Regulatory Decision Summary for Myfembree

The purpose for the filing of this submission was to obtain market approval for Myfembree (relugolix/estradiol/norethindrone acetate) for use in women suffering from symptoms associated with uterine fibroids.

Following review the following indication was recommended:

Myfembree (relugolix/estradiol/norethindrone acetate) is indicated in premenopausal women for the management of heavy menstrual bleeding associated with uterine fibroids.

Myfembree is indicated in premenopausal women for the management of heavy menstrual bleeding associated with uterine fibroids. The clinical safety and efficacy of Myfembree is supported by complete quality, non-clinical, clinical pharmacology, and clinical safety and efficacy programs.

This submission is considered to comply with the Quality data requirements of Section C.08.002 of the Food and Drug Regulations.

Non-clinical and clinical pharmacology studies assessing the pharmacodynamics, pharmacokinetics, and safety of relugolix support the recommended dose of 40 mg once daily in premenopausal women. Toxicology studies for relugolix provided sufficient organ toxicity safety margins compared to the recommended therapeutic dose. Relugolix was not genotoxic (in vitro and in vivo) or carcinogenic (in mice and rats). Reproductive toxicology studies suggest that relugolix may cause early pregnancy loss. Myfembree is contraindicated in women who are pregnant or suspected to be pregnant. Pregnancy should be excluded before initiating Myfembree. Relugolix was excreted into the milk of lactating rats. Breastfeeding is contraindicated during the use of Myfembree. No dosage adjustment is needed in patients with moderate or severe renal impairments. Myfembree is contraindicated in patients with liver dysfunction or liver disease. Concomitant use of Myfembree with oral P-gp inhibitors or P-gp and strong CYP3A inducers should be avoided. No dose adjustments are recommended for intrinsic or extrinsic factors. The reduction in relugolix exposure when taken with a high-fat, high-calorie meal is not expected to significantly affect the efficacy or safety of the drug. Myfembree may be administered with or without food.

In the two placebo-controlled clinical studies, 254 and 257 women with heavy menstrual bleeding associated with uterine fibroids received Myfembree or placebo, respectively, once daily for 24 weeks. Menstrual blood loss (MBL) was quantified by the alkaline hematin method. The primary efficacy endpoint was met; a significantly higher proportion of women treated with Myfembree achieved a response, defined in the studies as having both an MBL volume of <80 mL and at least a 50% reduction from baseline in MBL volume over the last 35 days of treatment, compared with placebo. Secondary endpoints including the assessment of amenorrhea, change in MBL volume, hemoglobin response, and uterine volume were also supportive of the primary endpoint. However, no significant reduction in uterine fibroid volume was observed from baseline to Week 24 in women treated with Myfembree compared to placebo. The efficacy results were consistent across the two well-controlled, adequately powered, Phase 3 clinical trials, providing substantial evidence of effectiveness for Myfembree to manage heavy menstrual bleeding associated with uterine fibroids in the target population. Efficacy results were generally maintained throughout the long-term extension study (52 weeks of cumulative exposure) and randomized withdrawal study (104 weeks of cumulative exposure).

The safety of Myfembree was evaluated in 451 women who were exposed to Myfembree for at least 24 weeks. Of these, 258 were exposed for at least 48 weeks, and 129 were exposed for over 52 weeks. Frequently reported adverse reactions included vasomotor symptoms (e.g. hot flushes), abnormal uterine bleeding (e.g. menorrhagia, metrorrhagia), alopecia, and libido decreased.

Key adverse effects of clinical interest for GnRH antagonists included bone loss, measured as bone mineral density (BMD) decrease. The addition of E2/NETA to relugolix attenuated BMD decreased compared to relugolix monotherapy, but did not completely prevent it. The mean reduction in BMD was greater in women treated with Myfembree at Week 24 compared to women treated with placebo, and at Week 52 compared to aged-matched women with uterine fibroids but not being treated for their condition. The mean decrease in BMD from baseline was not considered clinically significant up to 52 weeks of treatment; however, there were more patients with clinically significant reduction in BMD (>3%) in women treated with Myfembree at Week 24 compared to women treated with placebo or at Week 52 compared to untreated women. Assessment of BMD is recommended at baseline and periodically thereafter. Discontinuation of Myfembree should be considered if the risk associated with bone loss exceeds the potential benefit of treatment. It is unclear whether BMD loss has stabilized by 52 weeks of treatment. Limited BMD data suggest that Myfembree is not expected to further reduce BMD significantly with up to 2 years of treatment in most premenopausal women suffering from uterine fibroids. The impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown. Due to uncertainties regarding continued BMD loss with prolonged treatment, use of Myfembree is limited to 24 months. Myfembree is contraindicated in women with known osteoporosis.

Other relevant adverse reactions associated with Myfembree include mood disorders (depression, mood swings, depressed mood, irritability, and anxiety), increased lipids (cholesterol and LDL), gallbladder disease (cholelithiasis and cholecystitis), and hypertension. These adverse reactions have been appropriately addressed in the label of Myfembree. Additionally, appropriate contraindications and warnings and precautions regarding cardiovascular disease, hormone-sensitive malignancies, and liver disease have been added to the labelling.

Overall, Myfembree was well-tolerated in premenopausal women with uterine fibroids. All of the safety concerns identified during this review have been adequately mitigated through labeling and the risk management plan.

Labelling documents conform to the necessary regulatory requirements and are consistent with the labelling guidance documents. The submission is considered acceptable with respect to the labelling documents reviewed.

A Risk Management Plan (RMP) for Myfembree was submitted by Sumitomo Pharma Switzerland GmbH to Health Canada. Upon review, the RMP was considered to be acceptable.

Myfembree is expected to fill an unmet medical need in Canada by providing women with heavy menstrual bleeding associated with uterine fibroids a non-invasive longer-term treatment option. From an efficacy and safety perspective, the benefit-risk-uncertainty profile of Myfembree is favorable and a Notice of Compliance is recommended.