MODELING STRATEGY Base PANSS Total model

1. Longitudinal Analysis of Vabicaserin and Olanzapine Treatment Effects on PANSS Total Scores Using an Informed Dropout Model Adam Ogden1, Jing Liu1, Thomas A. Comery1, and Diane Mould2 1 Pfizer Worldwide Research & Development, Groton, CT 2 Projections Research, Inc., Phoenixville, PA BACKGROUND Vabicaserin (VABI) is a potent and selective 5-HT2C full agonist that has potential utility for the treatment of schizophrenia. Results of a Phase 2a trial of VABI, which included olanzapine (OLZ) as a positive control, in subjects with acute exacerbation of schizophrenia were recently reported [Shen et al. 2011]. VABI treatment improved positive and negative syndrome scale (PANSS Total) scores, relative to placebo, as determined using ANCOVAs with last observation carried forward (LOCF). • RESULTS • VABI data was best fit with a proportional quadratic function • OLZ data was best fit with a linear function • Dropout data was best fit with a Weibull hazard model • Inclusion of a dropout model resulted in a less steep slope of drug effect relative to the previous LOCF analysis. • Due to the significant overlap of observed VABI trough plasma concentrations at the doses tested, subject-level VABI concentrations could not be incorporated into the treatment effect model but were a significant covariate in the dropout model. • A statistically-significant treatment effect was observed for both VABI and OLZ relative to placebo. • The model-predicted mean change from baseline of PANSS Total scores was -25.4, -17.0, and -6.8 for OLZ, VABI, and placebo, respectively. FIGURE 6. Dropout Model for VABI and OLZ OBJECTIVE Due to the large percentage of dropouts (>50% distributed across all treatment groups) observed in this study, a disease progression model accounting for dropouts was developed to better characterize the effect of VABI treatment. FIGURE 1. Observed PANSS Total Data FIGURE 3. Base PANSS Total Models for Placebo, VABI, and OLZ Placebo VABI (400 mg) VABI (200 mg) Placebo VABI (200mg/400mg combined) OLZ (15 mg) *p<0.05 compared to placebo (ANCOVA-LOCF) FIGURE 6. Dropout Model for VABI and OLZ TABLE 1. High Percentage of Patients Dropped Out Of Study FIGURE 7. Model-Predicted PANSS Total Change from Baseline for Placebo, VABI, and OLZ Placebo Placebo Olanzapine VABI (200mg/400mg combined) FIGURE 2. Modeling Strategy Incorporating Dropout Model FIGURE 4. PANSS Total Scores in Completers and Dropouts Olanzapine TABLE 2. Model-Predicted PANSS Total Change from Baseline • MODELING STRATEGY • Base PANSS Total model • Estimated treatment effect for placebo, VABI (combined data from 200 and 400 mg groups), and OLZ • Time-dependent functions (linear, quadratic, Emax, Weibull distribution) were evaluated.. • Models included a LOGIT function to constrain the predictions to be within the range of possible PANSS Total scores (30-220). • Time-To-Event Dropout Model • Linear, exponential, Weibull, Gompertz, and hazard functions were examined. • Evaluated 3 types of reasons for drop out • Completely missing at random • Dropout independent of observed data • Missing at random • Dropout related to observed response • Missing not at random (Informed dropout) • Dropout related to unobserved response • Explored covariates: Age, sex, race, concomitant medications for movement AEs, sedative/hypnotic concomitant medications, anxiety/agitation concomitant medications, sum of only probable AEs of any type, sum of all AEs of any type, mean trough concentration • Combined PANSS Total Model + Dropout Model • Simultaneously fit both models • Estimated model-predicted mean changes from baseline were estimated for VABI, OLZ, and placebo. FIGURE 5. Trough Plasma Concentrations of VABI • CONCLUSIONS • Inclusion of a dropout model significantly improved the model fits relative to the previous LOCF analysis. • This analysis suggests that VABI and OLZ demonstrated greater improvement on PANSS Total scores compared to placebo. • The magnitude of VABI response was less than that observed following OLZ treatment in this study. • Model-predicted PANSS Total change for VABI was less than that for OLZ at both 4 and 6 weeks. REFERENCES Shenet. al. A 6-Week Randomized, Double-Blind, Placebo-Controlled, Comparator-Referenced, Multicenter Trial of Vabicaserin in Subjects with Acute Exacerbation of Schizophrenia. Neuropsychopharmacology (2011) 36: S106.