An in-depth data drop of a closely watched study involving lecanemab largely confirmed what was seen in a prior glimpse at the results: That the experimental Eisai/Biogen drug has a statistically significant treatment effect in patients with early Alzheimer’s disease. 

The drug’s safety profile also proved reassuringly devoid of drama, although a second patient’s death revealed just ahead of Tuesday night’s presentation is sure to stir ongoing debate.

Given the consistency with the topline data that the companies released in September, the full results bolstered analysts’ confidence in lecanemab’s efficacy and safety. The Food and Drug Administration is set to decide whether to grant accelerated approval early next year. 

“There were no fireworks,” wrote Wolfe Research analyst Tim Anderson in a note to investors about the presentation, which took place at the Clinical Trials on Alzheimer’s Disease conference in San Francisco. 

The comprehensive reveal, simultaneously published in the New England Journal of Medicine, also defused concerns over lecanemab’s data transparency. Biogen, which tried but failed to launch Alzheimer’s drug Aduhelm following its approval in June 2021, pushed off publication of the key data that led to the approval for more than two years after they appeared in a press release. 

“In contrast to the controversy (some would say scandal) that plagued the companies’ earlier attempt with Aduhelm…this time around the process has felt more wholesome and transparent,” Anderson added.

A Phase 2 trial did not show a significant difference. But as previously reported about two months ago, lecanemab met the primary endpoint in the Phase 3 trial, dubbed Clarity-AD, 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. 

The chief science officer of the Alzheimer’s Drug Discovery Foundation (ADDF) said in a statement that the results, while encouraging, indicate the need for combination drug approaches.

“Today’s results show that lecanemab slows cognitive decline, which is welcome news for the millions of patients and families living with Alzheimer’s,” said Dr. Howard Fillit, ADDF co-founder and CSO. “But this is only a start to stopping Alzheimer’s in its tracks. We have a lot of ground to cover to get from the 27% slowing lecanemab offers to our goal of slowing cognitive decline by 100%.”

According to ADDF, amyloid-clearing drugs like lecanemab are but one part of the solution. “There remains a pressing need to develop a new generation of drugs targeting all aspects of the biology of aging that can be combined to address the full array of underlying pathologies that contribute to the disease,” the group said.

Data generally supportive 

The CLARITY-AD trial 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.

At the trial’s start, the CDR-SB score for subjects in both groups clocked in at about 3.2 (with higher numbers correlating to higher levels of cognitive impairment). At 18 months, that score rose by 1.21 points in the treatment group versus 1.66 points in the placebo cohort. 

The clinical efficacy data for lecanemab were consistent across primary and secondary endpoints, with highly statistically significant differences beginning at six months and extending to 18 months.

Biomarker data confirmed that lecanemab, a monoclonal antibody, is doing its job of binding to amyloid beta, the sticky plaque that is a hallmark of the neurodegenerative brain disorder. By the three-month mark, lecanemab significantly reduced the amyloid, and the effect widened through 18 months. By that point, the lecanemab cohort’s average amyloid level had dropped by 55.48 centiloids and the placebo group had increased by 3.64 centiloids.

The confirmatory trial’s results suggest that “lecanemab treatment may provide meaningful benefits to patients, their care partners, physicians and society,” Eiasi said in a news release.

That doesn’t mean debate won’t continue, though, including with regard to the clinical meaningfulness of lecanemab. Statistical significance is one thing; it doesn’t necessarily equate to practical gains. 

“Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months,” the researchers concluded. 

As Constantine Lyketsos, M.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, told MM+M earlier this year, many clinicians view this as a modest benefit. After all, the standard set by the Alzheimer’s research field for a meaningfully important clinical difference is one point or more on CDR-SB. 

Unsurprisingly, Eisai CEO Ivan Cheung, who also serves as global head of its Alzheimer’s unit, called the 0.4 difference “very clinically meaningful,” and the FDA may stand ready to accept that view. 

Cheung acknowledged the contentiousness when he said following the topline release, “There are different opinions out there on defining what clinical meaningfulness is for this stage of the disease.”

Safety, coverage overhangs

That leads to an additional overhang on the drug — safety and the long-term debate around risk versus benefit, also not a new issue. While lecanemab was generally well-tolerated, 14% of those 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). Of particular note in that regard was a subgroup of trial participants consisting of carriers of apoE4, a version of the apolipoprotein E (apoE) gene associated with Alzheimer’s which dramatically increases the risk of illness.

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

Then there were the fatalities, an aspect which took on greater significance in light of news that broke this week of another patient death in the study due to hemorrhage, following a previous one in June

One patient, a 65-year-old woman who carried two copies of apoE4, was taking tissue plasminogen activator (tPA) for stroke. The other, an 87-year-old woman and apoE4 noncarrier, was taking Eliquis

Some analysts were dismissive of this as mere press hype, however, given the overall mortality rate from the trial: 0.7% of participants (six patients) in the active arm versus 0.8% of those in the placebo group (seven patients). Yet others worried that those safety findings could become more pronounced in a real-world setting versus a clinical trial. 

Still, it bears mentioning that no new safety signals emerged from the lecanemab safety results. Moreover, the presenters provided additional explanations for the two deaths, saying neither case should be attributed to the drug and that the cause of death is complicated due to the background anticoagulants the patients had been taking.

Nevertheless, “the two deaths and how much of a role lecanemab played in them will remain a key debate moving forward, as some KOLs noted that they may be related to lecanemab treatment,” wrote SVB Securities analyst Marc Goodman, adding that ARIA-E is among several important adverse events that would need to be monitored.

Were lecanemab to be approved in the U.S. at some point in 2023, its label could carry a Black Box warning, urging caution in apoE4 carriers, Anderson speculated. 

“This is possible,” he wrote. “In CLARITY-AD, apoE4 carriers made up about 70% of the enrolled population,” he pointed out, which is similar to other contemporary Phase 3 Alzheimer’s disease trials.

A final open question involves whether the Centers for Medicare and Medicaid Services could expand its coverage for this drug class. The companies are expected to file for regular approval by next March, but CMS could block access unless its restrictive reimbursement policy is changed. 

In July, the FDA accepted lecanemab’s BLA under its accelerated approval pathway. That 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. 

“The FDA is expected to decide whether to grant accelerated approval to lecanemab by January 6, 2023,” noted the Alzheimer’s Association in a statement. “Should the FDA do so, the current CMS policy will prevent thousands and thousands of Medicare beneficiaries with a terminal, progressive disease from accessing this treatment within the limited span of time they will have to access it. If a patient decides with their healthcare provider that a treatment is right for them, Medicare must stand behind them as it does for beneficiaries with every other disease.”

CMS, the association noted, “has pledged to move quickly to modify its national coverage determination (NCD) if warranted by new evidence. This evidence has now been delivered and CMS can begin its review immediately. The Alzheimer’s Association calls on CMS to revise its policy with the utmost urgency.”