In 1977, Doctors Andrew Schally and Roger Guillemin shared the Nobel Prize for the discovery of Gonadotropin Releasing Hormone (GnRH), the brain hormone that causes the pituitary release of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). FSH and LH lead to menstrual events, including ovulation, in the female, and sperm production in the male. GnRH is a small, ten amino acid-long protein and shortly after its discovery, investigators were substituting some of its amino acids to make GnRH-like (or GnRH agonist) drugs that would have a longer half-life and that could modulate reproductive function. In 1985, Leuprolide (Lupron™, AbbVie) was approved by the FDA and this injectable medication has been a mainstay in the treatment of endometriosis, uterine fibroids, early puberty, breast cancer and prostate cancer, as well as in treatments for IVF. A distinct disadvantage of GnRH agonists has been that they take 7-10 days to ”turn off” FSH and LH production and, in fact, there is an initial increased release of these pituitary hormones which can actually worsen the condition being treated.
Anticipated since the early 1990s have been GnRH antagonists, agents that would act immediately in suppressing FSH and LH production. Antagonists were developed by changing the part of the GnRH peptide that binds the pituitary receptor such that it was not activated. Since the early 2000s, injectable antagonists Ganirelix and Cetrorelix have been available for the same indications as Leuprolide, but are mostly used throughout the world in IVF treatment plans to inhibit premature ovulation of the eggs.
In July 2018, the FDA announced the approval of elagolix (Orlissa™, AbbVie) a non-protein, oral GnRH antagonist for treatment of moderate to severe endometriosis pain. Although it is the first new endometriosis treatment in over a decade, it is uncertain whether elagolix represents an advantageous option or is it just one more arrow in the therapeutic quiver. The FDA phase III trials and twelve month long extension studies showed improvement in menstrual pain as well as nonmenstrual pelvic pain for both the 150mg once daily and 200 mg twice daily preparations of elagolix compared with placebo. For example, in the extension study, 75-78 percent, 67-69 percent and 58-60 percent of women taking the 200mg twice daily dose reported improvement in menstrual pain, non-menstrual pelvic pain and painful intercourse, respectively. Other potential uses of elagolix include other estrogen-dependent diseases, oral contraception, post coital contraception, male contraception, and all non-contraceptive uses of oral contraceptives.
The annual cost for elagolix for one year is approximately $10,000, which if not altogether prohibitive, certainly limits its prescription. By working directly with insurance companies, however, AbbVie, the manufacturer, has taken action to make the medication more affordable.
Elagolix has demonstrated efficacy for endometriosis-associated pain and certainly represents another tool in the armamentarium; at this point, however, it remains unclear whether this new oral antagonist offers improved long-term patient satisfaction, safety and efficacy relative to continuous oral contraceptives, progesterone-like agents, and the depot form of Leuprolide. It is also critically important for healthcare providers to know which endometriosis patients will benefit from combined treatments, including surgical, medical, and physical therapies and other multidisciplinary pain management techniques.
In short, Yes! We heartily welcome Orilissa to the world of reproductive medicine and perhaps most exciting may be the myriad indications (other than endometriosis) for which it may be used.