Positive results from the Phase 3 Trailblazer-ALZ 2 study are announced showing that donanemab significantly slowed the progression of cognitive and functional decline in people with early symptoms of Alzheimer’s disease.
Donanemab met the primary endpoint of change from baseline to 18 months on the Alzheimer’s Disease Integrated Assessment Scale (iADRS), which assesses cognition and performance of activities of living such as managing finances, driving, participating in leisure activities, and discussing everyday events.
Based on these results, work will be done with the FDA and other regulatory entities at a global level to obtain approval of the drug in the shortest possible time.
Trailblazer-ALZ 2, a randomized, double-blind, placebo-controlled study, evaluated the safety and efficacy of donanemab, an investigational treatment targeting the removal of amyloid plaque. The study, the full results of which will be presented at the Alzheimer’s Association International Conference in July 2023, recruited people with early symptoms of Alzheimer’s who had mild cognitive impairment (MCI) and mild dementia, in whom this neuropathology had been confirmed. . Participants ended their donanemab treatment course once a pre-specified level of amyloid plaque clearance in the brain had been achieved.
Participants were stratified by their level of tau protein, a predictive biomarker for the progression of Alzheimer’s disease. The population in which the primary endpoint of the study was evaluated was composed of people with an intermediate level of tau and clinical symptoms of the disease. In this population, the iADRS scale showed a delay in cognitive deterioration of 35 percent, and one of the most relevant secondary objectives, specifically, through the use of the Clinical Assessment of Dementia scale or CDR-SB, for its acronym in English, showed a reduction in progression of 36 percent in this same variable after 18 months of treatment.
In turn, several additional secondary analyzes showed that 47 percent of participants treated with donanemab did not show worsening en la CDR-SBa key measure to assess progression of disease severity over one year, compared with 29 percent of placebo participants.
52 percent of the participants completed their treatment cycle in one year and 72 percent in 18 months, after achieving the removal of the amyloid plaque.
Patients who received donanemab had 40 percent less progression in deterioration in the ability to perform activities of daily living at 18 months. In addition, these patients had a 39 percent lower risk of progressing to the next stage of the disease compared with those who received placebo.
“Over the past 20 years, Lilly scientists have broken new ground in the fight against Alzheimer’s disease by elucidating the basic mechanisms of its pathology and developing neuroimaging tools and blood biomarkers to track the disease,” said Daniel Skovronsky, Director Lilly’s scientist and doctor. “This is the first phase 3 trial of any investigational drug for Alzheimer’s disease to demonstrate a 35 percent progression reduction in clinical and functional decline.”
On the other hand, fewer people with high tau levels at baseline were also included, representing a more advanced stage in disease progression. Because these participants were expected to deteriorate more rapidly and be less responsive to treatment, the target population for the study was patients with intermediate tau levels. Participants with high tau levels were pooled with the population with an intermediate tau level in an additional primary analysis of all enrolled participants. In this combined population, donanemab also demonstrated significant positive results across all clinical endpoints, with CDR-SB and iADRS showing delayed clinical deterioration by 29 percent and 22 percent, respectively.
Amyloid-related imaging abnormalities (ARIA) are the most common side effects. In the overall donanemab treatment group, 24 percent of treated participants had ARIA-Eand 6.1 percent experienced Symptomatic ARIA-E. In 31.4 percent of the donanemab group there was AIRA-H and in the placebo group it was 13.6 percent. Most cases of ARIA were mild to moderate and resolved or stabilized with appropriate management.
In this study, the incidence of severe ARIA was 1.6 percent, including two participants whose death was attributed to this adverse effect and a third participant who died of causes related to a severe ARIA episode. Likewise, reactions related to the administration of the treatment occurred in 8.7 percent of the participants, most of them being mild to moderate in severity.
“We are especially encouraged by the potential clinical benefits that donanemab may provide for people with Alzheimer’s disease, although, like many effective treatments for debilitating and fatal diseases, there are associated risks that can be serious and life-threatening,” explains Mark Mintun, vice president of pain and neurodegeneration therapeutics at Eli Lilly, and president of Avid Radiopharmaceuticals.
“These results suggest that people in the early stage of the disease might benefit more from targeted amyloid removal therapies,” says Mintun.
In addition to delaying cognitive and functional decline in the study, donanemab produced significant reductions in brain amyloid plaque levels evidenced as early as 6 months after initiation of treatment, as observed by brain amyloid positron emission tomography (PET) scan.
Main results of the study
In the population with an intermediate tau level, the baseline characteristics were similar to those of other contemporary studies in early phases. Consequently, the placebo arm progressed as expected (iADRS and CRD-SB progression of 9.3 and 1.9 points respectively after 18 months). The prespecified analyzes used standard Statistical Methods, including mixed model for repeated measures (MMRM) and natural cubic spline (NCS) analyses, with similar results in both methods.
In the pooled intermediate and high tau population, the baseline MMSE score was 22.3 and the placebo group showed greater disease progression compared with the intermediate tau population (worsening on iADRS and CDR -SB of 13.1 and 2.4 points respectively after 18 months).
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