Updates in the Pharmacotherapy of Endometriosis - Episode 5
Dr Robert N. Taylor examines the use of GnRH receptor antagonists, including elagolix, for the management of endometriosis.
Robert N. Taylor, MD, PhD: Let’s step back for a second and think a little about the history here because it’s really quite interesting. In 1977, Roger Guillemin and Andrew Schally were awarded the Nobel Prize for the discovery of the structure and biology of GnRH [gonadotropin-releasing hormone]. GnRH is a hypothalamic peptide hormone that is critical to the regulation of the hypothalamic-pituitary-ovarian axis and reproduction in both men and women. In women, this is what’s responsible for the cycle, and once the discovery of the GnRH molecule was made, a lot of pharmaceutical companies became interested in trying to see what could be done to manipulate that system. Thus, the first GnRH drugs that became available for the treatment of endometriosis-associated pain were what we call the GnRH superagonists. These are drugs like leuprolide, nafarelin, drugs that initially stimulate the pituitary gland to release gonadotropins, and then result in a downregulation of the GnRH receptors, so that those cells no longer become sensitive and gonadotropin levels fall. And as a result, the ovarian steroids that they stimulate fall. Because estrogen is the primary driver of the endometriosis lesion, these drugs were quite effective at very substantially suppressing the synthesis of the gonadotropins and thereby stimulating ovarian function. What has changed in just the last few years has been the development of, and it’s going on in a number of different pharmaceutical companies, but elagolix is the compound that’s become available to us first for the treatment of endometriosis. This came from the AbbVie pharmaceutical company. This is a GnRH antagonist, an orally active GnRH antagonist.
Now, GnRH is a peptide, and the superagonists are also peptides. Peptides, because they would be digested in the stomach and digestive tract, aren’t orally available. But the development of elagolix and the forthcoming other drugs in this class are peptidomimetic compounds, so these are nonpeptides, but they form a 3-dimensional structure of peptides so that they can be taken orally. This oral administration makes it much easier than the monthly or 3 monthly, or originally almost daily, injections of some of these medications. Thus, having them be orally active has been a real breakthrough. This has allowed different dosage regimens to be developed as well, and we’ll talk a little more about those later. Thus, we now have in pivotal clinical trials, at least 4 of these have demonstrated the efficacy of different doses of elagolix, the orally active GnRH antagonist. This works differently than Lupron and nafarelin in that it is a competitive inhibitor at the level of the GnRH receptor for GnRH, rather than downregulating the receptors, which is the effect that leuprolide and nafarelin have. This competitively inhibits the receptor, which allows for a less complete suppression of the hypothalamic-pituitary-ovarian axis and allows the ovary to make enough estrogen that it can help to protect the bone as well as prevent some of the menopausal adverse effects that are typical of the superagonists.
Now, I’ve mentioned before a couple of times that estrogen is really the driver for endometriosis growth and pain, we believe, so we don’t want there to be too much estrogen in the environment. But it’s possible now with these orally active agents to titrate the dose to get the estradiol level suppressed but not so suppressed that it has effects on osteoporosis and menopausal hot flashes. We’ll come back to talk about some of those adverse effects a little later.
Transcript Edited for Clarity