Brexpiprazole

Brexpiprazole (also called OPC-34712) is a novel D2 dopamine partial agonist investigational product currently in clinical trials for the treatment of depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). It has been designed to provide improved efficacy and tolerability (e.g., less akathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).

The drug is being developed by Otsuka, and is considered to be a successor of its top-selling antipsychotic agent Aripiprazole (brand names: Abilify, Aripiprex). Otsuka's US patent on aripiprazole expires on October 20, 2014; however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.

Partnership with Lundbeck
In November 2011, Otsuka and Lundbeck have announced a global alliance. Lundbeck has given Otsuka an upfront payment of $200 million, and the deal includes development, regulatory and sales payments, for a potential total of $1.8 billion. Specifically for OPC-34712, Lundbeck will obtain 50% of net sales in Europe and Canada and 45% of net sales in the US from Otsuka.

The partnership has been presented by Otsuka to its investors as a good fit for several reasons:
 * Geographic strategy: Otsuka in Japan, Asia, US; Lundbeck in Europe, South America and emerging markets
 * Research strategy: Otsuka has knowledge in antipsychotics, Lundbeck in anti-depressant and antianxiolytic.
 * CNS strategy: Otsuka has a robust portfolio in next-generation CNS drugs, while Lundbeck covers a wide range of CNS conditions from Alzheimer's to schizophrenia.
 * Similar corporate culture

Clinical Trials
OPC-34712 is currently in clinical trials for adjunctive treatment of MDD, adjunctive treatment of adult ADHD and schizophrenia.

Phase II
The Phase 2 multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three ADTs in the current episode. The study was designed to assess the efficacy and safety of OPC-34712 as an adjunctive treatment to standard ADT. The ADTs included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.

Phase III
A new Phase III study is currently in the recruiting stage: "Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)". Its goal is "to compare the effect of OPC-34712 to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with Major Depressive Disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT". Estimated enrollment is 1250 volunteers.

Phase II

 * Study of the Safety and Efficacy of OPC-34712 as a Complementary Therapy in the Treatment of Adult Attention Deficit/Hyperactivity Disorder (STEP-A)

Phase I

 * Trial to Evaluate the Effects of OPC-34712 on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder

Phase II

 * A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia

Phase III

 * Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)
 * Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)
 * Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)
 * A Long-term Trial of OPC-34712 in Patients With Schizophrenia

Conferences

 * Phase II results were presented at the American Psychiatric Association's 2011 annual meeting in May 2011.


 * The drug has been presented at the 2nd Congress of Asian College of Neuropsychopharmacology in September 2011.


 * At the US Psychiatric and Mental Health Congress in November 2011 in Vegas, Robert McQuade presented the Phase II Trial results for Schizophrenia

Side effects
The most common adverse events associated with OPC-34712 (all doses of OPC-34712 cumulatively greater than or equal to 5 percent vs. placebo) were upper respiratory tract infection (6.9% vs. 4.8%), akathisia (6.6% vs. 3.2%), weight gain (6.3% vs. 0.8%), and nasopharyngitis (5.0% vs. 1.6%).

Drug interactions
Based on information given on the consent forms, it seems OPC-34712 is a substrate of CYP2D6 and CYP3A4, like its predecessor Aripiprazole. Participants in the clinical trials are advised to avoid grapefruit, Seville oranges and related citruses.

Pharmacology
Based on the patent description and Otsuka press releases, the compound is described as having broad activity across multiple monoamine systems:
 * D2 dopamine receptor partial agonist (improving positive and negative symptoms, cognitive impairment and depressive symptoms)
 * Serotonin 5-HT2A receptor antagonist (improving negative symptoms, cognitive impairment, depressive symptoms, and insomnia)
 * Adrenalin α1 receptor antagonist (improving positive symptoms of schizophrenia)
 * Serotonin uptake/reuptake inhibitory effect (improving depressive symptoms)

Also, according to Phase II trial results, it also acts as:
 * 5-HT1A partial agonist (anxiolytic and antidepressive activity)
 * 5-HT7 antagonist (thermoregulation, circadian rhythm, learning and memory, sleep)

Dosage

 * As an adjunct to standard antidepressant therapy in adult patients with major depressive disorder:
 * Phase II trials: 1.5 ± 0.5 mg.
 * Phase III trials: 1 or 3 mg depending on group.
 * For schizophrenic/schizoaffective subjects, dosage is 4 or 12mg.
 * For ADHD, the dose is 0.25 to 2 mg/day.

Patents

 * WIPO PCT/JP2006/317704
 * Canadian patent: 2620688
 * Canadian patent: 2620688