Score another one for amyloid immunotherapy. The anti-pyroglutamated amyloid antibody donanemab has posted positive top-line results in the Phase 3 Trailblazer-Alz2 study, according to an Eli Lilly press release. The treatment slowed decline on the primary outcome, the combined cognitive and functional measure iADRS, by more than a third. Results on all secondary clinical endpoints were positive. Overall, donanemab cut the risk of progressing to the next stage of disease over 18 months by about 40 percent.
Donanemab slowed clinical progression by a third in Phase 3.
People with fewer tau tangles benefitted most.
ARIA remains a problem, with two deaths in the trial ascribed to it.
Eli Lilly said it will apply for approval from the U.S. Food and Drug Administration this quarter. If approved, donanemab will become the third amyloid immunotherapy in the U.S., after Aduhelm and Leqembi. Lilly plans to submit in other countries as well.
Alzheimer’s researchers hailed the news. "The donanemab Phase 3 trial is a major accomplishment on many levels," wrote David Knopman, Mayo Clinic, Rochester Minnesota. “The Trailblazer results represent a major advance in the treatment of AD,” agreed Stephen Salloway at Butler Hospital in Providence, Rhode Island. As did others, Salloway noted innovative trial features such as stratifying participants by tau tangle load, which helped target treatment to the right disease stage. Eric Siemers at Siemers Integration LLC, previously at Lilly, pointed out the consistency of findings between donanemab, lecanemab, and aducanumab. “Given these results, it can no longer be said that we have no treatments to slow the inexorable progression of AD,” he wrote. Indeed, the amyloid hypothesis is no longer a hypothesis, wrote Dennis Selkoe at Brigham and Women’s Hospital, Boston (comments below).
Others hoped that the accumulating weight of evidence in favor of anti-amyloid antibodies will prompt the Centers for Medicare and Medicaid Services to reconsider its decision limiting coverage (Apr 2022 news). “It is clear that this class of amyloid-removing therapies is effective, and this should encourage CMS to fully cover these treatments,” said Paul Aisen at the University of California, San Diego (comment below).
Benefit More Robust in Phase 3 Than 2
Often in drug development, a potential efficacy signal in Phase 2 vanishes in Phase 3. Not here. The earlier Phase 2 Trailblazer1 study of donanemab was positive on its primary outcome, reporting a 32 percent slowing of decline on the iADRS. However, it missed significance on some secondary measures such as the CDR-SB, notching only a 23 percent slowing there. That trial enrolled 257 people, half of whom received placebo (Mar 2021 news).
The Phase 3 trial enrolled 1,182 people in its primary analysis population. As in Phase 2, these participants had a tangle burden that fell between 1.1 and 1.46 SUVR on tau PET, the range where Lilly scientists predicted removing plaque would be most effective. In this group, about a third of people became amyloid-negative by six months, and 71 percent by one year. This was slightly more than in Phase 2, where 60 percent of participants reached this threshold by one year.
Cognitive and functional decline slowed on all outcome measures: 35 percent on the iADRS, 37 percent on the CDR-SB, 32 percent on the ADAS-Cog13, and 40 percent on ADCS-iADL. All results were statistically significant. Looking at the data another way, 47 percent of people on donanemab stayed stable on the CDR-SB over one year, compared with 29 percent on placebo.
Tangle Load May Be Key
Trailblazer-Alz2 also included 552 participants who had baseline tau PET scans above 1.46 SUVR. This “high tau” group was included to gather more data about the effects of immunotherapy later in disease. In its press release, Lilly reported that a combined analysis of the full 1,734 participant cohort was still positive, with slowing of 22 percent on the iADRS, 29 percent on the CDR-SB, 20 percent on the ADAS-Cog13, and 28 percent on the ADCS-iADL. The company did not report numbers for the high-tau subgroup alone; Lilly told Alzforum those data will be presented later.
“One can infer that they did not respond as well to the drug, which strengthens the argument for early treatment,” noted Erik Musiek at Washington University in St. Louis (comment below).
Some recent data hint that the 1.46 threshold may represent a point beyond which plaque removal does little good. In Lilly’s much smaller Trailblazer-Alz4 study comparing donanemab to aducanumab, participants above this threshold gained no benefit on downstream biomarkers after plaque clearance. Likewise, gantenerumab Phase 3 data found no benefit in women, whose baseline tangle load in the temporal lobe topped 1.46 SUVR, but a significant benefit in men, who started with a lower tau signal (Apr 2023 conference news). If the findings about such a threshold hold up, then the field might have an answer to the question of when to stop amyloid immunotherapy, as well as a clearer idea about when to start.
Some commenters noted clinical implications, especially if donanemab’s label requires baseline tau PET scans, as well as amyloid PET scans to determine when plaque is cleared, as was done in the trial. “If payers require explicit replication of the clinical trials for reimbursement, clinical use of donanemab could be limited to quaternary referral centers for the immediate future,” Siemers speculated. Others thought this might not be necessary. “While tau PET studies will not be available in the foreseeable future to the vast majority of early AD patients, the principal of treating at early clinical stages is achievable,” Selkoe wrote. Yet others saw this as another argument to get the leading fluid biomarkers ready for prime time.
The stopping provision of this trial—i.e., participants came off donanemab once their amyloid load fell below a predefined threshold—drew both questions and praise. Some asked how clinicians are to know when amyloid returns, and what to do then. But Gil Rabinovici of University of California, San Francisco, wrote “A limited duration of treatment, akin to induction of chemotherapy for cancer, could be a game-changer for patients, families, health systems, and third-party payers. This approach may also limit the time in which patients are exposed to the risk of ARIA, which is particularly critical given the reported deaths in the study.”
Safety Is a Concern
As in Phase 2, about a quarter of people taking donanemab developed the brain swelling known as ARIA-E. In 6 percent of people, it was symptomatic. The microhemorrhages known as ARIA-H occurred in 31 percent of people on drug, compared with 14 percent on placebo. Most concerning, 1.6 percent of participants had serious ARIA (either E or H). Lilly attributed two deaths in the trial to ARIA, and a third death is possibly related, as well, occurring after an episode of serious ARIA. Lilly's press release offered no further details about these deaths, but a company representative told Alzforum that antithrombotic medications, including anticoagulants, were not a factor.
In the open-label extension study of lecanemab, three deaths were associated with use of anticoagulants or acute thrombolytics, leading researchers to recommend excluding people who are on these therapies (Apr 2023 conference news). Both the lecanemab and donanemab Phase 3 trials allowed people on such drugs to enroll.
“The deaths are very worrisome,” Musiek said, calling for research to look for ways to lower the risk. On this, commenters were unanimous. Salloway asked for a thorough review of serious and fatal cases, and the relationship of APOE genotype to ARIA and safety outcomes. Selkoe noted that deep analysis of symptomatic versus asymptomatic ARIA cases in donanemab, lecanemab, and aducanumab might identify clinical and biomarker characteristics that could help predict its occurrence beyond the known effect of APOE4 gene dosage. On that, Siemers pointed out that across these three antibodies, despite differing amounts of ARIA with each, a consistent 20 to 25 percent of these cases were symptomatic. What might be going on there?
Despite these concerns, Michael Weiner at the University of California, San Francisco, noted that the overall risk/benefit ratio of donanemab remains favorable.
A fuller set of data from this trial will be presented at this summer’s Alzheimer’s Association International Conference in Amsterdam. “We all eagerly await full presentation of the data,” Aisen said.—Madolyn Bowman Rogers
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