AbbVie in cooperation with Neurocrine Biosciences has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration for elagolix, an investigational, orally administered gonadotropin-releasing hormone (GnRH) antagonist, being evaluated for the management of endometriosis with associated pain. In two replicate Phase 3 clinical studies, elagolix demonstrated superiority compared to placebo in reducing three types of endometriosis-associated pain – daily menstrual pelvic pain, non-menstrual pelvic pain and painful intercourse.
"The submission represents an important step forward for women suffering from endometriosis and physicians who are in need of additional medical treatment options to help manage this chronic and painful disease," said Michael Severino, M.D., Executive Vice President, Research and Development and Chief Scientific Officer, AbbVie. "Elagolix has the potential to be an important oral treatment option for women suffering from the most prevalent symptoms of endometriosis and we look forward to working with the FDA throughout the review process."
The NDA is supported by data from the largest prospective randomized endometriosis clinical trials conducted to date, which evaluated the safety and efficacy of elagolix in nearly 1,700 women with moderate-to-severe endometriosis-associated pain. The data from two replicate Phase 3 studies demonstrated that, at month three and month six, both elagolix doses (150 mg once daily and 200 mg twice daily) resulted in a statistically significant higher proportion of responders for menstrual pain (dysmenorrhea) and non-menstrual pelvic pain associated with endometriosis as measured by the Daily Endometriosis Pain Impact scale versus placebo. Significant improvements compared to placebo were also observed at month three for the 200 mg twice daily dose in scores for painful intercourse (dyspareunia). A reduction in the amount and frequency of rescue pain medication use, including nonsteroidal anti-inflammatory drugs and opioids, compared to placebo was also seen in the higher dose at month three and six. In clinical studies, elagolix treatment decreased endometrial proliferation in a dose-dependent manner after six months of treatment with no adverse endometrial findings.
The safety profile of elagolix was consistent with the partial hormone suppression associated with its mechanism of action. Findings were consistent across Phase 3 trials and prior elagolix studies. In the first Phase 3 study, the most frequently reported adverse events assessed over six months were hot flush, headache and nausea. The rates for hot flush were (7%, 24%, 42% for placebo, 150 mg once daily and 200 mg twice daily, respectively) and headache were (10%, 15%, 17% for placebo, 150 mg once daily and 200 mg twice daily, respectively). The majority of hot flushes were mild to moderate in severity. Elagolix treatment was associated with dose-dependent decreases in bone mineral density (BMD) in women with endometriosis-associated pain. After six months of treatment, all of the women had a BMD z-score above -2.0, within the normal age-adjusted range. The second Phase 3 study demonstrated similar results.
Endometriosis occurs when tissue similar to that normally found in the uterus begins to grow outside of the uterus, leading to long-term pelvic pain (during or between periods), pain with intercourse and other painful symptoms. These growths are called lesions and can occur on the ovaries, the fallopian tubes, or other areas near the uterus, such as the bowel or bladder. Estrogen fuels the growth of lesions. There is no cure for endometriosis, and the associated pain is currently managed with oral contraceptives, progestins, danazol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and GnRH agonists, many of which are not specifically indicated for the treatment of endometriosis. In more extensive cases, surgical interventions (e.g., laparotomy or laparoscopy) are often pursued, and may not be curative for all individuals.