Indirect comparisons of relative efficacy estimates of zuranolone and selective serotonin reuptake inhibitors for postpartum depression

Abstract

Aims

Estimate relative efficacy of zuranolone, a novel oral, Food and Drug Administration-approved treatment for postpartum depression (PPD) in adults vs. selective serotonin reuptake inhibitors (SSRIs) and combination therapies used for PPD in the United States.

Materials and methods

Randomized controlled trials (RCTs) for zuranolone and SSRIs, identified from systematic review, were used to construct evidence networks, linking via common comparator arms. Due to heterogeneity in placebo responses, matching-adjusted indirect comparison (MAIC) was applied, statistically weighting the zuranolone treatment arm of Phase 3 SKYLARK Study (NCT04442503) to the placebo arm of RCTs investigating SSRIs for PPD. MAIC outputs were applied in Bucher indirect treatment comparisons (ITCs) and network meta-analysis (NMA), using Edinburgh Postnatal Depression Scale (EPDS) and 17-item Hamilton Rating Scale for Depression (HAMD-17) change from baseline (CFB) on Days 3, 15, 28 (Month 1), 45, and last observation (Day 45, Week 12/18).

Results

Larger EPDS CFB was observed among zuranolone-treated vs. SSRI-treated patients from Day 15 onward. Zuranolone-treated (vs. SSRI-treated) patients exhibited 4.22-point larger reduction in EPDS by Day 15 (95% confidence interval: −6.16, −2.28) and 7.43-point larger reduction at Day 45 (−9.84, −5.02) with Bucher ITC. NMA showed EPDS reduction for zuranolone was 4.52 (−6.40, −2.65) points larger than SSRIs by Day 15 and 7.16 (−9.47, −4.85) larger at Day 45. Lack of overlap between study populations substantially reduced effective sample size post-matching, making HAMD-17 CFB analysis infeasible.

Limitations

Limited population overlap between SKYLARK Study and RCTs reduced feasibility of undertaking HAMD-17 CFB ITCs and may introduce uncertainty to EPDS CFB ITC results.

Conclusions

Analysis showed zuranolone-treated patients with PPD experienced greater symptom improvement than SSRI-treated patients from Day 15 onward, with largest mean difference at Day 45. Adjusting for differences between placebo arms, zuranolone may be associated with greater PPD symptom improvement (measured by EPDS) vs. SSRIs.

Keywords:

• Indirect treatment comparison (ITC)
• Bucher ITC
• network meta-analysis
• postpartum depression (PPD)
• MAIC
• zuranolone
• SSRIs

JEL CLASSIFICATION CODES:

• I10
• I1
• I
• I11
• I19
• L65
• L6
• L

This article is related to:

The cost-effectiveness of zuranolone versus selective serotonin reuptake inhibitors for the treatment of postpartum depression in the United States

Transparency

Declaration of financial/other interests

SS and NR are employees of Lumanity Inc and report consulting fees from Sage Therapeutics, Inc. and Biogen Inc. MEG, RT, and YT are employees of Sage Therapeutics, Inc., and may hold stock or stock options. CM and SC are employees of Biogen Inc. and may hold stock. SMB reports grants and other research funding from Sage Therapeutics, Inc., awarded to the University of North Carolina at Chapel Hill during the conduct of the study; and grants from the NIH and PCORI. She also reports advisory board or consulting fees from Embarck Neuro, Modern Health, and WebMD/MedScape outside the submitted work. KD serves as a consultant to Brii Biosciences, Inc.; Gerbera Therapeutics; GH Research Ltd.; Neuroscience Software, Inc.; Reunion Neuroscience; and Sage Therapeutics, Inc.; reports grants from Sage Therapeutics, Inc., awarded to Zucker Hillside Hospital/Feinstein Institutes for Medical Research during the conduct of the brexanolone injection and zuranolone clinical trials; and received grants from the NIH, Premier Healthcare, and Woebot Health and royalties from an NIH employee invention outside of the submitted work.

Author contributions

All authors were involved in study conception/design or data analysis and interpretation. All authors were involved in writing/critical review of draft versions of this manuscript, and all approved the final version to be submitted for publication.

Acknowledgements

Clinical trials used in the evidence networks were described in peer-reviewed literature; patient-level data were provided by Sage Therapeutics, Inc. The authors would like to thank Lasair O'Callaghan (Sage Therapeutics, Inc.) for her input and guidance during analytical methods development. Medical writing assistance was provided by Julie Bevilacqua and Francie Moehring-Moskal, employees of Boston Strategic Partners, Inc (funded by Sage Therapeutics, Inc. and Biogen Inc.).

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Previous presentations

The authors have no prior presentations of this work to report.

Additional information

Funding

This study was funded by Sage Therapeutics, Inc. and Biogen Inc. Support for medical writing assistance was funded by Sage Therapeutics, Inc. and Biogen Inc. The funding source was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. The publication of study results was not contingent on the funding source’s approval or censorship of the manuscript.