Allergan Announces FDA Acceptance of Supplemental New Drug Application For VRAYLAR® (cariprazine)

DUBLIN, Sept. 26, 2018 /PRNewswire/ -- Allergan plc (NYSE: AGN), a leading global pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has accepted for review the company's supplemental New Drug Application (sNDA) for VRAYLAR^® (cariprazine), seeking to expand the indication to include the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults in the current product label.

The sNDA is supported by data from three pivotal trials, including RGH-MD-53, RGH-MD-54 and RGH-MD-56. In all three pivotal studies, cariprazine demonstrated greater improvement than placebo for the change from baseline to week 6 on the Montgomery Asberg Depression Rating scale (MADRS) total score. Both cariprazine 1.5 mg and 3 mg demonstrated superiority to placebo in reducing depressive symptoms associated with bipolar I depression.

"Despite decades of development, bipolar depression remains difficult to treat. Importantly, bipolar I patients will need treatment for the full spectrum of of their disorder," said Gary Sachs, MD, Associate Clinical Professor of Psychiatry at Harvard Medical School. "If approved for bipolar depression, cariprazine would be the first and only partial agonist with proven efficacy for both the manic and depressive symptoms of bipolar I disorder. That is very encouraging news for patients, their families, and the psychiatry community."

Cariprazine was generally well tolerated in the trials. The most commonly reported adverse events (i.e., those reported by ≥ 5% of patients in any cariprazine treatment group and at twice the rate of placebo) were nausea, akathisia, restlessness and upper respiratory tract infection. Adverse events led to discontinuation in 6.7% of cariprazine-treated patients versus 4.8% of placebo treated patients.

"This sNDA filing provides an important step towards the availability of a potential treatment option for the approximately 5 million patients suffering with bipolar I depression. These positive pivotal studies, demonstrated the efficacy and safety of VRAYLAR for the treatment of bipolar depression," said David Nicholson, Chief Research & Development Officer at Allergan. " "VRAYLAR is the flagship product of our Psychiatry portfolio and demonstrates Allergan's commitment to the mental health community."

Cariprazine was approved by the FDA in September 2015 and is marketed as VRAYLAR^® in the US for the treatment of schizophrenia in adults and acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

About Cariprazine Trials in Bipolar I Depression

The efficacy and safety of cariprazine in bipolar depression was evaluated in a total of four, 6- and 8-week randomized, placebo-controlled studies. One exploratory study phase 2 study RGH-MD-52 in bipolar I & II patients, and 3 pivotal studies (RGH-MD-56, 53 & 54) in bipolar I patients.

RGH MD 52 was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose study comparing cariprazine to placebo in outpatients with a primary diagnosis of bipolar I or II disorder who were experiencing a major depressive episode. The study randomized 233 patients with bipolar I and bipolar II disorder to 1 of 3 dose groups for 8 weeks of double blind treatment: cariprazine 0.25 mg to 0.75 mg; cariprazine 1.5 mg to 3 mg; or placebo.

RGH-MD-56 was a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group clinical trial in adult patients with bipolar I depression. A total of 584 patients were randomized to evaluate the efficacy, safety, and tolerability of cariprazine 0.75 mg, 1.5 mg and 3 mg compared to placebo in the treatment of outpatients with bipolar I depression. Patients underwent a no-drug screening period of approximately 7-14 days, followed by 8 weeks of double-blind treatment (primary endpoint was 6-weeks) and a 1-week, no investigational product safety follow-up period.

RGH-MD-53 and RGH-MD-54 were identical Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter, fixed-dose clinical trials in adult patients with bipolar I depression. Patients were randomized in both studies aiming to evaluate the efficacy, safety, and tolerability of cariprazine 1.5 mg and 3 mg compared to placebo in outpatients with bipolar I depression. Patients underwent a no-drug screening period of approximately 7-14 days, followed by 6 weeks of double-blind treatment and a 1-week, no investigational product safety follow-up period.

About VRAYLAR^® (cariprazine)

VRAYLAR is an oral, once daily atypical antipsychotic approved for the treatment of schizophrenia in adults, with a recommended dose range of 1.5 to 6 mg/day and 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.

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 with high binding affinity at dopamine D₃, dopamine D₂, and serotonin 5-HT_1A receptors. 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 by Allergan, in the U.S. and Canada. For more than a decade both companies have conducted over 20 clinical trials enrolling thousands of patients worldwide to evaluate the efficacy and safety of cariprazine for patients suffering from a broad range of mental health illnesses. 

Visit www.vraylar.com for more information.

INDICATION AND USAGE
VRAYLAR (cariprazine) is indicated in adults for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes of bipolar I disorder.

IMPORTANT SAFETY INFORMATION

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 leader. Allergan is focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine 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, a model of research and development, which defines our approach to identifying and developing game-changing ideas and innovation for better patient care. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry.

Allergan's success is powered by our 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 on existing trends and information as of the date of this release. 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; the impact of uncertainty around timing of generic entry related to key products, including RESTASIS^®, on our financial results; risks associated with divestitures, acquisitions, mergers and joint ventures; uncertainty associated with financial projections, projected cost reductions, projected debt reduction, projected synergies, restructurings, increased costs, and adverse tax consequences; 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, 2017 and Allergan's Quarterly Report on Form 10-Q for the period ended June 30, 2018. Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements.

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