Pain of Endometriosis Eased by Elagolix Without Severe Bone Loss in Phase 3 Study, AbbVie Reports

Pain of Endometriosis Eased by Elagolix Without Severe Bone Loss in Phase 3 Study, AbbVie Reports

In the largest endometriosis trials to date, AbbVie demonstrated that the elagolix (ABT-620), an oral drug now in Phase 3 clinical testing, is not only effective in managing endometriosis-related pain, but also in controlling abnormal thickening of the endometrial tissue itself.

Although the treatment was linked to an increased risk of bone loss, the findings also suggest a lesser degree of bone mineral density loss than is seen with other drugs that also act on gonadotropin-releasing hormone (GnRH) to harness estrogen release.

The data was presented at the American Society for Reproductive Medicine (ASRM) 2016 Congress, held in Salt Lake City, Utah, on Oct. 15–19.

Abbvie contributed several presentations featuring data from the two trials  (NCT01620528 and NCT01931670), focusing on the safety and effectiveness of elagolix, as well as its effects on bone mineral density, in nearly 1,300 women.

“Endometriosis is often characterized by chronic pelvic pain, and can have a significant impact on patient function and quality of life,” Hugh S. Taylor, M.D., study investigator and chair of the Department of Obstetrics, Gynecology and Reproductive Sciences at Yale School of Medicine, said in a company press release. “The results presented today are encouraging for patients and demonstrate that Elagolix has the potential to be an important treatment option for women suffering from pain related to endometriosis.”

A better option

Like drugs that have been used to treat endometriosis for decades, elagolix acts on GnRH to lower estrogen. But unlike older medications, elagolix acts directly to block the actions of GnRH and harness hormone levels.

GnRh stimulates the release of two other reproductive hormones from the pituitary gland: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The duo is crucial for reproductive cycles, increasing estrogen in the process, which contributes to endometriosis.

Older drugs worked to stimulate GnRh. This may seem like an odd approach, but as the hormone triggers a surge in the levels of the other reproductive hormones, the body seeks to control the situation, and in the long run, hormone production is minimized.

Several attempts were made to create drugs that directly block the hormone, but early versions used peptides (protein parts). Such drugs need to be injected and could trigger immune reactions, in which the body reacts to the foreign protein.

Abbvie, and Neurocrine Biosciences — which first developed elagolix — appear to have overcome these issues. Elagolix is not a peptide drug, and so, it can be taken by mouth, lowering the risk of immune reactions. Since elagolix is directly blocking the production of hormones, patients may also benefit more quickly from treatment, and, if needed, the actions of the oral drug are reversible.

Two trials

The two Phase 3 trials evaluated how elagolix compared to placebo over a period of six months. Although pain reduction was the main focus of the studies, researchers also explored how the treatment impacted the endometrium.

The first, performed in North America, and included a total of 871 patients, while the second was a global study with sites in Europe, Australia, New Zealand, Brazil, and South Africa, as well as the U.S., and 815 women participating.

Participating premenopausal women, ages 18-49, had  been surgically diagnosed with endometriosis in the 10 years before the study’s start, and had moderate to severe endometriosis-associated pain.

Both studies randomized participants to receive either 150 mg elagolix once daily, 200 mg twice daily, or placebo. Researchers reported that the higher dose almost totally suppressed estrogen production.

Controlling Pain

The main goal of both trials was to measure the proportion of patients in which elagolix lowered daily menstrual and non-menstrual pelvic pain after three and six months. Patients provided pain measurements using an electronic diary.

Across the two studies, elagolix decreased menstrual pain in 43% to 46% of women taking the lower dose, and in 71% to 76% of women treated with the higher dose of elagolix. This was significantly better than placebo, which elicited a response in only 20% to 23% of women in the two trials.

Elagolix was also seen to lower non-menstrual pain. The lower dose produced a response in 50% of women in both studies, while the higher dose reduced pain in 55% and 58% of women in the first and second trials, respectively.

The effect on non-menstrual pain was also significantly better than placebo, with 36% to 37% of placebo-treated women reporting lower pain.

The most common side effects of elagolix treatment were hot flushes, which were mostly mild or moderate, but appeared in nearly half of women taking the 200 mg twice daily. Although also common, headache and nausea affected 16% to 23% of women in the higher dose group.

“These results from the largest clinical trials ever conducted in endometriosis support AbbVie’s continued efforts to pursue regulatory filing of Elagolix as a potential new treatment option for the disease’s most prevalent symptoms,” said Rob Scott, MD, vice president for Development at AbbVie and its chief medical officer. “There have been few recent scientific advancements for patients suffering from endometriosis and physicians are in need of additional treatment options to help manage this chronic and painful disease.”

The treatment also triggered increases in blood fats and decreased bone mineral density, with the 200 mg dose giving rise to more severe disturbances. No endometrial-related side effects were reported.

What about bone health?

Since drugs lowering estrogen are known to ramp up the risk for osteoporosis, researchers took a closer look at the bone mineral density of study participants. The team measured density in three bones: the lower spine, hip, and the femoral neck bone.

To protect against bias, specialists reviewing the bone images were not aware of the treatment given individual patients.

Elagolix lowered the bone mineral density after six months in a dose-dependent manner, meaning that the higher dose gave rise to a larger drop in density.

The 200 mg dose also gave rise to a larger proportion of patients who had a more than a 3% drop in spine bone density. The safety data echo earlier findings from a Phase 2 trial of elagolix.

“Elagolix resulted in a dose-dependent decrease in lumbar spine bone mineral density following 6 months of treatment, which is consistent with its mechanism of action,” Dr. Hugh Taylor, chair of Obstetrics, Gynecology and Reproductive Services at Yale University School of Medicine and the studies’ lead investigator, said in an interview with Endometriosis News. “Changes in bone occur slowly and the data from the ongoing extension studies will provide additional information on the long-term impact on bone mineral density.”

Trial participants will either continue to be followed without further treatment, or be invited to enroll in blinded extension trials, further exploring the treatment.

Thinning the endometrium   

In addition to pain assessments, the research team measured the thickness of the endometrium using transvaginal ultrasound at the start of both studies and again after six months of treatment. In the first trial, the team also collected biopsies from 867 participants at its start, and 644 at its conclusion.

Investigators found that elagolix reduced the patterns of both endometriosis cell expansions and secretion of hormones. The treatment also reduced the thickness of the endometrium, with the higher dose producing more robust results.

At the end of both studies, participants who received 200 mg elagolix twice daily were found to have significantly decreased endometrial thickness compared to those receiving placebo.

“There is no cure for endometriosis and patients are in need of additional treatment options to help manage this chronic and painful disease. Elagolix is an oral, GnRH antagonist that, according to recent study data, may offer reduced side effects. The two doses could offer patients different options to meet their own needs,” Taylor said. “The study results presented today are encouraging for patients and demonstrate that Elagolix has the potential to be an important treatment option for women suffering from pain related to endometriosis.”