Eli Lilly today released topline Phase II data showing that its modified beta amyloid-targeting antibody donanemab significantly slowed decline in a composite measure of cognition and daily function in patients with early symptomatic Alzheimer’s disease compared to placebo.

According to the data, from Lilly’s TRAILBLAZER-ALZ study (NCT03367403), donanemab met the primary endpoint of change from baseline to 76 weeks in the Integrated Alzheimer’s Disease Rating Scale (iADRS), slowing decline by a statistically significant 32% compared with placebo.

Donanemab also showed consistent improvements in all pre-specified secondary endpoints measuring cognition and function compared to placebo, but did not reach nominal statistical significance on every secondary endpoint, Lilly said.

By targeting N3pG beta amyloid, Lilly said, donanemab treatment showed itself to rapidly result in high levels of amyloid plaque clearance, as measured by amyloid imaging. In TRAILBLAZER-ALZ, donanemab-treated patients, on average, showed an 84 centiloid reduction of amyloid plaque at 76 weeks compared to a baseline of 108 centiloids (less than 25 centiloids is typical of a negative amyloid scan).

Patients stopped receiving 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,” Daniel Skovronsky, MD, PhD, Lilly’s chief scientific officer and 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.

“Gives us confidence”

“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,” Skovronsky added.

The safety profile of donanemab was consistent with observations from Phase I data. Amyloid-related imaging abnormalities (ARIA) were observed, which is consistent with amyloid plaque clearing antibodies. In the donanemab treatment group, amyloid-related imaging abnormalities—edema (ARIA-E) occurred in 27% of treated participants, with an overall incidence of 6% experiencing symptomatic ARIA-E.

TRAILBLAZER-ALZ is a randomized, placebo-controlled, double-blind, multi-center Phase II study designed 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 imaging.

Lilly said full results of TRAILBLAZER-ALZ will be presented at a future medical congress and submitted for publication in a peer-reviewed clinical journal. Lilly also plans to discuss these results with regulators as it assesses its next steps for donanemab.

“We are extremely pleased about these positive findings for donanemab as a potential therapy for people living with Alzheimer’s disease, the only leading cause of death without a treatment that slows disease progression,” stated Mark Mintun, MD, Lilly’s vice president of pain and neurodegeneration. “We look forward to discussing the TRAILBLAZER-ALZ study data and next steps with global regulators.”

Second Phase II trial

Mintun also said Lilly was committed to reproducing and extending its findings from TRAILBLAZER-ALZ in its second ongoing pivotal donanemab trial, the randomized, placebo-controlled, double-blind, multi-center TRAILBLAZER-ALZ 2 (NCT04437511), set to enroll 500 participants. That study has an estimated primary completion date of March 9, 2023.

The announcement touched off a stock surge for Lilly, which saw its share price climb 13% in response to the news, rising to $188.59 as of 9:36 a.m. before dipping to 185.43 from Friday’s close of $166.41, an 11% gain.

Lilly hopes to succeed where numerous other drug developers have failed in the long struggle to create successful new drugs for Alzheimer’s disease. Only a handful of drug successes have ever reached the market, and even they have merely slowed progression of symptoms by 6 to 12 months.

2014 Cleveland Clinic study found a 99.6% failure rate of clinical trials for Alzheimer’s disease drug candidates between 2002 and 2012. That study found high attrition rates for Alzheimer’s disease treatments, with 72% of agents failing in Phase I, 92% failing in Phase II, and 98% failing in Phase III.

According to a study published last July, 121 drug candidates were in clinical trials for the treatment of Alzheimer’s disease. Of those, 29 were in 36 Phase III trials, 65 were in 73 Phase II trials, and 27 in 27 Phase I trials.