Relugolix combination therapy cut heavy fibroid bleeding in two phase 3 trials

Two replicate phase 3 trials found that a once-daily pill combining relugolix with low-dose hormones sharply reduced heavy menstrual bleeding caused by uterine fibroids: more than 70% of women responded to the drug against under 20% on placebo [s1]. The trade-off sits in the label — US regulators cleared the combination for premenopausal women but limit its use to 24 months because of the risk of continued, possibly irreversible, bone loss [s2].

Uterine fibroids are among the most common causes of heavy menstrual bleeding, and the options between watchful waiting and surgery have long been thin. Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist; given alone it suppresses oestrogen and can drive bone loss and menopausal symptoms. The combination pairs it with estradiol (1 mg) and norethindrone acetate (0.5 mg) alongside 40 mg of relugolix, an "add-back" design meant to keep bleeding control while blunting those hypo-oestrogenic effects [s1].

What the trials did

The LIBERTY 1 and LIBERTY 2 trials were international, double-blind, 24-week studies in women with fibroid-associated heavy menstrual bleeding [s1]. Each randomised participants 1:1:1 to once-daily placebo, relugolix combination therapy, or a delayed-combination arm that took relugolix alone for 12 weeks before switching to the combination [s1]. LIBERTY 1 randomised 388 women; LIBERTY 2 randomised 382 [s1].

The primary endpoint was a responder measure: a menstrual blood-loss volume under 80 mL and a reduction of at least 50% from baseline [s1].

What they found

In the combination group, 73% of women in LIBERTY 1 and 71% in LIBERTY 2 met the responder endpoint, against 19% and 15% of the placebo groups — significant in both trials (P<0.001) [s1].

The combination also beat placebo on six of seven key secondary endpoints, including amenorrhoea, blood-loss volume, anaemia, pain, and distress from bleeding and pelvic discomfort [s1]. The exception matters: it did not significantly shrink fibroid volume [s1]. This is a bleeding-control treatment, not a way to make fibroids disappear — a distinction that bears directly on what a woman should expect from it.

On the safety question the design was built around, bone mineral density in the combination group was similar to placebo, whereas it fell in the arm taking relugolix alone [s1] — the result the add-back hormones were intended to produce, over the 24-week horizon the trials measured.

What the label says, and why the caveats are not incidental

The US Food and Drug Administration approved the combination, marketed as Myfembree, on 26 May 2021 for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women; a later approval extended it to moderate-to-severe pain from endometriosis [s2].

Two restrictions in the labelling temper the trial's headline numbers. First, use is limited to 24 months "due to the risk of continued bone loss which may not be reversible" [s2]. The trials' reassuring bone data ran to 24 weeks; the label's limit reflects a longer-term concern the trials were not long enough to settle. Second, the drug carries a boxed warning for thromboembolic and vascular events — the class risk of any oestrogen-progestin product — and is contraindicated in women with a history of blood clots, and in women over 35 who smoke or who have uncontrolled high blood pressure [s2].

What the evidence does and does not establish

The response rates are large and were replicated across two trials, which is the strongest form the efficacy evidence can take short of long-term outcome data. But the trials measured bleeding control and symptom scores over six months, not years, and not surgery avoided or quality of life over a full treatment course. The lack of effect on fibroid size means the underlying fibroids persist; the drug manages a symptom.

The comparison the trials did not make is also worth stating: they tested the combination against placebo, not against the alternatives a woman actually weighs — a hormonal intrauterine device, tranexamic acid, uterine-artery embolisation, or surgery. A large effect over placebo does not, by itself, rank a drug against its real competitors.

What to watch

Longer-term bone-density data, given the 24-month limit, and real-world evidence on what happens to bleeding after the drug is stopped. Head-to-head comparisons against other medical options for fibroid bleeding. And cost and access, since a branded daily pill with a defined treatment window sits in a different place for patients and health systems than older, cheaper options.

This article describes trial results and regulatory labelling. It is not medical advice, and treatment decisions for fibroids belong with a clinician who knows the individual case.

Sources

1. Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy — New England Journal of Medicine, 17 February 2021
2. Myfembree label and approval history, NDA 214846 — U.S. Food and Drug Administration, approved 26 May 2021