Elagolix (ABT-620), being developed by AbbVie, is under review by the U.S. Food and Drug Administration (FDA) as a possible therapy for women with endometriosis and is in advanced clinical testing for those with uterine fibrosis, two conditions with few treatment options.
Doctors with expertise in gynecology who worked on studies of elagolix in treating either condition — endometriosis or uterine fibroids — addressed their hopes for this potential treatment in interviews.
Result from Phase 3 and extension studies appear to support elagolix as a first-line oral treatment for endometriosis-associated pain, Dr. Hugh S. Taylor, chief of obstetrics, gynecology and reproductive services at the Yale School of Medicine and chief of obstetrics and gynecology at Yale-New Haven Hospital, told Endometriosis News.
“The data suggest that elagolix has the potential to be an important oral treatment option for women suffering from the most prevalent symptoms of endometriosis,” and potentially the first “treatment option for endometriosis-associated pain in more than a decade,” Taylor, an investigator in those trials, said. Should approval be given, this treatment would offer a needed alternative to the non-approved oral contraceptives that “are often prescribed as first-line therapy” for people with this condition, he added.
AbbVie submitted an approval request, known as an Investigational New Drug Application, to the FDA in September, based on trial findings that it was superior to placebo in reducing menstrual pelvic pain, non-menstrual pelvic pain, and painful intercourse associated with endometriosis.
Elagolix is an oral therapy that dampens the effect of gonadotropin-releasing hormone (GnRH) — that acts by stimulating the production and secretion of ovarian hormones — resulting in a lower production of estradiol and progesterone. These two key hormones underlie the development and progression of endometriosis and uterine fibroids.
In two Phase 3 trials — the Elaris EM-I study (NCT01620528) and the Elaris EM-II study (NCT01931670) — researchers investigated the effects of elagolix administered in two different doses — 150 mg once daily and 200 mg twice daily for a period of 6 months— in almost 1,700 endometriosis patients with moderate to severe pain.
Results showed that elagolix both eased patients’ pain perceptions and — at the 200 mg dose — reduced endometrial tissue proliferation after six months of treatment.
To further confirm these results, researchers performed two extension studies — Elaris EM-III (NCT01760954) and Elaris EM-IV (NCT02143713) — evaluating the long-term safety and efficacy of elagolix for an additional six months, with doses of 150 mg once daily and 200 mg twice daily.
In both studies “elagolix demonstrated sustained reduction in average monthly menstrual pelvic pain, non-menstrual pelvic pain and painful intercourse,” Taylor said. Long-term elagolix use maintained the safety profile previously reported without arising new safety concerns.
Patients at the 200 mg higher dose in the Phase 3 trials also reported — at three months of treatment — less pain during intercourse and, subsequently, less reliance on pain relievers, like nonsteroidal anti-inflammatories and opioids. These positive outcomes were also observed in the extension studies.
“Improvements in pain symptoms and quality of life observed in the pivotal studies were maintained over the 12-month treatment period,” Taylor said.
These findings carry promise as “there is no cure for endometriosis and there have been few recent scientific advancements for women suffering from the disease,” he added.
In fact, Taylor said, the only options available to treating physicians are “alternative means of treatment that are not specifically designed to treat endometriosis” while patients may have to “endure repetitive and costly surgical procedures.”
Although side effects are reported to be relatively limited with elagolix, during the Phase 3 trials patients at the higher dose (200 mg) reported changes in bone mineral density, especially in the lower lumber spine.
During the first 12 months of the Phase 3 extension studies, researchers observed a dose-dependent decrease in patients’ bone mineral density. But, “after 12 months of treatment, only one woman on the 200 mg BID dose had a BMD [bone mineral density] z-score below -2.0, which is the age-adjusted normal threshold,” Taylor said.
Hot flushes, the second adverse effect linked to elagolix therapy, “were generally mild to moderate in nature and the hot flush rates observed were dose dependent.”
Elagolix was administered every day during the trial, but the therapy may offer “oral administration and multiple dosing options, which could allow for more flexibility in the degree that ovarian sex hormones are decreased and provides the potential for physicians to deliver more individualized treatment,” Taylor said.
Elagolix has also been tested in women with uterine fibroids — a condition in which a part of the uterus muscle wall starts growing abnormally — and can also lead to heavy menstrual bleeding.
“Current non-surgical treatments indicated for uterine fibroids are limited. This situation results in many major surgeries, both myomectomies and hysterectomies, with significant morbidity,” said James A. Simon, a clinical professor of obstetrics and gynecology at George Washington University School of Medicine. “Women suffering from uterine fibroids need and deserve more long-term, medical management options.”
In a Phase 2b study (NCT01817530), Simon led a team of researchers who evaluated elagolix’s effects — administered with and without add-back therapy (estradiol/norethindrone acetate) — in premenopausal women with heavy menstrual bleeding associated with uterine fibroids. The women received either 300 mg of elagolix twice daily, or 600 mg of elagolix once daily.
“In a Phase 2 study, elagolix, with or without hormonal add-back therapy, significantly reduced heavy menstrual bleeding and was associated with improved quality of life. The addition of the hormonal add-back reduced bone loss and mitigated side effects,” Simon said.
Results showed that elagolix alone achieved slightly better results than when combined with add-back therapy (estradiol/norethindrone acetate) — a 92% reduction in menstrual blood loss vs. 85% reduction.
But add-back therapy “is used in an effort to reduce side effects associated with reduced estradiol levels, such as hot flush or reduced bone mineral density,” Simon added.
“The Phase 2b study data demonstrated that add-back therapy reduced the incidence of hot flushes in a dose-dependent manner. Reduction in bone mineral density associated with elagolix alone was attenuated when elagolix was co-administered with add-back therapy, with marginal effects on efficacy,” he concluded.
AbbVie has launched a Phase 3 program to further evaluate elagolix in uterine fibrosis. The study (NCT02691494) is looking at elagolix’s effectiveness and safety with six month’s of treatment — alone or in combination with add-back therapy — compared to placebo, and is followed by a six-month safety and effectiveness extension study (NCT02925494).
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