The first new oral medication for the treatment of endometriosis to emerge in more than a decade, elagolix (ABT-620; AbbVie/Neurocrine Biosciences), continues to show efficacy and good tolerability in two long-term extension studies now carried out to 1 year, new findings indicate.
In two double-blind, randomized, phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]), reported last year in the New England Journal of Medicine), both 150 mg once a day and 200 mg twice a day of elagolix, an investigational oral, nonpeptide gonadotropin-releasing hormone antagonist, improved dysmenorrhea and nonmenstrual pelvic pain at 6 months compared with placebo in women with endometriosis-associated pain.
Now, results from the same 2 studies out to 12 months confirm the long-term benefits, with a safety profile that is consistent with reduced estrogen levels, Eric Surrey, MD, from the Colorado Center for Reproductive Medicine, Lone Tree, and colleagues report in an article published online June 6 in Obstetrics & Gynecology.
"The first-line medication we typically use for endometriosis is a birth control pill, but large numbers of women fail to respond to a birth control pill: they have this progestin resistance, where the progestins don't work for endometriosis, either initially or later on, so we need other options," second author Hugh Taylor, MD, Anita O'Keeffe Young chair and professor of obstetrics, gynecology, and reproductive sciences at Yale School of Medicine, New Haven, Connecticut, told Medscape Medical News.
"Traditionally the next option is a gonadotropin-releasing hormone...agonist such as leuprolide (Lupron, among others), but it's an injectable, it takes a week or 2 before it kicks in, and it can actually make things worse because you can get this initial flare where the drug stimulates high estrogen production and then it drops estrogen levels down to near zero, so it's very extreme," he added.
"So the idea of having a more titratable drug that only partially suppresses estrogen and which is just more patient-friendly is very attractive, and it's going to fill a huge treatment gap [if approved]," Taylor said.
Earlier this year, the US Food and Drug Administration told AbbVie and Neurocrine Biosciences that they needed more time to review additional information regarding the results of liver function tests in women taking elagolix.
The agency is now in the process of doing this, and the companies have been given a revised Prescription Drug User Fee Act date sometime in the third quarter of 2018.
Neurocrine and AbbVie are also developing elagolix for the treatment of uterine fibroids.
Sustained Reductions in Pain and Dyspareunia Linked to Endometriosis
Elaris EM-III and Elaris EM-IV were the randomized double-blind extension studies involving the same women who completed either Elaris EM-I or Elaris EM-II.
"Women on elagolix treatment in the preceding Elaris EM-I and Elaris EM-II trials who met all entry criteria received the same elagolix dose as previously taken, either elagolix 150 mg daily or elagolix 200 mg twice daily, for 6 additional months in the extension studies," the investigators explain.
Participants were not allowed to use any form of hormonal therapy during either phase of the trials, but they were allowed to take rescue medication in the form of 500 mg naproxen, an opioid, or both during the 6-month extension studies.
Across both studies, a total of 569 women participated in the extension trials.
In both extension studies, the percentage of women who experienced a "clinically meaningful reduction" in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia was significantly higher in both active treatment groups compared with placebo patients.
Mean decreases from baseline in average daily rescue analgesic pill count were also observed at every visit during the extension study treatment period for nonsteroidal anti-inflammatory drugs or opioid use in each dose group in Elaris EM-III and Elaris EM-IV.
Table. Percentage of Women Who Experienced Clinically Meaningful Reductions in Primary Endpoints and Decreased or Stable Use of Rescue Analgesic Agents After 12 Months of Treatment
|Dysmenorrhea||Nonmenstrual Pelvic Pain||Dyspareunia|
|Elaris EM-III (150 mg, once a day)||52.1%||67.5%||45.2%|
|Elaris EM-III (200 mg, twice a day)||78.2%||69.1%||60.0%|
|Elaris EM-IV (150 mg, twice a day)||50.8%||66.4%||45.9%|
|Elaris EM-IV (200 mg/twice a day)||75.9%||67.2%||58.1%|
Rates of serious adverse events were low among women receiving either dose of elagolix in both studies, the most common being hot flushes, headache, and nausea.
However, the investigators did observe a decrease in bone mineral density (BMD) from baseline to extension study endpoint with both doses of the drug, leading to discontinuation of treatment in approximately 6% of women in Elaris EM-III and 8% of women in Elaris EM-IV.
As Taylor pointed out, estrogen levels, at least when receiving the lower dose of elagolix, actually remain quite high.
"In fact, changes in BMD we see with elagolix are much lower than what we've seen with Lupron, which is what we've been using, and...we can monitor BMD and in the short term, it's reversible," he noted, adding that hormone therapy can be used to counteract this adverse effect.
Elagolix treatment was also associated with changes in the lipid profile that were first observed during Elaris EM-I and Elaris EM-II, and no further increases were observed during the extension studies.
All changes were small and included both favorable (increase in high-density lipoprotein) and unfavorable (increase in low-density lipoprotein and triglycerides) alterations.
Reduction in Endometrial Thickening
At least 60% of women in each dose group in both studies also had an endometrial thickness of less than 8 mm after 12 months of treatment.
"When endometrial thickness is reduced, it means women have less heavy periods," Taylor explained, "and what happens in the endometrium typically reflects what's happening to the endometriosis as well, so if you are seeing a reduction in endometrial thickness, you are also probably shrinking endometriosis and the fibroids as well, so it's absolutely a positive finding," he observed.
In contrast, 20% to 27% of women receiving the lower doses of elagolix in both EM-III and EM-IV were amenorrheic at the end of 12 months, whereas 63% of women in EM-III and 61% of women in EM-IV also became amenorrheic after 12 months of being exposed to the higher dose of the drug.
Three months after discontinuing therapy, more than 90% of women in both dose groups had resumed menses, the researchers note.
"These long-term responder rates are similar to those reported in the preceding Elaris EM-I and Elaris EM-II trials, which demonstrates the sustained effect of elagolix for the treatment of endometriosis-associated pain," they say. "In parallel with reduction of pain symptoms, a majority of women demonstrated improved quality of life and a decrease from baseline in the use of rescue analgesic agents after 12 months of elagolix treatment (opioid use: greater than 30% mean reduction at 150 mg once daily, greater than 65% mean reduction at 200 mg twice daily)," they state, adding that the safety profile of the drug was "consistent" with the mechanism of action, and there were no new safety signals with an additional 6 months of treatment.
The study was funded by AbbVie and Neurocrine Biosciences. Taylor receives research support from OvaScience and Pfizer and has served as a consultant for AbbVie, Pfizer, Bayer, Obseva, and OvaScience. Other investigators also had financial disclosures to make, which are listed in the publication.
Obstet Gynecol. 2018;132:147-160. Abstract
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Cite this: Investigational Oral Medication Promising for Endometriosis Pain - Medscape - Jun 15, 2018.