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Donanemab, an investigational agent targeting N-terminal pyroglutamate beta amyloid {pyroglutamate-3), slowed decline in patients with early symptoms of Alzheimer's disease in the phase II trial, now published in a major journal.

In a study of 257 early symptomatic Alzheimer's patients -- 131 assigned to donanemab and 126 to placebo -- the intravenous drug met the primary endpoint of a composite measure of cognition and daily function known as the Integrated Alzheimer's Disease Rating Scale (), slowing decline relative to placebo.

Baseline iADRS score was 106 in both groups. Change from baseline in the iADRS score at 76 weeks was −6.86 with donanemab and −10.06 with placebo, a difference of 3.20 (95% CI 0.12-6.27; P=0.04), reported Mark Mintun, MD, of drug maker Eli Lilly in Indianapolis, and co-authors, in . The findings were presented simultaneously at the International Conference on Alzheimer's and Parkinson's Diseases ().

Secondary endpoints also showed differences in the trial, though many were unsubstantial. On the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score, the difference in change between groups was −0.36 (95% CI −0.83 to 0.12). On the 13-item cognitive subscale of ADAS-Cog (ADAS-Cog₁₃)_, it was −1.86 (95% CI −3.63 to −0.09); on ADCS-iADL, it was 1.21 (95% CI −0.77 to 3.20); and on the Mini–Mental State Examination (MMSE), it was 0.64 (95% CI −0.40 to 1.67).

Lilly had released topline results in January that lacked most of the numerical findings now published. A second phase II trial with 500 patients, , is underway.

The iADRS, a measurement developed by Lilly, combines scores from the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL). Together, these measures are better suited for detecting changes early in the Alzheimer's disease process, co-author John Sims, MD, Lilly's senior medical director for neurodegeneration research, told 番茄社区. Scores range from 0 to 144, with lower scores indicating greater cognitive and functional impairment.

What's unique about donanemab is its target, noted Cynthia Lemere, PhD, a basic and translational scientist at Brigham & Women's Hospital and Harvard Medical School in Boston, who wasn't involved with the trial. "The big difference is that this particular form of beta amyloid, called pyroglutamate-3 beta amyloid, is a pathogenic form," she said.

"Pyroglutamate-3 beta amyloid is not really hugely abundant in the brain in Alzheimer's; there's relatively small amounts compared to regular beta amyloid," Lemere told 番茄社区. "But the difference is that pyroglutamate-3 resists degradation. It's been shown to be very toxic to neurons in vitro. It aggregates not just amongst itself, but it can actually help regular beta amyloid aggregate and form plaques."

"In my own hands, when we've looked at unfixed human brain sections from Alzheimer's patients, we see pyroglutamate-3 in every single plaque, every single one," Lemere added. "We think it's an integral part of the plaque pathogenesis, the actual and the continuous deposition of plaques in the brain."

Pyroglutamate-3 beta-amyloid is normally not detected in blood or cerebrospinal fluid. In TRAILBLAZER-ALZ, overall reductions in amyloid plaque levels and global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo at 76 weeks. Patients stopped taking donanemab and switched to placebo once their plaque level was below 25 centiloids for two consecutive measures or below 11 centiloids at any one measure, Sims said.

"The antibody dropped the amyloid levels rather dramatically, rather quickly," noted Ronald Petersen, MD, PhD, of Mayo Clinic in Rochester, Minnesota, who wasn't involved with the study. "Then they stopped treating, and the effect persisted."

What this may mean is that, with certain drugs, "you might not have to treat Alzheimer's patients monthly for the rest of their lives," he told 番茄社区. "If this finding is replicated in other studies, it may be possible that you could drop the amyloid level to a baseline, then stop treating them."

TRAILBLAZER-ALZ randomly assigned participants to receive donanemab {700 mg for the first three doses and 1400 mg after) or placebo for up to 72 weeks. The dosing regimen aimed to achieve rapid amyloid plaque removal, Mintun said at the AD/PD meeting. Starting amyloid plaque levels were 107.6 and 101.1 centiloids for the donanemab and placebo groups, respectively.

Demographics, including age and sex, were balanced in the two arms. Mean baseline MMSE was 23.5, which "represents more advanced patients in this study than others in the field," Mintun pointed out. Almost three-quarters of participants carried APOE4.

All participants had positive PET scans for both amyloid and tau at baseline, but patients with the highest levels of tau, whose disease may be more resistant to anti-amyloid treatments, were excluded.

"We believe that it's important that all future Alzheimer's trials and Alzheimer's therapies should be based on the pathological stage of the patient, as it's done in oncology," Mintun noted. "As a field, it now seems obvious that Alzheimer's disease trials should have knowledge of the participants' amyloid status. I think it's going to be interesting to know if this will soon be true for tau as well."

Amyloid-related cerebral edema or effusions occurred in approximately one in four participants in the donanemab group, mostly asymptomatic. Overall, 6% of participants had symptomatic amyloid-related imaging abnormalities with edema (ARIA-E). This was more common in APOE4 carriers. There was no significant difference in the incidence of death or serious adverse events in the study groups.

The study had several limitations: its sample size was small and it mostly included white participants. The donanemab group had a higher incidence of discontinuing due to adverse events, which may have introduced survivor bias.

ARIA-E may have led to unblinding, but an analysis showed iADRS scores were similar in participants with and without ARIA-E, Mintun said. The minimal clinically important difference on the iADRS has not been established.

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