Profile of Linzagolix in the Management of Endometriosis, Including Design, Development and Potential Place in Therapy: A Narrative Review

Abstract

Estrogens play a critical role in the pathogenesis of endometriosis and it is logical to assume that lowering estradiol levels with oral gonadotropin-releasing hormone (GnRH) antagonists may prove effective, especially in women who fail to respond to progestogens. Indeed, due to progesterone resistance, oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis, but are ineffective in 33% of women. Oral GnRH antagonists have therefore been evaluated for management of premenopausal women with endometriosis-associated pelvic pain. The first publication on these drugs reported the efficacy of elagolix. The present paper is a narrative review of linzagolix, which is an orally administered GnRH receptor antagonist with low pharmacokinetic/pharmacodynamic variability. It binds to and blocks the GnRH receptor in the pituitary gland, resulting in a dose-dependent drop in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production. This reduction in LH and FSH levels in turn leads to a dose-dependent decline in estrogen. Phase 2 and 3 trials are reviewed and discussed here. There is a place for GnRH antagonists in the management of symptomatic endometriosis, and linzagolix with or without add-back therapy (ABT) is one option that can be used at low doses, avoiding the need for ABT, which is contraindicated in some patients.

Keywords: GnRH antagonist; dysmenorrhea; endometriosis; pelvic pain; progesterone resistance.

Figure 1

Mechanism of action of GnRH antagonists.

Figure 2

Estradiol levels up to week 24 in women given a placebo, 75 mg, 100 mg and 200 mg linzagolix. Patients taking a placorrectedcebo were switched to 100 mg linzagolix at week 12. E2: estradiol. Adapted from Donnez J, Dolmans MM. Endometriosis and Medical Therapy: From Progestogens to Progesterone Resistance to GnRH Antagonists: A Review. J Clin Med. 2021;10(5):1085 (https://creativecommons.org/licenses/by/4.0/).

Figure 3

Responder rates for overall dysmenorrhea and non-menstrual pelvic pain at 12 and 24 weeks.

Figure 4

EDELWEISS 3 is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial of linzagolix in women with moderate-to-severe endometriosis-associated pain.

Figure 5

Responder rates for DYS and NMPP after 24 weeks of treatment.

Figure 6

(A) Treatment-emergent adverse events occurring in over 5% of patients in either the placebo or active treatment arms. (B) BMD loss expressed as mean change from baseline as a percentage in the lumbar spine, femoral neck and total Hip.