Donanemab (LY3002813), Eli Lilly’s experimental antibody-based immunotherapy, slowed cognitive and functional decline in patients at the earlier stages of Alzheimer’s disease, according to data from a Phase 2 trial.
Findings from this trial, called TRAILBLAZER-ALZ (NCT03367403), also showed donanemab had a favorable safety profile, which was consistent with observations from previous clinical trials.
“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,” Mark Mintun, MD, vice president of pain and neurodegeneration at Eli Lilly, said in a press release.
“We look forward to discussing the TRAILBLAZER-ALZ study data and next steps with global regulators,” Mintun said.
Donanemab is an antibody — a protein that helps fight off infections — that is designed to recognize and bind to a form of the beta-amyloid protein that has already clumped together in plaques in people with Alzheimer’s. By doing so, donanemab is expected to trigger an immune response against these harmful plaques and help the body eliminate them. This, in turn, is expected to slow Alzheimer’s progression.
“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,” said Daniel Skovronsky, MD, PhD, chief scientific officer and president of Lilly Research Laboratories.
TRAILBLAZER-ALZ is an ongoing Phase 2 trial that’s assessing the safety, tolerability, and efficacy of donanemab in patients with early symptomatic Alzheimer’s. A total of 272 older adults, ages 60–85, with early Alzheimer’s, were randomly assigned to receive either donanemab, or a placebo, both given intravenously (into the vein) over approximately 18 months.
The study’s main goal was to assess changes in the participants’ scores on the Integrated Alzheimer’s Disease Rating Scale (iADRS), a composite measure of cognition and daily life functioning. Score changes were monitored from the start of the trial until week 76, or over the course of about 1.5 years.
Additional study goals included assessing changes in other measures of cognition, memory, and activities of daily living. The effects of treatment on the number of amyloid plaques also were assessed through brain imaging scans.
Data from TRAILBLAZER-ALZ, now announced by the company, showed that donanemab slowed patients’ cognitive and functional decline, based on their iADRS scores, by 32% compared with a placebo.
Consistent improvements in the scores of all other cognitive and functional measures, including the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and the Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living Scale (ADCS-iADL), also were observed in the patients treated with donanemab.
Yet, statistically significant improvements were not found for all key secondary endpoints.
Positive results were shown regarding the patients’ numbers of amyloid plaques for those participants receiving donanemab. This group saw the number of such plaques drop from an average of 108 centiloids at the study’s start to 24 centiloids at week 76. Importantly, brain scans detecting less than 25 centiloids are normally considered negative for the presence of amyloid plaques.
Of note, centiloids are a common standard measure used in amyloid-imaging assessments.
Patients who had less than 25 centiloids in two consecutive brain scans, and those who had less than 11 centiloids in a single imaging test, stopped treatment with donanemab and switched over to the placebo.
“Our expertise in amyloid and tau imaging … 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 said.
“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 said.
Safety assessments demonstrated a favorable safety profile, which was consistent with reports from previous trials.
Amyloid-related image abnormalities (ARIA), which are indicative of brain swelling (edema), were observed in about a third (27%) of the patients treated with donanemab. However, the percentage of patients experiencing symptoms of brain swelling was much lower, at 6%.
“These results reaffirm the strong belief of UsA2 that hope is indeed on the horizon — and that our nation remains on a path towards treatments and a cure,” George Vradenburg, chairman and co-founder of the nonprofit UsAgainstAlzheimer’s (UsA2), said in a press release.
“Our organization, together with the broader Alzheimer’s community, looks forward to learning more about the results of the trial and how donanemab could slow the progression of Alzheimer’s in those who are in mild stages of the disease,” Vradenburg said.
“We thank all those patients and individuals who have participated in donanemab clinical trials, and applaud Eli Lilly & Co. for their work in developing donanemab as a treatment for Alzheimer’s disease and for persevering in the fight to find a cure,” he added.
Eli Lilly is now planning to present full data from TRAILBLAZER-ALZ at a future medical conference and to publish the study findings in a peer-reviewed clinical journal.
In addition to TRAILBLAZER-ALZ, two other clinical trials, both sponsored by Lilly, are currently assessing the safety and efficacy of donanemab for the treatment of patients with early Alzheimer’s. These include the study’s long-term extension TRAILBLAZER-EXT (NCT04640077), and a second, pivotal Phase 2 trial, called TRAILBLAZER-ALZ 2 (NCT04437511), which is currently recruiting participants.
“We are committed to reproducing and extending these important findings in our second ongoing pivotal donanemab trial, TRAILBLAZER-ALZ 2,” Mintun said.
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