The Food and Drug Administration granted accelerated approval for lecanemab, a drug developed by Biogen and Eisai which has been found to slow cognitive decline in some patients with Azheimer’s disease, Friday afternoon. 

“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a statement. “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.”

The drug is generally well tolerated and has been approved for use in patients with mild Alzheimer’s. Eisai and Biogen welcomed the approval in a joint statement Friday afternoon.

“The approval of LEQEMBI provides new hope to patients with Alzheimer’s disease. Patients at an early stage of the disease and their caregivers can now consider a new treatment option with their doctors. Our focus now is on the path forward, working alongside Eisai with the goal of making LEQEMBI available to patients who may benefit from this treatment as soon as possible,” said Biogen CEO Christopher Viehbacher. “This approval is also a recognition of the many scientists and doctors who have, over many years, patiently and persistently worked to find a treatment for this highly complex disease. Eisai and Biogen have collaborated for nearly a decade to advance research to improve the lives of those suffering from Alzheimer’s, and we know that this commitment must and will continue in the fight against Alzheimer’s disease.”

Additionally, Eisai stated that the per patient societal value of the drug is $37,600 per year but issued a statement clarifying that its launch price will be $26,500 per year.

“The FDA’s approval of LEQEMBI under the Accelerated Approval pathway is an important milestone in Eisai’s four decades of research in Alzheimer’s disease and reflects our continued commitment to alleviating the burden of Alzheimer’s disease for patients and their families,” Eisai CEO Haruo Naito said in a statement. “Eisai has made great efforts to understand the reality of the challenges and concerns facing patients and their families who are living in the various stages of Alzheimer’s disease, and we are incredibly pleased to offer LEQEMBI as a new treatment option to help with the tremendous unmet needs of this community.”

The expedited approval, absent any input from the FDA’s advisory committee, came amid a specter of controversy that included a recently unsealed congressional investigation into the agency’s handling of the 2021 approval of Biogen’s amyloid-removal drug Aduhelm. Lawmakers found an “atypical” amount of collaboration between the FDA and the sponsor during Aduhelm’s review.  

On Thursday, Dr. Sidney Wolfe, head of consumer watchdog group Public Citizen, charged that the lecanemab decision was “being perceived as yet another Biogen/FDA done deal” and urged the agency to postpone it. 

Adding to the controversy was a December report of a third patient death in lecanemab’s clinical studies. In a recent statement, Eisai declined to provide further information on the fatality, saying it would be inappropriate to do so outside of a peer-reviewed journal or scientific conference.

The accelerated approval program allows for an earlier green light on drugs that treat serious conditions and full unmet medical needs, while the drugs are still being studied. If trials confirm clinical benefit, full approval is granted. If not, regulatory procedures could lead to removal of the drug from the market.

With expedited approval in hand, Biogen and Eisai are expected to apply for traditional approval for lecanemab and to proceed shortly with the commercialization phase. While Eisai has been mostly mum on this front, Biogen has said it may file for full approval at the same time in the U.S., Europe and Japan. 

Biogen management has acknowledged there is essentially no coverage for the drug with accelerated approval only. Thus, achieving traditional approval is a priority, although it isn’t likely until the second half of 2023, as is updating the Centers for Medicare and Medicaid Services coverage decision. 

“Alzheimer’s disease is a devastating illness that affects millions of Americans and their families,” said CMS Administrator Chiquita Brooks-LaSure in a statement. “At CMS, we will continue to expeditiously review the data on these products as they become available and are committed to timely access to treatments, including drugs, that improve clinically meaningful outcomes.”

Alzheimer’s advocacy groups applauded the FDA’s decision while also calling on CMS to take steps to make the drug available for patients suffering from the disease.

“Patients and their physicians finally have a treatment that can slow the progression of Alzheimer’s disease. With this approval, it is incumbent on CMS Administrator Chiquita Brooks-LaSure and the drug’s sponsors to offer this life-changing therapy to patients quickly, while prioritizing access and economic fairness,” Global Alzheimer’s Platform Foundation President John Dwyer said in a statement.

Here again, the companies must contend with Aduhelm’s complicated legacy. Also approved under the accelerated pathway, Aduhelm flopped commercially after CMS refused to extend coverage outside of a narrow range. Even slashing the price in half didn’t work. Some private payers and academic medical centers also balked at the drug’s high price, versus its uncertain clinical benefit.

Launch preparations also include rebuilding the sales infrastructure, which Biogen eliminated as part of a $1 billion cost savings plan. Reassembling the commercial team should be a fairly straightforward process, Biogen’s former CEO Michel Vounatsos, who has since been Viehbacher, said on the firm’s third-quarter earnings call. 

Convincing Medicare to widen reimbursement is another matter. As part of its national coverage decision (NCD) last April, CMS said that it would consider full coverage of future monoclonal antibody drugs directed against amyloid plaque – should any such agents receive full FDA approval.

“Eisai is already engaging with CMS to discuss this,” Priya Singhal, Biogen’s interim R&D chief, noted during the earlier earnings call. She added that “in the final scenario [of] that NCD…[CMS noted that it] would act with urgency and potentially a reconsideration could be [taken up]. That could take nine to 12 months.”

Finally, the companies will need to take care in setting lecanemab’s price. As Vounatsos later admitted, it was wrong to launch Aduhelm with a $56,000 a year price tag, which the company went ahead with despite anticipating that it would have an outsized financial impact on Medicare’s budget.

Lecanemab’s safety and efficacy were established in the Phase 3 CLARITY-AD trial, which involved 1,795 adults, ages 50 to 90, with mild cognitive impairment due to early Alzheimer’s disease or mild Alzheimer’s-related dementia. About half were randomly assigned to placebo while the others were given lecanemab intravenously every other week.

A Phase 2 trial did not show a significant difference. But, lecanemab met the primary endpoint in the Phase 3 trial, with a treatment difference of 0.45 on a major outcome measure called CDR-SB. That translated into a statistically significant 27% change versus placebo, and the full readout showed that lecanemab duplicated that treatment effect in CDR-SB across multiple subgroups. 

While statistically significant, the clinical meaningfulness of the 0.4 effect in slowing cognitive decline is very much a matter of debate. The standard set by the Alzheimer’s research field for a meaningfully important clinical difference is one point or more on CDR-SB. 

Lecanemab “resulted in moderately less decline on measures of cognition and function than placebo at 18 months,” the researchers concluded. 

The antibody’s long-term safety also remained an issue. While lecanemab was generally well-tolerated, 14% of patients had adverse events versus 11.3% in the control group. 

Most of these consisted of brain swelling and brain bleeding, two types of amyloid-imaging related abnormality (ARIA). A surprising finding in CLARITY-AD was that the efficacy benefit proved more modest in the apoE4 carriers, while the risk of brain swelling (ARIA-E) and bleeding (ARIA-H) was greater. Among noncarriers, ARIA were “numerically less common,” researchers wrote.

The third patient death, reported by daily news site Science in December based on medical records it obtained, renewed safety concerns. Although, the overall mortality rate from the trial was 0.7% of participants (six patients) in the active arm versus 0.8% of those in the placebo group (seven patients). 

While some worried that those safety findings could become more pronounced in a real-world setting versus a clinical trial, those who presented the data said neither of the first two deaths should be attributed to the drug.

Lecanemab was the first of two amyloid-targeting antibody drugs expected to advance this year. Phase 3 data for Eli Lilly’s fellow amyloid-removal drug donanemab are poised to arrive in the second quarter.

In an earlier forecast, analysts from Credit Suisse projected annual sales of $350 million by 2025 and $5.5 billion by 2025 for lecanemab and donanemab, respectively. Donanemab has a similar efficacy profile to lecanemab, but after the amyloid plaque is cleared, patients may be able to stop taking the drug.