Otsuka and Lundbeck Announce U.S. FDA Acceptance of New Drug Application for Aripiprazole 2-month, Ready-to-Use, Long-acting Injectable to Treat Schizophrenia and Bipolar I Disorder in Adults

• If approved, aripiprazole 2-month ready-to-use (RTU), long-acting injectable (LAI) would be the first 2-month, LAI antipsychotic indicated for both treatment of schizophrenia and the maintenance treatment of bipolar I disorder in U.S.
• Filing is supported by a 32-week bridging trial in which aripiprazole 2-month showed comparable effectiveness and consistent safety profile to aripiprazole 1-month.
• The FDA target date (PDUFA date) for completion of the review is April 27, 2023.

Otsuka America Pharmaceutical, Inc., (Otsuka) and H. Lundbeck A/S (Lundbeck) announce the U.S. Food and Drug Administration (FDA) acceptance of their New Drug Application (NDA) for aripiprazole 2-month, ready-to-use, long-acting injectable, a medication administered for the treatment of schizophrenia in adults and for maintenance monotherapy treatment of bipolar I disorder in adults.

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Aripiprazole 2-month, ready-to-use, long-acting injectable is provided in a single-chamber-type, prefilled syringe. It is intended for dosing every two months via intramuscular injection in the gluteal muscle.

“This is an important milestone in our efforts to offer adult patients with schizophrenia or bipolar I disorder a new option designed to support treatment goals and offer greater flexibility. The trial results reinforce the long-standing efficacy and safety profile of the once-monthly aripiprazole long-acting injectable,” said Johan Luthman, executive vice president, Lundbeck Research & Development.

The 2-month, ready-to-use, long-acting injectable of aripiprazole in 960 mg and 720 mg prefilled syringes will deliver sustained plasma concentrations similar to that demonstrated in studies with aripiprazole once-monthly long-acting injectable, resulting in consistent efficacy. Regulatory approval would be based on a multiple-dose, randomized, parallel-arm, clinical trial to assess safety, tolerability, and pharmacokinetics in adults with schizophrenia or bipolar I disorder.

“Stability is critical for patients with schizophrenia and bipolar I – which means delaying time to relapse or recurrence and supporting their role as functioning members of their community,” said Robert McQuade, PhD, executive vice president and chief strategy officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “As we continue our efforts to bring aripiprazole 2-month to market, we remain committed to our patients and confident that the favorable safety and tolerability profile will be clearly visible.”

About Schizophrenia

Schizophrenia is a severely debilitating mental illness characterized by delusions, hallucinations, and disordered cognition. Based on a systematic review of global data, the prevalence of schizophrenia in 2019 was estimated to be approximately 0.3% and did not vary widely across countries or regions. The worldwide lifetime prevalence of the disease has been estimated to be approximately 0.9% across diverse geographic, cultural, and socioeconomic categories. The course of schizophrenia is typically characterized by acute episodes of psychotic behaviors occurring at varying intervals between periods of relative symptomatic stability. Medication adherence in patients with schizophrenia is generally poor and several studies have demonstrated that the strongest predictor of further relapse is nonadherence with antipsychotic medications.

About Bipolar I Disorder

Bipolar I disorder is a recurrent, lifelong mood disorder with a variable course that results in functional and cognitive impairment and a reduction in quality of life that affects 0.6% of the population. The course of bipolar I disorder is characterized by recurrent manic and depressive episodes that may last weeks or months. Over 90% of people with bipolar disorder experience recurrences during their lifetime.

Bipolar I disorder often requires long-term pharmacologic treatment to delay time to recurrence or relapse of symptoms. Long-acting injectables provide continuous delivery of antipsychotic medication and maintain therapeutic plasma concentrations, which may help address the variable nature of bipolar disorder.

About aripiprazole 2-month, ready-to-use long-acting injectable

Aripiprazole 2-month, ready-to-use long-acting injectable is provided in a single-chamber-type, prefilled syringe (PFS) that does not require reconstitution, intended for dosing every two months via intramuscular (IM) injection in the gluteal muscle in the same patient populations as indicated for once-monthly ABILIFY MAINTENA^® (aripiprazole).

Results from the pivotal trial 031-201-00181, that enrolled 266 patients, demonstrated that aripiprazole ready-to-use LAI 960 mg met the primary endpoint criteria establishing similarity of aripiprazole plasma concentrations and thus comparable effectiveness to aripiprazole once-monthly 400 mg over a two-month dosing interval.

Multiple-dose administrations of aripiprazole 2-month, RTU, LAI 960 mg were generally safe and well tolerated in subjects with schizophrenia or bipolar I disorder and did not show any new safety concerns compared to aripiprazole once-monthly 400 mg.

INDICATIONS and IMPORTANT SAFETY INFORMATION for ABILIFY MAINTENA^® (aripiprazole)

INDICATIONS

ABILIFY MAINTENA^® (aripiprazole) is an atypical antipsychotic indicated for:

• Treatment of schizophrenia in adults
• Maintenance monotherapy treatment of bipolar I disorder 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 increased risk of death (1.6 to 1.7 times) compared to placebo-treated patients. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis.

Contraindication: Known hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of elderly patients with dementia-related psychosis treated with oral aripiprazole.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs including ABILIFY MAINTENA. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of ABILIFY MAINTENA, intensive symptomatic treatment, and monitoring.

Tardive Dyskinesia (TD): Risk of TD, and the potential to become irreversible, are believed to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even at low doses, or after discontinuation of treatment. Prescribing should be consistent with the need to minimize TD. If antipsychotic treatment is withdrawn, TD may remit, partially or completely.

Metabolic Changes: Atypical antipsychotic drugs have caused metabolic changes including:

• Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics including aripiprazole. Patients with diabetes mellitus should be regularly monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes), should undergo baseline and periodic fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
• Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
• Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Pathological Gambling and Other Compulsive Behaviors: Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking aripiprazole. Other compulsive urges have been reported less frequently. Prescribers should ask patients or their caregivers about the development of new or intense compulsive urges. Consider dose reduction or stopping aripiprazole if such urges develop.

Orthostatic Hypotension: ABILIFY MAINTENA may cause orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.

Falls: Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia, neutropenia and agranulocytosis have been reported with 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 ABILIFY MAINTENA at the first sign of a clinically significant decline in WBC and in severely neutropenic patients.

Seizures: ABILIFY MAINTENA should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment: ABILIFY MAINTENA may impair judgment, thinking, or motor skills. Instruct patients to avoid operating hazardous machinery, including automobiles, until they are certain ABILIFY MAINTENA does not affect them adversely.

Body Temperature Regulation: Use ABILIFY MAINTENA with caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Dysphagia: Esophageal dysmotility and aspiration have been associated with ABILIFY MAINTENA. Use caution in patients at risk for aspiration pneumonia.

Alcohol: Advise patients to avoid alcohol while taking ABILIFY MAINTENA.

Concomitant Medication: Dosage adjustments are recommended in patients who are CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days. Avoid concomitant use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days. Dosage adjustments are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.

Most Commonly Observed Adverse Reactions: The most commonly observed adverse reactions with ABILIFY MAINTENA in patients with schizophrenia (incidence ≥5% and at least twice that for placebo) were increased weight, akathisia, injection site pain, and sedation.

Injection Site Reactions: In a short-term, clinical trial with ABILIFY MAINTENA in patients with schizophrenia treated with gluteal administered ABILIFY MAINTENA, the percent of patients reporting any injection site-related adverse reaction was 5.4%, and 0.6% for placebo. In an open label study of ABILIFY MAINTENA administered in the deltoid or gluteal muscle, injection site pain was observed at approximately equal rates.

Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy: Neonates exposed to antipsychotic drugs, including ABILIFY MAINTENA, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. Consider the benefits and risks of ABILIFY MAINTENA and possible risks to the fetus when prescribing ABILIFY MAINTENA to a pregnant woman. Advise pregnant women of potential fetal risk.

Lactation: Aripiprazole is present in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and any potential risks to the infant.

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

About Otsuka

Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: Otsuka–people creating new products for better health worldwide. Otsuka researches, develops, manufactures, and markets innovative products, with a focus on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health.

In pharmaceuticals, Otsuka is a leader in the challenging areas of mental, renal, and cardiovascular health and has additional research programs in oncology and on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does.

Otsuka established a presence in the U.S. in 1973 and today its U.S. affiliates include Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Otsuka America Pharmaceutical, Inc. (OAPI). These two companies’ 2,000 employees in the U.S. develop and commercialize medicines in the areas of mental health, nephrology, and cardiology, using cutting-edge technology to address unmet healthcare needs.

OPDC and OAPI are indirect subsidiaries of Otsuka Pharmaceutical Company, Ltd., which is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 47,000 people worldwide and had consolidated sales of approximately USD 13.6 billion in 2021.

All Otsuka stories start by taking the road less traveled. Learn more about Otsuka in the U.S. at www.otsuka-us.com and connect with us on LinkedIn and Twitter at @OtsukaUS. Otsuka Pharmaceutical Co., Ltd.’s global website is accessible at https://www.otsuka.co.jp/en/

About H. Lundbeck A/S

Lundbeck is a global pharmaceutical company specialized in brain diseases. For more than 70 years, we have been at the forefront of neuroscience research. We are tirelessly dedicated to restoring brain health, so every person can be their best.

We are committed to fighting stigma and discrimination against people living with brain diseases and advocating for broader social acceptance of people with brain health conditions. Our research programs tackle some of the most complex challenges in neuroscience, and our pipeline is focused on bringing forward transformative treatments for brain diseases for which there are few, if any therapeutic options.

For additional information, we encourage you to visit our corporate site www.lundbeck.com and connect with us on Twitter at @Lundbeck and via LinkedIn.

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