On 17 August, Myovant Biosciences announced the FDA acceptance of its New Drug Application (NDA) for its combination tablet, relugolix plus hormonal add-back therapy (ABT), for the treatment of heavy menstrual bleeding associated with uterine fibroids. Relugolix is a once-daily, oral, gonadotropin-releasing hormone (GnRH) receptor antagonist. There are multiple companies competing in the space, each with their own oral GnRH antagonist for both endometriosis-associated pain and heavy menstrual bleeding associated with uterine fibroids. These include AbbVie / Neurocrine’s Orilissa (elagolix), Myovant / Takeda’s relugolix, and ObsEva’s linzagolix. While the competition in the space is intensifying, GlobalData believes that oral GnRH antagonists have potential beyond these indications for off-label use in the female infertility space, where they could replace subcutaneous (SC) GnRH antagonists, leading to an expanded market opportunity.
In the US, nearly 60% of assisted reproductive technology (ART) cycles in the infertility treatment setting involve protocols in which pituitary downregulation is achieved with the use of SC GnRH antagonists, according to primary research conducted by GlobalData. In 2020, 79,286 short GnRH antagonist cycles are projected to occur in the US alone, increasing to 94,126 cycles by 2024, as this type of protocol is being increasingly favoured over those involving GnRH agonists, according to a GlobalData forecast.
GnRH antagonists allow for the rapid onset of estrogen suppression, as estrogen is known to stimulate the growth of uterine fibroids or endometriosis, but does not include the hormonal flare effect seen with GnRH agonists. The biggest advantage offered by GnRH antagonists is their oral route of administration. Oral GnRH antagonists could notably improve the experience of patients undergoing infertility treatment by reducing the need for daily SC injections, which are often a burden to patients. The oral route of administration also eliminates the need to mix or reconstitute SC formulas before each administration. Key opinion leaders across the US, France, Germany, Italy, Spain, UK, and Japan who were interviewed by GlobalData stated that they are enthusiastic about the potential to have this class of drugs in a convenient, oral formulation for the first time, and anticipate their off-label use in the infertility treatment setting if sufficient pituitary downregulation is demonstrated and the appropriate dosing is determined in experimental protocols
While oral GnRH antagonists are targeted at pain associated with endometriosis, experts also see a place for them within the therapeutic paradigm of infertility-associated endometriosis. Ongoing trials are evaluating whether infertile women with endometriosis—a common cause of infertility—who are undergoing embryo transfer as part of an in vitro fertilisation cycle, may see an improvement in live birth rates when pretreated with a GnRH antagonist. Oral GnRH antagonists could, therefore, become a newer alternative with increased dosing convenience and fewer side effects, thus replacing the GnRH agonist therapies that are often used in this setting.
Currently, AbbVie markets Orilissa (elagolix) in the US for endometriosis-associated pain and Oriahnn (elagolix plus ABT) for the management of heavy menstrual bleeding in premenopausal women with fibroids. Myovant anticipates an NDA seeking the approval of relugolix plus ABT as a treatment for endometriosis in 2021, while its partner Takeda has launched Relumina (relugolix) in Japan in the uterine fibroid setting. ObsEva is planning regulatory submissions in Q4 2020 and H1 2021 in Europe and the US, respectively.