Forest and Gedeon's cariprazine is a pharmacologically unique atypical antipsychotic in Phase III development for both schizophrenia and bipolar mania. Data presented at APA 2012 hint that while cariprazine appears to be effective in both indications, its tolerability and failure to address the broader bipolar depression patient population will hinder uptake.
Cariprazine is an atypical antipsychotic, discovered by Gedeon Richter and being developed for the US market by Forest Laboratories. It differs from its competition in that it is a D2 and D3 receptor partial agonist, with a higher affinity for D3 receptors; traditional atypical antipsychotics are D2 and 5-HT2A receptor agonists. Given the novelty of cariprazine, it will be important for Forest and Gedeon to characterize how its pharmacology translates into tangible clinical differences.
Long-term extension study reveals a range of tolerability issues for cariprazine in schizophrenia patients
Both companies were present at the 165th Annual Meeting of the American Psychiatric Association (APA 2012) to announce cariprazine's long-term safety and tolerability in a 48-week extension study in schizophrenia patients. Patients that had completed a prior six-week study of placebo- and active-controlled study of cariprazine, with sufficient response to therapy, were eligible to enroll in the extension. 93 patients met the criteria, of which 49.5% completed the 48-week open-label extension period.
At least one common treatment-emergent adverse event was experienced by 66.7% of patients, with the most common side effects including akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). Worryingly for Forest, a total of 17 different side effects had an incidence of 5% or more during the extension period, with metabolic issues, extrapyramidal side effects, and sedation all featuring.
This trial, then, suggests that cariprazine does not compare favorably with its competitors on account of its tolerability. This will be detrimental to cariprazine's commercial prospects should it reach the market, as treatment decisions for schizophrenia are often governed by a drug's side-effect profile. Furthermore, such a high number of common side effects bodes badly for cariprazine's potential utility in bipolar disorder, where patients play a more active role in treatment decisions. Still, the drug's long-term effect on schizophrenia symptoms will be of consolation to Forest: continued treatment with cariprazine led to decreased Positive and Negative Syndrome Scale (PANSS) scores over the course of the study.
Cariprazine's antimanic efficacy will not guarantee bipolar market success
In addition to schizophrenia, cariprazine is also currently in Phase III development in the US for the treatment of bipolar mania. Following the February 2012 announcement of preliminary top-line results and ahead of a New Drug Application filing, anticipated in 2012, the companies took the opportunity to present data from a Phase III trial of cariprazine in bipolar mania at APA 2012.
The six-week, randomized, double-blind, placebo-controlled, parallel-group, flexible dose study involved voluntarily hospitalized adults with a primary diagnosis of mania. For the primary endpoint - change from baseline to week 3 in Young Mania Rating Scale (YMRS) score - the data showed that cariprazine-treated patients (3-12mg) experienced significant improvements in symptoms compared to placebo-treated patients (-4.3). Superiority over placebo was observed by day 4 and at every subsequent time point.
Although cariprazine treatment was associated with a higher incidence of akathisia and extrapyramidal side effects relative to placebo, it was not associated with mean increase in weight or metabolic parameters. Similarly, cariprazine was not associated with prolactin increase or QTc prolongation. The results of the study support an earlier positive Phase III trial that also demonstrated the efficacy and tolerability of cariprazine in the treatment of acute mania associated with bipolar I disorder.
Datamonitor regards these Phase III clinical trial data for cariprazine in bipolar mania as encouraging and, should cariprazine be successful in gaining regulatory approval for the treatment of bipolar mania, Forest's experience in the psychiatry market will be a distinct commercial advantage. However, cariprazine is not expected to be successful in addressing the principal unmet need in the management of bipolar disorders: that is, relieving bipolar depression. The candidate previously failed to achieve statistical significance in a Phase II bipolar disorder trial.
This factor is vital, as Forest and Gedeon will be entering a fiercely competitive and saturated market, with several major antipsychotic brands having recently lost US patent protection. In order to gain a competitive edge and in view of the increasing recognition of cognitive impairment among the bipolar disorder population, Datamonitor believes that Gedeon and Forest would be well served to further investigate the potential procognitive effects of cariprazine.