Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies

Article type: Research Article

Authors: Brashear, H. Robert^{a; *} | Ketter, Nzeera^{a; 1} | Bogert, Jennifer^b | Di, Jianing^{a; 2} | Salloway, Stephen P.^c | Sperling, Reisa^d

Affiliations: [a] Janssen Alzheimer Immunotherapy Research & Development, LLC, South San Francisco, CA, USA | [b] Janssen Research & Development, LLC, Raritan, NJ, USA | [c] Brown Medical School, Butler Hospital, Blackstone Blvd., Providence, RI, USA | [d] Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, MA, USA; General Hospital, Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: H. Robert Brashear, MD, Janssen Research & Development, 1800 American Boulevard, Pennington, NJ 08534, USA. Tel.: +1 609 730 2501; Fax: +1 609 730 2069; E-mail: rbrashea@janimm.com.

Note: [1] Present address: 141 Leland Avenue, Menlo Park, CA, USA.

Note: [2] Present address: Janssen ChinaR&DCenter, Shanghai, China.

Abstract: Background:Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer’s disease in bapineuzumab phase III studies. Objectives:Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function. Methods:A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE ɛ4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists. Results:Treatment-emergent ARIA-E occurred in 15.8% of bapineuzumab and 0.8% placebo-treated patients. In all treated APOE ɛ4 noncarriers, the percentage of patients with ARIA-E was 5.6%, 13.4%, and 19.9% in the 0.5, 1.0, and 2.0 mg/kg groups respectively, and the incidence of symptomatic ARIA-E was 1.5%, 1.5%, and 7.8%, respectively. In carriers, ARIA-E occurred in 21.2% in the 0.5 mg/kg group, and symptomatic ARIA-E occurred in 2.4%. The clinical severity of ARIA-E in those patients in whom it was detected during the study was mild in 57.1%, 61.3%, and 50.0% of cases in 0.5, 1.0, and 2.0 mg/kg noncarriers respectively, and in 73.8% of cases in 0.5 mg/kg carriers. Vascular risk factors did not appear to increase susceptibility to ARIA-E. Rate of decline in cognition and function measured by changes in ADAS-Cog/11 and DAD total scores did not meaningfully differ in patients with ARIA-E versus those without ARIA-E. Extent of cognitive decline was similar over all visit intervals. Conclusions:Overall, ARIA-E was mild and asymptomatic. ARIA-E did not demonstrate clinically meaningful acute or chronic impact on cognition or function.Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302)

Keywords: Amyloid-related imaging abnormality, bapineuzumab, clinical evaluation

DOI: 10.3233/JAD-180675

Journal: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1409-1424, 2018