A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate Alzheimer’s disease

Article type: Research Article

Authors: Brody, Mark^a | Liu, Enchi^{b; 1} | Di, Jianing^b | Lu, Ming^c | Margolin, Richard A.^{d; 2} | Werth, John L.^e | Booth, Kevin^e | Shadman, Anna^{f; 3} | Brashear, H. Robert^f | Novak, Gerald^{g; *}

Affiliations: [a] Brain Matters Research, Delray Beach, FL, USA | [b] Janssen Research & Development, San Diego, CA, USA | [c] Janssen Research & Development, Spring House, PA, USA | [d] Janssen Alzheimer Immunotherapy, South San Francisco, CA, USA | [e] Pfizer Inc., Collegeville, PA, USA | [f] Janssen Research & Development, Fremont, CA, USA | [g] Janssen Pharmaceutical Research and Development, Titusville, NJ, USA

Correspondence: [*] Correspondence to: Gerald Novak, MD, Janssen Pharmaceutical Research & Development, LLC, 1125, Trenton-Harbourton Rd, Titusville, NJ 08560, USA. Tel.: +1 609 730 4416; Fax: +1 908 730 2069 E-mail: [email protected].

Note: [1] Present affiliation: Prothena Biosciences, Inc., South San Francisco, CA, USA.

Note: [2] Present affiliation: CereSpir Inc., New York, NY, USA.

Note: [3] Present affiliation: Amgen, Thousand Oaks, CA, USA.

Abstract: Background: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-β (Aβ1-40/1 -42) that is believed to play a key role in the pathogenesis of Alzheimer disease (AD). Objectives: To assess the effects of monthly subcutaneous (SC) bapineuzumab versus placebo on cerebral amyloid signal in amyloid-positive patients with mild to moderate AD. The incidence of amyloid-related imaging abnormalities–edema/effusion (ARIA-E), pharmacokinetics, pharmacodynamics, immunogenicity, and other safety aspects of bapineuzumab were also evaluated. Methods: In this multicenter, double-blind study, 146 patients were randomized (1 : 1:1 : 1) to SC bapineuzumab 2, 7, or 20 mg/month or placebo. Lack of efficacy of intravenous (IV) bapineuzumab in Phase III studies led to truncation of the treatment duration from 24 months to 12 months. Primary endpoint: change from baseline to month 12 in brain amyloid signal as measured by standardized uptake value ratio (SUVR) using florbetapir positron emission tomography (PET). Results: Florbetapir PET SUVR decreased significantly (p = 0.038) from baseline to month 12 for the bapineuzumab 7 mg/month group only; reductions versus placebo were not significant for any dosage. One patient each in bapineuzumab 2 mg/month and 20 mg/month groups had ARIA-E. The percentages of patients with treatment-emergent adverse events were similar in placebo (77.8%) and bapineuzumab 2 mg/month (78.4%) group, but higher in 7 mg/month (94.4%) and 20 mg/month (89.2%) groups. Conclusion: Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab.

Keywords: Alzheimer’s disease, amyloid burden, bapineuzumab, biomarker, pharmacokinetics

DOI: 10.3233/JAD-160369

Journal: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1509-1519, 2016