Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N ¼ 511), and results were also stratified by apolipoprotein E (APOE) genotype (n ¼ 323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE e4 allele status and ADAS-Cog (P ¼ 0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE e4-negative patients on 8 mg RSG (P ¼ 0.024; not corrected for multiplicity). APOE e4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P ¼ 0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE e4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE e4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.

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included electrocardiogram (ECG) QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%). Grade 3/4 AEs in ≥10% of patients were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). ORR was 78% (n = 18), including a CR rate of 57%, a CRi/CRp rate of 13%, and an MLFS rate of 9%. The CR+CRh rate was 70% (n = 16). Median time to response was 1.8 months (range, 0.7-3.8) and to CR was 3.5 months (range, 0.8-6.0); median response duration not yet reached. mIDH1 clearance was seen in 10 of 16 patients (63%) with CR/CRh, including 9 of 13 (69%) with CR. Summary/Conclusion: IVO+AZA was well tolerated, and had a safety profile consistent with IVO or AZA monotherapy. All-grade cytopenia-related AEs were infrequent relative to other nonintensive therapies. CR rate and ORR exceeded those of AZA alone (Dombret et al. Blood 2015) and a majority of responders achieved mIDH1 mutation clearance. Based on these findings, a phase 3 double-blind placebo-controlled study of IVO+AZA (AGILE, NCT03173248) is actively enrolling patients.

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