Combination Therapy Receives FDA Approval for Endometriosis

The US Food and Drug Administration (FDA) approved the combination therapy relugolix, estradiol, and norethindrone acetate (Myfembree) for the management of moderate to severe pain associated with endometriosis.

Endometriosis is often accompanied by debilitating symptoms. The condition is characterized by the presence of uterine tissue outside of the uterine cavity leading to disruptive symptoms including painful periods, lower back and abdomen pain, heavy menstrual pain, and painful intercourse.

While there are prescription and over-the-counter medications available, as well as surgical options to remove the cysts, these approaches don't work for all patients. Additionally, it's a difficult condition to diagnose with some women going 4-11 years before receiving a diagnosis.

“Approximately 7.5 million premenopausal women in the US have endometriosis and 75-80% of them are symptomatic,” Juan Camilo Arjona Ferreira, MD, Chief Medical Officer of Myovant Sciences, said in a statement. “The data published in The Lancet underscore the value relugolix combination therapy may provide as a potential new treatment option for women with endometriosis-associated pain.” 

Reviewing the Data

In June, results were published in The Lancet from the phase 3 SPIRIT 1 and SPIRIT 2 studies, which supported the FDA decision. The agency requested supplemental data and an update throughout the review process.

Most recently, Myovant Sciences and Pfizer Inc. announced that they updated the medication's supplemental New Drug Application (sNDA), which was already undergoing review by the FDA. The agency had notified the companies of deficiencies it identified, halting the discussion of labeling and post-marketing requirements until they were addressed.

Within a week of the notice, the companies were able to submit an update. The drug is a once-daily oral treatment consisting of relugolix 40 mg, estradiol 1 mg and norethindrone acetate 0.5 mg.

“The data from the SPIRIT studies showed the clinical benefit that relugolix combination therapy can have on moderate to severe pain associated with endometriosis and how it can impact patients,” Linda Giudice, MD, PhD, Distinguished Professor, University of California, San Francisco (UCSF), Chair, SPIRIT Program Steering Committee said in a statement.

“This newly approved option for patients with pain from endometriosis offers the convenience of one pill taken once daily with a mean change in bone mineral density of <1% that did not appear to worsen at 12 months of treatment; however, monitoring is recommended.”

Myfembree Clinical Trials for Endometriosis

Both studies demonstrated clinically meaningful reductions of 75% in dysmenorrhea (menstrual pain) and non-menstrual pelvic pain, compared with 27% and 30% in the placebo groups, achieving their co-primary endpoints. The 2 replicate, phase 3, multicenter, randomized, double-blind, placebo-controlled trials spanned 219 community and hospital research centers across the globe.

The studies also met their secondary endpoints. SPIRIT 1 achieved 7 key secondary endpoints and SPIRIT 2 met 6. The evaluation included changes in mean dysmenorrhea, non-menstrual pelvic pain, overall pelvic pain, impact of pain on daily activities as measured by the Endometriosis Health Profile-30 (EHP-30) pain domain, the proportion of women not using opioids, the proportion of women not using analgesics, and change in mean dyspareunia (painful intercourse).

As for the seventh endpoint of SPIRIT 2, reduction in analgesic use (based on pill count), it did not achieve statistical significance. However, investigators speculated that could be due to the low number of average pills per day and variability in day-to-day pill consumption.

In a post-hoc analysis of SPIRIT 2, the percentage of patients who were analgesic-free at end of treatment was greater among patients in the combination therapy group as opposed to those in placebo.

The most common adverse events reported in both groups were headache, nasopharyngitis, and hot flushes.

Prior to this decision, relugolix, estradiol, and norethindrone acetate combination therapy was indicated for managing heavy bleeding associated with uterine leiomyomas (fibroids) in premenopausal women, with a limitation of 24 months.