Results of clinical phase III study of once-monthly aripiprazole IM depot formulation for the treatment of schizophrenia presented at APA

In a 52-week, double-blind, randomized, placebo-controlled study, aripiprazole IM depot significantly delayed time-to-impending relapse compared to placebo, the primary endpoint of the study (Hazard ratio = 5.03, p<0.0001). In addition, improvements in the symptoms [as measured by the Positive and Negative Syndrome Scale (PANSS) total score] were maintained throughout the study in patients treated with aripiprazole IM depot formulation, while patients who received placebo reported significantly worsening scores (mean change from baseline at week 52 was 1.4 for aripiprazole IM depot compared to 11.6 for placebo; LOCF analysis, p<0.0001). Results also demonstrated that aripiprazole IM depot was well tolerated, with a discontinuation rate due to treatment-related adverse events less than placebo (7.1% vs. 13.4%, respectively).

“Otsuka and Lundbeck are committed to advancing care and addressing unmet needs for patients with schizophrenia,” said William H. Carson, M.D., President and CEO, Otsuka Pharmaceutical Development & Commercialization, Inc. “We are pleased to report on the positive data from the pivotal Phase 3 study designed to evaluated the efficacy and tolerability of aripiprazole IM depot as a long-term maintenance treatment for patients with schizophrenia.”.

“We are very encouraged by these data of aripiprazole IM depot formulation which shows that a once-monthly injection of this compound is effective in delaying the time to relapse for patients with schizophrenia” says Executive Vice President Anders Gersel Pedersen, Head of Research & Development at Lundbeck, and continues: “As relapsed patients experience further erosion of his or her mental and overall physical health, which again can lead to decreased functioning, increased morbidity and thereby worsen the overall outcome.”

Study design and findings

This clinical phase III multi-center, double-blind, placebo-controlled study included 710 adult patients with schizophrenia who required chronic treatment with an antipsychotic agent. The study was designed to assess the efficacy, safety and tolerability of aripiprazole IM depot formulation, as a long-term maintenance treatment for schizophrenia. In addition, due to the placebo-controlled nature of the study, an interim analysis was conducted after 50% of the targeted events of impending relapse were accrued. An independent Data Monitoring Committee evaluated the data from this interim analysis and determined that the study should be stopped based on meeting pre-specified efficacy criteria. The data reported here represent the final data analysis following termination of the study.

The study was comprised of four phases: 1) an oral conversion phase (4-6 weeks) in which study patients not currently being treated with aripiprazole were converted to oral aripiprazole monotherapy; 2) an oral stabilization phase (4-12 weeks) in which all patients were treated with oral aripiprazole (10-30mg/day) until achieving pre-specified stability criteria for at least 4 weeks; 3) an IM depot stabilization phase where patients received aripiprazole IM depot injections every four weeks (400 mg with a permissible single decrease to 300 mg, with co-administration of oral aripiprazole during the first two weeks (n=576) ; and 4) a maintenance treatment phase where patients received an injection of aripiprazole IM depot or placebo once every 4 weeks for 52 weeks (n=403). When patients participating in Phase 3 of the study met stability criteria for 12 weeks they were randomized (2:1) to aripiprazole IM depot (n=269) or placebo (n=134) for the maintenance phase (Phase 4).

The primary efficacy endpoint was time to impending relapse. The key secondary efficacy endpoint was the percentage of subjects who met the impending relapse criteria at the endpoint of the Double-blind, Placebo-controlled Phase. Other secondary efficacy evaluations included mean changes from baseline in PANSS, as well as mean changes from baseline in the Personal and Social Performance (PSP) scale scores, Clinical Global Impression of Severity (CGI-S) scores and in the Investigator’s Assessment Questionnaire (IAQ) scores, a scale designed to evaluate response to antipsychotics. Tolerability and safety also were assessed.

In addition to delayed time-to-impending relapse, the rate of impending relapse was significantly lower with aripiprazole IM depot compared to placebo after 52 weeks of treatment (10.0% vs. 39.6%, respectively; p<0.0001). Improvements in symptoms, functioning and overall response to treatment that were achieved during the stabilization phase were sustained during the maintenance treatment phase of the study:

• During the maintenance treatment phase, PANSS subscale scores showed both positive and negative symptom stability with aripiprazole IM depot but showed significant worsening for patients who received placebo [mean change from baseline in PANSS positive symptom subscale scores was 0.4 for aripiprazole IM depot compared to a mean change of 4.3 for placebo (LOCF analysis, p<0.0001); and a mean change in baseline of 0.2 vs. 1.6 for PANSS negative subscale scores (LOCF analysis, p<0.0001)].
• Mean change from baseline in PSP scale scores during the maintenance treatment phase of the study showed greater stability of social functioning with aripiprazole IM depot compared to placebo (-1.7 vs. -6.2, respectively; LOCF analysis, p=0.0002).
• Mean change from baseline in the IAQ (a 12-item assessment of overall effectiveness) total scores also remained more stable amongst patients who received aripiprazole IM depot than those receiving placebo during the maintenance treatment phase (mean change was +1.3 for aripiprazole IM depot vs. +3.8 for placebo; LOCF analysis, p<0.0001).

Similar adverse events (AEs) were reported across all phases of the study for aripiprazole or aripiprazole IM depot and placebo. Most AEs were mild to moderate and severe AEs were rare (<5.0% incidence for aripiprazole or aripiprazole IM depot in all phases; the incidence of severe AEs in the maintenance phase was 4.1% for aripiprazole IM depot vs. 6.7% for placebo). The most common treatment-emergent AEs (occurring in > 5% of aripiprazole IM depot patients and greater than placebo) during the maintenance treatment phase were: insomnia (10.0% vs. 9.0%); tremor (5.9% vs. 1.5%); and headache (5.9% vs. 5.2%). The incidence of injection site pain was 3.0% for aripiprazole IM depot and 3.7% for placebo in the maintenance treatment phase. The incidence of clinically relevant weight gain (> 7% increase from baseline) was 6.4% for aripiprazole IM depot vs. 5.2% for placebo (LOCF analysis).

About aripiprazole IM depot formulation

Aripiprazole IM depot is a sterile lyophilized cake that, when reconstituted with sterile water for injection, forms an injectable suspension. On 22 November, 2011, Otsuka announced that the US Food and Drug Administration (FDA) determined that the company’s new drug application (NDA) for investigational once-monthly aripiprazole IM depot formulation for the indication of maintenance treatment of schizophrenia in adults was sufficiently complete to permit a substantive review. Otsuka and Lundbeck have entered into a long-term agreement in the field of central nervous system disorders and the two companies will collaborate on the development and commercialization (following approval of regulatory authorities) of aripiprazole IM depot formulation worldwide.

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