Overviewing Encouraging Early-Stage Data on Mivelsiran, RNA Therapeutic for Alzheimer Disease: Sharon Cohen, MD, FRCPC

WATCH TIME: 8 minutes

"We're seeing the kinds of side effects you would see in patients who have LPs (lumbar punctures)... So, safe drug and when we look at usual blood work and cardiograms... we're not seeing any signal that there's any concern."

Alzheimer disease (AD) is the most common neurodegenerative disease and the most common form of dementia, affecting over 30 million people worldwide. In AD, the accumulation of amyloid-ß (Aß) plaques and neurofibrillary tangles leads to chronic inflammation in the brain which ultimately results in significant brain atrophy. The therapeutic pipeline for AD is filled with various agents, each with different mechanisms of action and routes of administration.

Mivelsiran (Alnylam Pharmaceuticals) is an investigational, intrathecally administered RNAi therapeutic targeting amyloid precursor protein (APP) in development for the treatment of AD and cerebral amyloid angiopathy (CAA). The agent is built to decrease APP mRNA in the central nervous system, thus potentially reducing synthesis of APP protein and all downstream intracellular and extracellular APP-derived cleavage products, including Aß. It is currently being tested in a 2-part, phase 1 study (NCT05231785) study of patients with early-onset AD, with results that were presented at the recently concluded 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 1, in Philadelphia, Pennsylvania.

As of November 2023, 20 patients (mean age, 61.3 years) were randomly assigned to mivelsiran or placebo in 25 mg (n = 6; 2:1 randomization), 50 mg (n = 8; 3:1), and 75 mg (n = 6; 2:1) cohorts. Led by principal investigator Sharon Cohen, MD, FRCPC, mivelsiran 50 mg and 75 mg were well tolerated and produced robust, durable reductions in cerebrospinal levels of soluble APP and downstream Aß42 and Aß40, key proteins implicated in progression of AD and CAA. Cohen, a behavioral neurologist and medical director of the Toronto Memory Program at the University of Toronto, sat down following the meeting to give an overview of the results, focusing on the safety, target engagement, and biomarker impacts observed. Furthermore, she provided a comprehensive overview of the future potential of mivelsiran, including its alluring administration regimen.

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REFERENCE
1. Cohen S, Ducharme S, Brosch JR, et al. Single ascending dose results from an ongoing phase 1 study of mivelsiran (ALN-APP), the first investigational RNA interference therapeutic targeting amyloid precursor protein for Alzheimer’s disease. Presented at: 2024 Alzheimer’s Association International Conference; July 28-August 1; Philadelphia, PA. ABSTRACT 84521