FDA Accepts Supplemental New Drug Application (sNDA) For VRAYLAR (cariprazine)

DUBLIN, Ireland, March 8, 2017 /PRNewswire/ -- Allergan plc (NYSE: AGN), a leading global pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has accepted for filing the company's supplemental New Drug Application (sNDA) for VRAYLAR (cariprazine), seeking the addition of new clinical data evaluating VRAYLAR for the maintenance of efficacy in adults with schizophrenia to the current product label.

"Most patients with schizophrenia are at very high risk of relapse in the absence of antipsychotic treatment," said Dr. Herbert Meltzer, Professor of Psychiatry at Northwestern Feinberg School of Medicine. "Without maintenance treatment, 60–70 percent of patients relapse within one year, and almost 90 percent relapse within two years. These new data show that VRAYLAR may be a treatment option for the maintenance treatment of schizophrenia."

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.

"These Phase 3 data offer additional information about the long-term efficacy and safety of VRAYLAR for the maintenance treatment of schizophrenia," said David Nicholson, President and EVP, Global R&D at Allergan. "This sNDA filing is part of our commitment to mental health, and we continue to pursue research that will provide physicians and patients with comprehensive information needed to make educated choices regarding treatment options."

Cariprazine was approved by the FDA in September 2015 and is marketed as VRAYLAR™ in the US for the acute treatment of manic or mixed episodes of Bipolar I Disorder and the treatment of Schizophrenia in adults.

About VRAYLAR (cariprazine)

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-HT_1A receptors and antagonist activity at serotonin 5-HT_2A 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-HT_1A. 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-HT_2B and 5-HT_2A 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-HT_2C and α_1A- 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 Plc and is licensed to Actavis, now Allergan, in the U.S. and Canada.

Visit www.VRAYLAR.com for more information on this once daily option for the acute treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adults.

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for treatment of patients with dementia-related psychosis.

Contraindication: VRAYLAR is contraindicated in patients with known hypersensitivity. Reactions have included rash, pruritus, urticaria, and events suggestive of angioedema.

Cerebrovascular Adverse Reactions, Including Stroke: In clinical trials with antipsychotic drugs, elderly subjects with dementia had a higher incidence of cerebrovascular adverse reactions, including fatalities vs placebo. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with antipsychotic drugs. NMS may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and monitoring.

Tardive Dyskinesia (TD): Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood it will become irreversible may increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses, or after treatment discontinuation. If signs and symptoms of TD appear, drug discontinuation should be considered.

Late-Occurring Adverse Reactions: Adverse events may first appear several weeks after initiation of VRAYLAR, probably because plasma levels of cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures. Monitor for adverse reactions, including extrapyramidal symptoms (EPS) or akathisia, and patient response for several weeks after starting VRAYLAR and after each dosage increase. Consider reducing the dose or discontinuing the drug.

Metabolic Changes: Atypical antipsychotics have caused metabolic changes, such as:

• Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. Assess fasting glucose before or soon after initiation of treatment, and monitor periodically during long-term treatment.
• Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after starting an antipsychotic, obtain baseline fasting lipid profile and monitor periodically during treatment.
• Weight Gain: Weight gain has been observed with VRAYLAR. Monitor weight at baseline and frequently thereafter.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia/neutropenia have been reported with antipsychotics, including VRAYLAR. Agranulocytosis (including fatal cases) has been reported with other antipsychotics. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue VRAYLAR at the first sign of a clinically significant decline in WBC and in severely neutropenic patients.

Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope, with the greatest risk during initial titration and with dose increases. Monitor orthostatic vital signs in patients predisposed to hypotension and in those with cardiovascular/cerebrovascular diseases.

Falls: VRAYLAR may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures, or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotics and recurrently for patients on long-term therapy.

Seizures: Use VRAYLAR with caution in patients with history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment: Somnolence was reported with VRAYLAR. Caution patients about performing activities requiring mental alertness (eg, operating hazardous machinery or a motor vehicle).

Body Temperature Dysregulation: Use VRAYLAR with caution in patients who may experience conditions that increase body temperature (eg, strenuous exercise, extreme heat, dehydration, or concomitant anticholinergics).

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotics. Antipsychotic drugs, including VRAYLAR, should be used cautiously in patients at risk for aspiration.

Drug Interactions: Strong CYP3A4 inhibitors increase VRAYLAR concentrations, so VRAYLAR dose reduction is recommended. Concomitant use with CYP3A4 inducers is not recommended.

Adverse Reactions: In clinical trials, the most common adverse reactions (≥5% and at least twice the rate of placebo) are listed below:

• Schizophrenia: The incidences within the recommended dose range (VRAYLAR 1.5 – 3 mg/day and 4.5 – 6 mg/day vs placebo) were: EPS (15%, 19% vs 8%) and akathisia (9%, 13% vs 4%)
• Bipolar mania: The incidences within the recommended dose range (VRAYLAR 3 – 6 mg/day vs placebo) were: EPS (26% vs 12%), akathisia (20% vs 5%), dyspepsia (7% vs 4%), vomiting (10% vs 4%), somnolence (7% vs 4%), and restlessness (7% vs 2%)

Please also see full Prescribing Information, including Boxed Warning.

About Allergan plc
Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a bold, global pharmaceutical company and a leader in a new industry model – Growth Pharma.  Allergan is focused on developing, manufacturing and commercializing branded pharmaceuticals, devices and biologic products for patients around the world.

Allergan markets a portfolio of leading brands and best-in-class products for the central nervous system, eye care, medical aesthetics and dermatology, gastroenterology, women's health, urology and anti-infective therapeutic categories.

Allergan is an industry leader in Open Science, the Company's R&D model, which defines our approach to identifying and developing game-changing ideas and innovation for better patient care.  This approach has led to Allergan building one of the broadest development pipelines in the pharmaceutical industry with 70+ mid-to-late stage pipeline programs in development.

Our Company's success is powered by our more than 16,000 global colleagues' commitment to being Bold for Life. Together, we build bridges, power ideas, act fast and drive results for our customers and patients around the world by always doing what is right.

With commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives every day.

For more information, visit Allergan's website at www.Allergan.com.

Forward-Looking Statement

Statements contained in this press release that refer to future events or other non-historical facts are forward-looking statements that reflect Allergan's current perspective of existing trends and information as of the date of this release. Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements. Actual results may differ materially from Allergan's current expectations depending upon a number of factors affecting Allergan's business. These factors include, among others, the difficulty of predicting the timing or outcome of FDA approvals or actions, if any; the impact of competitive products and pricing; market acceptance of and continued demand for Allergan's products; difficulties or delays in manufacturing; and other risks and uncertainties detailed in Allergan's periodic public filings with the Securities and Exchange Commission, including but not limited to Allergan's Annual Report on Form 10-K for the year ended December 31, 2016. Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements.

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