A recent phase three study conducted by Eli Lilly examined the safety and efficacy of the study drug donanemab in participants with early Alzheimer's disease (AD).

Study: Lilly's Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer's Disease. Image Credit: Ground icture/Shutterstock.com

Background

The pharmaceutical company Eli Lilly announced in a press release on May 3, 2023, that a clinical trial of the experimental Alzheimer's drug, donanemab, showed it could significantly slow the progress of cognitive decline, allowing patients increased independence.

The drugmaker's announcement revealed that the drug succeeded in halting early AD progression in nearly half of the participants, slowing cognitive decline rates by 35% compared to control participants.

Donanemab is an antibody that targets protein aggregates, known as amyloid beta proteins, which are the causative agents of brain plaques. Despite the direct causes of Alzheimer's being unknown, brain plaques have been thought to slow brain function and thus advance cognitive decline.

If the therapy were approved by the Food and Drug Administration (FDA), it would become the third Alzheimer’s drug to enter the market in the past three years. Safety concerns remain despite the promising trial results, with at least two participants experiencing fatal brain swelling.

About the study

The study, known as TRAILBLAZER-ALZ 2, is a phase three, placebo-controlled, double-blind study that aimed to explore the safety, tolerability, and efficacy of N3Pg antibody in early AD patients with brain tau pathology.

The study enrolled 1,736 participants that were selected following cognitive assessments, amyloid plaque imaging, and tau staging.

All participants had early AD, including individuals with mild cognitive impairment (MCI) and mild dementia. The primary analysis population comprised 1,182 individuals with an intermediate tau level and clinical AD symptoms. The study also enrolled 552 individuals with high tau levels at baseline, representing those at a later disease progression.

All participants were aged between 60 to 85 and were not undergoing immunoglobin G therapy. The study measured the efficacy of donanemab by evaluating how likely participants were to progress across Alzheimer's categories, such as MCI to mild dementia or from mild dementia to moderate.

More information on the study will be revealed in the peer-reviewed journal paper that has yet to be published.

Results

In the primary analysis population, the primary endpoint, the integrated Alzheimer's Disease Rating Scale (iADRS), showed a 35% slowing of decline (p<0.0001). The secondary endpoint (Clinical Dementia Rating Sum of Boxes, CDR-SB) showed a 36% slowing of decline (p<0.0001) over 18 months.

Additionally, in this primary population, 47% of participants that took donanemab showed no CDR-SB decline, a key measure of cognitive disease. 52% of participants had completed treatment within 12 months, and 72% within 18 months. Finally, participants on donanemab were at a 39% lower risk of progressing to a worse disease stage than placebo.

The secondary analysis population also showed promising results across both endpoints, with iARDS and CDR-SB showing a 22% and 29% decline, respectively.

In addition, TRAILBLAZER-ALZ-2 also reduced brain amyloid plaque levels from six months following treatment, with many patients reaching levels characterized as negative for pathology. Of these, 34% in the primary study population reached amyloid clearance at six months and 71% at 12 months.

What's next?

In sum, donanemab treatment slowed clinical decline by 35% compared to the placebo. Furthermore, it resulted in a 40% lowered decline in the ability to perform daily activities, bettering individual quality of life.

All primary and secondary study endpoints and aims were met, showing a clinically significant benefit. Lilly will proceed rapidly with global regulatory submissions and make an FDA submission. The FDA, Lilly, and other regulators will work together to achieve traditional approvals.

Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience, said…

These Phase 3 data confirm the benefit observed in our TRAILBLAZER-ALZ study and show that donanemab if approved, may represent a significant step forward for people with early symptomatic Alzheimer's disease, and allow them to continue to participate in activities that are meaningful to them,"

Furthermore, Anne White claims…

We believe our data meets the 'high level of evidence' the Centers for Medicare & Medicaid Services (CMS) has described as the trigger for reconsideration of its National Coverage Determination. People with early Alzheimer's disease need and deserve full coverage and access for approved therapies."

Written by

Lily Ramsey

Lily graduated from the University of Nottingham with a first-class degree in Microbiology in 2021. More recently, Lily has graduated with an LLM specializing in Medical Law and Ethics from the University of Edinburgh. As part of her master's program, Lily focussed her research on public health ethics, with a particular interest in health equity and social justice, more specifically in antibiotic resistance ethics.