Donanemab Reduced Amyloid Plaque and May Slow Cognitive Decline

In the phase 2 TRAILBLAZER-ALZ study (NCT03367403), 40% of individuals with early symptomatic Alzheimer disease (AD) treated with donanemab (Eli Lilly and Company, Indianapolis, IN) had amyloid negativity after 6 months of treatment. After 18 months of treatment 68% of those who received donanemab were amyloid negative . Overall, those treated with donanemab had approximately an 85 centiloid reduction in amyloid plaque compared with those treated with placebo. No substantial differences in levels of tau were seen between those treated with donanemab vs placebo. These results were published in  the New England Journal of Medicine. 

Disease progression was measured with the integrated Alzheimer Disease Rating Scale (iADRS), a composite measure of cognition and daily function with a range of 0 to 144. Those treated with donanemab had a mean decline of 6.86 points compared with a 10.07-point decline in those treated with placebo (P<.04). The clinically meaningful threshold for change on the iADRS has not yet been established. . Participants treated with donanemab had less decline on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and Alzheimer’s Disease Assessment Scale (ADAS-COG), although these differences did not reach statistical significance. On volumetric MRI, there were no differences in hippocampal volume with donanemab vs placebo. At weeks 52 and 76, those treated with donanemab had a larger decrease in total brain volume (TBV) and a larger increase in ventricular volume compared with those treated with placebo.

"We are confident in the results of the TRAILBLAZER-ALZ study," said Daniel Skovronsky, MD, PhD, Lilly's chief scientific officer and president of Lilly Research Laboratories. "This is the first late-stage study in AD to meet its primary endpoint at the primary analysis. Donanemab has the potential to become a very important treatment for AD. 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. 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."

There were amyloid-related imaging abnormalities – edema (ARIA-E) observed in phase 1 in 26.7 percent of treated participants, with an overall incidence of 6.1 percent experiencing symptomatic ARIA-E. Adverse events that commonly occured in the donanemab treatment include microhemorrhages (7.6%), superficial siderosis of central nervous system (13.7%), nausea (10.7%), and infusion-related reaction (IRR) (7.6 %). Of the participants treated with donanemab, 2.3% experienced serious hypersensitivity. In the donanemab arm, 30.5% of participants discontinued treatment due to an adverse event and ARIA-related events.