Vanutide Cridificar and the QS-21 Adjuvant in Japanese Subjects with Mild to Moderate Alzheimer’ s Disease: Results from Two Phase 2 Studies

Objective: Multiple lines of evidence indicate that pathological accumulation of amyloid beta (Aβ) peptide in the brain is linked to the pathophysiology of Alzheimer's disease (AD). Removal of Aβ from the brain by binding to anti-Aβ specific antibodies is under active investigation. Vaccination with a full-length Aβ42 peptide (AN1792) successfully elicited anti-Aβ antibodies in human subjects with AD, but was associated with meningoencephalitis. To avoid this safety issue, an aminoterminal Aβ1-7 peptide conjugate, vanutide cridificar (ACC-001), was designed and is currently in clinical development. This report describes two phase 2 multiple ascending-dose studies in Japanese subjects with mild to moderate AD. Safety and immunogenicity evaluation were the primary and secondary objectives, respectively. Methods: ACC-001 was administered to three cohorts of subjects at doses of 3, 10, or 30 μg, with or without a QS-21 adjuvant in Study 1, and with a QS-21 adjuvant in Study 2; control groups consisted of QS-21 alone (both studies) and phosphate-buffered saline (Study 1 only). Results: A variety of treatment-emergent adverse events (TEAEs) were reported from most subjects during the studies; most of these were mild or moderate in intensity. Three subjects withdrew from the study because of an adverse event (in Study 2). The most common treatment-associated TEAE was injection site reactions. No deaths were observed in either study. All doses of ACC-001 + QS-21 elicited high, sustained anti-Aβ antibody titers; QS-21 was necessary for this effect. Conclusion: These data will provide valuable information on further investigation of anti-Aβ vaccine therapy for AD. Keywords: Alzheimer's disease, amyloid-beta, amyloid plaques, antibody, immunotherapy, vaccine.