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–– Company Plans to Initiate Pivotal Development Program in 2015 ––
“Olanzapine is considered one of the most efficacious atypical
antipsychotics, yet it has one of the highest incidences and greatest
amounts of weight gain among the widely prescribed products in this
class of drugs, severely limiting its clinical use,” said
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.
“The unequivocal results of the first 12 weeks of this study confirm and
advance the results seen in earlier studies and suggest that ALKS 3831
has the potential to be a meaningful new treatment option for patients
suffering with schizophrenia,” said
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.
Phase 2 Study Design
This phase 2, randomized, multicenter, double-blind, active-controlled, dose-ranging study was 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 alone in adult patients with stable schizophrenia. 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.
About ALKS 3831
ALKS 3831 is a proprietary, investigational medicine designed as a broad-spectrum antipsychotic for the treatment of schizophrenia. ALKS 3831 is composed of samidorphan, a novel, potent mu-opioid antagonist, in combination with the established antipsychotic drug, olanzapine. ALKS 3831 is designed to attenuate olanzapine-induced metabolic side effects, including weight gain, in patients with schizophrenia and to have utility in the treatment of schizophrenia in patients with alcohol use.
The ALKS 3831 comprehensive phase 2 clinical program is comprised of two
separate studies, including this study focused on the attenuation of
weight gain associated with olanzapine. Weight gain is a common and
clinically relevant metabolic 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 second phase 2 study, initiated in
About Schizophrenia
Schizophrenia is a chronic, severe and disabling brain disorder. The disease is marked by positive symptoms (hallucinations and delusions) and negative symptoms (depression, blunted emotions and social withdrawal), as well as by disorganized thinking. An estimated 2.4 million American adults have schizophrenia,3 with men and women affected equally. Worldwide, it is estimated that one person in every 100 develops schizophrenia, which is one of the most serious types of mental illness.
About
Note Regarding Forward-Looking Statements
Certain statements set forth in this press release constitute
“forward-looking statements” within the meaning of the Private
Securities Litigation Reform Act of 1995, as amended, including, but not
limited to statements concerning: the therapeutic value, development
plans and commercial potential of ALKS 3831. You are cautioned that
forward-looking statements are inherently uncertain. Although the
company believes that such statements are based on reasonable
assumptions within the bounds of its knowledge of its business and
operations, the forward-looking statements are neither promises nor
guarantees and they are necessarily subject to a high degree of
uncertainty and risk. Actual performance and results may differ
materially from those projected or suggested in the forward-looking
statements due to various risks and uncertainties. These risks and
uncertainties include, among others: whether preclinical and clinical
results for ALKS 3831 will be predictive of future clinical study
results; whether ongoing or future clinical trials for ALKS 3831 will be
initiated or completed on time or at all; potential changes in cost,
scope and duration of the ALKS 3831 clinical development program;
whether ALKS 3831 could be shown ineffective or unsafe during clinical
studies; and those risks described in the
1Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Duggan L, Kissling W, Leucht S. Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews. 2010, Issue 3. Art. No.: CD006654.
2Regier D, Farmer M, Rae D, Locke B, Keith S, Judd L, Goodwin F. Comorbidity of Mental Disorders With Alcohol and Other Drug Abuse. JAMA. 1990, 264: 2511-2518.
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