Regulatory Decision Summary for Myfembree

The purpose of this New Drug Submission (NDS) was to seek regulatory approval for the use of Myfembree (relugolix, estradiol, norethindrone acetate, 40 mg/1 mg/0.5 mg) in premenopausal women for the management of moderate to severe pain associated with endometriosis in Canada.

The clinical efficacy and safety of Myfembree (relugolix, estradiol, norethindrone acetate, 40 mg/1 mg/0.5 mg) for the management of moderate to severe pain associated with endometriosis was assessed in two replicate, 24-week, multinational, randomized, double-blind, placebo-controlled phase 3 clinical trials (S1 and S2). Upon completion of the 24-week studies S1 and S2, eligible participants were enrolled in an 80-week, open-label, single-arm extension safety study (S3) with a total of 104 weeks of treatment period.

The primary objective of S1 and S2 trials was to demonstrate a reduction in dysmenorrhea and non-menstrual pelvic pain (NMPP) for 24 weeks. Two co-primary endpoints were used: 1) the proportion of women (i.e. dysmenorrhea responder) comparing the Myfembree group with placebo group, who achieved a reduction from baseline in dysmenorrhea numerical rating scale (NRS) of at least 2.8 points; 2) the proportion of women (i.e. non-menstrual pelvic pain responder), comparing the Myfembree group with the placebo group, who achieved a reduction from baseline in non-menstrual pelvic pain (NMPP) NRS score of at least 2.1 points. Key secondary endpoints included changes from baseline in the Endometriosis Health Profile-30 (EHP-30) pain domain scores, dyspareunia NRS scores, and opioid use.

In Studies S1 and S2, a statistically higher proportions of women treated with Myfembree achieved each of the co-primary endpoints of meeting dysmenorrhea and NMPP responder definition. In Study S1, 74.5% of patients in the Myfembree group met the dysmenorrhea responder definition versus 26.9% of patients in the placebo group for a treatment difference of 47.6% with a 95% confidence interval (CI) (39.3%, 56.0%) (p<0.0001). Similarly, 58.5% of patients in the Myfembree group met the NMPP responder definition versus 39.6% of patients in the placebo group, for a treatment difference of 18.9% with a 95%CI (9.5%, 28.2%) (p<0.0001). In Study S2, 75.1% of patients in Myfembree group met the dysmenorrhea responder definition versus 30.5% of patients in the placebo group for a treatment difference of 44.6% with a 95% CI (35.9%, 53.3%) (p<0.0001). Similarly, 65.9% of patients in Myfembree group met the NMPP responder definition versus 42.5% of patients in the placebo group for a treatment difference of 23.4% with a 95%CI (13.9%, 32.8%) (p<0.0001). Results of key secondary efficacy endpoints supported the results of the co-primary endpoints. Myfembree-treated women reported a statistically significant (p<0.0001) improvement from baseline in EHP-30 pain domain score compared to placebo at Week 24 in both Studies S1 and S2. Among women who engaged in sexual activity at baseline and during treatment (68% of enrolled women), Myfembree-treated women experienced a greater reduction in dyspareunia from baseline to Week 24 compared with placebo. In both studies, a greater proportion of Myfembree-treated women maintained opioid-free to the end of treatment compared with that of the placebo-treated women.

In Studies S1 and S2, the most common adverse reactions reported in at least 3% of women treated with Myfembree and with an incidence greater than placebo included headache (33.0% vs. 26.4%), vasomotor symptoms (hot flush, hyperhidrosis, night sweats, and flushing) (13.2% vs. 7.2%), mood disorders (affect lability, affective disorder, anxiety, depressed mood, depression, emotional distress, irritability, mood altered/swings, suicidal ideation) (9.1% vs.7.2%), abnormal uterine bleeding (menorrhagia, metrorrhagia, polymenorrhoea, menstruation irregular, vaginal haemorrhage) (6.7% vs. 4.6%), nausea (6.0% vs. 4.1%), back pain (4.8% vs. 2.9%), decreased sexual desire/arousal (libido decrease, libido disorder, female sexual arousal disorder) (4.3% s. 1.2%), arthralgia (3.6% vs. 2.9%), dizziness (3.1% vs. 1.2%), fatigue (3.1% vs. 2.4%). The most common serious adverse reactions in Myfembree group included uterine hemorrhage, suicidal ideation, cholelithiasis, and cholecystitis. The most common adverse reaction (1.7%) leading to discontinuation in Myfembree-treated women was mood-related disorders. The safety profile reported in the long-term safety study (S3) were similar to that of observed in the placebo-controlled studies.

In Studies S1 and S2, a decline in lumbar spine bone mineral density (BMD) of >3% was observed in 17.1% of women treated with Myfembree for 6 months compared with 8.8% of women in placebo. One patient in the Myfembree and no patients in placebo group had a decline of BMD >8%. In Study S3, a decline in lumbar spine BMD of >3% was observed in 19.7% of women following 12 months of Myfembree treatment, and in 9.1% of untreated women in an Observational Endometriosis Cohort.

The benefit of Myfembree has not been assessed 1) in premenopausal women less that 18 or over 50 years of age; 2) in menopausal women; and 3) beyond 104 weeks of treatment.

The safety of Myfembree was not evaluated in women with a history/current osteoporosis/other metabolic bone disease, breast cancer, stroke, myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE). Potential risks of serious adverse events such as mood disorders (depression, suicidal ideation) and cardiovascular disorders (DVT or PE or MI or stroke) will be further characterized in post-marketing surveillance activities. Data on loss of BMD beyond 24 months of treatment, and potential impact on pregnant outcomes were not available. Additional pharmacovigilance observational studies for BMD and pregnant outcomes have been committed.

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

Comprehensive non-clinical package and clinical pharmacology package for relugolix were submitted. 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 suggested 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. Non-clinical and clinical pharmacology of estradiol and norethindrone acetate were based on a marketed product in Canada (Activelle).

Phase 3 clinical trials were conducted using co-administration of separate tablets of relugolix 40 mg and a commercially available fixed-dose combination of estradiol and norethindrone acetate, 1 mg/0.5 mg (Activella) as co-packaged tablets. However, the commercial product Myfembree is a fixed-dose combination tablet of relugolix/ estradiol/ norethindrone acetate, 40 mg/1 mg/0.5 mg. Therefore, a comparative bioavailability study was carried out to compare the pharmacokinetics between the co-packaged tablets versus the commercial product Myfembree. The results of this study indicated that the bioavailability profiles of Myfembree versus the co-packaged tablets used in phase 3 trials are equivalent.

A Risk Management Plan (RMP) for Myfembree was submitted to Health Canada and reviewed by Marketed Health Products Directorate (MHPD), and was considered acceptable.

The totality of evidence submitted in this NDS supports the safety and efficacy of Myfembree for the management of moderate to severe pain associated with endometriosis in premenopausal women 18-50 years of age. The benefit-risk profile of Myfembree (relugolix 40 mg/estradiol 1 mg/norethindrone 0.5 mg) for the recommended indication and dosage recommendation is favorable. The Product Monograph of Myfembree dated October 10, 2023 (sequence number 0051) has been revised extensively to accurately reflect the efficacy, safety, and uncertainties identified in this NDS.

For further details about Myfembree, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.