DUBLIN & BUDAPEST, Hungary—In December of 2017, Allergan plc, a global pharmaceutical company, and Gedeon Richter plc announced positive topline results for a Phase 3 study of cariprazine for the treatment of adults with major depressive episodes associated with bipolar I disorder. This is the second positive pivotal trial of cariprazine for this investigational use.
“Cariprazine is an atypical antipsychotic currently FDA-approved under the brand name Vraylar for the acute treatment of adult patients with manic or mixed episodes associated with bipolar I disorder, and for the treatment of schizophrenia in adults,” explains Armin Szegedi, Allergan’s vice president of clinical development/CNS. “Cariprazine is also being investigated for the treatment of adults with major depressive episodes associated with bipolar I disorder (bipolar I depression).
“Although the exact way cariprazine works is unknown, it is thought to affect the activity of neurotransmitters such as dopamine and serotonin. Pharmacodynamic studies with cariprazine have shown that it acts as a partial agonist with high binding affinity at dopamine D3, dopamine D2 and serotonin 5-HT1A receptors. Cariprazine demonstrated up to an approximately eightfold greater in-vitro affinity for dopamine D3 vs D2 receptors. Cariprazine also acts as an antagonist at serotonin 5-HT2B and 5-HT2A receptors with high and moderate binding affinity, respectively; it binds to the histamine H1 receptors as well. Cariprazine shows lower binding affinity to the serotonin 5-HT2C and α1A- adrenergic receptors and has no appreciable affinity for cholinergic muscarinic receptors.”
RGH-MD-54 is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter, fixed-dose clinical trial in patients with bipolar I depression. A total of 488 patients were randomized in this study aiming to evaluate the efficacy, safety and tolerability of cariprazine 1.5 mg/day and 3 mg/day, compared to placebo, in patients with bipolar I depression. Subjects underwent a no-drug screening period of approximately seven to 14 days, followed by six weeks of double-blind treatment and a one-week, no investigational product safety follow-up period.
In this study, the primary efficacy objective was met for both cariprazine 1.5 mg and 3 mg dose groups. Both showed a significantly greater improvement than placebo for the change from baseline to week 6 on the Montgomery-Asberg Depression Rating Scale (MADRS) total score.
“These Phase 3 data provide further support for cariprazine as a potential treatment for adults with bipolar depression, and adds to the growing clinical profile of this compound in mental health disorders,” said David Nicholson, chief research and development officer at Allergan.
“This trial (RGH MD-54) is the second successful Phase 3 trial for cariprazine in bipolar I
depression,” adds Szegedi.
Although this and many other trials for bipolar medications are often brief (six to eight weeks), with many psychiatric medications it can take up to six weeks for patients to begin to feel any effects. Asked if there were any longer studies planned, Szegedi notes, “Long-term studies with cariprazine have been completed for other indications. Cariprazine has been evaluated in schizophrenia for up to 92 weeks. In that study, cariprazine was shown to be safe and efficacious in the prevention of relapse. A future long-term study of cariprazine in the prevention of relapse in bipolar disorder is planned to begin enrollment in 2018.”
In this study, cariprazine was generally well tolerated. Sedation, somnolence, dizziness, akathisia and nausea were the most commonly reported adverse events (reported with a frequency of 5 percent or greater and at least twice that of placebo). Five percent of cariprazine-treated patients discontinued due to adverse events versus 2.5 percent of placebo-treated patients.
“Cariprazine has a novel mechanism of action. Cariprazine is a partial agonist at the D3/D2 and 5HT1A receptor and antagonist at 5HT2A receptor. It also has preferential binding to D3 receptors,” Szegedi tells DDNews. “Cariprazine [also] has a unique pharmacokinetic profile. In addition to the parent compound, cariprazine has two active metabolites (desmethyl cariprazine [DCAR] and didesmethyl cariprazine [DDCAR]), both of which have equipotency to the parent. DDCAR also has a longer half-life than other antipsychotic agents. This longer half-life may factor favorably in clinicians’ medication choice, particularly for patients where medication non adherence may be a concern.
“Having another product proven to treat the full range of bipolar disorder, from mania through depression, would be an important addition to the treatment options currently available to the psychiatry community and patients. Once diagnosed, bipolar depression is difficult to treat, with high treatment-failure rates and limited therapeutic options for patients.
“Additionally, patients with bipolar disorder may experience transitions directly from depression to mania or mania to depression, as well as mixed states. More treatment options are needed so that physicians can find a treatment that works best for each individual. With this data, cariprazine, which also has proven efficacy for treatment of mania and mixed episodes, has the potential to treat the whole spectrum of bipolar I disorder,” Szegedi concludes.
Allergan and Richter plan to submit a supplemental New Drug Application to the U.S. Food and Drug Administration in the second half of 2018.
