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Despite showing better composite scores for cognition and ability to perform activities of daily living, a number of the secondary outcomes showed mixed results with the Eli Lilly investigational agent.
New data from the phase 2 TRAILBLAZER-ALZ study (NCT03367403) of donanemab, published in the New England Journal of Medicine and presented at AD/PD 2021, suggest that treatment with the therapy results in better composite scores for cognition and ability to perform activities of daily living after 76 weeks compared to placebo in patients with early Alzheimer disease.1
The primary outcome was the change from baseline in the score on the Integrated Alzheimer’s Disease Rating Scale (iADRS), which ranged from 0 to 144, with lower scores indicating greater cognitive and functional impairment. At baseline, iADRS score was 106 in both the donanemab (n = 131) and placebo (n = 126; 1 participant was excluded from the modified intent-to-treat population) groups.
After 76 weeks, the treatment group’s scores changed by –6.86 points while the placebo group’s changed by −10.06 (difference, 3.20; 95% CI, 0.12-6.27; P = .04). This change was equivalent to a 32% difference in slowing decline for the donanemab group, a significant difference that was identifiable by month 9.
"We are confident in the results of the TRAILBLAZER-ALZ study," said Daniel Skovronsky, MD, PhD, chief scientific officer, and president, Lilly Research Laboratories, Eli Lilly and co., donanemab’s developer, in a statement.2 "This is the first late-stage study in Alzheimer's disease to meet its primary endpoint at the primary analysis. Donanemab has the potential to become a very important treatment for Alzheimer's disease. We were pleased to see not only slowing of cognitive and functional decline, but also very substantial clearance of amyloid plaques and slowing of spread of tau pathology."
“The constellation of clinical and biomarker results indicates the potential for long-term disease modification. We are grateful to the patients, caregivers, and investigators who participated in this landmark study,” Skovronsky added.
At the 76-week mark, reductions in the amyloid plaque level were 85.06 centiloids (−84.13 vs. 0.93) greater with donanemab than with placebo. Amyloid-related cerebral edema or effusion (ARIA-E), which were mostly asymptomatic, occurred with donanemab treatment. As early as 6 months, 40% of those treated with donanemab achieved amyloid negativity (defined as an amyloid plaque level of <24.10 centiloids), with 68% achieving this at 18 months. The percentage of participants in the donanemab group who had amyloid-negative status at 24, 52, and 76 weeks was 40.0%, 59.8%, and 67.8%, respectively.
"The combination of changes in Alzheimer's biomarkers and the slowing of clinical symptoms of the disease seen in this study is promising," said Howard Fillit, MD, founding executive director and chief science officer, Alzheimer's Drug Discovery Foundation (ADDF), in a statement on the data.3 "We are encouraged by today's news, and if these results are confirmed in the larger study now in progress, donanemab could offer the potential for a disease-modifying therapy that can help patients maintain cognitive abilities and their independence longer. We eagerly await results from future trials.”
In the safety population, 90.8% (n = 119) of the donanemab group and 90.4% (113 of 125) of the placebo group had at least 1 adverse event (AE) during the double-blind intervention period. The incidence of ARIA-E was significantly higher in the donanemab group (26.7%) than in the placebo group (0.8%; P <.001). Symptomatic ARIA-E was reported by 6.1% of all participants in the donanemab group (22% of those with ARIA-E), as compared with 0.8% of all participants in the placebo group.
Most cases of ARIA-E occurred at or by week 12 of the intervention period, with the serious symptomatic cases (n = 2; 1.5%) occurring in the donanemab group. The symptoms resolved in both of those patients, in a mean time of 18 weeks.
The results for the secondary outcomes of the trial were mixed. Those measures included the change in scores on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog13), the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on positron emission tomography (PET).
The difference between the donanemab group and the placebo group in the change from baseline at 76 weeks was −0.36 (95% CI, −0.83 to 0.12) for CDR-SB score, −1.86 (95% CI, −3.63 to −0.09) for ADAS-Cog13 score, 1.21 (95% CI, −0.77 to 3.20) for ADCS-iADL score, and 0.64 (95% CI, −0.40 to 1.67) for MMSE score.
Lead author Mark A. Mintun, MD, vice president, Pain and Neurodegeneration Research and Clinical Development, Eli Lilly and Company; president, Avid Radiopharmaceuticals, and colleagues noted that several features of the trial design are worth consideration, including the selection of the dosing regimen (700 mg for first 3 doses, 1400 mg thereafter) which was done to facilitate aggressive removal of amyloid plaques. Additionally, all participants were required to meet flortaucipir PET screening criteria, which “may have narrowed the range of underlying pathologic features and in turn decreased variation in clinical decline” as well as led to the exclusion of those with the highest levels of tau.
As the trial followed the Baysien disease progression model proposed by the European Prevention of Alzheimer’s Dementia project, Mintun et al noted that it produced estimates of disease slowing that were similar to the single point estimate of the MMRM.
"As a clinician and researcher, I'm particularly encouraged by the significant plaque lowering and the slowing of clinical decline with donanemab," said Stephen P. Salloway, MD, MS, director, Memory and Aging Program, and Martin M. Zucker professor of Psychiatry and Human Behavior, Department of Neurology, Warren Alpert Medical School, Brown University, in a statement.2 "The donanemab results are a significant and encouraging milestone for people impacted by Alzheimer's disease and we are eager to continue on in this fight."