Allergan Receives Refusal to File Letter from FDA for Vraylar

Allergan has received a Refusal to File (RTF) letter from the U.S. Food and Drug Administration (FDA) regarding its Supplemental New Drug Application (sNDA) for Vraylar (cariprazine) for treatment of negative symptoms associated with schizophrenia in adult patients. VRAYLAR is an oral, once daily atypical antipsychotic approved in the United States for the treatment of schizophrenia and the acute treatment of adult patients with manic or mixed episodes associated with bipolar I disorder.

Upon its preliminary review, FDA determined that the sNDA for treatment of negative symptoms was not sufficiently complete to permit a substantive review. 

"We are disappointed with the FDA decision on our submission. We will request a meeting with FDA to discuss and determine our next steps," said David Nicholson Ph.D., Chief Research & Development Officer, Allergan. "Vraylar is an important treatment option for patients suffering from bipolar I disorder and schizophrenia. We remain committed to our mental health program and to cariprazine and its potential as a treatment option for patients suffering from negative symptoms associated with schizophrenia."

Schizophrenia is a chronic and disabling disorder that includes positive symptoms (i.e. hallucinations, delusions and thought disorders) and negative symptoms (i.e. loss of motivation and social withdrawal). These symptoms are strongly associated with long term morbidity, poor psychosocial functioning and considerable social and economic costs.

Cariprazine is approved in Europe for the treatment of schizophrenia. The approval includes data from the 460-patient negative symptoms study which was conducted by Gedeon Richter and published in the Lancet on February 6, 2017.

The company will seek immediate guidance, and is in the process of planning a meeting with the FDA, to respond to the issues, and to seek clarification of what additional information will be required.

VRAYLAR is an oral, once daily atypical antipsychotic approved for the acute treatment of adult patients with manic or mixed episodes associated with bipolar I disorder, with a recommended dose range of 3 to 6 mg/day, and for the treatment of schizophrenia in adults, with a recommended dose range of 1.5 to 6 mg/day.

While the mechanism of action of VRAYLAR in schizophrenia and bipolar I disorder is unknown, the efficacy of VRAYLAR could be mediated through a combination of partial agonist activity at central dopamine D₂ and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.

Pharmacodynamic studies with cariprazine have shown that it acts as a partial agonist at dopamine D3, dopamine D2, and with high binding affinity at the serotonin 5-HT1A. Cariprazine demonstrated up to ~8-fold 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 as well as it binds to the histamine H1 receptors. Cariprazine shows lower binding affinity to the serotonin 5-HT2C and α1A- adrenergic receptors and has no appreciable affinity for cholinergic muscarinic receptors. The clinical significance of these in vitro data is unknown.

VRAYLAR was discovered and co-developed by Gedeon Richter and is licensed to Allergan in the U.S. and Canada.