Iloperidone is a 5HT2/D2 antagonist ("atypical") antipsychotic currently under review by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia. Additional data were presented identifying genetic markers that may help predict response to iloperidone, which Vanda believes could lead to unique, individualized treatment for schizophrenia. These data were presented today at the 161st American Psychiatric Association (APA) Annual Meeting in Washington, D.C.

"The data from the clinical trials studying the efficacy and safety of iloperidone suggest that iloperidone could be a useful long-term treatment option for people with schizophrenia," said Peter Weiden, M.D., Director of the Psychosis Program of the Department of Psychiatry at the University of Illinois at Chicago and one of the leading experts on adverse events of antipsychotic medications.

The data presented are part of the New Drug Application (NDA) submitted and currently under review by the FDA and demonstrate that iloperidone is effective in the short-term treatment of schizophrenia and that iloperidone is non-inferior to haloperidol in long-term maintenance measured as time to relapse over 52 weeks. In these trials, iloperidone showed short- and long-term safety with respect to movement disorders and metabolic effects, including extrapyramidal symptoms (EPS) and akathisia, as well as blood glucose, body weight and lipid profiles.

Schizophrenia is a chronic, severe and disabling disorder that affects approximately one percent of Americans. A high degree of treatment dissatisfaction remains among patients with schizophrenia and the physicians who treat them. The recent CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, conducted by the National Institute of Mental Health (NIMH) and reported in the New England Journal of Medicine, evaluated several antipsychotic medications and revealed that 74 percent of patients taking antipsychotics discontinued treatment within 18 months, primarily because of insufficient efficacy and tolerability issues.*

Iloperidone's Efficacy Profile

In data presented on a 4-week Phase III trial, iloperidone (24 mg/day) was more effective than placebo in the short-term treatment of acutely exacerbated schizophrenia, providing relief across both positive and negative symptom domains. Iloperidone showed significantly greater improvement than placebo in Positive and Negative Symptom Scale Total (PANSS-T) scores, as did ziprasidone (-12.0; p=0.006 for iloperidone vs. placebo and -12.3; p=0.012 for ziprasidone vs. placebo); these improvements were seen in both the mean PANSS Negative (PANSS-N), PANSS Positive (PANSS-P) subscales. Additionally, Brief Psychiatric Rating Scale (BPRS) scores improved significantly with iloperidone (-7.4; p=0.013) and ziprasidone (-7.2; p=0.042) versus placebo; and Clinical Global Impression Severity (CGI-S) scores also significantly improved with iloperidone (-0.65; p=0.007) and ziprasidone (-0.67; p=0.013) versus placebo.

In data presented from three prospective, 52-week Phase III trials comparing a dose range of iloperidone (4-16 mg/day given BID, n=981) to haloperidol (5-20 mg/day given BID, n=300), iloperidone was statistically non-inferior to haloperidol in time to relapse (89.8 days with iloperidone vs. 101.8 days with haloperidol; p=0.764). Additionally, the three trials found similar relapse rates and improvements in Clinical Global Impression of Change (CGI-C) and PANSS-T scores.

Iloperidone's Safety Profile

Data presented from a 4-week Phase III trial demonstrated that rates of worsened Barnes Akathisia Scale (BAS) total score was similar between iloperidone and placebo (8.3% vs. 11.6%; p=0.302) but significantly higher with ziprasidone versus placebo (26.0% vs. 11.6%; p<0.01). Iloperidone also showed significant improvements versus placebo on six Extrapyramidal Symptom Ratings Scale (ESRS) subscales (p<0.05), while ziprasidone was associated with improvements over three ESRS subscales (p<0.05). The incidence of treatment-emergent EPS was 3.0% in the iloperidone group, 2.0% in the placebo group and 9.3% in the ziprasidone group. On average, no patients in either treatment group had clinically meaningful increases in metabolic parameters such as blood glucose, body weight, total cholesterol, triglycerides, or prolactin elevation.

In data presented from three 52-week Phase III trials, comparing a dose range of iloperidone (4-16 mg/day given BID) to haloperidol (5-20 mg/day given BID), iloperidone demonstrated significant improvements in EPS at endpoint, as measured by ESRS, versus haloperidol (-1.6 vs. 0.6; p<0.001); and a significantly lower percentage of patients on iloperidone experienced worsening EPS (13.5% for iloperidone vs. 36.4% for haloperidol; p<0.001) and akathisia (9.2% for iloperidone vs. 23.7% for haloperidol; p<0.001). There were no clinically meaningful changes in serum cholesterol, glucose, or triglycerides. Mean weight increases were 2.6 and 0.6 kg for iloperidone and haloperidol during the 6-week phase and an additional weight gain of 1.2 and 1.7 kg was observed at endpoint for iloperidone and haloperidol, respectively.

Study of Genetic Markers to Predict Likelihood of Response to Iloperidone

Pharmacogenetic analysis in a Phase III trial studying the efficacy of iloperidone in acute schizophrenia identified six single nucleotide polymorphisms (SNPs) associated with efficacy of iloperidone.

* The highest specificity and positive predictive value were observed with rs11851892 (NPAS3) with a change from baseline to endpoint PANSS-T score of -20.12 (p=0.000093)

* The highest sensitivity and negative predictive value were seen with rs9643483 (XKR4) with a change from baseline to endpoint PANSS-T score of -15.02 (p=0.00017)

* None of the six SNPs was significantly associated with response to ziprasidone

The combination of six markers defined several groups of patients with different probability of response to iloperidone. Twenty-seven percent of patients carried at least five of the most favorable genotypes and constituted a group of iloperidone responders who showed a response of greater magnitude and of an earlier onset as compared to patients with alternative genetic make-up. These genetic markers for iloperidone response were not correlated to prediction of ziprasidone response. These results, while requiring further confirmation, are encouraging and suggest that pharmacogenetics may have the potential to identify likely responders and differentiate antipsychotics.

"Whenever a new antipsychotic becomes available, it may be possible to help some of our patients who had not responded well to other available medications," said Dr. Weiden. "Based on my experience, individual patients may have very different responses to individual antipsychotics and one of the frustrating parts of trying new medications is that we have no good way of knowing in advance which patient will respond well to a medication. Research to help clinicians determine whether one medication might work better than another for a patient would be a big advancement."

"Pharmacogenetics research to help identify markers of schizophrenia treatment response is fundamental and may help usher us into an era of personalized treatments in schizophrenia and bring us one step closer to providing the optimal treatment for each patient," said Paolo Baroldi, M.D., Ph.D., Chief Medical Officer, Vanda Pharmaceuticals Inc.-Vanda Pharmaceuticals