Summary Basis of Decision (SBD) for Myfembree

Clinical Pharmacology

Myfembree is a combination product containing relugolix, estradiol, and norethindrone acetate.

Relugolix is a non‑peptide gonadotropin releasing hormone (GnRH) receptor antagonist that competitively binds to GnRH receptors in the anterior pituitary gland reducing the secretion of luteinizing hormone and follicle‑stimulating hormone. The reduction of follicle‑stimulating hormone and luteinizing hormone limits the production of estrogen and progesterone, respectively, lowering the bleeding associated with uterine fibroids and pain associated with endometriosis.

Estradiol is an agonist of the nuclear estrogen receptor subtypes with organ‑specific effects. Exogenously administered estradiol in Myfembree may alleviate certain effects that can occur due to a decrease in circulating estrogen concentrations from relugolix alone, such as bone mineral density loss and vasomotor symptoms.

Norethindrone acetate is a synthetic progestin that acts on progesterone receptors and reduces the estrogen-induced risk of endometrial hyperplasia.

The clinical pharmacology program for relugolix was conducted in healthy premenopausal women in 23 dedicated studies. The clinical pharmacology of the estradiol and norethindrone acetate components in Myfembree are based on a previous submission (estradiol/norethindrone acetate) approved by Health Canada for the treatment of menopause‑related symptoms.

Pharmacokinetic parameters for relugolix, area under the concentration‑time curve (AUC) and maximum concentration (C_max), increased approximately in proportion to the dose over the repeated dose range of 10 to 40 mg once daily. Relugolix concentrations reached steady‑state within 12 days, and the degree of accumulation was approximately 2‑fold, upon once‑daily administration. The mean (percent coefficient of variation [CV%]) absolute bioavailability of relugolix is 12%. After oral administration of a single 80 mg radiolabeled dose of relugolix, approximately 81% of the radioactivity was recovered in feces (4.2% as unchanged) and 4.1% in urine (2.2% as unchanged).

No dose adjustment is needed in patients with moderate or severe renal impairment as no clinically meaningful effects on the exposure to relugolix were observed. The effects of end‑stage renal disease, with or without hemodialysis, on the pharmacokinetics of relugolix have not been evaluated. No clinically meaningful effects of mild or moderate hepatic impairment on the exposure to relugolix were observed. No studies have been conducted to evaluate the effects of renal or hepatic impairment on the pharmacokinetics of estradiol and norethindrone acetate. The previously approved drug containing estradiol and norethindrone acetate is contraindicated in patients with known liver impairment or disease, therefore, Myfembree is contraindicated in patients with any hepatic impairment or disease.

The sponsor submitted a total of 11 drug‑drug interaction studies for relugolix. Relugolix is a sensitive substrate of intestinal P‑glycoprotein (P‑gp), which limits its oral bioavailability. Relugolix is also a substrate for the drug metabolizing enzymes cytochrome P450 (CYP) 3A and CYP2C8. The co‑administration of relugolix with erythromycin (a P‑gp and moderate CYP3A inhibitor) increased the AUC and C_max of relugolix by 4.1‑ and 3.8‑fold, respectively. The co‑administration of relugolix with voriconazole (a strong CYP3A inhibitor) did not result in a clinically relevant increase in exposure to relugolix. The co‑administration of relugolix with azithromycin (an oral P‑gp inhibitor devoid of CYP3A inhibition) resulted in an increase in exposure to relugolix, while a 6‑hour dose separation between relugolix and azithromycin resulted in a smaller increase in exposure. The concomitant use of Myfembree with oral P‑gp inhibitors should be avoided. If concomitant use is unavoidable, take Myfembree first and separate dosing by at least 6 hours. The co‑administration of relugolix with rifampin (a P‑gp and strong CYP3A inducer) decreased the AUC and C_max of relugolix by 55% and 23%, respectively. The use of Myfembree with combined a P‑gp inducer and a strong CYP3A inducer should be avoided. There were no clinically significant differences in the pharmacokinetics of midazolam (a sensitive CYP3A substrate), rosuvastatin (breast cancer resistance protein [BCRP] substrate) or dabigatran etexilate (a P‑gp substrate) upon co‑administration with relugolix.

In a randomized, double‑blind, placebo‑ and positive‑controlled, parallel‑group electrocardiogram assessment study in healthy subjects (number of subjects [n] = 70 per treatment arm; 51% male and 49% female) receiving single supratherapeutic doses of relugolix 60 mg or 360 mg, no pharmacodynamic effect was observed on the QT interval corrected for heart rate (QTc). The potential effects of multiple‑dose relugolix treatment were not assessed in this study.

Based on population pharmacokinetic analysis, the effect of body weight, race, and age on the pharmacokinetics of relugolix is not considered clinically meaningful. Overall, clinical pharmacology studies support the administration of relugolix at the recommended dose of 40 mg once daily in premenopausal women. No dose adjustments are recommended for intrinsic or extrinsic factors.

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

Clinical Efficacy

The clinical efficacy of Myfembree (a combination product containing relugolix, estradiol [E2], and norethindrone acetate [NETA]) for the management of heavy menstrual bleeding associated with uterine fibroids is supported by two Phase III, randomized, double‑blinded, placebo‑controlled combination therapy trials, Study L1 and Study L2. Across the two clinical trials (Studies L1 and L2), 254 women received Myfembree once daily for 24 weeks. Additionally, 256 women received a placebo for 24 weeks, and 258 women received relugolix 40 mg monotherapy once daily for 12 weeks followed by Myfembree for 12 weeks. Of these, 476 women were then treated with Myfembree in a 28‑week open‑label long‑term extension trial (Study L3) for a total treatment duration of up to 12 months. Of those women who completed Study L3 and were responders (defined as a patient who demonstrated an menstrual blood loss volume of <80 mL and at least a 50% reduction from the pivotal study baseline menstrual blood loss volume per alkaline hematin analysis of the feminine products returned at Week 48 in the long-term extension study), 228 women then enrolled into an additional 52‑week randomized withdrawal clinical trial (Study L4) where they were re‑randomized to receive either Myfembree or a placebo. In both pivotal studies (L1 and L2), the mean age of the participants was 42 years (age range:18 to 50) and the majority were White or Black and enrolled in North America. The demographics and baseline characteristics of the study participants were similar across studies and representative of the target population for whom the drug is intended.

The primary endpoint was the proportion of women who were responders in the Myfembree group versus the placebo group. A responder was defined as achieving a menstrual blood loss volume of <80 mL and at least a 50% reduction from baseline menstrual blood loss volume over the last 35 days of treatment, as measured by the alkaline hematin method. In Study L1, 73.4% of women treated with Myfembree were responders compared to 18.9% of women treated with a placebo. In Study L2, 71.2% of women treated with Myfembree were responders compared to 14.7% of women treated with a placebo. The difference from placebo was statistically significant (54.5% and 56.5%, respectively; p <0.0001) in both studies.

Key secondary endpoints included the assessment of menstrual blood loss volume, amenorrhea, hemoglobin levels, uterine volume, and uterine fibroid volume. The mean reduction in menstrual blood loss volume from baseline to Week 24 in the Myfembree group was 84.3% in both studies, which was significantly greater than placebo (23.2% and 15.1%, respectively; p <0.0001). Of the women treated with Myfembree, 52.3% and 50.4% achieved amenorrhea compared with 5.5% and 3.1% treated with a placebo (p <0.0001) in Studies L1 and L2, respectively.

A hemoglobin response was defined as a hemoglobin increase of >2 g/dL from baseline to Week 24 in the subgroup of women with anemia at baseline (hemoglobin ≤10.5 g/dL). In Study L1, 50.0% of women treated with Myfembree were hemoglobin responders compared to 21.7% of women treated with a placebo. In Study L2, 61.3% of women treated with Myfembree were hemoglobin responders compared to 5.4% of women treated with a placebo. The difference from placebo was statistically significant (28.3% [p = 0.0377] and 55.9% [p <0.0001], respectively) in both studies.

In Study L1, the uterine volume (measured by transvaginal ultrasound) was reduced by 12.9% in women treated with Myfembree compared to a gain in uterine volume by 2.2% in women treated with placebo. In Study L2, the uterine volume was reduced by 13.8% in women treated with Myfembree compared to 1.5% in women treated with a placebo. In both studies the difference from placebo was statistically significant, with a reduction of 15.1% (p = 0.0002) and 12.2% (p = 0.0078), respectively. However, no significant reduction in uterine fibroid volume was observed from baseline to Week 24 in women treated with Myfembree, with a 12.1% reduction (p = 0.0921) compared to a placebo in Study L1, and a 10.0% reduction (p = 0.2153) compared to a placebo in Study L2.

Subjects who completed Studies L1 and L2 and who met the eligibility criteria were offered to join Study L3. Although the primary objective of Study L3 was to evaluate the safety of Myfembree over a treatment duration of 52 weeks, the efficacy results derived from this study support the observed efficacy response obtained at Week 24 and that efficacy was maintained up to 52 weeks of treatment. Subjects who completed the extension study and who met the eligibility criteria were then offered to join Study L4. Based on the exploratory results obtained from Study L4, efficacy also appeared to be maintained through an additional 52 weeks of Myfembree treatment (total of 104 weeks from pivotal baseline).

In conclusion, there is substantial evidence based on the two pivotal Phase III clinical trials (Studies L1 and L2) that treatment with Myfembree was associated with a statistically significant and clinically meaningful improvement in heavy menstrual bleeding in patients with symptomatic uterine fibroids. Therefore, from an efficacy perspective, the benefit‑risk‑uncertainty profile of Myfembree is favorable for the recommended indication.

Indication

The New Drug Submission for Myfembree was filed by the sponsor with the following proposed indication:

Myfembree (relugolix/E2/NETA) is indicated for the treatment of moderate to severe symptoms associated with uterine fibroids in premenopausal women.

Health Canada revised the proposed indication as follows:

Myfembree (relugolix/E2/NETA) is indicated in premenopausal women for the management of heavy menstrual bleeding associated with uterine fibroids.

The indication was amended as data discussing the pain endpoint was removed from the Product Monograph. Although a statistically significant improvement in the Pain Score was observed with Myfembree compared to a placebo, due to limitations in the study design, it is unclear whether the pain is specifically associated with uterine fibroids.

For more information, refer to the Myfembree Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Myfembree in the management of heavy bleeding associated with uterine fibroids in premenopausal women was evaluated in two pivotal placebo‑controlled clinical trials, Study L1 and Study L2 (see Clinical Efficacy section). Both studies excluded women who had a history of or current diagnoses of osteoporosis, other metabolic bone disease, or bone mineral density Z-score of less than ‑2.0; women who had any contraindication to treat with low‑dose estradiol or norethindrone acetate (such as breast cancer, deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction); and women who had other clinically significant cardiovascular disease, jaundice or active liver disease including clinical laboratory abnormalities. The mean age at study entry was 42 years (range 19 to 51 years old).

Across the two clinical trials (Studies L1 and L2), 254 women received Myfembree once daily for 24 weeks. Additionally, 256 women received a placebo for 24 weeks, and 258 women received relugolix 40 mg monotherapy once daily for 12 weeks followed by Myfembree for 12 weeks. Of these, 476 women were then treated with Myfembree in a 28‑week open‑label long‑term extension trial (Study L3) for a total treatment duration of up to 12 months. Of those women who completed Study L3 and were responders, 228 women then enrolled into an additional 52‑week randomized withdrawal trial (Study L4) where they were re‑randomized to receive either Myfembree or a placebo.

Overall, Myfembree was well-tolerated. Adverse events reported in at least 2% of patients and at a greater frequency in the Myfembree group compared to placebo after 24 weeks of treatment, included hot flush (8.3% versus 5.9%), hypertension (4.7% vs 1.6%), alopecia (3.5% versus 0.8%), abdominal pain (3.5% vs 1.6%), menorrhagia (2.8% vs 0.4%), libido decreased (2.8% vs 0.4%), irritability (2.4% vs 0%), metrorrhagia (2.0% vs 0.4%), hyperhidrosis (2.0% versus 0.8%) , dyspepsia (2.0% vs 0.4%), and breast cyst (2.0% vs 0%). The majority of adverse events reported were mild to moderate in severity and resolved without treatment. In the Myfembree group, serious adverse drug reactions included uterine myoma expulsion and menorrhagia experienced by one woman, uterine leiomyoma (prolapse), cholecystitis, and pelvic pain reported for one woman each.

The adverse reactions most commonly reported in the open‑label extension trial (Study L3) were similar to those in the placebo‑controlled studies. No adverse events were reported disproportionately more frequently with the longer treatment duration (up to 52 weeks) of Myfembree.

The effect of Myfembree on bone mineral density was assessed in Studies L1 and L2. The mean percent change from baseline (95% confidence interval [CI]) in lumbar spine bone mineral density at Week 24 for women with uterine fibroids was ‑0.23% (‑0.64, 0.18) in the Myfembree group compared to -0.18% (‑0.21, 0.58) in the placebo group. In Study L3, continued bone loss was observed with Myfembree treatment. The mean percent change from baseline in lumbar spine bone mineral density for women with uterine fibroids treated with Myfembree for an additional 28 weeks in the extension study (52 weeks total) was ‑0.80% (‑1.36, ‑0.25).

A separate concurrent prospective observational study enrolled 262 women with uterine fibroids who were age‑matched to participants in the pivotal clinical studies. Changes in bone mineral density were assessed in these women who did not receive treatment for uterine fibroids. Mean percent changes from baseline (95% CI) in bone mineral density at the lumbar spine at Week 24 and Week 52 in the uterine fibroids cohort were 0.00 (‑0.32, 0.31) and ‑0.41 (‑0.77, ‑0.05), respectively. Women treated with Myfembree for 52 weeks experienced bone loss at the lumbar spine that was twice that of the observational uterine fibroids cohort (-0.80% vs -0.41%).

Although the mean decrease in bone mineral density from baseline was not considered clinically significant up to 52 weeks of treatment, there were more patients with clinically significant reduction in bone mineral density (>3%) in women treated with Myfembree compared to women treated with a placebo at Week 24 (15.9% vs 9.1%) or untreated women at Week 52 (23% vs 17.4%). In limited post‑treatment follow‑up data, the loss in bone mineral density in some patients may not be completely reversible. Assessment of bone mineral density 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 bone mineral density loss has reached a plateau after 52 weeks of treatment. Limited bone mineral density data suggest that Myfembree is not expected to further reduce bone mineral density significantly with up to two years of treatment in most premenopausal women suffering from uterine fibroids. However, the sample size of patients with two years of consecutive Myfembree treatment is too small to confidently determine whether stabilization in bone mineral density is achieved. The impact of the observed bone mineral density loss on long‑term bone health and future fracture risk in premenopausal women is unknown. Due to uncertainties regarding continued bone mineral density loss with prolonged treatment, use of Myfembree is limited to 24 months. Myfembree is also contraindicated in women with known osteoporosis.

Estrogen/progestin replacement therapy have been associated with an increased risk of cardiovascular events. No major cardiovascular, embolic, or thrombotic adverse events were reported in the Myfembree clinical program. Given that cardiovascular events in premenopausal women are rare, limitations of this review include the relatively small number of women included in the analysis, short duration of treatment (up to 52 weeks), and the exclusion of women with significant cardiovascular disease from the clinical program. A low rate of hepatic transaminase elevations was observed with Myfembree, with no evidence of clinically apparent liver injury. The endometrial biopsy data do not raise any endometrial safety concerns with Myfembree treatment in this population. Appropriate contraindications and warnings and precautions regarding cardiovascular disease, hormone‑sensitive malignancies, and liver disease have been added to the Myfembree Product Monograph.

A greater proportion of women treated with Myfembree compared with a placebo reported depression (including depression, mood swings, and depressed mood) (2.4% versus 0.8%), irritability (2.4% versus 0%), and anxiety (1.2% versus 0.8%). In one of the two Phase III clinical studies, more women experienced the adverse reaction of new or worsening hypertension with Myfembree as compared to a placebo (7.0% versus 0.8%). More women treated with Myfembree for 24 weeks had increases in total cholesterol and/or low-density lipoprotein to levels above normal compared to women treated with a placebo. Gallbladder disease, such as cholelithiasis and cholecystitis, have been reported to occur or worsen in women treated with estrogen and progestogen use in general, including women treated with Myfembree. These adverse reactions have been appropriately addressed through appropriate labelling in the Myfembree Product Monograph.

In conclusion, there is substantial evidence based on the safety data provided that Myfembree is generally well‑tolerated in the target population. Safety issues identified during the review have been adequately mitigated through labelling and the risk management plan. Therefore, from a safety perspective, the benefit‑risk‑uncertainty profile of Myfembree is favourable for the recommended indication.

For more information, refer to the Myfembree Product Monograph, approved by Health Canada and available through the Drug Product Database.

The non‑clinical development program consisted of in vitro and in vivo absorption, distribution, metabolism, and elimination (ADME), pharmaco- and toxicokinetic studies for relugolix to support its use as part of the combination with E2 and NETA for the treatment of uterine fibroids. In vitro studies evaluated receptor binding and potential for drug-drug interaction. In vivo studies were conducted in mice, rats, monkeys, and rabbits using single and repeat dosing to evaluate the pharmacology, pharmacokinetics, and toxicology of relugolix (new medicinal ingredient in the Myfembree combination product). In vitro, relugolix exhibited similar binding affinities to human and monkey gonadotropin hormone releasing‑hormone (GnRH) receptors in contrast to a >19,000 times reduction in binding affinity for the rat receptors. Relugolix showed a GnRH antagonist effect in vitro and suppressed the pituitary‑gonadal axis, causing a decrease in plasma luteinizing hormone in castrated monkeys. No relugolix‑related adverse effects on the central nervous and respiratory systems in rats were reported and the observed QT/QTc prolongations in monkeys corresponded to an estimated peak concentration (C_max) of approximately 220‑fold higher than the mean total human C_max associated with the clinical dose of relugolix (40 mg). In ADME studies conducted by oral or intravenous delivery the highest levels of relugolix‑derived radioactivity following a single oral dose were observed in the liver, intestine, thyroid, stomach, and pituitary gland. Relugolix‑related radioactivity was secreted into the milk after oral administration of [¹⁴C]‑relugolix to lactating rats. Therefore, based on this non‑clinical evidence, the use of relugolix is contraindicated during lactation.

The non‑clinical toxicology program for relugolix consisted of six single‑dose, ten repeat‑dose, three genotoxicity, two carcinogenicity, one mechanistic, two phototoxicity, and seven reproductive and developmental studies. The non‑clinical pharmacology, pharmacokinetics and safety for E2 and NETA were evaluated based on published literature and prescribing information derived from a similar marketed health product in Canada. In single‑dose studies, the maximum tolerated oral dose was 2,000 mg/kg in mice, rats, and monkeys. In repeat‑dose studies, daily oral administration of relugolix caused mortality in rats at 2,000 mg/kg/day. The most‑prominent relugolix‑related effect seen in mice, rats, and monkeys was phospholipidosis (intracellular phospholipid accumulation). Phospholipidosis associated changes included cytoplasmic vacuolization and foamy cell infiltration in various tissues. Overall, relugolix safety margins (due to generalized phospholipidosis) were low in the monkey (approximately 2 times), moderate in the rat (>15 times) and large in the mouse (≥726 times), while organ toxicity safety margins were large in all species tested (≥48times). The significance of the generalized phospholipidosis finding in humans is unknown. Relugolix was not genotoxic in in vitro and in vivo studies and was not carcinogenic in two year studies conducted in mice and rats.

In rats, the daily administration of relugolix up to 1,000 mg/kg/day did not induce any significant changes in estrous cycling, fertility, and embryofetal development, with a no observed adverse effect level (NOAEL) for embryo‑fetal development of 1,000 mg/kg/day. In monkeys, the daily administration of relugolix to pregnant females caused total litter loss, high post‑implantation loss rate, significant decrease in live fetus numbers, and low fetal viability rate with no observed fetal malformations at 9 mg/kg/day. The NOAEL for reproductive toxicity and embryo‑fetal development was 3 mg/kg/day (approximately 0.23 times the exposure in human females). In a pre‑ and post‑natal development study in pregnant and lactating rats, the daily oral administration of relugolix had no effects on embryo‑fetal development as well as postnatal development of rat pups, with an NOAEL of 1,000 mg/kg/day for maternal functions in F0 dams, development in F1 pups/animals, reproductive functions in F1 animals, and early embryonic development in F2 embryos. Based on reproductive studies conducted in animals, 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. A relugolix‑related phototoxicity is not anticipated in humans based on an absence of phototoxic response in an in vivo phototoxicity study. Finally, undesirable pharmacodynamic interactions, as well as potential adverse additive or synergistic interactions between relugolix, E2, and NETA are not expected. Overall, the non‑clinical toxicology program for Myfembree is deemed acceptable.

For more information, refer to the Myfembree Product Monograph, approved by Health Canada and available through the Drug Product Database.

The chemistry and manufacturing information submitted for Myfembree has demonstrated that the drug substances and drug product (combination product) can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of is acceptable when the drug product is stored at room temperature.

Proposed limits of drug‑related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with good manufacturing practices.

None of the non‑medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.