Two Phase 2 Multiple Ascending–Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer’s Disease

Article type: Research Article

Authors: Pasquier, Florence^{a; *} | Sadowsky, Carl^b | Holstein, Ann^c | Leterme, Ghislaine Le Prince^d | Peng, Yahong^c | Jackson, Nicholas^c | Fox, Nick C.^e | Ketter, Nzeera^f | Liu, Enchi^f | Ryan, J. Michael^c | for the ACC-001 (QS-21) Study Team

Affiliations: [a] Inserm U1171, Memory clinic of CHU and University of Lille, Lille, France | [b] Premiere Research Institute, Palm Beach Neurology, Nova SE University, West Palm Beach, FL, USA | [c] Pfizer Vaccine R&D, Collegeville, PA, USA | [d] Pfizer Global Research and Development, Paris cedex 14 – France | [e] Dementia Research Centre, Department of Neurodegeneration, UCL Institute of Neurology, London, UK | [f] Janssen Research and Development, San Diego, CA, USA

Correspondence: [*] Correspondence to: Florence Pasquier, MD, PhD, Clinique Neurologique, Hôpital Roger Salengro, Avenue du Pr Emile Laine - 59037 Lille Cedex, France. Tel.: +33 320 44 5785; Fax: +33 320 44 6022; E-mail: [email protected].

Abstract: Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer’s disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party–unblinded, placebo-controlled, multiple ascending–dose studies of ACC-001 (3μg, 10μg, 30μg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30μg + QS-21; ACC-001 10μg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aβ IgG titers compared with ACC-001 alone. Plasma Aβx–40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16–56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD.

Keywords: Active immunization, Alzheimer’s disease, amyloid-β peptides, amyloid-β protein, amyloid plaques, clinical trial, immunotherapy

DOI: 10.3233/JAD-150376

Journal: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1131-1143, 2016