In August, ObsEva announced that the publication of topline results from its highly anticipated EDELWEISS III study is expected in the fourth quarter of this year. EDELWEISS III is a Phase III clinical trial investigating Yselty (linzagolix) in the treatment of moderate to severe endometriosis-associated pain. Yselty provides promise in the endometriosis drug market because of its ability to alleviate pain while also minimising additional adverse effects, such as bone mineral density (BMD) loss. BMD loss is a result of the hypoestrogenic state induced by most endometriosis therapies. The medication’s once-daily oral administration could also bolster adherence rates compared to endometriosis therapies that require multiple dosages in one day or injection by a healthcare professional.
Kissei Pharmaceuticals has licensed out the marketing and development rights for Yselty to ObsEva, excluding those for Asia. Similar large-scale collaborations include Myovant Sciences and Pfizer’s collaboration last year to develop and commercialise relugolix, and Bayer and Evotec’s strategic alliance in 2012 to create therapies for polycystic ovary syndrome (PCOS) and endometriosis. Bayer/Evotec has so far developed six non-hormonal therapy candidates for endometriosis, four of which have gone on to Phase I or II.
According to GlobalData’s Pharma Intelligence Centre database, there are 46 pipeline drugs currently being developed for endometriosis worldwide, from pre-clinical to Phase III. As a difficult-to-manage and often misdiagnosed or overlooked indication, new endometriosis therapies are needed. An EU key opinion leader shared there is a need for endometriosis therapies that clinically, not statistically, significantly reduce pain. He highlighted other unmet needs as a drug with a positive side-effect profile, as well as more therapy options that are not contraceptives, for women trying to become pregnant.
ObsEva’s EDELWEISS III is a randomised, double-blind study that has enrolled 486 female participants with moderate to severe endometriosis-associated pain. The women are treated with either 75mg of Yselty, 200mg of Yselty with add-back therapy (ABT) or a placebo once daily for 24 weeks, after which participants have the option to enter a six-month treatment extension. ABT replenishes the body’s hormones to alleviate hypoestrogenic effects that create negative side effects such as hot flashes, vaginal dryness and loss in BMD.
The trial results will represent an important milestone for ObsEva, founded in 2012, as a recent entrant into the female health space. Its current focuses are uterine fibroids, endometriosis, in vitro fertilisation (IVF) and spontaneous preterm labour. The company is advancing three product candidates through clinical development, with Yselty being the most developmentally advanced of these. Yselty is also in development for the treatment of uterine fibroids, for which ObsEva plans to file a new drug application (NDA) with the US Food and Drug Administration (FDA) in the third quarter of this year, and European marketing approval recommendation anticipated in the fourth quarter of this year.
Yselty is a gonadotropin-releasing hormone (GnRH) receptor antagonist. GnRH antagonists have become increasingly popular as an endometriosis therapy option. Compared to their agonist counterparts, GnRH antagonists allow oestrogen production to be inhibited without causing hormonal flares. Known as the flare-up effect, hormonal flares occur when agonists do not dissociate from the GnRH receptor quickly enough, leading to an increase in follicle-stimulating hormone (FSH) and luteinising hormone (LH). Irregular FSH and LH levels can cause a number of problems, including but not limited to infertility, changes in ovarian function and irregular menstrual periods. Two other GnRH antagonists have either been marketed or are in development, namely Myovant and Pfizer’s relugolix, which is in Phase III worldwide, and AbbVie’s Orilissa (elagolix sodium), which received FDA approval in 2018.
Due to Orilissa being a first-in-class GnRH antagonist for endometriosis, AbbVie currently enjoys a market free from GnRH antagonist competition. Myovant and Pfizer are also eyeing approval and market entry, with Phase III data for relugolix having already been published. Success from Myovant’s SPIRIT clinical trial originally pointed to an NDA filing to be submitted in the first half of this year. A filing has not yet, however, been submitted and updates have not yet been provided for a new NDA filing date.
Yselty could be the third GnRH antagonist entrant, in which case ObsEva would be at a considerable disadvantage. AbbVie’s launch of Orilissa, however, was said to be disappointing, with poor uptake. If EDELWEISS III finds benefits with both the moderate (75mg) dose without hormonal ABT and the high (200mg) dose with ABT, then ObsEva would be able to provide dosing tailored to individual patients. This could allow Yselty to gain market share as Orilissa is only provided as a monotherapy without ABT, either 150mg once a day or 200mg twice a day, with the higher dosage option contributing to considerable BMD loss. The data readout in the fourth quarter of this year for EDELWEISS III, therefore, is vital in gaining an understanding of Yselty’s potential efficacy and success in the face of other competitive GnRH antagonists.