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Safety and Effectiveness of SEP−363856 in Schizophrenia: Results of a 6-Month, Open-Label Extension Study
- Christoph U. Correll, Kenneth S. Koblan, Seth C. Hopkins, Justine Kent, Hailong Cheng, Robert Goldman, Antony Loebel
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, pp. 148-149
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Background
SEP-363856 is a novel psychotropic agent without dopamine D2 receptor occupancy. Although its mechanism of action has not been fully elucidated, preclinical data suggest that agonism at trace amine receptor 1 (TAAR1) and the serotonin 5-H1A receptor contributes to its efficacy. In a double-blind (DB), placebo-controlled study, SEP−363856 demonstrated significant efficacy in the treatment of an exacerbation of schizophrenia (Koblan et al, NEJM 2020; 82:1497–1506). We present results of a 6-month extension study whose aim was to evaluate the safety and effectiveness of longer-term treatment with SEP−363856.
MethodPatients with an acute exacerbation of schizophrenia who completed a 4-week, DB, placebo-controlled, flexible-dose (50 or 75 mg) study of SEP−363856 were given the option to enroll in an extension study in which they were treated, open-label (OL), with flexible doses (25/50/75 mg/d) of SEP−363856 for 26-weeks. The primary outcomes were safety measures; effectiveness outcomes were secondary and included the PANSS total score and the Brief Negative Symptom Scale (BNSS) total score.
ResultsA total of 193 patients completed the 4-week DB study, and 156 (80.8%) were dosed in the OL extension study and received at least one dose of SEP−363856 (safety population). Study completer rate was 66.9%; reasons for discontinuation consisted of adverse event (11.5%), withdrawal of consent (10.2%), lack of efficacy (5.1%), and other (6.4%). 15 patients experienced an SAE: schizophrenia (n=11); acute psychosis (N=1); uterine hemorrhage and suicidal ideation (N=1 each); there were no deaths in the study. Individual AEs with an incidence =2% were schizophrenia (12.2%), headache (11.5%), insomnia (8.3%), anxiety (5.1%), somnolence (4.5%), nasopharyngitis (4.5%), nausea (3.8%), irritability (3.2%), influenza (3.2%), weight decreased (3.2%), and prolactin increased (2.6%). On movement scales, minimal mean change from OL-baseline to Week 26 occurred on the Barnes total score (−0.1), AIMS total score (0.0) and SAS score (−0.1). Mean month 6 change from DB baseline in weight was −0.3 kg. No clinically meaningful median changes were observed at week 26 in metabolic laboratory parameters (total and LDL cholesterol, triglycerides, hemoglobin A1c) or in prolactin levels. During 6 months of OL treatment, one patient had an increase in QTcF =60 msec; no patients had a QTcF interval =480 msec. Treatment with SEP−363856 was associated with significant improvement from OL baseline to week 26 in PANSS total score (−22.6) and BNSS total score (−11.3).
ConclusionTreatment with SEP−363856 was associated with continued improvement from open-label baseline in the PANSS total (−22.6) and BNSS total (−11.3) scores. The most frequently reported adverse events (= 5%) were schizophrenia, headache, insomnia and anxiety. SEP−363856 had minimal effects on weight, lipids, glycemic indices, prolactin, and was associated with minimal risk of extrapyramidal symptom.
FundingSunovion Pharmaceuticals Inc.
138 Efficacy and Safety of SEP-363856, a Novel Psychotropic Agent with a Non-D2 Mechanism of Action, in the Treatment of Schizophrenia
- Kenneth S. Koblan, Seth Hopkins, Justine Kent, Hailong Cheng, Robert Goldman, Antony Loebel
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 287-288
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Background:
SEP-363856 is a novel psychotropic agent that has shown broad efficacy in animal models of schizophrenia and depression. Its antipsychotic effects appear to be mediated by agonist activity at both trace amine-associated receptor 1 (TAAR1) and 5-HT1A receptors. Notably, SEP-363856 does not bind to any dopaminergic, serotonergic (except 5-HT1A), glutamatergic, or other neuroreceptors thought to mediate the effects of currently available antipsychotics. The aim of this study was to evaluate the efficacy and safety of SEP-363856 in acutely symptomatic patients with schizophrenia.
Method:Patients aged 18-40 years meeting DSM-5 criteria for schizophrenia (PANSS total score ≥80) were randomized, double-blind, to 4-weeks of flexible-dose SEP-363856 (50 or 75 mg/d) or placebo. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total score (primary), PANSS subscale scores, and the Clinical Global Impressions-Severity (CGI-S) score. Change from baseline in primary and secondary measures were analyzed using a mixed model for repeated measures (MMRM) analysis.
Results:Study treatment groups were similar at baseline: SEP-363856 (N=120; male, 64.2%; mean age, 30.0 years; PANSS total score, 101.4) and placebo (N=125; male, 63.2%; mean age, 30.6 years; PANSS total score, 99.7). Least-squares (LS) mean reduction from baseline to week 4 was significantly greater for SEP-363856 vs. placebo on the PANSS total score (-17.2 vs. -9.7; P=0.001; effect size, 0.45), PANSS positive subscale score (-5.5 vs. -3.9; P=0.019; effect size, 0.32), PANSS negative subscale score (-3.1 vs. -1.6; P=0.008; effect size, 0.37), PANSS general psychopathology subscale score (-9.0 vs. -4.7; P<0.001; effect size, 0.51), and the CGI-Severity score (-1.0 vs. -0.5; P<0.001; effect size, 0.52). Discontinuation rates for SEP-363856 vs. placebo were similar overall (21.7% vs. 20.8%) and due to an adverse event (8.3% vs. 6.4%). Change in weight, lipids, glucose and prolactin was similar in SEP-363856 and placebo groups. Adverse events occurring with an incidence ≥2% on SEP-363856 or placebo (with SEP-363856 incidence higher than placebo) were: somnolence (6.7% vs. 4.8%), agitation (5.0% vs. 4.8%), nausea (5.0% vs. 3.2%), diarrhea (2.5% vs. 0.8%), and dyspepsia (2.5% vs. 0%). The proportion of patients who reported any extrapyramidal symptom was 3.3% on SEP-363856 and 3.2% on placebo.
Conclusion:In this placebo-controlled study, treatment with SEP-363856, a novel psychotropic agent, was associated with statistically significant and clinically meaningful improvement in schizophrenia symptoms as demonstrated by endpoint change in PANSS total and subscale scores, and CGI-Severity scores. Safety and tolerability findings for SEP-363856 were in general similar to placebo. In particular, SEP-363856 was not associated with extrapyramidal symptoms, akathisia, or hyperprolactinemia, consistent with its non-D2 mechanism of action.
ClinicalTrials.gov:NCT02969382
Funding Acknowledgements:Supported by funding from Sunovion Pharmaceuticals Inc.
19 - Legislated collaboration in a conservation conflict: a case study of the Quincy Library Group in California, USA
- from Part III - Approaches to managing conflicts
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- By R. J. Gutiéerrez, University of Minnesota, Antony S. Cheng, Colorado State University, Dennis R. Becker, University of Minnesota, Scott Cashen, California, David Ganz, United States Aid for International Development, John Gunn, Spatial Informatics Group, Michael Liquori, Soundwatershed, Amy Merrill, Stillwater Sciences, D. S. Saah, Spatial Informatics Group, William Price, Pinchot Institute for Conservation
- Edited by Stephen M. Redpath, University of Aberdeen, R. J. Gutiérrez, University of Minnesota, Kevin A. Wood, Bournemouth University, Juliette C. Young, NERC Centre for Ecology and Hydrology, UK
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- Book:
- Conflicts in Conservation
- Published online:
- 05 May 2015
- Print publication:
- 07 May 2015, pp 271-286
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Summary
Nearly 258 million ha (28%) of the United States is publicly owned land that is managed by federal government agencies. For example, the US Department of Agriculture's Forest Service (USFS) manages over 77 million ha of national forests and grasslands for the benefit of the American public. Given its legal directive to manage multiple uses, it is not surprising that conflicts arise among stakeholders over how this land should be used (Lansky, 1992). The USFS has much discretion in how land is managed, yet must often balance conflicting values of public use and benefit (Nie, 2004). As national priorities, social preferences and public awareness of national forest goods, services and values have changed over time, USFS managers have faced increased pressure to balance consumptive uses with the need for environmental protection. Competing stakeholder demands coupled with increased environmental risks (wildfires, tree diseases and insect epidemics) have resulted in an escalating conservation conflict that is manifested in administrative appeals, lawsuits and a growing distrust of the agency.
Over time, the USFS has embraced new directions and management paradigms to reduce conflict. Some of these have been ecosystem management, adaptive management and now collaborative management (e.g. Holling, 1978; Maser, 1988; Franklin, 1992; Boyce and Haney, 1997; Wondolleck and Yaffee, 2000; Brown et al., 2004). These approaches reflect changing societal values, political pressures and new scientific information.
A persistent conflict has been the logging of trees in national forests and related impacts on forest ecosystems (Lansky, 1992). The USFS’ timber sale programme has supported jobs and community stability through economic development. Logging has also been a mechanism to reduce the risk of wildfire by reducing tree density (fuel for fires) and vertical stand diversity (‘ladder’ fuels; North et al., 2009). However, logging can also negatively affect forest integrity, watershed quality, wildlife, aesthetic and spiritual values of forests (Satterfield, 2002; North et al., 2009).
Contributors
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- By A. Adams, P.J.D. Andrews, A. Antoniou, D. Bainbridge, M. Banasch, R. Blank, J.M. Blum, J. Brookes, C.H. Brown, I. Bruni, A. Cave, E.H.L. Chau, D. Cheng, M. Chin, F. Chung, C. Clarke, J. Cooke, P. Cowie, A. Dhir, S. Dhir, G. Evans, L. Fleisher, G.M. Flood, M.P.W. Grocott, C. Harle, A. Howie, S. Jack, G. Jarvis, R. Kishen, M. Koutra, L. Loughney, N. Ludwig, I. McConachie, A. McLeod, M. McFarling, S. Morrison, M. Pariser, S. Patel, C. Railton, L.R. Rochlen, A. Schlachter, V. Schulz, F. Sieber, P.M. Singh, A.C. Sinha, C. Smyth, A. Suphathamwit, J. Vergel de Dios, M. West, J. Wong, M. Yoder, Z. Zafirova
- Edited by Ian McConachie
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- Book:
- Anesthesia and Perioperative Care of the High-Risk Patient
- Published online:
- 05 September 2014
- Print publication:
- 04 September 2014, pp vii-x
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