Eisai and Biogen yesterday announced positive topline results from the Phase 3 Clarity trial of their anti-amyloid antibody lecanemab. The drug slowed decline on the primary endpoint, CDR-SB, by 27 percent over 18 months, and also nudged down decline on all secondary clinical endpoints. The incidence of the brain edema known as ARIA-E was 12.5 percent, about one-third of that seen with Biogen’s approved anti-amyloid antibody Aduhelm.
- In Phase 3, lecanemab met primary and secondary endpoints.
- Biomarker data and detailed analyses will be presented at CTAD.
- The drug’s sponsors will apply for regulatory approval in the U.S., Europe, and Japan.
More detailed data, including biomarker findings, will be presented at the Clinical Trials on Alzheimer’s Disease conference in San Francisco on November 29. The companies plan to apply for regulatory approval in the U.S., Europe, and Japan, according to a press release.
Alzheimer’s researchers hailed the news as a major advance. In particular, they welcomed the straightforward findings after the highly contested rollout of aducanumab last year. “What the field needed was a clearly positive result from a trial completed and conducted per protocol,” Gil Rabinovici at the University of California, San Francisco, wrote to Alzforum. David Knopman at the Mayo Clinic in Rochester, Minnesota, agreed. “This pattern of clear-cut clinical benefits and a manageable adverse event profile is what the field has hoped for,” he wrote (comments below).
Developed originally by Lars Lannfelt of Sweden's Uppsala University, lecanemab, aka BAN2401, had shown a cognitive benefit in Phase 2 as well. Alas, those data were clouded by an uneven distribution of APOE4 carriers between treatment groups, which resulted from EMA requesting midway through the trial that APOE4 carriers no longer be allocated to the highest dose (Jul 2018 conference news; Nov 2018 conference news).
So far, at least, the Phase 3 data seem free of any controversy. Eisai and Biogen reported that the primary outcome was highly statistically significant at p=0.00005, and that secondary outcomes, comprising the ADAS-Cog14, ADCOMS, and ADCS MCI Activities of Daily Living, were all below p=0.01.
“I am pleased by the robustness of the topline results,” said Dennis Selkoe at Brigham and Women’s Hospital, Boston. Lon Schneider at the University of Southern California agreed the outcome is strong enough that it is unlikely to be overturned in sensitivity analyses that look for confounding effects. “The strong statistical effect facilitates the potential for reliable subgroup analyses that could give meaningful information on who might benefit,” he added (comments below).
That said, researchers also noted the absolute difference in CDR-SB scores was small, at 0.45, with some questioning how clinically meaningful this is. Others said they are awaiting the full dataset to examine issues such as subgroup effects, especially for APOE4 carriers, potential unblinding due to ARIA, and safety data. Many are eager to see biomarker findings, especially for tau.
Others noted that the focus will now shift toward how scientists can build on this result to grow the therapeutic benefit for patients. "Promising strategies include earlier intervention and/or combination with other treatment candidates, such as anti-tau immunotherapy. And, of course, we must continue to vigorously pursue new therapeutic approaches," wrote Paul Aisen of the University of Southern California.
In the bigger picture, researchers said the data strengthen the amyloid cascade hypothesis. “This confirms the importance of Aβ in disease pathogenesis,” said David Holtzman at Washington University in St. Louis (full comment below). "This is the first time a therapeutic antibody has clearly changed the course of Alzheimer's disease. It is a pivotal moment in the history of Alzheimer's therapy," said Randall Bateman, also at WashU.
Earlier trial results from lecanemab, donanemab, and aducanumab had linked plaque removal to slowing of cognitive decline, but the findings were often muddied by conflicting results or small sample size. “We are seeing converging data showing that significant plaque lowering can slow clinical decline in early stage AD, with Clarity AD providing the strongest evidence to date,” Rabinovici noted.
Researchers widely expect the data will lead the Food and Drug Administration to grant regular marketing approval. Some wondered whether the clear evidence of clinical benefit might also cause the Centers for Medicare and Medicaid Services to update its coverage determination for anti-amyloid antibodies as a class.
Many see this as the beginning of a new era of Alzheimer’s treatment. “The controversial accelerated approval of aducanumab may have served as a ‘soft opening’ for the amyloid therapy era, but if full FDA approval of lecanemab awaits, it could be for real this time,” Erik Musiek at WashU wrote to Alzforum (comment below).—Madolyn Bowman Rogers
- BAN2401 Removes Brain Amyloid, Possibly Slows Cognitive Decline
- Second Look at BAN2401 Data Still Positive, Despite Snafu