Immunotherapy with ponezumab for probable cerebral amyloid angiopathy

• Published in: Annals of clinical and translational neurology 2019-04, Vol.6 (4), p.795-806
• Main Authors: Leurent, Claire, Goodman, James A., Zhang, Yao, He, Ping, Polimeni, Jonathan R., Gurol, Mahmut Edip, Lindsay, Monica, Frattura, Linda, Sohur, Usharbudh Shivraj, Viswanathan, Anand, Bednar, Martin M., Smith, Eric E., Greenberg, Steven M., Cordonnier, Charlotte, Werring, David John, Black, Sandra Elizabeth, Honig, Lawrence Sterling, Klijn, Catharina J.M., Lee, Jin‐Moo, Restrepo, Lucas, Kase, Carlos, Savitz, Sean I.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Alzheimer Disease - complications; Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Antibodies, Monoclonal, Humanized - therapeutic use; Cancer therapies; Cerebral Amyloid Angiopathy - complications; Cerebral Amyloid Angiopathy - drug therapy; Cerebral Hemorrhage - drug therapy; Cerebral Hemorrhage - etiology; Cognition & reasoning; Dementia; Double-Blind Method; Double-blind studies; Female; Humans; Immunologic Factors - therapeutic use; Immunotherapy; Immunotherapy - methods; Magnetic Resonance Imaging - methods; Male; Middle Aged; NMR; Nuclear magnetic resonance; Peptide Fragments - metabolism; Peptides; Treatment Outcome
• ISSN: 2328-9503; 2328-9503
• DOI: 10.1002/acn3.761

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 Aβ1–40. 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.