Otsuka and Lundbeck Announce FDA Acceptance of Supplemental New Drug Application; Receive Priority Review for Treatment of Schizophrenia in Adolescents

Submission is based on extrapolation analysis and results examining the effects of Rexulti^® (brexpiprazole) 2 to 4 mg/day in treating symptoms of schizophrenia in adolescent patients (13-17 years old). Schizophrenia often starts developing during adolescence.

Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) report that the U.S. Food and Drug Administration (FDA) has accepted a Supplemental New Drug Application (sNDA) for the treatment of schizophrenia in adolescents with Rexulti^® (brexpiprazole) and has granted Otsuka and Lundbeck Priority Review. Up to one-third of patients with schizophrenia develop the disease during adolescence. Currently, Rexulti is approved in the U.S. for treatment of schizophrenia in adults and adjunctive treatment of major depressive disorder in adults.

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The submission has been completed one year earlier than planned, with the hope of benefitting adolescent patients with schizophrenia who need more treatment options.

“There is significant unmet need for treatment options among pediatric schizophrenia patients, so we are pleased to submit this sNDA for Rexulti one year ahead of schedule with the hope of eventually serving this important community,” says Christoph Koenen, M.D., executive vice president, and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc.

The acceleration of the program was made possible by doing an extrapolation analysis using data from prior studies in adult patients, pharmacokinetic results from adult and pediatric trials, and 6-month data from the ongoing open-label, long-term trial in adolescent schizophrenia patients (Trial 331-10-236).

“By using an extrapolation approach in accordance with new regulatory guidance, our goal is to offer a new treatment option to adolescent patients at an accelerated pace compared to previous regulatory guidance,” says Johan Luthman, executive vice president, Research and Development, Lundbeck.

Based on an interim analysis of the ongoing open-label, long-term trial, brexpiprazole appears to be a potential treatment option for adolescent patients with schizophrenia, with a safety profile consistent of that observed in adult patients. The most common adverse event was somnolence with an incidence of 10.2%, and the incidence of akathisia was 2.4%.

The results of the more than 100 adolescent patients treated for at least 6 months from the trial will be presented at the Psych Congress taking place October 29 to November 1, 2021, and is intended to be published in a peer-reviewed scientific journal during 2022.

The FDA is expected to complete its review of the sNDA by December 2021.

About the Global Brexpiprazole Pediatric Development Program in Schizophrenia

The current global pediatric clinical program includes two completed phase 1 trials and two ongoing phase 3 trials. The two completed phase 1 trials investigated the PK, safety, and tolerability of brexpiprazole.

The pharmacokinetic extrapolation was done using data from the two pediatric phase 1 trials together with data from three adult phase 1 trials to build a model that assesses whether the blood concentration of brexpiprazole was similar in adolescents compared to that in adults. Two phase 3 trials are currently underway in adolescents (13-17 years old) with schizophrenia to evaluate short-term efficacy and safety (Trial 331-10-234) and long-term safety and tolerability (Trial 331-10-236) of brexpiprazole as part of the initial agreement on the pediatric program with both FDA and the European Medicines Agency (EMA).

About Rexulti/Rxulti (brexpiprazole)

Brexpiprazole was discovered by Otsuka and is being co-developed by Otsuka and Lundbeck. The mechanism of action for brexpiprazole is not fully understood. However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT_1A and dopamine D₂ receptors, and antagonist activity at serotonin 5-HT_2A receptors. Brexpiprazole exhibits high affinity (sub-nanomolar) for these receptors as well as for noradrenaline alpha_1B/2C receptors. Depending on the market, brexpiprazole is known as Rexulti^® or Rxulti^®.

INDICATIONS and IMPORTANT SAFETY INFORMATION for REXULTI^® (brexpiprazole)

INDICATIONS

REXULTI is indicated for:

• Use as an adjunctive therapy to antidepressants in adults with major depressive disorder
• 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 increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increase the risk of suicidal thoughts and behaviors in patients aged 24 years and younger. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors. The safety and effectiveness of REXULTI have not been established in pediatric patients.

Contraindication: In patients with known hypersensitivity reaction to brexpiprazole or any of its components. Reactions have included: rash, facial swelling, urticaria and anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: In clinical trials, elderly patients with dementia randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs including REXULTI. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of REXULTI, 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. For chronic treatment, use the lowest dose and shortest duration of REXULTI needed to produce a clinical response. If signs and symptoms of TD appear, drug discontinuation should be considered.

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

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

Pathological Gambling and Other Compulsive Behaviors: Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking REXULTI. 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 REXULTI if such urges develop.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia and neutropenia have been reported with antipsychotics. Agranulocytosis (including fatal cases) has been reported with other agents in this class. 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 REXULTI 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. Generally, the risk is greatest during initial dose titration and when increasing the dose. Monitor in patients vulnerable to hypotension, and those with cardiovascular and cerebrovascular diseases.

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.

Seizures: REXULTI may cause seizures and should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Body Temperature Dysregulation: Use REXULTI 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 antipsychotics, including REXULTI, and should be used with caution in patients at risk for aspiration.

Potential for Cognitive and Motor Impairment: REXULTI has the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are reasonably certain REXULTI does not affect them adversely.

Concomitant Medication: Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers.

Most commonly observed adverse reactions: In clinical trials, the most common adverse reactions were:

• Major Depressive Disorder (MDD) (adjunctive treatment to antidepressant therapy; ≥5% incidence and at least twice the rate of placebo for REXULTI vs. placebo): akathisia and weight increase
• Schizophrenia (≥4% incidence and at least twice the rate of placebo for REXULTI vs. placebo): weight increased

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

Pregnancy: Adequate and well-controlled studies to assess the risks of REXULTI during pregnancy have not been conducted. REXULTI should be used during pregnancy only if the benefit justifies the risk to the fetus.

Lactation: It is not known if REXULTI is excreted 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.

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 Schizophrenia in Adolescents

Schizophrenia often starts developing during adolescence, with symptoms that tend to be severe. Development of schizophrenia during adolescence is associated with poor long-term outcomes relating to social adjustment, functional impairment, and socioeconomic dependence. Early detection and treatment are currently regarded as the most promising strategies to improve treatment outcomes and long-term prognosis. For adolescents with schizophrenia, antipsychotics offer improvements in symptom control and functioning; however, younger patients may be particularly vulnerable to antipsychotic side effects, highlighting the need for new treatment options.

About Lundbeck

H. Lundbeck A/S (LUN.CO, LUN DC, HLUYY) 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.

Millions of people worldwide live with brain diseases and far too many suffer due to inadequate treatment, discrimination, a reduced number of working days, early retirement, and other unnecessary consequences. Every day, we strive for improved treatment and a better life for people living with brain diseases – we call this Progress in Mind.

Our approximately 5,600 employees in more than 50 countries are engaged in the entire value chain throughout research, development, production, marketing, and sales. Our pipeline consists of several R&D programs and our products are available in more than 100 countries. We have research centers in Denmark and the US and our production facilities are located in Denmark, France, and Italy. Lundbeck generated revenue of DKK 17.7 billion in 2020 (EUR 2.4 billion; USD 2.7 billion).

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.

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’ 1,700 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 13.3 billion in 2020.

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 www.otsuka.co.jp/en/.

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