|
|
|
|
||
SAGE-217 abstracts at ECNP Oct 7thHealth-related quality of life in a Phase 2, randomized, placebo-controlled trial of the GABA(A)R modulator SAGE-217 in major depressive disorderV. Bonthapally (1), H. Gunduz-Bruce (2), C. Silber (3), A. Rothschild (4), R. Riesenberg (5), A. Sankoh (6), H. Li (6), E. Li (6), E. Suthoff (1), C. Zorumski (7), D. Rubinow (8), S. Paul (2), J. Jonas (9), J. Doherty (10), S. Kanes (11) (1)Sage Therapeutics- Inc., Department of Health Economics and Outcomes Research, Cambridge, USA (2)Sage Therapeutics- Inc., Department of Medical Science, Cambridge, USA (3)Sage Therapeutics- Inc., Department of Development Management, Cambridge, USA (4)University of Massachusetts Medical School and UMass Memorial HealthCare, Department of Psychiatry, Worcester, USA (5)Atlanta Center for Medical Research, Chief Executive Officer, Atlanta, USA (6)Sage Therapeutics- Inc., Department of Data Science, Cambridge, USA (7)Washington University of St. Louis, Department of Psychiatry, St. Louis, USA (8)University of North Carolina School of Medicine, Department of Psychiatry, Chapel Hill, USA (9)Sage Therapeutics- Inc., Chief Executive Officer, Cambridge, USA (10)Sage Therapeutics- Inc., Chief Research Officer, Cambridge, USA (11)Sage Therapeutics- Inc., Chief Medical Officer, Cambridge, USA Introduction: Major depressive disorder (MDD) is a disabling and potentially life-threatening condition with significant impact on physical, social, and mental health-related quality of life (HRQoL), estimated to affect over 300 million people worldwide. SAGE-217 is a novel, orally-bioavailable γ-aminobutyric acid A (GABAA) receptor positive allosteric modulator that demonstrated reductions in depressive symptoms in a double-blind, randomized, placebo-controlled Phase 2 study in MDD. Aim: This analysis assessed the impact of SAGE-217 treatment on HRQoL measures in MDD in a Phase 2 randomized, double-blind, placebo-controlled trial. Methods: This study included 89 subjects (55 female, 34 male) from 7 US centers. Inclusion required an MDD diagnosis and a 17-item Hamilton Rating Scale for Depression (HAM-D) total score ≥22. Subjects were randomized 1:1 to receive 30 mg SAGE-217 or placebo on Days 1-14, with 4 weeks of follow up. The primary endpoint was the reduction in depressive symptoms, compared to placebo, assessed by HAM-D total score change from baseline to Day 15. The Medical Outcomes Study Short Form-36 (SF-36v2) acute version, which reports eight health domains and two summary scores on mental and physical functioning, was used to assess HRQoL at baseline and throughout the study as an exploratory endpoint. The SF-36v2 facilitated comparison of study subjects to the general population by normative based scoring. Domain and summary scores with minimally important differences (MID) reported for the general population were applied to MDD trial data [1]. Descriptive analysis of scores was performed at Baseline and Day 15. Safety and tolerability were assessed by standard safety parameters, including reporting of adverse events (AEs). Results: At the Day 15 primary endpoint, the SAGE-217 group showed a greater LS mean reduction from baseline in HAM-D total score versus the placebo group (-17.4 versus -10.3; p<0.0001). Baseline SF-36v2 scores across multiple domains and summary scores were consistently lower than population norms at baseline, indicating notable HRQoL impairment in the patient population. In these post hoc descriptive analyses, Day 15 scores in the SAGE-217 group approached the general population normative levels for several health domains and summary scores, reaching normative levels for body pain, general health, vitality, and the physical component summary score. Improvements from Baseline to Day 15 in the SAGE-217 group exceeded those in the placebo group by more than the MID for six of the eight domains (role physical [8.3 vs. 4.7], bodily pain [7.3 vs.4.0], general health [7.8 vs. 4.6], vitality [15.0 vs. 8.0], role emotional [15.0 vs. 11.5], mental health [18.1 vs. 12.2]) and both of the summary (physical component [3.3 vs. 0.9] and mental component [19.4 vs. 14.0]) scores. There were no deaths, serious or severe AEs. Common AEs (≥5%) in the SAGE-217 group included headache, dizziness, nausea, and somnolence. Conclusions: In this first randomized, placebo-controlled trial of the oral GABAA receptor positive allosteric modulator SAGE-217 in MDD, administration for 14 days resulted in improvements in multiple domains of HRQoL, which reached general population normative levels, supporting further development of SAGE-217 in MDD. References [1] Blum, S.I., Tourkodimitris, S., Ruth, A. 2015. Evaluation of functional health and well-being in patients receiving levomilnacipran ER for the treatment of major depressive disorder. J Affect Disord 170, 230-236. Conflict of interest: Disclosure statement: This study was supported by Sage Therapeutics, Inc. VB, HGB, CS, AJS, HL, EL, ES, SMP, JJ, JD, and SJK are employees of Sage Therapeutics, Inc. with stock/stock options. DRR is a member of the Sage Therapeutics, Inc. Clinical Advisory Board and has stock/stock options. CZ is a member of the Sage Therapeutics, Inc. Scientific Advisory Board and reports consulting fees outside the submitted work. ----------------------------------------------------------------------------- SAGE-217 in major depressive disorder: a multicenter, randomized, double-blind, Phase 2 placebo-controlled trialH. Gunduz-Bruce (1), C. Silber (2), A. Rothschild (3), R. Riesenberg (4), A. Sankoh (5), H. Li (5), E. Li (5), C. Zorumski (6), D. Rubinow (7), S. Paul (1), J. Jonas (8), J. Doherty (9), S. Kanes (10) (1)Sage Therapeutics- Inc., Department of Medical Science, Cambridge, USA (2)Sage Therapeutics- Inc., Medical, Department of Development Management, USA (3)University of Massachusetts Medical School and UMass Memorial HealthCare, Department of Psychiatry, Worcester, USA (4)Atlanta Center for Medical Research, Chief Executive Officer, Atlanta, USA (5)Sage Therapeutics- Inc., Department of Data Science, Cambridge, USA (6)Washington University of St. Louis, Department of Psychiatry, St. Louis, USA (7)University of North Carolina Medical School, Department of Psychiatry, Chapel Hill, USA (8)Sage Therapeutics- Inc., Chief Executive Officer, Cambridge, USA (9)Sage Therapeutics- Inc., Chief Research Officer, Cambridge, USA (10)Sage Therapeutics- Inc., Chief Medical Officer, Cambridge, USA Introduction: Major depressive disorder (MDD) is a disabling and potentially life-threatening condition treated pharmacologically with antidepressants. MDD has been linked to GABA signaling dysfunction, presenting a new mechanism of action for potential development of novel therapeutics. SAGE-217 is an orally bioavailable positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. A prior, open-label study of SAGE-217 in subjects with MDD showed promising anti-depressive effects. Aim: This study is the first to evaluate the efficacy and safety of SAGE-217 in MDD in a randomized, double-blind, placebo-controlled trial. Methods: This Phase 2 study included 89 subjects (34 male, 55 female), ages 18-65, at 7 US centers. Inclusion required an MDD diagnosis and a 17-item Hamilton Rating Scale for Depression (HAM-D) total score ≥22. Subjects were randomized 1:1 to receive a nightly dose of SAGE-217 Capsule 30 mg or placebo on Days 1-14 and were subsequently followed for 4 weeks. The primary endpoint was the reduction in depressive symptoms, compared to placebo, assessed by HAM-D total score change from baseline to Day 15. Secondary endpoints included HAM-D total score change from baseline, HAM-D response (≥50% reduction in total score), HAM-D remission (HAM-D ≤7), and HAM-D subscales (e.g. Bech-6). Safety and tolerability were assessed by standard safety parameters, including adverse events, the Columbia-Suicide Severity Rating Scale, clinical laboratory measures, vital signs, and electrocardiograms. Results: At the Day 15 primary endpoint, the SAGE-217 group showed a greater LS mean reduction from baseline in HAM-D total score versus the placebo group (-17.4 versus -10.3; p<0.0001). Statistically significant mean differences in HAM-D from placebo were observed as early as Day 2 (p=0.0223) and were maintained through Day 28 (p=0.0243). The SAGE-217 group showed statistically significant improvements in HAM-D response (78.6% versus 40.5%; p=0.0002) and remission (64.3% versus 26.2%; p=0.0005) compared to the placebo group at Day 15 that persisted through Day 28. Analysis of the change from baseline in the Bech-6 subscale at Day 15 showed a significant mean difference of -15.1 (p=0.0005) for the SAGE-217 group versus the placebo group, with decreases seen across all six items. The significant differences in Bech-6 change from baseline were maintained through Day 28 (p≤0.049). There were no deaths, serious or severe adverse events. Common adverse events (≥5%) in the SAGE-217 group included headache, dizziness, nausea, and somnolence. Conclusions: In this first randomized, placebo-controlled trial of an orally bioavailable, neuroactive steroid, GABAA receptor positive allosteric modulator in MDD, SAGE-217 administration for 14 days resulted in robust, rapid, and sustained (over the study period) reductions in depressive symptoms and was generally well tolerated in women and men. This study supports further development of SAGE-217 for the treatment of MDD and the concept of positive allosteric modulation of GABAARs as a viable path of investigation in the treatment of MDD. Conflict of interest: Disclosure statement: This study was supported by Sage Therapeutics, Inc. HGB, CS, AJS, HL, EL, SMP, JJ, JD, and SJK are employees of Sage Therapeutics, Inc., with stock/stock options. CZ is a member of the Sage Therapeutics, Inc. Scientific Advisory Board and reports consulting fees outside the submitted work. DRR is a member of the Sage Therapeutics, Inc. Clinical Advisory Board and has stock/stock options. ------------------------------------------------------ A phase 1/2 double-blind, placebo-controlled study of SAGE-217 in a phase advance model of transient insomniaA. Bullock (1), H. Gunduz-Bruce (1), G. Zammit (2), A. Sankoh (3), H. Li (3), M. Qin (3), C. Silber (4), S. Kanes (5), J. Jonas (6), J. Doherty (7) (1)Sage Therapeutics- Inc., Department of Medical Science, Cambridge, USA (2)Clnilabs Drug Development Corporation, Chief Executive Officer, New York, USA (3)Sage Therapeutics- Inc., Department of Data Science, Cambridge, USA (4)Sage Therapeutics- Inc., Department of Development Management, Cambridge, USA (5)Sage Therapeutics- Inc., Chief Medical Officer, Cambridge, USA (6)Sage Therapeutics- Inc., Chief Executive Officer, Cambridge, USA (7)Sage Therapeutics- Inc., Chief Research Officer, Cambridge, USA Introduction: SAGE-217 is an orally-bioavailable, positive allosteric modulator (PAM) of synaptic and extrasynaptic GABAA receptors (GABAAR) being investigated in clinical studies in sleep disorders. Aims: This Phase 1/2, double-blind, placebo-controlled study used a 5-hour phase advance model of insomnia to evaluate the safety and efficacy of 30 mg and 45 mg SAGE-217 doses. Methods: This double-blind, three-way, crossover study used a 5-hour phase advance model of insomnia, with lights-out beginning 5 hours prior to habitual bedtimes. Healthy volunteers (n=45) were randomized to receive 30 mg SAGE-217, 45 mg SAGE-217, or placebo once each on three separate visits, with 7-day washout periods between dosing. Blinded study drug was administered 30 minutes before lights-out. Participants remained in bed for eight hours. Sleep Efficiency (SE; percentage of time in bed spent asleep), measured by polysomnography (PSG), was the primary endpoint. Secondary sleep measure endpoints included PSG outcomes of Wake After Sleep Onset (WASO) and Total Sleep Time (TST) and subjective outcomes of sWASO, sTST sleep latency (sSL), and subjective sleep quality (sSQ). Sleep architecture PSG outcome measures included duration of Stages N1, N2, N3 and REM sleep, and latency to REM sleep. Cognitive effects post-sleep were assessed using the digit symbol substitution test (DSST). Safety and tolerability were evaluated by standard safety parameters, including adverse events (AEs). Results: Both SAGE-217 doses achieved the primary endpoint by significantly improving SE to medians of 85% (30 mg) and 88% (45 mg) compared to 73% for placebo (both doses p<0.0001). Subjective sleep measures were overall consistent with the primary endpoint. SAGE-217 30 mg and 45 mg produced statistically significant improvements in subjective assessments of sSQ, sWASO, sTST, and sSL (45 mg only) compared to placebo. Overall, SAGE-217 increased the number of minutes spent in Stage N2 (258.16 min for 30 mg and 266.79 min for 45 mg versus 192.30 for placebo; both doses p<0.001) and Stage N3 (slow wave sleep; 68.38 min for 30 mg, p=0.004; 74.71 min for 45 mg, p<0.001; 56.12 min for placebo) sleep. Rapid eye movement (REM) sleep and stage N1 sleep showed no statistically significant changes. No significant overall differences in DSST scores were observed between SAGE-217 treatment and placebo (p=0.9490). SAGE-217 was generally well tolerated, with low AE rates across all treatment groups (11.4% 30 mg; 4.8% 45 mg; and 9.8% placebo). All AEs were mild; no serious or severe AEs were reported. Most common AEs across all periods and groups were headache (2.3% 30 mg; 2.4% 45 mg; and 4.9% placebo) and fatigue (4.5% 30 mg; 2.4% 45 mg; and 0% placebo). Conclusions: This randomized, placebo-controlled trial was the first examination of the orally bioavailable, GABAAR PAM SAGE-217 in an insomnia model. SAGE-217 met the primary endpoint of improved sleep efficiency, demonstrated improvements in both objective and subjective sleep measures, and was generally well tolerated. SAGE-217 showed no next-day residual cognitive effects. These findings support further development of SAGE-217 for sleep disorders. Conflict of interest: Disclosure statement: This study was supported by Sage Therapeutics, Inc. AB, HGB, AJS, HL, MQ, CS, SK, JJ, and JD are employees of Sage Therapeutics, Inc., with stock/stock options. |
return to message board, top of board |