Summary Basis of Decision (SBD) for Orgovyx

As outlined in the What steps led to the approval of Orgovyx? section, the clinical review of the New Drug Submission for Orgovyx was conducted as per Method 1 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

Relugolix, the medicinal ingredient in Orgovyx, is a non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist. It competitively binds to pituitary GnRH receptors, thereby reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the systemic circulation, and consequently reducing the production of testosterone in the testes. In humans, FSH and LH concentrations rapidly decline after oral administration and testosterone concentrations are suppressed to below physiologic concentrations.

The clinical pharmacology data package included reports on the human pharmacodynamic and pharmacokinetic studies. Relugolix is a substrate for intestinal P-glycoprotein (P-gp). After oral administration, relugolix is rapidly absorbed and the mean absolute bioavailability of relugolix is approximately 12% (coefficient of variation [CV]: 62%). The median time to maximum concentration (T_max) of relugolix is 2.25 hours (range: 0.5 to 5.0 hours).

Relugolix is 68% to 71% bound to plasma proteins, primarily to albumin and to a lesser extent to α1-acid glycoprotein. The mean blood-to-plasma ratio is 0.78. Based on the apparent volume of distribution, relugolix distributes widely to tissues such as the pituitary gland, liver, kidney, and gastrointestinal tract.

Relugolix is metabolized primarily by cytochrome P450 (CYP)3A. Human absorption, distribution, metabolism, and elimination studies and absolute bioavailability studies showed that relugolix was the primary drug-related component in plasma (approximately 42% to 68% of total radioactivity in plasma), with low levels of radioactivity associated with Metabolites-A and -B (2.2% to 3.8%). Metabolite-C was present at low concentrations (approximately 0.8 to 4.5%), likely from absorption of trace amounts after formation in the intestine.

The mean effective half-life of relugolix is 25 hours and the mean terminal elimination half-life is 60.8 hours (CV: 11%). The mean total clearance of relugolix is 29.4 L/h (CV: 15%) and the renal clearance is 8 L/h.

Differences in the pharmacokinetics of relugolix in patients with mild or moderate hepatic impairment are not considered to be clinically meaningful therefore, no dose adjustment is required. The effects of severe hepatic impairment on the pharmacokinetics of relugolix have not been evaluated.

No dose adjustments are required for patients with mild, moderate or severe renal impairment as increases in relugolix exposure in patients with renal impairment were not clinically meaningful.

During the comparative bioavailability review, it was identified that the area under the concentration-time curve (AUC) and the maximum concentration (C_max) of relugolix decreased by 19% and 21%, respectively, after a high fat high-calorie meal. The observed effect of food was not considered to be clinically relevant. In addition, the population pharmacokinetic/pharmacodynamic modelling predicted that with a two-fold clearance and a 50% reduction in relugolix plasma concentrations, more than 90% of the patients still maintained testosterone concentrations at castration levels. Therefore, Orgovyx can be taken with or without food.

The clinical pharmacology data support the use of Orgovyx for the recommended indication. For further details, please refer to the Orgovyx Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Orgovyx was primarily evaluated in the pivotal Phase III, randomized, active-controlled, HERO study. A total of 930 patients with androgen-sensitive advanced prostate cancer were randomized 2:1 to receive Orgovyx 120 mg orally once daily (following a loading dose of 360 mg on Day 1) or leuprolide acetate subcutaneous injections (22.5 mg or 11.25 mg in Japan and Taiwan) every 3 months for a total of 48 weeks.

Patients enrolled in the study were required to have received at least one year of androgen deprivation therapy. Eligible patients had either evidence of biochemical (prostate-specific antigen [PSA]) or clinical relapse following local primary intervention or had newly diagnosed androgen-sensitive metastatic disease or had advanced localized disease unlikely to be cured by primary intervention with either surgery or radiation. In addition, patients needed to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (fully active or restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature). Patients with disease progression during the treatment period were encouraged to remain on study and if indicated, may have received radiotherapy as prescribed by the investigator. If patients had PSA progression, they were allowed to receive enzalutamide or docetaxel during the study.

Across both treatment groups, patients had a median age of 71 years (range: 47 to 97 years). The ethnic/racial distribution was 68% White, 21% Asian, 5% Black, and 5% other. Disease stage was distributed as follows: 32% metastatic (M1), 31% locally advanced (T3/4 NX M0 or any T N1 M0), 28% localized (T1 or T2 N0 M0), and 10% not classifiable.

The primary efficacy endpoint was medical castration rate, defined as achieving and maintaining serum testosterone suppression to castrate levels (<50 ng/dL) by Day 29 through 48 weeks of treatment.

There were two separate evaluation criteria for the primary efficacy endpoint. The first was to determine whether the sustained castration rate, defined as achieving and maintaining serum testosterone suppression to castrate levels (<50 ng/dL) by Day 29 through 48 weeks of treatment, was ≥90% for Orgovyx treated patients. The second was the establishment of non-inferiority of Orgovyx compared with leuprolide (administered as a 3-month depot subcutaneous injection), as assessed by the cumulative probability of sustained testosterone suppression. Other key secondary endpoints included castration rates on Day 4 and 15, castration rates with testosterone <20 ng/dL at Day 15, PSA response rate at Day 15, and follicle-stimulating hormone (FSH) level at Day 176 (Week 25, Day 1).

Biostatistical consultation concluded that the pre-specified 10% non-inferiority margin for the comparison of Orgovyx versus leuprolide was acceptable. However, given that Health Canada does not require a comparative trial for the androgen deprivation therapy drug approval and products with similar indications have been approved based solely on the demonstration of sustained testosterone suppression, the comparative trial data were accepted as supportive information only.

A total of 96.7% of patients treated with Orgovyx met the study primary endpoint, that is, achieved and maintained sustained testosterone suppression below castrate levels (<50 ng/dL) from Day 29 (Week 5, Day 1) to Day 337 (Week 49, Day 1) (95% Confidence Interval [CI]: 94.9%, 97.9%) with the lower bound of the 95% CI exceeding 90%. In patients treated with leuprolide, 88.8% achieved and sustained testosterone suppression below castrate levels from Day 29 (Week 5, Day 1) to Day 337 (Week 49, Day 1) (95% CI: 84.6%, 91.8%), resulting in a between-group difference of 7.9% (95% CI: 4.1%, 11.8%).

Orgovyx reduced testosterone rapidly without hormonal or clinical flare. With respect to key secondary endpoints, the cumulative probability of testosterone suppression to less than 50 ng/dL (the castration rate) prior to dosing on days 4, 15, and 29 was 56.0%, 98.7%, and 79.4%, respectively, for the Orgovyx group, as compared with 0%, 12.1%, and 19.8%, respectively for the leuprolide group. The cumulative probability of testosterone suppression to less than 20 ng/dL at Day 15 was 78.4% in the Orgovyx group compared with 1.0% in the leuprolide group. Finally, the mean FSH level at Day 176 was 1.7 IU/L for the Orgovyx group verus 6.0 IU/L for the leuprolide group.

A post hoc analysis in a subset of 184 patients from the HERO study (137 patients in the Orgovyx group and 47 patients in the leuprolide group) demonstrated that Orgovyx therapy was associated with a faster recovery in testosterone concentrations compared with leuprolide. Ninety days after discontinuation of treatment, testosterone recovered to within normal limits in more patients treated with Orgovyx compared with leuprolide. The cumulative incidence rate of testosterone recovery to >280 ng/dL at 90 days after discontinuation of study drug was 53.93% in the Orgovyx group compared with 3.23% in the leuprolide group.

Indication

The New Drug Submission for Orgovyx was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Orgovyx (relugolix tablets, 120 mg) is indicated for the treatment of adult patients with advanced prostate cancer.

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

Clinical Safety

The clinical safety or Orgovyx was primarily evaluated in the pivotal HERO study described in the Clinical Efficacy section. Throughout the study, the most commonly observed adverse reactions during treatment with Orgovyx were hot flush (54%), musculoskeletal pain (30%), fatigue (26%), and weight increase (8%). Diarrhea and constipation were also very commonly reported (12% each). All adverse events (AEs) that were reported for 5% or more of patients occurred in similar proportions for both the Orgovyx and leuprolide groups, with the exception of constipation, diarrhea, arthralgia, and hypertension. Most of the AEs reported were expected as a consequence of androgen deprivation, including hot flush, fatigue, increased weight, insomnia, gynecomastia, and hyperhidrosis. Constipation and diarrhea were reported for a higher proportion of patients in the Orgovyx group (12.2% for each) than in the leuprolide group (9.7% and 6.8%, respectively). All constipation and diarrhea AEs were mild or moderate (Grade 1 or 2).

Grade 3 and higher AEs, including those related to the study drug, were reported with similar frequencies across the treatment groups. Adverse events leading to drug withdrawal and interruption, AEs related to the study drug, and serious adverse events (SAEs) leading to treatment discontinuation were reported at higher incidences in the Orgovyx group relative to the leuprolide group. This was attributed to the different route of administration for the study drugs, where action could be taken more often for Orgovyx (daily oral administration) versus leuprolide (3-month depot subcutaneous injection). As such, depending on the individual patient schedule for leuprolide dosing relative to the time of onset of a given AE, interruption or withdrawal of treatment was not possible for patients in the leuprolide group. This difference was also observed in the proportion of patients with serious adverse events (SAEs) leading to study drug discontinuation (1.6% in the Orgovyx group versus [vs.] 0.3% in the leuprolide group).

All clinical laboratory tests, including hematology, chemistry, and lipids, were comparable between the two groups. There were also no notable findings in assessments of visual acuity, which was assessed because of phospholipidosis observed in non-clinical toxicity studies. No evidence of phospholipidosis has been observed in the Orgovyx clinical development program.

Events of lipid effects, hypersensitivity, mood disorders, bone mineral density, and QTc prolongation were reported in similar proportions of patients for both groups. The most common laboratory abnormalities included increased glucose, increased triglycerides, increased cholesterol, and increased alanine transaminase (ALT) and aspartate transaminase (AST).

Effects on glucose metabolism with Orgovyx appeared to be less than those observed with leuprolide, with smaller increases in mean glucose concentrations over time. No meaningful differences in hemoglobin A1c (HbA1c) were observed between groups.

Hepatic transaminase elevations were reported as AEs for a higher proportion of patients in the Orgovyx group compared with the leuprolide group (7.6% vs. 5.5%, respectively). Although these elevations were higher in the Orgovyx group, both the box-plots of alanine transaminase (ALT) and aspartate transaminase (AST) values over time and the summary of hepatic laboratory abnormalities demonstrated a similar profile of hepatic transaminases throughout the study for both groups. The incidence of AEs of clinical interest (ALT or AST levels three times the upper limit of normal or higher) was also comparable between patients treated with Orgovyx (1.4%) and leuprolide (1.3%); all but one event was non-serious and most events resolved with no action taken with study drug. No evidence of drug-induced liver injury was observed. The one SAE of abnormal liver function test was reported for a leuprolide-treated patient with extensive metastatic disease.

Adverse events potentially related to hypersensitivity were reported in 7.1% of patients treated with Orgovyx and 8.4% of patients treated with leuprolide in the HERO Study.

Bone mineral density with bone densitometry was not assessed in the HERO study as the 48-week treatment duration would not be expected to be a sufficient timeframe to result in significant bone mineral density loss. Bone health events, including fracture-related events (1.4% in the Orgovyx group vs. 1.0% in the leuprolide group), were comparable between the two groups (3.2% and 3.9%, respectively).

The incidence of major cardiovascular events (MACE) (defined as all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke) after 48 weeks of androgen deprivation therapy was 2.9% in the Orgovyx group compared with 6.2% in the leuprolide group.

Effect on QT/QTc Interval Prolongation

In a randomized, double-blind, placebo- and positive-controlled, parallel group electrocardiogram (ECG) assessment study in healthy subjects (total number [n] = 70 per treatment arm; 51% male and 49% female) receiving single doses of relugolix 60 mg (0.2 times the loading dose) or 360 mg (the loading dose), no pharmacodynamic effect was observed on the QTc interval. However, androgen deprivation therapy can prolong the QT interval. In an active-controlled, open-label, parallel group clinical study of patients with prostate cancer randomized to receive oral doses of Orgovyx 120 mg once-daily (n = 65) or subcutaneous injections (4-week depot) of degarelix (n = 38), the mean changes from baseline in the corrected QT interval by Fridericia (QTcF) at two hours post dose on Day 1 of weeks 5 and 13 were 13.0 ms (95% CI: 8.8, 17.2) and 11.0 ms (95% CI: 6.8, 15.2), respectively, for Orgovyx and 14.7 ms (95% CI: 7.0, 22.3) and 10.3 ms (95% CI 1.6, 19.1), respectively, for degarelix. The proportion of patients who were observed to have one or more QTcF value >480 ms was 5% in the Orgovyx group and 3% in the degarelix group. The proportion of patients who were observed to have one or more QTcF value >500 ms was 2% in the Orgovyx group and 3% in the degarelix group. A Serious Warnings and Precautions Box was included in the Product Monograph for warning of potential QT prolongation in patients treated with Orgovyx.

Safety Conclusion

Overall, the safety profile of Orgovyx 120 mg in men with advanced prostate cancer was characterized by signs and symptoms associated with the hypoandrogenic state resulting from treatment with a gonadotropin-releasing hormone receptor antagonist. Appropriate warnings and precautions are in place in the approved Orgovyx Product Monograph to address the identified safety concerns.

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

The nonclinical data package included studies conducted to evaluate the pharmacology, pharmacokinetics, toxicity, and safety pharmacology of relugolix, the medicinal ingredient in Orgovyx.

Several in vitro, ex vivo, and in vivo studies were conducted to characterize the primary and secondary pharmacodynamics of relugolix. In vitro mechanism of action studies for relugolix showed that it was highly species-specific as the binding affinity for human and monkey gonadotropin-releasing hormone (GnRH) receptors compared with rat GnRH receptors was of approximately 19,000- and 24,000-fold greater potency, respectively. Results of an in vitro study evaluating the off-target effects in a series of 134 enzyme and radio-ligand binding assays suggest there is a low risk for off-target pharmacological effects with relugolix.

In rats and monkeys, single oral doses of relugolix were rapidly absorbed (time to maximum concentration [T_max] of approximately 1 to 3 hours) and eliminated with a half-life (t_½) of 2.1 and 5.6 hours, respectively. Relugolix was mainly absorbed from the small intestine after oral administration to rats. Following oral administration of [¹⁴C]-relugolix in rats, relugolix-related degradation products were absorbed by the portal route, not via the lymphatic system. There was a negative food effect in monkeys where the plasma exposure (C_max and area under the concentration-time curve [AUC]) of relugolix after oral administration to monkeys under fasted conditions were markedly higher (5.3- and 20.8-fold, respectively) than when administered in the fed state.

Intrinsic permeability in vitro studies showed that relugolix is a substrate of P-glycoprotein (P-gp) and P-gp‑mediated efflux may limit the oral bioavailability of relugolix. These non-clinical data are consistent with the results of the drug-drug interaction study in healthy human subjects with erythromycin (a moderate P-gp inhibitor) where a 6.2-fold increase in relugolix AUC_0-∞ was observed, with increases in exposure largely driven by increases in C_max (6.2-fold), not elimination half-life.

Following repeated oral doses of relugolix in rats, rabbits, and monkeys, exposure increased with dose, generally dose proportional. Relugolix exhibited low to moderate distribution into blood cells based on distribution ratios for rats (45.3 to 48.7%), monkeys (57.4 to 58.5%), and humans (45.9 to 50.8%) resulting in an in vitro human blood to plasma concentration ratio of approximately 0.9.

Studies involving [¹⁴C]-relugolix showed that relugolix was widely distributed to tissues in non-pigmented rats, with maximum concentrations in most tissues attained between 4 to 8 hours post dose. Relugolix was almost completely eliminated from tissues by 72 hours post dose. The highest activity in male rats was in the pituitary gland, thyroid gland, liver, intestine, and stomach.

The metabolic profiles of relugolix were qualitatively similar across species both in vitro and in vivo. The liver and gastrointestinal tract are the primary sites of metabolism for relugolix. There are no major metabolites identified for relugolix for humans. Relugolix was primarily metabolized to two oxidative metabolites, Metabolite-A (O-demethylation) and Metabolite-B (hydroxylation). Metabolite-A is primarily formed by cytochrome P450 (CYP) 3A4/5 and Metabolite-B is primarily formed by CYP2C8. The primary CYP enzymes responsible for the in vitro metabolism of relugolix are CYP3A4/5 (45%), CYP2C8 (37%), and CYP2C19 (<1%), with approximately 18% of the total relugolix metabolism attributed to other clearance pathways. Metabolite-C, an N-demethoxylated metabolite of relugolix, was predominantly found in feces. Intestinal microflora/gut metabolism plays a major role in producing Metabolite-C in feces; however, it does not play a major role in relugolix disposition (i.e., plasma pharmacokinetics).

The primary route of excretion after oral administration of radioactive relugolix in rats and monkeys was via feces (>96% and >90% of the dose, respectively). In bile duct-cannulated rats, approximately 40% of the oral dose of radioactivity was absorbed and, of the absorbed radioactivity, most (approximately 37% of dose) was excreted into the bile in rats. Considering the relatively low oral bioavailability of relugolix, elimination of dose-related material into urine was a contributing pathway to the systemic clearance of relugolix and relugolix-related radioactivity. Results from non-clinical studies indicate that unchanged relugolix is excreted into the milk of lactating rats and can be transferred into fetus.

In vitro data and plasma exposures associated with an oral once-daily dose of 120 mg relugolix indicated that there is a potential for CYP3A4/5 drug interactions with the clinical dose of relugolix.

The principal adverse effects in toxicity studies of relugolix involved findings in the liver and kidney and mortality in all the species tested (mice, rats and monkeys) at dosages higher than the expected human clinical exposure of relugolix. Additionally, phospholipidosis was observed in various tissues following repeated relugolix administration in rats and monkeys. The systemic exposures at the no-observed-adverse-effect level (NOAEL) in animal toxicity studies of relugolix are significantly higher than the expected clinical exposures. Relugolix was not found to be mutagenic or clastogenic in in vitro and in vivo studies conducted in rats.

In human GnRH-receptor knock-in male mice, oral administration of relugolix decreased prostate and seminal vesicle weights at doses ≥3 mg/kg. The effects of relugolix were reversible, except for testis weight, which did not fully recover within 28 days after drug withdrawal. In pregnant rabbits orally dosed with relugolix during the period of organogenesis, spontaneous abortion and total litter loss were observed at exposure levels less than that achieved at the recommended human dose of 120 mg/day.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Orgovyx Product Monograph. In view of the intended use of Orgovyx, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

As outlined in the What steps led to the approval of Orgovyx? section, the review of the quality component of the New Drug Submission for Orgovyx was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The chemistry and manufacturing information submitted for Orgovyx has demonstrated that the drug substance and drug 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 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

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 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 is of human or animal origin and none are prohibited by the Food and Drug Regulations.