Eli Lilly's Anti-Amyloid Antibody Donanemab Meets Primary Endpoint in Phase 2 Trial for Early Alzheimer’s Disease

Today, Eli Lilly and Company announced that donanemab, its monoclonal antibody targeting β-amyloid, met the primary endpoint in a Phase 2 clinical trial, demonstrating a 32% slowing in the decline of a composite measure assessing cognitive function and daily activities in patients with early Alzheimer’s disease. This announcement has immediately sparked widespread attention and heated discussion within the industry. As is well known, Alzheimer’s disease is the most common neurodegenerative disorder among the elderly, exerting serious and far-reaching negative impacts not only on patients themselves but also on their families, communities, and society as a whole.

However, over the past 15 years, multiple investigational therapies for Alzheimer’s disease have failed in late-stage clinical development, including several candidates targeting beta-amyloid. Consequently, doubts have arisen regarding whether beta-amyloid is indeed the cause of cognitive decline in patients with Alzheimer’s disease. Nevertheless, last year Biogen announced that its beta-amyloid antibody, aducanumab, demonstrated positive clinical results in Phase 3 trials. Its regulatory application has been granted Priority Review by the U.S. FDA, with a response expected this spring.

While the data on donanemab, another β-amyloid-targeting therapy, has garnered significant attention, it has also raised certain questions. As a β-amyloid-targeting agent, how does Eli Lilly’s donanemab differ from other targeted therapies? Have we discovered the “key” to successfully targeting β-amyloid? And how far are we from developing effective treatments for Alzheimer’s disease? Today, WuXi AppTec’s content team will explore these questions based on publicly available information.

Clinical Trial Results of Donanemab

Let us first examine the performance of donanemab in its Phase 2 clinical trial, which enrolled a total of 272 patients with early-stage Alzheimer’s disease. Upon enrollment, these patients underwent not only cognitive assessments but also imaging evaluations to detect amyloid and tau protein deposition in the brain. They were randomly assigned to receive either donanemab or placebo.

After 76 weeks of treatment, analysis of a composite endpoint assessing cognitive ability and daily function showed that the rate of decline in the donanemab group was slowed by 32% compared with the placebo group, thereby meeting the trial’s primary endpoint. Furthermore, imaging assessments of amyloid deposition demonstrated a substantial reduction in amyloid plaques in the brains of patients treated with donanemab. After 76 weeks of treatment, amyloid plaque levels in the brain, measured using the Centiloid scale for assessing amyloid burden, decreased by an average of 84 units. The baseline level was 108, and a value below 25 is considered indicative of a negative amyloid scan, comparable to that of healthy individuals.

What Makes Donanemab Different?

Donanemab specifically binds to an amyloid protein subtype known as N3pG. By targeting this subtype, donanemab can selectively bind to amyloid plaques in the brain, thereby promoting their clearance. The “amyloid hypothesis” posits that Alzheimer’s disease originates from the cleavage of amyloid precursor protein (APP) in the patient’s brain to generate amyloid-beta (Aβ). These Aβ monomers continuously aggregate into dimers and oligomers, ultimately forming deposited amyloid plaques. Many investigational therapies aim to inhibit Aβ production or the formation of dimers and oligomers. However, a study published in Neuron in 2012 demonstrated that monoclonal antibodies capable of binding to Aβ monomers were less effective at clearing amyloid plaques than antibodies that specifically bind to amyloid plaques.

This occurs because, within the therapeutic dose range, monoclonal antibodies capable of binding to Aβ monomers bind to Aβ monomers and oligomers in the blood and cerebrospinal fluid before they can bind to amyloid plaques, thereby preventing their subsequent binding to amyloid plaques. In contrast, antibodies that specifically bind to amyloid plaques can bypass the “barrier” posed by Aβ monomers and oligomers, thus more effectively clearing amyloid plaque deposits in the brain.

"New Approaches to Targeting Amyloid Proteins"

Dr. Daniel Skovronsky, Chief Scientific Officer of Eli Lilly and Company, stated that donanemab’s rapid clearance of amyloid plaques, combined with the company’s expertise in amyloid and tau imaging technologies, enabled researchers to test the hypothesis that reducing amyloid plaque levels in patients with Alzheimer’s disease to those comparable to healthy individuals could significantly slow cognitive decline. The positive results from this clinical trial have strengthened their confidence in this hypothesis.

A review of the trial results for Biogen’s aducanumab also reveals that, among patients with Alzheimer’s disease who were able to receive continuous high-dose aducanumab treatment, PET scans showed a greater reduction in amyloid levels in their brains, and the rate of cognitive decline in these patients was significantly slowed.

These results appear to indicate that the previous failures of investigational therapies targeting amyloid may be attributed to their inability to reduce amyloid plaque deposition in the brain to sufficiently low levels.

Guided by this concept, Roche has launched two Phase 3 clinical trials to evaluate the efficacy of high-dose gantenerumab, an amyloid-beta antibody, in patients with early-stage Alzheimer’s disease. This monoclonal antibody preferentially binds to aggregated Aβ proteins in the brain and facilitates the degradation of amyloid plaques by recruiting microglia and activating macrophages. The company has also developed a “Brain Shuttle” technology that enables gantenerumab to cross the blood-brain barrier, thereby enhancing the clearance of amyloid deposits in the brain.

The Future of Alzheimer’s Disease Treatment

Admittedly, the clinical trial of donanemab enrolled only 272 patients, and these results still need to be validated in Phase III clinical trials with larger patient populations. Nevertheless, data from aducanumab and donanemab support the notion that more precise assessment of trial participants through amyloid and tau imaging may facilitate the enrollment of a more homogeneous patient cohort, thereby helping to demonstrate the efficacy of investigational therapies.

In addition to amyloid-targeting therapies, innovative anti-inflammatory treatments have recently yielded positive results in Phase 2b/3 clinical trials for Alzheimer’s disease. Novo Nordisk has also recently initiated a Phase 3 clinical trial to evaluate the efficacy of its GLP-1 receptor agonist, semaglutide, in treating patients with Alzheimer’s disease.

Note: This article is intended to introduce medical and health research and does not constitute a recommendation for treatment plans. For guidance on treatment options, please consult a licensed healthcare provider at a reputable hospital.

References:

[1] Lilly's Donanemab Slows Clinical Decline of Alzheimer's Disease in Positive Phase 2 Trial. Retrieved January 11, 2021, from https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-slows-clinical-decline-alzheimers-disease

[2] Therapeutic development for Alzheimer’s disease at Eli Lilly and Company. Retrieved January 11, 2021, from https://media.nature.com/full/nature-cms/uploads/ckeditor/attachments/8368/Lilly.pdf.

[3] DeMattos et al, A Plaque-Specific Antibody Clears Existing b-amyloid Plaques in Alzheimer’s Disease Mice. Neuron, http://dx.doi.org/10.1016/j.neuron.2012.10.029.

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