Immunotherapy with ponezumab for probable cerebral amyloid angiopathy

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.

Figure 1

Locations of Regions of Interest (ROI). ROI1 is shown on the left, and ROI2 is shown on the right.

Figure 2

CONSORT flow diagram.

Figure 3

Primary outcome for log_e(slope) change from baseline, mean ± SE.

Figure 4

Mean plasma Aβ _1–40 concentration versus time.

Figure 5

FLAIR and T2*‐weighted images of ARIA‐E event. (A) FLAIR (top row) and T2*‐weighted images (bottom row) taken at baseline (left), Day 45 (middle) and Day 90 (right). The arrow in the Day 90 FLAIR image indicates the presence of new ARIA‐E, and the associated T2*‐weighted image at Day 90 shows a new colocalized subarachnoid hemorrhage. Baseline findings in this subject included multiple areas of superficial siderosis of both cerebral hemispheres. (B) Baseline findings also included four old parenchymal macro‐hemorrhages, as show in three different levels in the baseline T2‐weighted images.