EXPLORATORY ANALYSES OF COGNITIVE EFFECTS OF CRENEZUMAB IN A MILD ALZHEIMER'S DISEASE SUBPOPULATION OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP PHASE 2 STUDY (ABBY)

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Crenezumab is a humanized IgG4 anti-amyloid-beta (Aβ) monoclonal antibody in development for the treatment of Alzheimer’s disease (AD). In a Phase 2 study of crenezumab in patients with mild-to-moderate AD (NCT01343966; ABBY), the co-primary endpoints ADAS-Cog12 and ADCS-ADL did not achieve statistical significance. However, effects on these endpoints improved in patients with higher MMSE scores treated with the higher dose. Further exploratory analyses are presented here. A total of 433 patients aged 50–80 years with an MMSE score of 18–26 at screening were randomized at a 2:1 ratio to receive either crenezumab (higher-dose 15mg/kg IV q4w or lower-dose 300mg SC q2w) or placebo for 68 weeks. Randomization was stratified by APOE4 status, MMSE score (≤21 vs > 21) and study site. A mixed model for repeated measures was used to analyze treatment effects on the co-primary endpoints ADAS-Cog12 and CDR-SB and the exploratory endpoints MMSE and DSST at Week 73 in higher-dose patients by baseline MMSE score. At Week 73, the difference between crenezumab and placebo groups in percentage reduction from baseline in ADAS-Cog12 and CDR-SB was greater in patients with higher MMSE scores at baseline (MMSE 20–26, 24% and -1%; MMSE 22–26, 35% and 20%; MMSE 24–26, 38% and 45%, for ADAS-Cog12 and CDR-SB, respectively). Analysis of the CDR-SB subdomains “Judgment & Problem Solving” and “Memory” also showed increasing effects in percentage reduction with crenezumab over placebo in progressively milder patients (MMSE 20–26, 16% and 22%; MMSE 22–26, 30% and 43%; MMSE 24–26, 56% and 49%, respectively). Similar effects were seen in DSST and MMSE changes. In the higher-dose crenezumab group, consistent and increasing treatment effects in ADAS-Cog12, CDR-SB, CDR-SB subdomains, DSST and MMSE, were observed in progressively milder AD populations (MMSE ≥20), potentially reflecting effects on higher cognitive functions, episodic memory, psychomotor speed and general cognition. These data are consistent with emerging clinical trial findings that earlier treatment is associated with improved clinical outcomes and support the inclusion of prodromal-to-mild patients in crenezumab Phase 3 trials (Blaettler et al., AAIC 2016, submitted).