Clinical Trials

Date: 2015-04-06

Type of information: Results

phase: 2

Announcement: results

Company: Alkermes (Ireland)

Product: ALKS 3831

Action mechanism:

• ALKS 3831, a proprietary drug compound for the treatment of schizophrenia, is the combination of ALKS 33, a potent opioid modulator, and the established antipsychotic agent, olanzapine. Weight gain is a common and clinically relevant side effect of atypical antipsychotic medications, and olanzapine has one of the highest incidences and greatest amounts of weight gain among the widely prescribed products in this class of drugs.1 The weight gain side effect from atypical antipsychotics may be associated with the onset or exacerbation of diabetes and dyslipidemia, which are known risk factors for cardiovascular disease and mortality.
• In preclinical models, an ALKS 3831 regimen was shown to mitigate olanzapine-induced weight gain without affecting olanzapine's ability to demonstrate efficacy in a standard preclinical model used to assess antipsychotic activity. In another preclinical study, ALKS 3831 was shown to attenuate olanzapine-induced weight gain and abdominal adipose accretion.

Disease: schizophrenia

Therapeutic area: Mental diseases

Country: USA, Europe

Trial details:

• This phase 2, double-blind, active-controlled, dose-ranging study is designed to assess the efficacy, safety and tolerability of ALKS 3831, as well as evaluate the impact of ALKS 3831 on weight and other metabolic factors in comparison to olanzapine in adult patients with schizophrenia. In the study, following a one-week oral lead-in of olanzapine, patients are randomly assigned to olanzapine or three different doses of ALKS 3831 for a period of 12 weeks, followed by a 12-week period in which all patients will receive ALKS 3831. A total of 309 patients were randomized in the study, and the 300 patients who had at least one post baseline PANSS assessment were included in the full study population. In the study, following a one-week oral lead-in of olanzapine, patients were randomly assigned to treatment with olanzapine or one of three different doses of ALKS 3831 (olanzapine + 5 mg, 10 mg or 20 mg samidorphan) for a period of 12 weeks.
• The primary efficacy endpoint of the study was the change from baseline at Week 12 in PANSS total score, to assess equivalence of ALKS 3831 to olanzapine using a Mixed-Effect Model Repeated Measure (MMRM) model. Secondary endpoints evaluated the effects of ALKS 3831 on weight gain and other metabolic factors. All participants who completed the 12-week, double-blind portion of the study are eligible to continue in an extension portion and receive ALKS 3831 for an additional 12 weeks. The objective of the 12-week extension period is to assess the safety and long-term durability of effect of ALKS 3831 on PANSS total score reductions and attenuation of weight gain. A total of 187 patients completed the six-month treatment period.
• This study is the first of two studies in the ALKS 3831 phase 2 clinical program. The second phase 2 study was initiated in June 2014 and is designed to evaluate ALKS 3831 for the treatment of patients with schizophrenia and alcohol use. Alcohol use complicates the clinical course of more than one-third of patients with schizophrenia,2 a population that is commonly excluded from clinical trials and is often undertreated.

Latest news:

• • On April 6, 2015, Alkermes announced positive topline results from the complete, six-month, randomized, dose-ranging phase 2 study of ALKS 3831, an investigational, novel, oral atypical antipsychotic drug candidate designed to be a broad-spectrum treatment for schizophrenia. The study was designed in two stages: for the initial three months, patients were randomized to receive olanzapine or one of three doses of ALKS 3831, and antipsychotic efficacy and weight gain were assessed. Positive topline data from this stage were announced in January 2015 , showing that ALKS 3831 met the study's primary endpoint, demonstrating antipsychotic efficacy equivalent to olanzapine, as well as key secondary endpoints showing ALKS 3831's favorable effects on weight gain compared to olanzapine. For the second three months, all patients who received ALKS 3831 during the initial three months continued to receive ALKS 3831, and patients who had received olanzapine were switched to ALKS 3831. Data from the completed study support and extend the initial positive results showing ALKS 3831's favorable efficacy and mean weight gain profile and show for the first time that switching patients from olanzapine to ALKS 3831 resulted in a cessation of mean weight gain.
• For patients who received ALKS 3831 throughout the entire six-month treatment period, efficacy, as evaluated by the reduction from baseline in Positive and Negative Syndrome Scale (PANSS) total scores, was equivalent to olanzapine during the initial three-month stage and this efficacy was maintained throughout the second three-month stage (change in PANSS total score from Week 12 to Week 24 was -1.7 points, 95% confidence interval (CI): (-2.7, -0.7)). The beneficial effect on weight gain observed during the initial three months was also maintained during the second three-month stage. Mean percent change in body weight, from Week 12 to Week 24, was 0.5%, 95% CI: (-0.2%, 1.2%), indicating a consistent and durable blockade of olanzapine-induced weight gain.
• Patients who received olanzapine in the initial three-month stage were transitioned to receive ALKS 3831 for the second three-month stage. For these patients, efficacy as evaluated by PANSS scores was maintained (change in PANSS total score from Week 12 to Week 24 was -1.3 points, 95% CI: (-3.3, 0.7)). During the initial three-month stage, this patient population experienced significant weight gain, consistent with previously reported studies of olanzapine (mean percent change in body weight from baseline was 4.3%, 95% CI: (2.4%, 6.2%)). When these patients were transitioned to ALKS 3831 in the second three-month stage, overall no further weight gain was observed (mean percent change in body weight from Week 12 to Week 24 was 0.1%, 95% CI: (-1.0%, 1.2%)).
• ALKS 3831 was generally well tolerated in the six-month study. For the initial three-month, active-controlled stage of the study, the most common adverse events in the ALKS 3831 treatment groups relative to olanzapine were somnolence, sedation and dizziness. Alkermes will present comprehensive safety and efficacy data from the phase 2 study at an upcoming medical meeting and submit the results for publication in a peer-reviewed journal. Alkermes plans to meet with the FDA for an End-of-Phase 2 meeting and advance ALKS 3831 into a pivotal development program in 2015. • On January 7, 2015, Alkermes announced positive topline results from the 12-week, randomized, double-blind, active-controlled, dose-ranging stage of a phase 2 study of ALKS 3831. Data from the 300-patient study showed that ALKS 3831 achieved the study's primary efficacy endpoint, demonstrating equivalence to olanzapine in reduction from baseline in Positive and Negative Syndrome Scale (PANSS) total scores at Week 12. ALKS 3831 also met the principal pre-specified secondary endpoint of the study, demonstrating a 37% lower mean weight gain compared to olanzapine at Week 12 in the full study population (p=0.006), and a 51% lower mean weight gain compared to olanzapine at Week 12 in a pre-specified subset of patients who gained weight in the one-week olanzapine lead-in (p<0.001). ALKS 3831 was generally well tolerated in the study. The most common adverse events in the ALKS 3831 treatment groups relative to olanzapine were somnolence, sedation and dizziness. Based on the positive results from this phase 2 study, Alkermes plans to request an End-of-Phase 2 meeting with the FDA and advance ALKS 3831 into a pivotal development program in 2015.
• All patients enrolled in the study received olanzapine alone for a one-week period prior to randomization to treatment with olanzapine or one of three different doses of ALKS 3831 (olanzapine + 5 mg, 10 mg or 20 mg samidorphan) for a period of 12 weeks. The one-week lead-in period enabled the determination of early weight gain on olanzapine alone. These data were used to balance treatment groups upon randomization and enabled the pre-specification of two analysis groups for the key secondary endpoints related to weight. The first group comprised all patients in the study ("full study population"), and the second was comprised of those patients showing any early weight gain in the one-week lead-in period ("early weight gain population"). Of the 300 patients randomized in the full analysis set, 195 patients (65%) comprised the early weight gain population.
• Data from the full study population comparing all doses of ALKS 3831 to olanzapine showed that the study met its primary endpoint, with treatment with ALKS 3831 resulting in PANSS score reductions comparable to olanzapine (mean difference ALKS 3831 vs. olanzapine: 0.6 points, 95% confidence interval (CI): -1.2 - 2.5). The principal secondary endpoint of the study was the overall percentage change from baseline in body weight of the combined ALKS 3831 treatment groups compared to olanzapine alone at Week 12. Data from the phase 2 study showed: In the full study population, treatment with ALKS 3831 demonstrated a 37% lower mean weight gain from baseline, compared to olanzapine alone (p=0.006). In the early weight gain population, treatment with ALKS 3831 demonstrated a 51% lower mean weight gain from baseline, compared to olanzapine alone (p<0.001). Weight gain observed in the olanzapine-only arm was consistent with that reported in the olanzapine label. Additional analyses focused on those patients with weight gain of at least 5%, 7% and 10% of their baseline body weight at Week 12. Although the study was not powered for statistical significance on these endpoints, the results showed ALKS 3831's effect in attenuating significant weight gain in these clinically significant cohorts, compared to olanzapine alone. Across the full study population, the risk of weight gain of at least 10% of baseline body weight with olanzapine was 2.7 times that of ALKS 3831 ((95% CI 1.1 - 6.7), p=0.023). In the early weight gain population, the risk of weight gain of at least 10% of baseline body weight with olanzapine was 4.1 times that of ALKS 3831 ((95% CI 1.4 - 12.3), p=0.008). The phase 2 study met the objective of providing clear information relating to dose response of samidorphan and dose selection for the phase 3 program. All patients who completed this 12-week, double-blind portion of the phase 2 study were eligible to continue in an extension phase and receive one of the three doses of ALKS 3831 for an additional 12 weeks. This 12-week extension is currently ongoing and data to date indicate the durability of ALKS 3831's effect on weight. Complete results from the 12-week extension stage are expected in the second quarter of 2015. Data from the study showed that ALKS 3831 was generally well tolerated, and the safety profile of ALKS 3831 was similar to that reported with oral olanzapine, with the exception of significantly lower weight gain. The most common adverse events in the ALKS 3831 treatment groups relative to olanzapine were somnolence, sedation and dizziness. Discontinuations due to adverse events were low and similar to olanzapine.
• •  On September 3, 2014, Alkermes announced completion of patient enrollment in a phase 2 study of ALKS 3831. The double-blind, active-controlled, dose-ranging study will assess ALKS 3831’s efficacy, safety and tolerability in the treatment of schizophrenia and its attenuation of weight gain, compared with olanzapine. Weight gain is a common and clinically relevant metabolic side effect of atypical antipsychotic medications.
• This double-blind, olanzapine-controlled phase 2 study randomized 309 patients at multiple centers in the U.S. and Europe. Alkermes expects topline results from the 12-week, double-blind treatment period of this phase 2 study in early 2015. The double-blind treatment period will be followed by an additional 12-week period in which all patients will receive ALKS 3831. • On July 17, 2013, Alkermes has announced the initiation of a phase 2 study of ALKS 3831, a novel oral atypical antipsychotic drug candidate designed to be a broad spectrum treatment for schizophrenia. The double-blind, active-controlled, dose-ranging study in approximately 400 patients with schizophrenia will assess ALKS 3831, a proprietary combination of a novel opioid modulator, ALKS 33, and olanzapine, an approved atypical antipsychotic medicine, compared to olanzapine alone. In addition to safety and tolerability, the phase 2 study is designed to evaluate the impact of ALKS 3831 on weight and other metabolic factors in patients and confirm the attenuation of olanzapine-induced weight gain observed in the phase 1 study of ALKS 3831. Alkermes expects to provide topline results from the study in the first half of 2015.

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