ALZ results revealed by Eli Lilly and Company at the recent 15th International Conference on Alzheimer’s & Parkinson Diseases 2021 (AD/PD 2021) expand on previously reported top-line data.
The data found donanemab met its primary endpoint and showed significant slowing of decline on the integrated Alzheimer’s Disease Rating Scale (iADRS), a composite measure of cognition and daily function, in patients with early symptomatic Alzheimer’s disease compared to placebo1,2.
The results have been published simultaneously in the New England Journal of Medicine (NEJM).
In addition, data from secondary analyses showed donanemab consistently slowed cognitive and functional decline, with ranges between 20-40 percent in all secondary endpoints [Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog13), Alzheimer’s Disease Cooperative Study-instrumental Activities of Daily Living (ADCS-iADL), Mini-Mental State Examination (MMSE)] with nominal statistical significance at multiple times compared to placebo.
Moreover, prespecified exploratory analyses showed donanemab brought down the accumulation of tau across key brain regions in patients affected by Alzheimer’s disease.
Daniel Skovronsky, M.D., Ph.D., Lilly chief scientific officer and president of Lilly Research Laboratories, said, “We are confident in the results of the TRAILBLAZER-ALZ study.”
He said further: “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.”
Daniel added: “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.”
Particularly, at 76 weeks compared to baseline, treatment with donanemab slowed decline by 32 percent compared to placebo as measured by the iADRS, which was statistically significant. As early as nine months (36 weeks) after initiation of treatment, a significant difference in decline by iADRS was observed.
Additionally, 40 per cent of participants treated with donanemab achieved amyloid negativity as early as six months after starting treatment and 68 percent achieved this target by 18 months.
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Donanemab by Lilly is a monoclonal antibody that was designed to bind a specific form of post-translationally modified Aß, N-terminal pyroglutamate, and thereby yield rapid and complete clearance of amyloid plaques.
Liana G. Apostolova, M.D., M.Sc., FAAN, Indiana University (IU) Distinguished Professor and Barbara and Peer Baekgaard Professor in Alzheimer’s Disease Research at IU School of Medicine, stated, “Tau has become increasingly validated as a predictive biomarker for Alzheimer’s disease progression, as shown again in this trial.”
Apostolova added: “A key insight of the results from the TRAILBLAZER-ALZ study is that donanemab not only significantly reduced the amount of amyloid deposition in these patients but also slowed the clinical progression of the disease suggesting that this could be a disease-modifying therapy. We believe these amyloid and tau imaging data lay the foundation for precision medicine-based Alzheimer’s disease treatments.”
The safety profile of donanemab was consistent with observations from Phase 1 data. In the donanemab treatment group, amyloid-related imaging abnormalities – edema (ARIA-E) occurred in 26.7 percent of treated participants, with an overall incidence of 6.1 percent experiencing symptomatic ARIA-E; the majority ARIA-E cases occurred within the first 12 weeks after initiation of treatment.
Superficial siderosis
Other common AEs in the donanemab treatment group include ARIA-H related events such as microhemorrhages (7.6 percent) and superficial siderosis of central nervous system (13.7 percent), nausea (10.7 percent), and infusion-related reaction (IRR) (7.6 percent).
It is reported that serious IRR or hypersensitivity occurred in 2.3 percent of participants treated with donanemab. In the donanemab arm, 30.5 percent of patients discontinued treatment due to an adverse event and half of these discontinuations were due to ARIA-related events. Patients with treatment discontinuations were allowed to continue in the trial.
According to Stephen P. Salloway, M.S., M.D., Director of the Memory and Aging Program and the Department of Neurology at Butler Hospital and Martin M. Zucker professor of Psychiatry and Human Behavior, Department of Neurology, Warren Alpert Medical School of Brown University, “As a clinician and researcher, I’m particularly encouraged by the significant plaque lowering and the slowing of clinical decline with donanemab.”
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, they added.
(With inputs from The OnLook News Research Bureau)
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