Donanemab, an investigational agent targeting beta-amyloid, appeared to slow decline in patients with early symptoms of Alzheimer's disease, on Monday.
The drug, which targets a modified form of beta amyloid known as N3pG, showed significant slowing versus placebo on a composite measure of cognition and daily function in the phase II study, the company said. The findings have not yet been published or peer-reviewed.
Donanemab met the primary endpoint of change from baseline to 76 weeks in the Integrated Alzheimer's Disease Rating Scale (), slowing decline by 32% relative to placebo. The iADRS is a composite tool that combines scores from the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL). In the – another Lilly drug targeting beta amyloid -- the iADRS was the only tool that consistently differentiated between solanezumab and placebo in people with mild Alzheimer's dementia.
Over many years, multiple beta amyloid-targeting drugs have failed in clinical trials. In recent months, an FDA advisory committee concluded that trial findings didn't support Biogen's controversial anti-amyloid drug, aducanumab. (The FDA is scheduled to decide aducanumab's fate in March.)
But donanemab is different, Lilly said: by targeting N3pG beta amyloid, donanemab treatment can rapidly result in high levels of amyloid plaque clearance. In TRAILBLAZER-ALZ, donanemab-treated patients showed an 84 centiloid reduction of amyloid plaque on average at 72 weeks, compared with a baseline level of 108 centiloids. Patients stopped taking donanemab and switched to placebo once their plaque level was below 25 centiloids for two consecutive measures or below 11 centiloids at any one measure.
"This unique mechanism and antibody for clearing plaques, discovered at Lilly, has the potential to provide high levels of durable amyloid plaque clearance after limited duration dosing," chief science officer Daniel Skovronsky, MD, PhD, president of Lilly Research Laboratories, said in a statement.
"In conjunction with our expertise in amyloid and tau imaging, this allowed us to conduct a trial to test if reducing amyloid plaques in Alzheimer's patients to levels seen in scans of healthy individuals could result in clinically meaningful slowing of cognitive decline," Skovronsky added. "The positive results we have obtained today give us confidence in donanemab and support its rapid and deep plaque clearance for the potential treatment of Alzheimer's disease."
The trial enrolled 272 patients with early symptomatic Alzheimer's disease who were selected based on cognitive assessments and imaging data. Donanemab also showed improvements in prespecified secondary endpoints relative to placebo, but not all secondary endpoint findings were statistically significant.
Safety was consistent with the drug's profile from phase I studies. Amyloid-related imaging abnormalities (ARIA) were observed. In the donanemab treatment group, ARIA-edema (ARIA-E) occurred in 27% of treated participants, with an overall incidence of 6% experiencing symptomatic ARIA-E.
Donanemab's safety, tolerability, and efficacy are being evaluated in the ongoing phase II study. Full results of TRAILBLAZER-ALZ will be presented at a future medical meeting and submitted to a peer-reviewed clinical journal, Lilly said. The company also plans to discuss TRAILBLAZER-ALZ findings with regulators to assess its next steps.