A Randomized Open-Label Study of Relugolix Alone or Relugolix Combination Therapy in Premenopausal Women

Abstract

Background and objective: Relugolix is a gonadotropin-releasing hormone receptor antagonist. Relugolix 40-mg monotherapy is associated with vasomotor symptoms and long-term bone mineral density loss due to hypoestrogenism. This study assessed whether the addition of estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg to relugolix 40 mg (relugolix combination therapy) provides systemic E2 concentrations in the 20-50 pg/mL range to minimize these undesirable effects.

Methods: This was a randomized, open-label, parallel-group study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of relugolix 40 mg alone or in combination with E2 1 mg and NETA 0.5 mg in healthy premenopausal women. Eligible women were randomized 1:1 to receive relugolix alone or relugolix plus E2/NETA for 6 weeks. Study assessments included pharmacokinetic parameters of E2, estrone, and relugolix in both treatment groups, and norethindrone in the relugolix plus E2/NETA treatment group at weeks 3 and 6.

Results: Median E2 24 h average concentrations with the relugolix plus E2/NETA group (N = 23) were 31.5 pg/mL, 26 pg/mL higher compared with the relugolix-alone group (6.2 pg/mL) (N = 25). There were 86.4% of participants in the relugolix plus E2/NETA group who had E2 average concentrations exceeding 20 pg/mL, the threshold expected to minimize bone mineral density loss, compared with 21.1% in the relugolix-alone group. Both treatments were generally safe and well tolerated.

Conclusions: Relugolix 40 mg in combination with E2 1 mg and NETA 0.5 mg provided systemic E2 concentrations within a range expected to minimize the risk of undesirable effects of hypoestrogenism associated with the administration of relugolix alone.

Clinical trial registration: Clinicaltrials.gov identifier no. NCT04978688. Trial registration date: 27 July, 2021; retrospectively registered.

Fig. 1

Study schema. AE adverse event, CRU clinical research unit, E1 estrone, E2 estradiol, FSH follicle-stimulating hormone, LH luteinizing hormone, NETA norethindrone acetate, PD pharmacodynamics, PK pharmacokinetic, R randomization

Fig. 2

Participant disposition. ^aRelugolix 40 mg alone for 6 weeks. ^bRelugolix 40 mg with estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg for 6 weeks

Fig. 3

Mean (standard deviation) relugolix concentration–time profiles at a week 3 and b week 6. ^aRelugolix 40 mg alone. ^bRelugolix 40 mg with estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg

Fig. 4

Weekly median (and individual) predose (trough) E2 (estradiol) serum concentration–time profiles during the 6-week treatment period and at the follow-up visit. ^aRelugolix 40 mg alone. ^bRelugolix 40 mg with E2 1 mg and norethindrone acetate (NETA) 0.5 mg

Fig. 5

Individual and median (range) a estradiol (E2) and b estrone (E1) concentration–time profiles at week 6. ^aRelugolix 40 mg alone. ^bRelugolix 40 mg with estradiol 1 mg and norethindrone acetate (NETA) 0.5 mg. hr hour

Fig. 6

Mean (± standard deviation) pre-dose a follicle-stimulating hormone (FSH), b luteinizing hormone (LH), and c progesterone (P) serum concentrations over time with relugolix alone and relugolix + estradiol/norethindrone acetate (E2/NETA). ^aRelugolix 40 mg alone. ^bRelugolix 40 mg with E2 1 mg and NETA 0.5 mg

Fig. 7

Mean (± standard deviation) percent change from baseline in N-telopeptide (NTx) and C-telopeptide (CTx). ^aRelugolix 40 mg alone. ^bRelugolix 40 mg with estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg