally severe side effects. Nevertheless, my neurologist friends tell me that they’re being inundated with inquiries about Leqembi from Alzheimer’s patients and their families.

Alzheimer’s disease is an irreversible, progressive brain disorder that afflicts more than 6.5 million Americans. It slowly destroys memory and cognitive skills and eventually, the ability to perform even simple tasks. Although the specific causes of Alzheimer’s are not fully understood, it is characterized by changes in the brain, including the formation of various abnormal structures that result in loss of neurons and their connections.

The FDA had previously granted Leqembi accelerated approval based on a “surrogate endpoint” short of demonstrated clinical benefit, based on its ability to reduce amyloid plaques, or clumps, in the brain, a hallmark of Alzheimer’s. As a postmarketing condition of the accelerated approval, the drug manufacturer, Eisai, was required to conduct a clinical trial to confirm the anticipated clinical benefit of Leqembi.  Safety and efficacy were evaluated in a Phase 3 multicenter, randomized, placebo-controlled clinical trial that included 1,795 patients.

That confirmatory trial, which was reported earlier this year in the New England Journal of Medicine, showed that in patients in the early stages of the disease, the drug slowed cognitive and functional decline modestly – perhaps by about five months – over 18 months compared with placebo.

The primary efficacy endpoint was the change in patients’ scores on the CDR-SB, a complex measure “used in clinical trials of Alzheimer’s disease that is obtained by interviewing patients and their care partners and captures cognition and function. It assesses six domains that patients and caregivers identify as important (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care).”

There were also numerous secondary measures of efficacy, including changes between baseline and 18 months in brain scans, chemical tests on cerebrospinal fluid, and behavioral tests. All were either statistically significant in the drug’s favor compared to placebo, or in the direction of efficacy.

Leqembi is not without side effects, some of which are serious. Almost 13% of patients receiving the drug experienced swelling of the brain (compared to fewer than 2% in the placebo group), but most cases were mild or moderate, asymptomatic, and generally resolved within a few months. About 17% of the patients receiving Leqembi experienced brain bleeding (compared to 9% of patients who got the placebo), the most common symptom of which was dizziness. In addition, Leqembi needs to be used with caution in patients taking anticoagulants (blood thinners).

The FDA notes that the drug was studied in clinical trials only in patients with mild cognitive impairment or mild dementia from Alzheimer’s disease but, as stated in the labeling, there are no safety or effectiveness data, encouraging or otherwise, on treating at other stages of the disease.

That last observation by the FDA brings up some dilemmas about who should receive Leqembi, given the unknowns and its high cost – list price of $26,500 per year, of which Medicare has said it will pay 80%. If it were administered to all 6.5 million Alzheimer’s patients in the U.S., the total annual cost to Medicare would be almost $140 billion. That would leave patients and their families and possibly private supplemental insurance to pick up the resulting yearly tab of more than $5,000 per patient.

However, that is just for the drug itself; there will be significant additional ancillary expenses, such as for medical visits to receive the infusions and regular brain scans to check for swelling or bleeds. Also, before starting treatment, patients will need a test – either a lumbar puncture or PET scan – to confirm that they have amyloid buildup in the brain diagnostic of early-stage Alzheimer’s.

There are additional dilemmas presented by drugs like Leqembi that were summarized thusly in a thoughtful STAT News article by Alzheimer’s specialist professor Jason Karlawish, of the University of Pennsylvania’s Perelman School of Medicine:

The workup of mildly symptomatic presentations of memory loss is tricky and time-intensive; biomarker testing carries nuance; the drugs’ risks can be serious and are associated with a gene for Alzheimer’s disease and may be heightened in persons on anticoagulants and CAA (cerebral amyloid angiopathy, which causes microscopic bleeds in the brain); the measures of value are difficult to translate into clinical practice and policy; Medicare wants patients enrolled in a registry; the drugs’ costs are notable; and there are lots of patients and not enough clinicians to accurately diagnose and treat them.

Finally, the risks are vivid, and they happen within the first few months of treatment. The benefits of disease slowing, in contrast, are far less evident.

The FDA’s approval of Leqembi is not the end of the Alzheimer’s journey, but it could be a way station. As we physicians say after completing a specialty consultation on a patient, “Will follow with interest.”

Henry I. Miller, a physician and molecular biologist, is the Glenn Swogger Distinguished Fellow at the American Council on Science and Health. He was the founding director of the FDA’s Office of Biotechnology.