FDA Evaluating New Drugs for Schizophrenia Treatment

Several new antipsychotics have been submitted to the Food and Drug Administration (FDA) for marketing review, making the therapeutic landscape for schizophrenia and bipolar disorder in the near future hard to predict.

One of the most recent new drug applications (NDAs) was for asenpine sublingual tablet, developed by Organon. The drug binds with both dopamine D₂ receptor and a host of serotonin 5-HT receptors subtypes, with a greater antagonism to all serotonin receptor subtypes except 5-HT_1a and 5-HT_1b, according to Steven Potkin, M.D., of the Department of Psychiatry and Human Behavior at the University of California, Irvine, and two researchers from Organon in their study published in the October 2007 Journal of Clinical Psychiatry.

In this randomized, double-blind, controlled study, asenapine was compared with placebo and risperidone in 174 patients with acute schizophrenia for six weeks. The asenapine group saw a significantly greater reduction in mean Positive and Negative Syndrome Scale total, negative symptom, and positive symptom scores compared with placebo. Asenapine had a better profile than risperidone in terms of weight gain and prolactin levels, but the authors acknowledged that the 6 mg/day of risperidone given in this study was at the high end of usual dosage.

In an earlier phase 3 study in 488 patients, asenapine produced a significantly greater reduction in bipolar manic symptoms compared with placebo after three weeks. The study results were presented at APA's 2007 annual meeting in San Diego in May.

Asenapine has a somewhat curious history. Initially developed by Organon, it was licensed to Pfizer. In late 2006, however, Pfizer terminated the deal and gave the molecule back when an interim assessment of the phase 3 trials of asenapine became available. Schering-Plough acquired Organon last November, shortly before the announcement that the FDA had accepted the new drug application for a standard review.

Regulatory success is, however, far from certain for novel antipsychotics. Another previously promising molecule, bifeprunox, was rejected by the FDA last August as “unapprovable” based on the submitted clinical data; the agency appeared to be lukewarm about the drug's efficacy compared with other available antipsychotics in treating acute schizophrenia, according to the announcement from Wyeth, the manufacturer. The company stated that it would continue with the development of bifeprunox.

An NDA for paliperidone palmitate intramuscular injection, intended for once-monthly use, was filed with the FDA in October 2007 by its makers, Johnson and Johnson and Elan Pharmaceuticals. The oral extended-release tablet formulation of paliperidone has been approved for acute and maintenance treatment for schizophrenia. Paliperidone is an active metabolite of risperidone.

A third new antipsychotic, iloperidone, is also waiting for the FDA to render a judgment on its NDA, which was filed by Vanda Pharmaceuticals last September and accepted by the agency in late November. The drug binds to a spectrum of dopamine and serotonin receptors and, according to the company,“ provides a favorable profile on adverse symptoms such as weight gain, extrapyramidal symptoms, akathisia, and prolactin elevation.”

An abstract of “Efficacy and Tolerability of Asenapine in Acute Schizophrenia: A Placebo- and Risperidone-Controlled Trial” is posted at<www.psychiatrist.com/abstracts/200710/100704.htm>.▪