Allergan Receives FDA Approval For Use of VRAYLARtm (cariprazine) in the Maintenance Treatment of Schizophrenia

DUBLIN, Nov. 13, 2017 /PRNewswire/ -- Allergan plc (NYSE: AGN) today announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for VRAYLARtm (cariprazine) for the maintenance treatment of adults with schizophrenia. VRAYLAR is also approved in the U.S. in adults for the acute treatment of schizophrenia and acute treatment of manic or mixed episodes of bipolar I disorder.¹

"Schizophrenia is one of the most challenging mental health disorders to manage ? particularly due to the complexity of patient symptoms, varying response to treatment and high rates of relapse," said Dr. Herbert Meltzer, Professor of Psychiatry and Behavioral Sciences at Northwestern Feinberg School of Medicine. "The goal of clinicians is to minimize relapses, which can cause significant personal distress, and can often have serious implications for a patient's health. The approval of VRAYLAR for the maintenance treatment of schizophrenia provides an important therapy for patients and physicians who are in need of long-term treatment options."

Without maintenance treatment, 60 ? 70 percent of schizophrenia patients relapse within one year. Once a schizophrenia patient reaches the stable or maintenance phase of treatment, it is important for the physician to develop a long-term treatment management plan to minimize relapse risk, monitor for and reduce severity of side effects, and address residual symptoms where possible.²

The efficacy of VRAYLAR in the maintenance treatment of schizophrenia was based on an up to 72-week, multinational, double-blind, placebo-controlled, randomized withdrawal study in the prevention of relapse in adult patients with schizophrenia. 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 either to continue their VRAYLAR dose (3, 6 or 9 mg per day) or be switched to placebo for up to 72 weeks or until a relapse occurred. The primary endpoint was time to relapse during the randomized, double blind phase.¹ 
The study demonstrated that VRAYLAR y significantly delayed the time to relapse compared to placebo (P=0.0010). Relapse occurred in nearly twice as many placebo-treated patients (49.5%, n=49/99) as VRAYLAR-treated (29.7%, n=30/101) patients. The safety results were consistent with the profile observed to-date for VRAYLAR.¹

"The differences in how people with schizophrenia respond to treatment underscores the importance of having additional treatment options," said David Nicholson, Chief Research & Development Officer at Allergan. "We are pleased that the FDA has recognized the benefits of VRAYLAR for maintenance treatment of adults with schizophrenia. This approval demonstrates our continued investment in VRAYLAR, as well as our commitment to developing treatments that address unmet needs facing people living with mental illness."

About Schizophrenia

Schizophrenia is a chronic and disabling disorder that affects about 2.4 million American adults.³ It imposes significant burden on patients, their families and society. Symptoms fall into three broad categories: positive symptoms (hallucinations, delusions, thought disorders and movement disorders), negative symptoms (such as loss of motivation and social withdrawal) and cognitive symptoms (problems with executive functioning, focusing and working memory).⁴

About VRAYLARtm (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 D? 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 ?_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.

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 company and a leader in a new industry model ? Growth Pharma. 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 with 55+ mid-to-late stage pipeline programs currently in development.

Allergan's success is powered by our more than 18,000 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 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; 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 and Allergan's Quarterly Report on Form 10-Q for the period ended September 30, 2017. Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements.

References

1.    VRAYLARtm [package insert]. Irvine, CA: Allergan USA, Inc.; 2017. 
2.    Practice Guidelines for the Treatment of Patients with Schizophrenia. American Psychiatric Association. Available at: https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/schizophrenia.pdf. Accessed November 2017. 
3.    Schizophrenia. NIH Research Portfolio Online Reporting Tools (RePORT). U.S. Department of Health & Human Services.. Available at: https://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=67. Accessed November 2017. 
4.    Schizophrenia. National Institutes of Mental Health (NIMH). Available at: https://infocenter.nimh.nih.gov/nimh/product/Schizophrenia/TR%2015-3517. Accessed November 2017.

CONTACTS: Allergan: 
Investors: 
Daphne Karydas 
(862) 261-8006

Media: 
Mark Marmur 
(862) 261-7558 
Frances DeSena 
(862) 261-8820

SOURCE Allergan plc