Positive phase 2 data resulted in a breakthrough therapy designation for donanemab, (Eli Lilly), prompting a biologics license application submission for the agent.
AFTER POSITIVE PHASE 2 FINDINGS resulted in breakthrough therapy designation for donanemab, manufacturer Eli Lilly submitted a biologics license application for the agent at the end of October 2021.
Donanemab, an investigational therapy that targets a modified form of amyloid-ß called N3pG, is currently being evaluated for safety and efficacy in the pivotal phase 3 TRAILBLAZER-ALZ 2 study (NCT04437511). The double-blind, randomized controlled trial is meant to replicate the findings of the TRAILBLAZER-ALZ study (NCT03367403), in which donanemab was shown to slow Alzheimer disease (AD) progression by 32% as measured by Integrated Alzheimer’s Disease Rating Scale (iADRS) scores.1
The phase 3 study is currently enrolling and is expected to reach approximately 1500 participants, aged 60 to 85 years, with early symptomatic AD (TABLE). Investigators will continue to use change from baseline on iADRS as the primary end point, with secondary end points including Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale– Cognitive Subscale (ADAS-Cog-13), and Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) scores, among others.
Results of the phase 2 TRAILBLAZER-ALZ study were published in the New England Journal of Medicine in March 2021 and suggested that treatment with the therapy results in better composite scores for cognition and ability to perform activities of daily living. After 76 weeks of treatment, those treated with donanemab (n = 131) had iADRS scores change by –6.86 points, whereas the placebo group’s (n = 126) changed by –10.06 (difference, 3.20 [95% CI, 0.12-6.27]; P = .04). Equivalent to a 32% difference in slowing decline, the significant observations were identifiable by month 9.2
In June, the FDA granted breakthrough therapy designation to donanemab as a treatment for AD based on results from TRAILBLAZER-ALZ. “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,” Daniel Skovronsky, MD, PhD, chief scientific and medical officer, Lilly Research Laboratories, Eli Lilly, said in a statement at the time of announcement.3
Reductions in the amyloid plaque level were 85.06 centiloids (–84.13 vs 0.93) greater in the donanemab group compared with those on placebo at the end of the study, as well. As early as 6 months, 40% of those treated with donanemab achieved amyloid negativity (defined as an amyloid plaque level < 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.2
Despite achievement of statistical significance on the primary end point, results for the secondary outcomes of the trial were mixed. Following the conclusion of the trial, investigators observed a difference of −0.36 (95% CI, −0.83 to 0.12) for CDR-SB score, −1.86 (95% CI, −3.63 to −0.09) for ADAS-Cog-13 score, 1.21 (95% CI, −0.77 to 3.20) for Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory score, and 0.64 (95% CI, −0.40 to 1.67) for MMSE score.
During the double-blind period, at least 1 adverse event (AE) was reported in 90.8% (n = 119) of the donanemab group and 90.4% (113 of 125) of the placebo group. The incidence of amyloid-related cerebral edema or effusion (ARIA-E) was significantly higher in the donanemab group (26.7%) than in the placebo group (0.8%; P < .001). In total, 6.1% of participants who received donanemab had symptomatic ARIA-E compared with 0.8% of those 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 patients in a mean time of 18 weeks.
In addition to TRAILBLAZER-ALZ and TRAILBLAZER-ALZ 2, other clinical trials are assessing the safety and efficacy of donanemab. These include TRAILBLAZER-ALZ’s long-term extension, TRAILBLAZER-EXT (NCT04640077), and another phase 3 trial, TRAILBLAZER-ALZ 3 (NCT05026866), which was announced in July.4 TRAILBLAZER-ALZ 3 is a randomized, placebo-controlled study that is in collaboration with Banner Alzheimer’s Institute. As part of the collaboration, Banner will support enrollment of the trial participants with and without the e4 type of the apolipoprotein gene through the Alzheimer’s Prevention Registry’s GeneMatch program.