SAGE-217 In Major Depressive Disorder: A Multi-Center, Randomized, Double-Blind, Phase 2 Placebo-Controlled Trial

Introduction

Methods

Aim

Handan Gunduz-Bruce, MD, MBA1, Christopher Silber, MD1, Anthony J. Rothschild, MD2, Robert Riesenberg, MD3, Abdul J. Sankoh, PhD1, Haihong Li, PhD1,

Ella Li, PhD1, Charles Zorumski, MD4, David R. Rubinow, MD5, Steven M. Paul, MD1, Jeffrey Jonas, MD1, James Doherty, PhD1, Stephen J. Kanes, MD, PhD1

Results

Poster # P.032

CharacteristicPBO

(N=44)SAGE-217

(N=45)

Age (years) 38.3 (12.2) 49.1 (13.6) Gender Female 30 (68.2) 25 (55.6)

Male 14 (31.8) 20 (44.4)

Ethnicity Hispanic/ Latino

7 (15.9) 1 (2.2)

Race African- American

28 (63.6) 36 (80.0)

White 16 (36.4) 7 (15.6) Other 0 2 (4.4)

Weight (kg) 83.9 (14.7) 87.7 (19.0)

BMI (kg/m2) 29.9 (5.2) 30.0 (6.3)

Baseline % anti- depressant use

10 (22.7) 12 (26.7)

Baseline HAM-D 25.7 (2.4) 25.2 (2.6)

• Data are n (%) or mean (SD).

Demographics and Baseline Characterisics

Generally Well Tolerated

PBO (N=44)

SAGE-217 (N=45)

Overall summary, n (%)

Any AE 20 (45.5) 24 (53.3)

Severe AE 0 0

Serious AE 0 0

AE Leading to drug discontinuation

0 2 (4.4)

Deaths 0 0

AEs ≥3 subjects, n (%) Headache 7 (15.9) 8 (17.8)

Dizziness 1 (2.3) 5 (11.1)

Nausea 1 (2.3) 5 (11.1)

Somnolence 1 (2.3) 3 (6.7)

Dry mouth 2 (4.5) 2 (4.4)

Sedation 2 (4.5) 2 (4.4)

Chromaturia 4 (9.1) 1 (2.2)

Decreased appetite

2 (4.5) 1 (2.2)

Insomnia 2 (4.5) 1 (2.2)

Pruritus 2 (4.5) 1 (2.2)

Diarrhea 3 (6.8) 0

Irritability 3 (6.8) 0

• No deaths, serious or severe AEs. • The most common AEs (≥5%) in the SAGE-

217 group included headache, dizziness, nausea, and somnolence.

1 Sage Therapeutics, Inc., Cambridge MA; 2 University of Massachusetts Medical School and UMass Memorial HealthCare, Worcester, MA; 3 Atlanta Center for Medical Research, Atlanta, GA; 4 Washington University of St. Louis, St. Louis, MO; 5 University of North Carolina, Chapel Hill, Chapel Hill, NC

• Major depressive disorder (MDD) can be a disabling and potentially life-threatening condition. Phar-macological treatment of MDD primarily relies on monoaminergic agents.1-7

• Current antidepressants may be associated with substantial latency to effect, and many patients do not achieve reponse.8, 9, 10

• MDD has been linked to GABA signaling dysfunction, presenting a potential new mechanism of action for development.11, 12

• Levels of the GABAA receptor positive allosteric

modulator allopregnanolone increase following treatment with selective serotonin re-uptake inhibitors and correlate with depressive symptom improvement.12

• SAGE-217 is an investigational, orally bioavailable positive allosteric modulator (PAM) of synaptic and extrasynaptic GABA

A receptors (GABA

AR).13

• A prior, open-label study of SAGE-217 in subjects with MDD (N=13) showed promising antidepressant effects.13

• To assess the efficacy and safety of SAGE-217 in MDD in a randomized, double-blind, placebo-con-trolled trial.

• Male and female subjects (n=89), 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 (PBO) on Days 1-14 and were subsequently followed for 4 weeks.

• Primary endpoint was the reduction in depressive symptoms, compared to PBO, assessed by HAM-D total score change from baseline at 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-614). • Bech-6 scores were normalized to a scale of 100

• Safety and tolerability were assessed by standard safety parameters, including adverse events (AEs), the Columbia-Suicide Severity Rating Scale, clinical laboratory measures, vital signs, and electrocardio-grams.

Conclusions • This study was the first randomized, placebo-

controlled trial of an orally bioavailable, neuroactive steroid, GABA

AR PAM in MDD.

• SAGE-217 administration for 14 days resulted insignificant, rapid (Day 2), and sustained (over the study period) reductions in depressive symptoms and was generally well tolerated in women and men.

• Significant reductions in the Bech-6 subscale, which is a unidimensional measure of depression, are indic-ative of the antidepressant effects of SAGE-217.

• This study supports further development of SAGE-217 for the treatment of MDD and the concept of positive allosteric modulation of GABA

ARs as a

viable path of investigation in the treatment of MDD.

• SAGE-217 group showed a greater LS mean reduction from baseline in HAM-D total score versus the PBO group at the Day 15 primary endpoint (-17.4 versus -10.3; p<0.0001).

• Statistically significant mean differences observed at Day 2 (p=0.0223) and maintained through Day 28 (p=0.0243).

• 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) in the SAGE-217 group at Day 15.

Primary Endpoint (HAM-D Change at Day 15) Achieved

References

1. McKeever A et al. Psychiatry Danub 2017;29(Suppl 3):222-231. 2. Gartlehner, G et al. Ann Intern Med

2011; 155: 772-85. 3. Uher R et al. BJ Psych 2009; 194:252-9. 4. Kasper S et al. Int Clin Psychopharm 2006;

21: 105-10. 5. Behnke K et al. J Clin Psychopharm 2003; 23:358-64. 6. Benkert O et al. J Clin Psych 2000; 61:

656-63. 7. Dierick M et al. Prog Neuro-Psychopharmacol & Biol. Psychiat 1996; 20: 57-71. 8. Cipriani A et al.

Lancet 2018 S0140-6736(17)32802-7; 9. Rush A et al. Am J Psychiatry 2006; 163:1905-1917 10. Cipriani A et

al Lancet Psych 2018: 5(6): 461-3. 11. Sanacora et al. Arch Gen Psychiatry 2004; 61(7): 705-13. 12. Uzunova

V et al. Proc Natl Acad Sci 1998; 95:3239-44. 13. Gunduz-Bruce H et al. 2017 Society of Biological Psychia-

try Meeting, San Diego, CA. 14. Bech P, Allerup P, Gram LF, et al. Acta Psychiatr Scand 1981; 63(3): 290-9.

Disclosures

HGB, CS, AJS, HL, EL, SMP, JJ, JD, SJK are employees of Sage Therapeutics, Inc. with stock/stock options.

CZ is a member of the Sage Therapeutics, Inc. Scientific Advisory Board and owns stock options. DRR is a member of the Sage Therapeutics, Inc. Clinical Advisory Board and owns stock options. AR is a consultant to

Sage Therapeutics, Inc. and a member of the Clinical Advisory Board. The remaining authors have nothing to

declare.

Support

This study was funded by Sage Therapeutics, Inc. Editorial support for this poster was provided by Boston Strategic Partners, Inc.

and supported by Sage Therapeutics, Inc.

Presented at the 2018 Annual Meeting of the European Congress of Neuropsychopharmacology

October 6-9, 2018 Barcelona, Spain

• Statistically significant changes favoring the SAGE-217 group were observed for 5 of the 6 Bech-6 items.

Bech-6 Subscale of HAM-D: Improvements Across Multiple Items

-1.5 -1 -0.5 0 0.5 1 1.5

← SAGE-217 BETTER PBO BETTER →

Depressed Mood

Anxiety Psychic

Work and Activities

Feelings of Guilt

Somatic Symptoms General

Retardation

*

**

** * *

**

*

-20

-15

-10

-5

0

0 7 14 21 28 35 42

LS

Me

an

HA

M-D

Ch

an

ge

Fro

m B

ase

lin

e

Time (Day)

PBO (n=44)

SAGE-217 (n=45)

Primary Endpoint

(Day 15)

14 Day Treatment Follow-up Period, Days 15-42

*p<0.05 vs. PBO

MRC-217-00219

Significant Improvement in Bech-6 Subscale of HAM-D

• Statistically significant difference of -15.1 (p<0.001) in LS mean change from baseline HAM-D for the SAGE-217 group versus the PBO group at Day 15.

• SAGE-217 group showed significant improvements versus PBO as early as Day 3 (p=0.005).