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This article originally appeared in NeurologyLive.
Donanemab may give better composite scores for cognition and the ability to perform activities of daily living after 76 weeks compared to placebo in patients with early-onset Alzheimer’s disease, new data from the study shows. phase 2 TRAILBLAZER-ALZ, published in the New England Journal of Medicine and presented at AD / PD 2021.
Primary outcome measure was change from baseline for Integrated Assessment Scale for Alzheimer’s Disease (iADRS) score, which ranged from 0 to 144, with lower scores indicating greater cognitive impairment and functional. At baseline, the iADRS score was 106 in the donanemab (n = 131) and placebo (n = 126; 1 participant was excluded from the modified intention-to-treat population).
After 76 weeks, the scores in the treatment group changed by -6.86 points while those in the placebo group changed by -10.06 (difference, 3.20; 95% CI, 0.12-6.27 ; P = 0.04). This change was equivalent to a 32% difference in slower decline for the donanemab group, a significant difference that was identifiable at month 9.
“We are confident in the results of the TRAILBLAZER-ALZ study,” said Daniel Skovronsky, MD, PhD, Scientific Director and President of Lilly Research Laboratories, Eli Lilly and co., Developer of donanemab, in a statement. As the first advanced stage Alzheimer’s disease study to achieve its primary endpoint in primary analysis, donanemab has the potential to become a very important treatment for Alzheimer’s disease.
“We were pleased to see not only a slowing of cognitive and functional decline, but also a very substantial clearance of amyloid plaques and a slowing of the spread of tau pathology,” Skovronsky added. “The constellation of clinical and biomarker findings indicates the potential long-term modification of the disease. We thank the patients, caregivers and investigators who participated in this landmark study. “
At 76 weeks, the reductions in amyloid plaque were 85.06 centiloids (-84.13 vs. 0.93) greater with donanemab than with placebo.
Amyloid-related edema or brain effusion (ARIA-E), which was mostly asymptomatic, has occurred with treatment with donanemab. By 6 months, 40% of people treated with donanemab achieved amyloid negativity (defined as an amyloid plaque level <24.10 centiloid), 68% by 18 months. The percentage of participants in the donanemab group who had negative amyloid status at 24, 52, and 76 weeks was 40.0%, 59.8%, and 67.8%, respectively.
“The combination of the 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 scientific director of the Alzheimer’s Drug Discovery Foundation (ADDF ), in a press release. on the data. “We are encouraged by today’s news, and if these results are confirmed in the larger study currently underway, donanemab may offer the potential for a disease-modifying therapy that may help patients maintain their cognitive abilities and independence for longer. We look forward to the results of future trials. “
In the tolerant population, 90.8% (n = 119) of the donanemab group and 90.4% (113 out of 125) of the placebo group had at least 1 adverse event (AE) during the intervention period in double blind. 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), 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 severe symptomatic cases (n = 2; 1.5%) occurring in the donanemab group. Symptoms resolved in these two patients, in an average of 18 weeks.
The results for the secondary outcomes of the trial were mixed. These measures included the variation in scores on the Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB), the 13-item Cognitive Subscale of the Alzheimer’s Disease Rating Scale ( ADAS-Cog13), the cooperative study on Alzheimer’s disease – instrumental activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the evolution of amyloid and tau load on positron emission tomography (PET).
The difference between the donanemab group and the placebo group in 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 the ADAS-Cog13 score, 1.21 (95% CI, −0.77 to 3.20) for the ADCS-iADL score and 0.64 (95% CI, −0.40 to 1.67) for the MMSE score.
Senior Author Mark A. Mintun, MD, Vice President, Pain and Neurodegeneration Clinical Research and Development, Eli Lilly and Company; President, Avid Radiopharmaceuticals, and colleagues noted that several features of the trial design merit consideration, including the choice of dosing regimen (700 mg for the first 3 doses, 1400 mg thereafter) which was done to facilitate the aggressive removal of amyloid plaques.
In addition, all participants had to meet the PET screening criteria for flortaucipir, which “may have reduced the range of underlying disease characteristics and in turn decreased the variation in clinical decline” and 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 Alzheimer’s Dementia Prevention Project, Mintun et al noted that it produced estimates of disease slowing similar to the point estimate. unique of MMRM.
“As a clinician and researcher, I am particularly encouraged by the significant reduction in dental plaque and the slowing of clinical decline with donanemab,” said Stephen P. Salloway, MD, MS, director of the Memory and Aging program, and Professor Martin M. Zucker of Psychiatry and Human Behavior, Department of Neurology, Warren Alpert Medical School, Brown University, in a press release.2 “Donanemab results are an important and encouraging step for those affected by Alzheimer’s disease and we look forward to continuing in this fight. “
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