Phase 2 cAPPricorn Study to Assess RNA Therapeutic Mivelsiran in Cerebral Amyloid Angiopathy

Steven M. Greenberg, MD, PhD

A new phase 2 study, dubbed cAPPricorn-1 (NCT069393712), will assess the therapeutic potential of mivelsiran (Alnylam Pharmaceuticals), an intrathecally administered RNAi therapeutic targeting amyloid precursor protein (APP), in patients with cerebral amyloid angiopathy (CAA). The global study is currently aiming to enroll 200 patients across sites in North America, Europe, and Australia.¹

The design of the trial was presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, in Madrid, Spain. In cAPPricorn, patients are randomly assigned 1:1 to either intrathecal mivelsiran or placebo for a 24-month double-blind period, followed by an optional 18-month open-label extension. The study, which will include patients with sporadic CAA (aged ≥50 years with probable CAA per Boston Criteria Version 2.0) or Dutch-type CAA (aged ≥30 years with a known E693Q APP variant) will use annualized rate of new lobar cerebral microbleeds as the primary end point.

Senior author Steven M. Greenberg, MD, PhD, director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital, and colleagues, will employ a blinded, centrally-adjudicated MRI tool to measure the primary end point. In addition, the study will also include several other key secondary end points, including changes in vascular reactivity, white matter hyperintensities, CAA total small vessel disease severity score, pharmacodynamic activity as measured by soluble APP in cerebrospinal fluid, and frequency of adverse events (AEs).

Mivelsiran, which is also in development for Alzheimer disease (AD), 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 amyloid-ß (Aß).

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CAPPricorn has a few exclusion criteria, including patients with moderate or severe stage AD or significant cognitive impairment. In addition, the study excludes those with a history of previous clinical intracerebral hemorrhage with onset less than 90 days prior to randomization in the study, patients treated with anti-amyloid therapies, and those with alanine aminotransferase or aspartate aminotransferase limits at least 3 times normal at screening.

Mivelsiran is currently being tested in a 2-part, phase 1 study (NCT05231785) of patients with early-onset AD, with results that were recently presented at the 2024 Alzheimer’s Association International Conference. All told, the data revealed that mivelsiran at doses of 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 the progression of AD and CAA. The analysis featured data on 20 patients (mean age, 61.3 years) who 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.²

Following the positive phase 1 data, NeurologyLive^® sat down with study author Sharon Cohen, MD, a behavioral neurologist, to discuss the findings and more on the mechanism behind mivelsiran. As part of an episode of the Mind Moments podcast, Cohen who also serves as the medical director of the Toronto Memory Program at the University of Toronto, discussed the potential of RNA therapeutics for treating AD, the unique mechanism of action of mivelsiran, and some of the early promising safety, efficacy, and pharmacokinetic data observed in the phase 1 trial.

In the episode below, Cohen touched upon the idea of how RNA therapeutics could be used in combination with previously approved novel treatments and the benefits mivelsiran brings with no observed amyloid-related imaging abnormalities. Furthermore, she covered some of the potential of this investigational agent, what to expect in the multi-dose part B of the study, and the phase 2 cAPPricorn study in CAA.

Click here for more CTAD 2024 coverage.

REFERENCES
1. Lee JM, Van Etten ES, Van Osch MLP, et al. Design and rationale of cAPPricorn-1, a phase 2 study of mivelsiran in patients with cerebral amyloid angiopathy. Presented at: Clinical Trials on Alzheimer’s Disease (CTAD) conference; October 29-November 1, 2024; Madrid, Spain.
2. 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