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Immunotherapy with ponezumab for probable cerebral amyloid angiopathy.


Maximus Peto’s Commentary

This group reports disappointing results of intravenous monoclonal beta-amyloid (1-40) antibody, ponezumab, in patients with cerebral amyloid angiopathy.


Immunotherapy with ponezumab for probable cerebral amyloid angiopathy.
Ann Clin Transl Neurol. 2019 Mar 18;6(4):795-806.
Leurent C, Goodman JA, Zhang Y, He P, Polimeni JR, Gurol ME, Lindsay M, Frattura L, Sohur US, Viswanathan A, Bednar MM, Smith EE; Ponezumab Trial Study Group, Greenberg SM
DOI: 10.1002/acn3.761
PubMed publication date (edat): 4/26/2019

Abstract

OBJECTIVE:
Cerebral amyloid angiopathy (CAA) is caused by cerebrovascular deposition of β-amyloid fragments leading to cerebrovascular dysfunction and other brain injuries. This phase 2, randomized, double-blind trial in patients with probable CAA assessed the efficacy and safety of ponezumab, a novel monoclonal antibody against Aβ 1-40.

METHODS:
Thirty-six participants aged 55-80 years with probable CAA received intravenous placebo (n = 12) or ponezumab (n = 24). The change from baseline to Days 2 and 90 in cerebrovascular reactivity (CVR) was measured in the visual cortex as the natural log of the rising slope of the BOLD fMRI response to a visual stimulus. Safety and tolerability were also assessed.

RESULTS:
The mean change from baseline to Day 90 was 0.817 (ponezumab) and 0.958 (placebo): a mean ratio of 0.852 (90% CI 0.735-0.989) representing a trend towards reduced CVR in the ponezumab group. This trend was not present at Day 2. There was one asymptomatic occurrence of amyloid-related imaging abnormality-edema in the ponezumab group. The total number of new cerebral microbleeds from baseline to day 90 did not differ between groups. The ponezumab group had a participant with nonfatal new cerebral hemorrhage with aphasia and a participant with subdural hemorrhage that site investigators deemed to be nondrug related. In the placebo group one participant had a fatal intracerebral hemorrhage and one participant had migraine with aura.

INTERPRETATION:
Ponezumab was safe and well-tolerated. The ponezumab group showed a trend towards treatment effect at Day 90 that was opposite to the hypothesized direction. The prespecified efficacy criteria were thus not met.

PMID: 31020004
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469253/

Maximus Peto

Max Peto is a longevity researcher and founder of Long Life Labs. A biochemist by training, he studies the biochemistry of aging and longevity and has worked with research organizations such as SENS Research Foundation, Methuselah Foundation, BioAge Labs, Life Extension Foundation, and Ichor Therapeutics. His work at Long Life Labs is focused on empowering people to understand and manage the most critical factors for better health and longer life.

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