Phase 2 TRAILBLAZER-ALZ results presented at the 15th International Conference on Alzheimer's & Parkinson Diseases 2021 and published simultaneously in the New England Journal of Medicine ( NEJM ) expand on previously reported top-line data that 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 placebo.
Additionally, data from secondary analyses have shown Donanemab consistently slowed cognitive and functional decline, with ranges between 20-40% 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.
Further, prespecified exploratory analyses have shown Donanemab slowed the accumulation of tau across key brain regions in patients affected by Alzheimer's disease.
Specifically, at 76 weeks compared to baseline, treatment with Donanemab slowed decline by 32% 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.
In addition, 40% of participants treated with Donanemab achieved amyloid negativity as early as six months after starting treatment and 68% achieved this target by 18 months.
Donanemab is a monoclonal antibody that was designed to bind a specific form of post-translationally modified Aß ( amyloid-ß ), N-terminal pyroglutamate, and thereby yield rapid and complete clearance of amyloid plaques.
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% of treated participants, with an overall incidence of 6.1% experiencing symptomatic ARIA-E; the majority ARIA-E cases occurred within the first 12 weeks after initiation of treatment.
Other common adverse effects in the Donanemab treatment group include ARIA-H related events like microhemorrhages ( 7.6% ) and superficial siderosis of central nervous system ( 13.7% ), nausea ( 10.7% ), and infusion-related reaction ( IRR ) ( 7.6% ).
Serious IRR or hypersensitivity occurred in 2.3% of participants treated with Donanemab.
In the Donanemab arm, 30.5% 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.
TRAILBLAZER-ALZ is a randomized, placebo-controlled, double-blind, multi-center phase 2 study to assess the safety, tolerability and efficacy of Donanemab in patients with early symptomatic Alzheimer's disease.
The trial enrolled 272 patients who were selected based on cognitive assessments in conjunction with amyloid plaque imaging and tau staging by PET imaging.
The study's primary endpoint is change from baseline until 76 weeks in the iADRS ( Integrated Alzheimer's Disease Rating Scale ), a composite tool combining ADAS-Cog13 ( Alzheimer's Disease Assessment Scale-Cognitive subscale ) and ADCS-iADL ( Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living ) for function.
Key secondary endpoints include changes between baseline and 76 weeks in ADAS-Cog13, ADCS-iADL, MMSE, and CDR-SB ( Clinical Dementia Rating Scale Sum of Boxes ) scores. Other secondary biomarker endpoints include changes from baseline to week 76 in brain amyloid deposition and brain tau deposition and volumetric MRI. The safety, tolerability and efficacy of Donanemab are also being evaluated in the ongoing randomized, placebo-controlled, double-blind, multi-center phase 2 study TRAILBLAZER-ALZ. ( Xagena )
Source: Lilly, 2021