A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease

Abstract

4,500 mild-moderate AD patients randomized to placebo and 0.5mg/kg i.v.every 13 weeks for 18 months in APOE4 carriers, and randomized to placebo, 0.5, 1.0mg/kg i.v.every 13 weeks for 18 months in APOE4 noncarriers in 4 trials (ClinicalTrials.govidentifiers lNCT00575055, NCT00574132, NCT00676143, NCT00667810).Trials were halted after completion of 2 trials demonstrated a failure to meet primary outcome measures on ADAS-cog and activities of daily living.109 Solanezumab, humanized monoclonal antibody directed at amino acids 16-24 of Ab peptide.Amyloid plaque clearance mediated via peripheral sink mechanism.52 mild-moderate AD patients were randomized to placebo, 100mg every 4 weeks, 100mg weekly, 400mg every 4 weeks, 400mg weekly i.v.solanezumab for 12 weeks.There was a significant dose-dependent increase in Ab42 peptide in CSF.132 2,000 mild-moderate AD patients randomized to placebo and 400mg solanezumab monthly i.v. for 18 months (ClinicalTrials.govidentifiers NCT00905372, NCT00904683).Trials failed to meet their primary outcome measures on ADAS-cog and ADCS-ADL.A secondary analysis of mild AD patients pooled from both trials showed a significant effect on cognition.115 Gammagard, intravenous immunoglobulin.55 mild-moderate AD patients randomized to placebo, 0.2, 0.5, 0.8g/kg/4 weeks, or 0.1, 0.25, 0.4g/kg/2 weeks for 24 weeks.There was no increase in Ab40 peptide in plasma at any dose.129 Trial data currently unpublished.390 mild-moderate AD patients randomized to 0.2g/kg/2 weeks and 0.4g/kg/2 weeks vs placebo for 18 months (ClinicalTrials.govIdentifier NCT00818662).Gammagard failed to reach its coprimary outcomes of ADAS-cog and ADCS-ADL.AD 5 Alzheimer disease; ADAS-cog 5 Alzheimer's Disease Assessment Scale-Cognitive Subscale; ADCS-ADL 5 Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory; b.i.d. 5 twice daily; CDR-SB 5 Clinical Dementia Rating-Sum of Boxes; CSF 5 cerebrospinal fluid; i.v. 5 intravenous; o.d. 5 once per day.