2021-01-15| R&DTrials & Approvals

Lilly’s Donanemab Aces Phase 2 Trial, Slows Clinical Decline in Alzheimer’s Patients

by Eduardo Longoria
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At the 39th JPMorgan Healthcare Conference, Eli Lilly discussed how 2020 taught the firm to manage large scale clinical trials remotely. Despite the expectations, Eli Lilly saw a surprisingly low dropout rate in clinical trials that were managed remotely. The company announced that its investigational antibody, donanemab demonstrated rapidly high levels of amyloid plaque clearance in Alzheimer’s patients, as measured by amyloid imaging.

Alzheimer’s disease is a type of dementia characterized by the build-up of beta-amyloid plaques and groups of proteins called tau bundles. These groups of proteins are seen to come from the alternative splicing or incorrect folding of proteins into a form that impairs the connections between neurons in the brain.

“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.“ said Mark Mintun, M.D., Vice President of pain and neurodegeneration, Eli Lilly and Company.


Phase 2 Trial

TRAILBLAZER-ALZ (NCT03367403) is a clinical trial focused on early symptomatic Alzheimer’s disease. The randomized, placebo-controlled, Phase 2 study evaluated donanemab, an investigational antibody that targets Aβ(p3-42), a pyroglutamate form of amyloid-beta (Aβ). Donanemab showed significant slowing of decline in a composite measure of cognition and daily function in patients with early symptomatic Alzheimer’s disease.

The trial selected 272 patients based on cognitive assessments in conjunction with amyloid plaque and tau protein (produced by alternative splicing of microtubule-associated protein tau) imaging. The primary endpoint was the change observed from baseline until 76 weeks in the Integrated Alzheimer’s Disease Rating Scale (iADRS), a composite tool combining the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog13) and the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCS-iADL) for function. Donanemab was found to slow decline by a statistically significant 32%, relative to the placebo.

Donanemab-treated patients, on average, showed an 84 centiloid (the standard unit of beta-amyloid imaging tracers for positron emission tomography) reduction of amyloid plaque at 76 weeks. This is compared to a baseline of 108 centiloids (less than 25 centiloids is typical of a negative amyloid scan). In this 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.

“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, M.D., Ph.D., Lilly’s chief scientific officer and president of Lilly Research Laboratories.


Side Effects and Considerations

The safety profile of donanemab was consistent with observations from Phase 1 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 percent of treated participants, with an overall incidence of 6 percent experiencing symptomatic ARIA-E.

The full results of the TRAILBLAZER-ALZ study will be presented at a future medical congress and submitted for publication in a peer-reviewed clinical journal. Lilly plans to discuss these results with regulators to assess the next steps.

With Alzheimer’s affecting 6 million Americans, a drug that could slow disease progression and improve quality of life is indeed valuable. As of 2018, the disease was responsible for $277 billion worth of medical expenses in the US and an even greater loss in productivity caused by people being unable to properly function and the unpaid care given by family members. This also comes as good news to Biogen, whose Alzheimer’s drug aducanumab was turned down by an independent panel last November.

Related Article: Biogen’s Alzheimer’s Drug Turned Down by Independent Panel



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