Atypical antipsychotic agent
Bipolar I disorder and schizophrenia
Approved in the US
Vraylar® (cariprazine) is a once-daily, oral, atypical antipsychotic drug indicated for the treatment of adults with bipolar I disorder and schizophrenia, discovered and co-developed by Gedeon Richter and licenced to Allergan in the US and Canada.
The drug was approved by the US Food and Drug Administration (FDA) in September 2015 for the acute treatment of manic or mixed episodes associated with bipolar I disorder and schizophrenia. The approval followed the resubmission of new drug application (NDA) for the drug in January 2015.
The European Medicines Agency (EMA) accepted the marketing authorisation application of the drug for schizophrenia treatment in March 2016. The drug received the Committee for Medicinal Products for Human Use (CHMP) positive opinion in May 2017, followed by the European Commission (EC) approval in July that year. The drug is being marketed in the EU under the brand name Reagila.
In November 2017, the FDA expanded the drug’s indication as a maintenance therapy to treat schizophrenia in adult patients. The indication was expanded in May 2019 to include the treatment of adults with bipolar depression, which are depressive episodes related to bipolar I disorder.
The drug also secured the regulatory approval for treating schizophrenia patients in Singapore and Thailand, in August 2019.
Bipolar I disorder and schizophrenia
Bipolar I disorder and schizophrenia are chronic mental health disorders. Patients with bipolar I disorder often experience mood swings, fluctuations in energy and activity levels and difficulty in conducting day-to-day tasks. It affects approximately 3.6 million people in the US.
Schizophrenia is associated with hallucinations, speech difficulties and poor social behaviour. Symptoms of the disorder broadly fall under three categories, namely positive, negative and cognitive. An estimated 2.6 million adults suffer from schizophrenia in the US.
Vraylar’s mechanism and action and dosage
Though Vraylar’s mechanism of action in treating bipolar I disorder and schizophrenia is not clearly known, its efficacy could be linked to the combination of partial agonist activity and antagonist activity exhibited at the central dopamine D2 and serotonin 5-HT1A 5-HT2A receptors.
While cariprazine acts as a partial agonist at the dopamine D3 and D2 receptors, it acts as an antagonist at serotonin 5-HT2B and 5-HT2A receptors.
The recommended dose range of the drug for adult patients with manic or mixed episodes associated with bipolar I disorder is between 3mg / day and 6mg / day and between 1.5mg / day to 6mg / day for schizophrenia patients.
Clinical trials on Vraylar
FDA approval for Vraylar was based on the results from a clinical trial programme conducted to establish the safety and efficacy of the drug in patients with manic or mixed episodes of bipolar I disorder and schizophrenia.
The drug’s efficacy in the treatment of schizophrenia was established in three six-week, randomised, double-blind and placebo-controlled trials. The primary and secondary efficacy measures to assess psychiatric signs and symptoms in each trial were determined using the positive and negative syndrome scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) rating scales. The primary endpoint in each study was the change from baseline in PANSS total score at the end of week six.
Study 1 was a placebo-controlled study, which enrolled 711 patients, and involved three fixed doses of Vraylar and active control (risperidone). All drug doses, including the active control, demonstrated superior results compared to placebo on the PANSS total score and the CGI-S.
Study 2 enrolled 604 patients and involved two fixed doses of Vraylar and active control (aripiprazole), all proving superior to placebo on the PANSS total score and the CGI-S.
Study 3 enrolled 439 subjects and involved two flexible-dose range groups of Vraylar; both were superior to placebo on the PANSS total score and the CGI-S.
The drug demonstrated efficacy at doses between 1.5mg / day and 9mg / day compared to placebo. The maximum recommended dose was fixed at 6mg / day, however, following the observance of adverse reactions with an increase in the dose.
Vraylar’s efficacy in the acute treatment of bipolar disorder was observed in three three-week, placebo-controlled trials. The primary and secondary efficacy measures to assess the psychiatric signs and symptoms were determined using the Young Mania Rating Scale (YMRS) and the Clinical Global Impressions-Severity scale (CGI-S). The primary endpoint in each study was the decrease from baseline in YMRS total score at the end of week three.
Study one enrolled 492 patients and involved two flexible-dose range groups of Vraylar; both were found superior to placebo on the YMRS total score and the CGI-S.
Furthermore, study two admitted 235 patients and involved a flexible dose range of the drug, which was found superior to placebo on the YMRS total score and the CGI-S.
Lastly, study three, with 310 subjects, was similar to the previous study and again demonstrated that the drug was superior to placebo.
The most common adverse reactions observed during the trials for bipolar mania included extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence and restlessness, while those observed in schizophrenia patients were extrapyramidal symptoms and akathisia.
EC approval for schizophrenia was granted based on findings from three placebo and partly active-controlled studies conducted in more than 1,800 participants and one long-term study. The primary efficacy endpoints of the studies were the severity of schizophrenia symptoms and time to relapse.
The FDA approved the drug as the maintenance treatment for schizophrenia based on results from a 72-week withdrawal study with a 20-week open-label period. The study assessed 3mg, 6mg and 9mg dosages of Vraylar per day, which delayed the time to relapse versus placebo.
Approval of the drug to treat bipolar depression in the US was given after the review of data from RGH-MD-53, RGH-MD-54 and RGH-MD-56 trials that showed the statistical significance of the drug over placebo.
In August 2016, Richter agreed to provide an exclusive licence to Recordati for the commercialisation of cariprazine in Western Europe, Algeria, Tunisia and Turkey.
Mitsubishi Tanabe Pharma has the license to commercialise the drug in Singapore and Thailand. In May 2019, Richter entered an exclusive licence agreement with Seqirus to provide the drug in Australia and New Zealand.
In June 2019, Richter and Allergan expanded their agreement, allowing the latter to register the drug in Argentina, Venezuela, Brazil, Peru, Chile, Mexico, Colombia and Ecuador.
Richter also signed an agreement to provide Hikma Pharmaceuticals with exclusive rights to commercialise cariprazine in Bahrain, the UAE, Egypt, Syria, Jordan, Sudan, Iraq, Qatar, Saudi Arabia, Oman, Kuwait, Morocco, Lebanon and Libya, in July 2019.