New Alzheimer’s Drug Lecanemab Granted Accelerated Approval
The US Food and Drug Administration has given a new Alzheimer’s drug the green light. The compound, lecanemab (Leqembi) is a monoclonal antibody (mAb), part of a new class of treatments that target the underlying mechanism of disease. It was approved using the FDA’s accelerated approval pathway.
While a significant step in the fight against the leading cause of dementia, which affects more than 6 million Americans, the extent to which Leqembi will be adopted by providers remains unclear. Fellow mAb aducanumab (Aduhelm), approved in 2021, failed to find favor with insurers and was not approved by the European Medicines Authority (EMA). It remains to be seen whether Leqembi’s more promising trial data will give it a smoother path to acceptance.
What is the accelerated approval pathway?
Introduced in 1992, the accelerated approval pathway is an FDA process that recognizes a drug’s performance against an intermediate clinical target and expedites the compound’s approval based on that performance. The rationale for accelerated approval is that it allows drugs that fill an unmet clinical need to be approved without waiting for data that may potentially take years or decades to emerge from trials. For example, approving a cancer medication on the basis that it increases survival for cancer patients may require the FDA to wait until it has survival data from a long period of time. But if that same medication reduces tumor size within a month, then that can be used as a surrogate marker of efficacy, because reducing tumor size is likely to predict better cancer survival. With Leqembi, the FDA are hoping that initially small improvements to cognition will predict more significant benefits in subsequent as untreated individuals’ cognition deteriorates more quickly. Follow-up trials showing that this prediction does come true are a required part of the approval process.
Lecanemab targets amyloid-β, a protein that builds up in the brains of people with Alzheimer’s and that has been a central target for disease research since the early 1990s. “This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease,” said Dr. Billy Dunn, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research.
Leaders at Alzheimer’s charities reacted positively to the approval: “Today’s decision by the regulators in the US, who have deemed the Alzheimer’s drug lecanemab sufficiently safe and effective, marks another important milestone in the global effort to bring about treatments that target the underlying diseases of dementia,” said Hilary Evans, chief executive at Alzheimer’s Research UK.
Leqembi was tested in a clinical trial called CLARITY AD. The drug was assessed for its ability to slow cognitive decline in 1,795 people with mild, early-stage Alzheimer’s and those with the precursor condition mild cognitive impairment.
Eisai shared Leqembi’s performance in a press release in September 2022 and followed this up with a publication in the New England Journal of Medicine (NEJM). The results showed that Leqembi had a small but statistically significant impact on the rate of cognitive decline experienced by those with mild Alzheimer’s.
The clinical significance of the improvement is, however, likely to be minimal. This modest impact was reflected in some of the reactions to Leqembi’s approval from researchers in the field.
“Lecanemab had better clinical results than Aduhelm. Lecanemab was tested in a well-conducted randomized clinical trial and showed a small reduction in cognitive decline on patients with Alzheimer’s disease who took it compared to those on the placebo,” said Gill Livingston, a professor in psychiatry of older people at University College London.
“I am unsure what this will mean in the US, as insurers and individuals try to work out if the small clinical benefit is worth the risks and costs,” Livingston continued.
Side effects to be considered
Those costs are both financial and potentially clinical. Eisai intends to sell the drug at $26,500 per year (based on a dosage of 10 mg/kg IV administered biweekly to an average-sized US patient). The Centers for Medicare & Medicaid Services announced last year that it would not cover any anti-amyloid antibodies approved using the accelerated pathway until further real-world trial data has been produced. This means that most patients will need to pay the full cost to access the drug.
The treatment is also not free of side effects. The NEJM paper showed that significant numbers of patients developed imaging-related abnormalities that are collectively termed amyloid-related imaging abnormalities-edema/effusion (ARIA-E). These side effects, common to other anti-amyloid therapies, involve brain swelling and bleeding, although many of these are smaller effects that go unnoticed by patients. Two case studies, reported by Science, involving patients who developed more serious brain bleeds after taking the drug further complicate Leqembi’s cost-benefit analysis.
Aduhelm’s controversial approval
Leqembi’s approval was also announced under the cloud of a congressional report that sharply criticized the authorization process for Aduhelm, finding that the approval process was “rife with irregularities.” These included an unusually close level of correspondence between the regulator and the drug’s sponsor, Biogen, which was not fully documented by the FDA. The congressional investigation, a joint venture between the House Energy and Commerce Committee and the House Committee on Oversight and Reform, concluded that the FDA “must take swift action to ensure that its processes for reviewing future Alzheimer’s disease treatments do not lead to the same doubts about the integrity of FDA’s review.”
While Leqembi’s approval represents a forward movement for a field that has been bogged down by failed trials for decades, much uncertainty remains about whether that advance is a giant leap or just a modest step.