O4‐09‐03: Ttp488: From futile to fast track
摘要
TTP488 is an oral antagonist of the Receptor for Advanced Glycation Endproducts (RAGE), which was evaluated in a 18-month Phase 2 study in mild to moderate AD patients. Study treatment was discontinued, and the development of TTP488 was halted, when a pre-specified analysis met futility criteria. However, when protocol-specified analyses were executed as originally planned, it was evident that the study had reached its primary endpoint, contrary to the futility analysis predictions. To examine the risks of futility analysis and the precautions that should be taken when executing and interpreting these analyses. Futility analysis was performed on a snapshot of dynamic data, using descriptive statistics only. At study completion and final database lock, pre-specified primary ITT analysis (using ANCOVA with MI) was on the ADAS-cog11. Four pre-specified supportive analyses (MMRM, LOCF, completers, GEE) and a post hoc on-treatment analysis based on the presence of drug in plasma were also employed. Contrary to the futility analysis, ITT analysis demonstrated a decreased decline in ADAS-cog at 18 months (delta=3.1, p=0.008), relative to placebo, in the group initially randomized to low dose TTP488. This was confirmed by all 4 pre-specified supportive analyses. The benefit of the drug was also confirmed in the “on-treatment” analyses. There were no differences between treatment groups in the incidence of adverse events, except for psychiatric disorders, which occurred less frequently in the group treated with TTP488 (nominal p=0.04). The results of the ITT analysis, and the observed beneficial effects on psychiatric adverse events of special interest for AD patients, justify further investigation of low dose TTP488 in Phase 3 trials in patients with mild AD. TTP488 has been granted Fast Track Status by FDA and is entering Phase3 under a Special Protocol Agreement. Futility analyses in AD trials may be misleading and argue for conducting the full analysis plan even when fut