Results from a placebo-controlled phase 2 trial of the study antiamyloid drug donanemab show that the novel agent met the main effect of reducing mental retardation in patients with early-onset Alzheimer’s disease (AD).
Results from the TRAILBLAZER-ALZ trial were presented at the 2021 International Conference on Alzheimer’s and Parkinson’s Diseases (AD / PD) and were simultaneously published online March 13 in the New England Journal of Medicine.
As previously reported by Medscape Medical News, Highline results showed that donanemab delayed mental decline on the Integrated AD Assessment Scale (iADRS) by 32% from baseline to 76 weeks compared to placebo.
The recently released detailed findings showed that “donanemab use resulted in a better combined score for psychiatry and for the ability to perform activities of daily living than placebo at 76 weeks, although results for high school results were mixed, “said the researchers, originally author Mark A. Mintun, MD, an employee of Eli Lilly.
Results showed an improvement in scores on the Clinical Dementia Clinical Scale (CDR-SB Boxes) and the 13-scale cognitive subscale of the AD Assessment Scale (ADAS-Cog13), but the differences were not between the two groups important treatment. In addition, score changes on the Daily Account Instrument Collaborative AD-Active Study (ADCS-iADL) and the Minor State Mind Survey (MMSE) were not “substantial.”
However, the donanemab group showed a greater 85-centiloid reduction in amyloid plaque level at 76 weeks, as seen on PET, compared to the placebo group.
Proof of concept?
The human antibody donanemab, formerly known as LY3002813, targets a modified form of the deposited amyloid-Beta (Aß) peptide called N3pG.
The randomized, placebo-controlled, double-blind, TRAILBLAZER-ALZ experiment, described as a “Phase 2 concept validation test” in the AD / PD program, was conducted at 56 sites in the United States and Canada. and included 257 patients between the ages of 60 and 85 years (52% women). PET confirmed tau and amyloid deposition in all participants.
The active treatment group (n = 131) was randomly assigned to receive 700 mg donanemab for three doses; thereafter, treatment was curtailed up to 1400 mg. Both the donanemab and placebo groups (n = 126) received intravenous treatment every 4 weeks for up to 72 weeks.
Participants also underwent F-florbetapir and F-flortaucipir PET scans at different times and completed several psychiatric tests.
The main outcome of the study was change between baseline and 76 weeks after treatment on a combined score for psychiatry, as measured by the iADRS. The iADRS combines the ADAS-Cog13 and the ADCS-iADL.
This range ranges from 0 to 144, with lower scores associated with greater brain impairment. Both treatment groups achieved an iADRS score of 106 at baseline.
More research is needed
Results showed that the baseline score change on the iADRS for the active treatment group was 6.6.86 for -10.06 for the placebo group (group difference, 3.2; 95% confidence interval). [CI], 0.12 – 6.27; P. = .04). While important, “the 6-point difference test was empowered to reveal,” which was not achieved, the investigators note.
Differences in score changes from baseline to 76 weeks for treatment versus placebo groups on the following secondary outcome measures were:
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CDR-SB: -0.36 (95% CI, -0.83 to -0.12)
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ADAS-Cog13: -1.86 (95% CI, -3.63 to -0.09)
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ADCS-iADL: 1.21 (95% CI, -0.77 to 3.2)
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MMSE: 0.64 (95% CI, 00.4 to 1.67)
The CDR-SB was identified as the first secondary outcome, and because it did not show a significant difference between groups, “the hierarchy failed and definitive conclusions cannot be drawn from data regarding the between. differences between organizations in the change in the ADAS- Cog13, “the researchers write.
Moreover, the differences in scores on the last two high school results were not “substantial,” they report.
However, at 76 weeks, the donanemab group showed a decrease of 84.13 centiloids in amyloid plaque level vs. an increase of 0.93 centiloids in the placebo group (intergroup difference, 85.06 centiloids). At 24 weeks, the active treatment group had a greater reduction of 67.83-centiloids vs. the placebo group.
In addition, 40%, 59.8%, and 67.8% of the donanemab group achieved “amyloid-negative status” at 24, 52, and 76 weeks, respectively. Amyloid-negative status was defined as amyloid plaque level less than 24.1 centiloids.
There was no significant difference in the frequency of deaths or adverse events between the groups. However, the donanemab group of ARIA-E had significantly more reports compared to the placebo group (26.7% vs 0.8%).
Overall, the researchers note that more long-term trials with larger patient numbers are needed “to further confirm the efficacy and safety of donanemab” in AD.
A positive sign?
In a statement sent to Medscape Medical News, Maria Carrillo, PhD, chief science officer for the Alzheimer’s Society, said the group is “encouraged by this promising data.”
“It is the first stage 2 Alzheimer’s test to show positive results on primary outcome measurement related to memory and thinking,” Carrillo said. However, “more work needs to be done on this experimental drug treatment.”
Carrillo noted that, given that the trial was moderate and that only about 180 participants completed the study, “we are looking forward to the results of a larger second Phase 2 trial of this drug.”
However, she said there were a number of “innovations and innovations” in the way the study was conducted noting that it reflects an evolution of the HR study.
“I’m optimistic for the future,” Carrillo said.
Also mention the results for Medscape Medical News, Howard Fillit, MD, neuroscientist and founding executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation, said the study showed “the drug works” and that the drug did what it should have done in terms of removing the Aß table.
“It also gave us an indication in a relatively small phase 2 study that there may be a small mental benefit,” said Fillit, who was not involved in the research.
He noted that while the rate of slow decline was statistically significant, it remains to be seen whether this means clinically, especially since secondary outcome outcomes were mixed.
“Basically, it was a progressive study that may need to be followed by another, much larger study in order for us to see the real benefit,” Fillit said.
The study was funded by Eli Lilly. Mintun is an employee of Eli Lilly. Carrillo and Fillit have not reported any material financial relationships.
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