Products

Date: 2017-09-22

Type of information: Refusal of a Market Autorisation in the US

Product name: Vraylar® (US)/Reagila® (EU)

Compound: cariprazine

Therapeutic area: CNS diseases - Mental diseases

Action mechanism:

• dopamine D3 receptor partial agonist. Cariprazine has been discovered by researchers at Gedeon Richter. This orally active, potent dopamine D3-preferring D3/D2 receptor partial agonist is an atypical antipsychotic for the treatment of patients with schizophrenia and for patients with manic or mixed episodes associated with bipolar I disorder. The safety and efficacy of cariprazine was studied in a clinical trial program of more than 2700 patients. In addition, cariprazine is being investigated for the treatment of bipolar depression and adjunctive MDD in adults.
• Cariprazine is licensed to Actavis, now Allergan, in the U.S. and Canada. In August 2016 Richter and Recordati signed an exclusive license agreement to commercialize cariprazine in Western Europe, in Algeria, in Tunisia and in Turkey.

Company: Allergan (Ireland) Gedeon Richter (Hungary) Recordati (Italy)

Disease:

• schizophrenia
• manic or mixed episodes associated with bipolar I disorder in adults
• maintenance of efficacy in adults with schizophrenia

Latest news:

• • On September 22, 2017, Allergan announced that it received a Refusal to File (RTF) letter from the FDA regarding its Supplemental New Drug Application (sNDA) for Vraylar® (cariprazine) for treatment of negative symptoms associated with schizophrenia in adult patients. Upon its preliminary review, FDA determined that the sNDA for treatment of negative symptoms was not sufficiently complete to permit a substantive review. Allergan 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.
• • On May 18, 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Reagila® intended for the treatment of schizophrenia. The drug will be available as 1.5 mg, 3 mg, 4.5 mg and 6 mg hard capsules. The most common side effects are akathisia and parkinsonism. The marketing authorization application has been submitted to EMA in March 2016.
• • On March 8, 2017, Allergan announced that the FDA  has accepted for filing the company's supplemental New Drug Application (sNDA) for Vraylar® (cariprazine), seeking the addition of new clinical data for the maintenance of efficacy in adults with schizophrenia to the current product label. The data included in the sNDA are from a Phase 3 multinational, randomized, double-blind, placebo-controlled, parallel-group study of cariprazine in adults with schizophrenia (RG-MD-06), which found cariprazine compared to placebo significantly delayed the time to relapse (p=.0010, hazard ratio [HR]: 0.45 [95% CI: 0.28, 0.73]). The study included a 20-week open-label phase where patients with schizophrenia were treated with cariprazine 3, 6 or 9 mg per day. Patients who responded and met the stabilization criteria during the open-label period were then randomized to continue their cariprazine dose (3, 6 or 9 mg per day) or switched to placebo for up to 72 weeks or until a relapse occurred. The primary endpoint was time to first symptom relapse during the double blind phase. Relapse occurred in nearly twice as many placebo- (47.5%) as cariprazine-treated (24.8%) patients. At the end of the double-blind treatment period, analysis of exploratory endpoints also showed a greater mean worsening of symptoms in placebo- vs cariprazine-treated patients on all efficacy parameters as measured by Positive and Negative Syndrome Scale (PANSS) total and subscale scores, the Clinical Global Impressions-Severity (CGI-S) rating scale, the 16-Item Negative Symptom Assessment (NSA-16) and the Personal and Social Performance Scale (PSP) total score. The safety results were consistent with the profile observed to date for cariprazine; no new safety concerns were observed.
• • On March 16, 2016, Allergan announced that Vraylar® (cariprazine), a once-daily oral atypical antipsychotic, is now available by prescription in pharmacies throughout the U.S. Vraylar® was approved by theFDA in September 2015 for the treatment of acute manic or mixed episodes of bipolar I disorder and schizophrenia in adults. Vraylar® will be commercially available in 30 count bottles in 1.5mg, 3mg, 4.5mg and 6mg and a 7 count mixed blister pack (one 1.5mg and six 3mg tablets).
• • On September 17, 2015, the FDA approved Vraylar® (cariprazine) capsules to treat schizophrenia and bipolar disorder in adults. The efficacy of Vraylar® in treating schizophrenia was demonstrated in 1,754 participants in three six-week clinical trials. In each of the trials, Vraylar was shown to reduce the symptoms of schizophrenia compared to placebo. The efficacy of Vraylar® in treating bipolar disorder was shown in three three-week clinical trials of 1,037 participants. Vraylar was shown to reduce symptoms of bipolar disorder in each of the trials.
• Vraylar® and all other FDA-approved drugs used to treat schizophrenia and bipolar disorder have a Boxed Warning alerting health care professionals about an increased risk of death associated with the use of these drugs in older people with dementia-related psychosis. Neither Vraylar nor any other drug in this class is approved to treat such patients.
• The most common side effects reported by participants receiving Vraylar in the clinical trials for schizophrenia were extrapyramidal symptoms, such as tremor, slurred speech, and involuntary muscle movements. The most common side effects reported by trial participants receiving Vraylar for bipolar disorder were extrapyramidal symptoms, the urge to move (akathisia), indigestion (dyspepsia), vomiting, drowsiness (somnolence) and restlessness.
• • On June 16, 2015, Gedeon Richter and Allergan announced that the FDA notified the companies that it will require a three-month extension to complete its review of data supporting the resubmission of the New Drug Application (NDA) for cariprazine. Cariprazine is being reviewed for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. The FDA has determined that a recent response to an FDA question about the cariprazine NDA is a "major amendment", requiring the three-month extension. The NDA for cariprazine was submitted in late 2012. The FDA issued a complete response letter (CRL) in November 2013, and the companies resubmitted information in December 2014.
• • On January 6, 2015, Gedeon Richter and Actavis  announced that the FDA has acknowledged receipt of Actavis' New Drug Application (NDA) resubmission for its atypical antipsychotic, cariprazine. The Prescription Drug User Fee Act (PDUFA) date is expected to be in the second quarter of 2015.
• • On November 21, 2013, Forest Laboratories and Gedeon Richter have announced that the FDA issued a complete response letter regarding the New Drug Application (NDA) for cariprazine, an atypical antipsychotic for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.
• In the complete response letter, the FDA acknowledged that cariprazine clearly demonstrated effectiveness in the treatment of schizophrenia and mania associated with bipolar disorder. However, the Agency indicated more information, including additional clinical trial data, would be needed. Forest and Gedeon Richter plan to meet with the FDA in the very near future to discuss the complete response letter and define a path forward.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2015-09-17

UE authorization: 2017-07-13

Favourable opinion UE: 2017-05-18

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes