TX-001HR is associated with a clinically meaningful effect on severity of moderate to severe vasomotor symptoms in the REPLENISH trial

Ginger D Constantine, James A Simon, Andrew M Kaunitz, James H Pickar, Dennis A Revicki, Shelli Graham, Brian Bernick, Sebastian Mirkin, Ginger D Constantine, James A Simon, Andrew M Kaunitz, James H Pickar, Dennis A Revicki, Shelli Graham, Brian Bernick, Sebastian Mirkin

Abstract

Objective: The aim of the study was to evaluate the clinically meaningful effect of oral TX-001HR (17β-estradiol [E2]/progesterone [P4]) capsules on hot flushes severity (vasomotor symptoms [VMS] severity scale) using the patient-reported Clinical Global Impression (CGI).

Methods: REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated TX-001HR in postmenopausal women (40-65 y) with a uterus. Those with frequent moderate to severe hot flushes (≥7/d or ≥50/wk) were randomized in a VMS substudy to daily E2/P4 (1/100, 0.5/100, 0.5/50, or 0.25/50 mg/mg), or placebo. Patients rated VMS severity from 1 (mild) to 3 (severe) and symptom improvements with the CGI. CGI results were an anchor in a nonparametric discriminant analysis to define clinically important differences (CIDs) and minimal CID in VMS severity at weeks 4 and 12.

Results: In the VMS substudy (n = 726), determined CID and minimal CID severity thresholds were reductions of 0.525 and 0.350 points at week 4, respectively, and 0.775 and 0.225 points at week 12. Significantly more women taking the two highest E2/P4 doses (1/100 and 0.5/100) versus placebo met CID severity thresholds at weeks 4 (40% and 44% vs 17%; P < 0.05) and 12 (56% and 48% vs 29%; P < 0.05).

Conclusion: REPLENISH trial data demonstrated that E2/P4 1/100 and 0.5/100 provided clinically meaningful improvements in hot flushes severity in postmenopausal women. In conjunction with previously demonstrated clinically meaningful VMS frequency improvements, these data support oral E2/P4 1/100 and 0.5/100 for postmenopausal women with a uterus seeking treatment for moderate to severe VMS.

Conflict of interest statement

Financial disclosure/conflicts of interest: Dr. Constantine consults to multiple pharmaceutical companies including but not limited to TherapeuticsMD, and has stock options from TherapeuticsMD. Dr. Simon has served (within the past year, or current) as a consultant/advisor to AbbVie, AMAG, Bayer Healthcare, CEEK Enterprises, Covance, Dare Bioscience, Duchesnay, Hologic, KaNDy/NeRRe Therapeutics, Mitsubishi Tanage, Shionogi, Sprout2, and TherapeuticsMD; has received (within the past year, or current) grant/research support from AbbVie, Bayer Healthcare, Endoceutics, GTx, Ipsen, Myovant Sciences, ObsEva SA, TherapeuticsMD, and Viveve Medical; has also served (within the past year, or current) on the speaker's bureaus of AbbVie, AMAG, Duchesnay, and TherapeuticsMD; and is a stockholder (direct purchase) in Sermonix Pharmaceuticals. Dr. Pickar has consulted for Pfizer, Shionogi, and TherapeuticsMD and has stock options with TherapeuticsMD. Dr. Kaunitz has served as a consultant to or on the advisory board of AMAG, Mithra, and Pfizer; and has received research support (to University of FL) from Mithra and TherapeuticsMD. Dr. Revicki is a consultant for AMAG, Palatin Technologies, and TherapeuticsMD. Dr. Graham, Dr. Bernick, and Dr. Mirkin are employees of TherapeuticsMD with stock/stock options.

Figures

FIG. 1
FIG. 1
Reductions in moderate to severe vasomotor symptoms severity in the REPLENISH trial. P < 0.05 from aweeks 3 to 12, bweeks 7, 9 to 12, cweeks 6, 7, 9 versus placebo. E2, estradiol; P4, progesterone. Figure adapted from Lobo et al 2018.
FIG. 2
FIG. 2
Clinical Global Impression (CGI) responses at (A) week 4 and (B) week 12. aP < 0.01; bP < 0.001 versus placebo, calculated with Fisher's exact test.
FIG. 3
FIG. 3
Clinical meaningfulness threshold analysis at (A) week 4 and (B) week 12; CGI-based CID and MCID in VMS severity at (C) week 4 and (D) week 12. aP < 0.05; bP < 0.01; cP < 0.001 versus placebo, calculated with Fisher's exact test. CID, clinically important difference; CGI, Clinical Global Impression; E2, estradiol; MCID, minimal clinically important difference; P4, progesterone.

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