Forest Laboratories, Inc. (NYSE: FRX) and Gedeon Richter Plc announced positive top-line results from a Phase IIb clinical trial of the novel, investigational antipsychotic agent cariprazine for the treatment of acute exacerbation of schizophrenia.
For the primary endpoint, the Positive and Negative Syndrome Scale (PANSS), the data showed that patients with schizophrenia treated with cariprazine experienced significant symptom improvement compared to placebo patients within the first week of treatment and at each subsequent time point studied.
Based on this latest schizophrenia data, subject to a complete review of the full results, and the previously announced Phase II results in patients suffering from acute mania associated with bipolar I disorder, the companies intend to initiate Phase 3 trials for both indications in early 2010. Cariprazine is currently also undergoing Phase II clinical trials in patients with Bipolar Depressive Disorder and as adjunctive therapy in Major Depressive Disorder.
Discovered by researchers at Gedeon Richter and licensed in the United States and Canada by Forest Laboratories in 2004, cariprazine is an orally active D3/D2 partial agonist with preferential binding to D3 receptors. Additionally, cariprazine has a relatively low potency at other receptor sites, such as 5-HT2C, histamine H1, muscarinic, and adrenergic receptor sites, that have been associated with adverse events in some other drugs in the class.
"Both the latest clinical trial results for cariprazine in patients suffering from schizophrenia and the previous proof of concept results in bipolar mania, confirm our long held belief in this compound. I congratulate the research teams who have persevered in their pursuit to develop cariprazine through sophisticated and sometimes difficult clinical trial programs," said Howard Solomon, Chairman and Chief Executive Officer of Forest Laboratories. "Our strategy to invest in promising product opportunities that have been discovered by highly creative and innovative partners, around the world, continues to bear fruit and we look forward to advancing the late-stage cariprazine development program."
Dr. Marco Taglietti, President of Forest Research Institute, said: "With positive potentially pivotal trials in both schizophrenia and bipolar mania, we are excited about the opportunity to expedite our Phase III clinical programs and bring this important therapy to the market as quickly as possible. We have worked closely with Gedeon Richter since the time we licensed cariprazine and we will continue to explore the clinical potential of cariprazine for other conditions, including bipolar depression and as adjunctive therapy in Major Depressive Disorder."
"We are very encouraged by these results as we believe that cariprazine has the potential to be a valuable new treatment option for people suffering from schizophrenia. These results are considered as a further step towards our commitment conducting original research in the field of CNS disorders, where our team has excellent expertise," said Erik Bogsch, Chief Executive Officer, Gedeon Richter Plc.
About the Study
This was a placebo- and active-controlled, fixed dose study in patients with acute exacerbation of schizophrenia. Patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for schizophrenia and had a PANSS total score between 80 and 120 were eligible for enrollment into the study.
Following a washout period of no antipsychotic therapy for up to seven days, a total of 732 patients between 18 and 60 years old were randomized to one of the following treatment arms: 1.5 mg/d cariprazine, 3.0 mg/d cariprazine, 4.5 mg/d cariprazine, 4 mg/d risperidone or placebo given daily for six weeks followed by an additional two week safety follow-up period, where no drug was administered. Patients were hospitalized during the washout period and for the first four weeks of the double-blind treatment. Thereafter, patients were followed either as inpatients or outpatients, as determined by the site investigator and based on patient status.
The protocol specified primary endpoint was the change from baseline to Week 6 in the PANSS total score for the individual cariprazine fixed dose treatment groups compared to placebo treatment using a sequential multiple-comparison test procedure and last observation carried forward (LOCF) analyses. The PANSS is a scale used to evaluate symptom severity in schizophrenia. The secondary endpoint was the change from baseline to Week 6 in the Clinical Global Impression-Severity Score (CGI-S), a scale used to assess treatment response. Statistically significant (p < 0.001) improvement in the PANSS total score at the end of Week 6 was observed for the comparison of each cariprazine dose group relative to the placebo treatment group (change of -7.5, -8.9, and -10.4 points for the 1.5, 3.0, and 4.5 mg/day dose groups, respectively) by LOCF analyses. Statistically significant improvements were also noted in each cariprazine dose group relative to placebo treatment in the CGI-S by LOCF analysis. Statistically significant improvements were also seen in the comparator risperidone group relative to placebo treatment in the total PANSS and CGI-S measures by LOCF analysis.
Overall, 64% of the patients completed the study. Cariprazine was generally well tolerated; more patients in the placebo group discontinued due to adverse events than in the active treatment groups (15% for placebo, 10%, 5% and 8% for the cariprazine 1.5, 3.0, and 4.5 mg/d dose groups, respectively and 9% for the risperidone group). The most common adverse events (AEs) observed in any cariprazine dose group were insomnia, extrapyramidal disorder, akathisia, sedation, nausea, dizziness, and constipation.
About Schizophrenia
A severe and disabling brain disorder, people with schizophrenia typically are affected by hallucinations in which they may hear voices other people don't hear, or delusions where they believe others are plotting to harm them.(1) Approximately one percent of American adults, or 2.4 million people are affected with schizophrenia in a given year,(2) with men and women affected equally.(3) Treatment for schizophrenia can include antipsychotic medications and various psychosocial treatments.(1)
About Forest Laboratories
Forest Laboratories (NYSE: FRX) is a U.S.-based pharmaceutical company with a long track record of building partnerships and developing and marketing products that make a positive difference in people's lives. In addition to its well-established franchises in therapeutic areas of the central nervous and cardiovascular systems, Forest's current pipeline includes product candidates in all stages of development and across a wide range of therapeutic areas. The company is headquartered in New York, NY. To learn more about Forest Laboratories, visit www.frx.com.
About Gedeon Richter Plc.
Gedeon Richter, (www.richter.hu) headquartered in Budapest/Hungary, is a major pharmaceutical company in Hungary and one of the largest in Central Eastern Europe, with consolidated sales of approximately 1 billion € (1,4 billion USD) and 2 billion € (3 billion USD) market capitalization in 2008. Gedeon Richter plays the role of a regional multinational company in Central Eastern Europe and in the CIS and has a growing presence via its strategic partners in the US and through its commercial subsidiaries in key EU countries. The product portfolio of the company covers almost all important therapeutic areas, such as cardiovascular, central nervous system, gynecology, etc. The company has the largest R&D unit in Central Eastern Europe. Original research activity focuses exclusively on CNS disorders with main clinical targets are being schizophrenia, anxiety, chronic pain and depression. With its widely acknowledged steroid chemistry expertise the company is a significant player in the female healthcare field worldwide.
1. U.S. Department of Health & Human Services. National Institute of Mental Health. Schizophrenia Brochure. NIH PublicationNo. 09-3517. Revised 2009.
2. Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK. The de facto mental and addictive disorders service system. Epidemiologic Catchment Area prospective 1-year prevalence rates of disorders and services. Archives of General Psychiatry. 1993 Feb;50(2):85-94.
3. Robins LN, Regier DA, eds. Psychiatric disorders in America: the Epidemiologic Catchment Area Study. New York: The Free Press, 1991.