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

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.

• Authors: Florence Pasquier, Carl Sadowsky, Ann Holstein, Ghislaine Le Prince Leterme, Yahong Peng, Nicholas Jackson, Nick C Fox, Nzeera Ketter, Enchi Liu, J Michael Ryan, ACC-001 (QS-21) Study Team
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 51 Issue 4 Pg. 1131-43 ( 2016) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 26967206 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Amyloid beta-Peptides
• Antipsychotic Agents
• Peptide Fragments
• Recombinant Fusion Proteins
• Saponins
• amyloid beta-protein (1-42)
• saponin QA-21V1
• Interferon-gamma
• vanutide cridificar

Topics

• Adjuvants, Immunologic (therapeutic use)
• Aged
• Alzheimer Disease (diagnostic imaging, drug therapy)
• Amyloid beta-Peptides (blood)
• Antipsychotic Agents (therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Follow-Up Studies
• Humans
• Interferon-gamma (blood)
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Neuropsychological Tests
• Peptide Fragments (blood)
• Recombinant Fusion Proteins (therapeutic use)
• Saponins (therapeutic use)
• Single-Blind Method
• Treatment Outcome