INDIANAPOLIS—Eli Lilly and Co. has announced new Phase 2 data from the investigational antibody donanemab (once known as LY3002813) that show it can help Alzheimer’s disease patients by clearing a modified form of beta amyloid out of the brain. The active immunotherapy is designed to stimulate the patient’s immune system to attack and destroy beta amyloid plaques that form in the brain and trigger Alzheimer’s, according to Eli Lilly.
Donanemab targets a modified form of beta amyloid called N3pG. It showed significant slowing of decline in a composite measure of cognition and daily function in patients with early symptomatic Alzheimer’s disease, as compared to placebo, in results from Lilly’s Phase 2 TRAILBLAZER-ALZ study. The drug candidate met the primary endpoint of change from baseline to 76 weeks in the Integrated Alzheimer’s Disease Rating Scale (iADRS), slowing decline by 32 percent relative to placebo. The iADRS is a clinical composite tool that combines the cognitive measure ADAS-Cog13 and functional measure ADCS-iADL, two commonly used measures in Alzheimer’s disease. While donanemab showed consistent improvements in all prespecified secondary endpoints measuring cognition and function compared to placebo, it did not reach nominal statistical significance on every secondary endpoint.
Donanemab treatment has been demonstrated to rapidly clear high levels of amyloid plaque by targeting N3pG beta amyloid, as measured by amyloid imaging tests. On average, in TRAILBLAZER-ALZ, donanemab-treated patients 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.) In the study, 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.
TRAILBLAZER-ALZ (NCT03367403) 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 imaging.
Currently, no treatments approved by the FDA can decelerate cognitive decline in Alzheimer’s disease patients. Almost 10 million new cases of dementia are diagnosed each year worldwide. With an estimated 5.5 million Americans afflicted with this deadly neurodegenerative disorder, the first drug approved for Alzheimer’s could generate annual sales of more than $10 billion.
Dr. Mark Mintun, vice president of pain and neurodegeneration at Eli Lilly, said, “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. We look forward to discussing the TRAILBLAZER-ALZ study data and next steps with global regulators. In addition, we are committed to reproducing and extending these important findings in our second ongoing pivotal donanemab trial, TRAILBLAZER-ALZ 2. With more than 30 years of dedication to finding solutions for this devastating disease, we are proud of our progress moving the field forward and advancing the science. These positive results give us hope for patients and their families.”
“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,” added Dr. Daniel Skovronsky, Lilly’s chief scientific officer and president of Lilly Research Laboratories. “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. 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 safety profile of donanemab was consistent with the observations from Phase 1 studies. Lilly indicated that amyloid-related imaging abnormalities (ARIA) were seen, which is consistent with amyloid plaque clearing antibodies. In the donanemab treatment group, amyloid-related imaging abnormalities–edema (ARIA-E) occurred in 27 percent of treated participants, with an overall incidence of 6 percent experiencing symptomatic ARIA-E.