Summary Basis of Decision for Orilissa

 

Clinical Pharmacology

Orilissa (elagolix) is a novel, orally administered, highly potent, short-acting, selective, non-peptide small molecule gonadotropin hormone-releasing hormone (GnRH) receptor antagonist that blocks endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland.

Orilissa is an orally administered tablet with an immediate release formulation. The pharmacokinetics of elagolix have been evaluated in Phase 1 clinical trials with healthy volunteers at doses ranging from 50 mg to 900 mg. Elagolix is rapidly absorbed; systemic exposure increased dose proportionally up to 400 mg administered twice daily (BID) and greater than dose proportionally above 400 mg BID. The unchanged drug is the major drug-derived material in human plasma. Elagolix is primarily metabolized by cytochrome P450 (CYP) enzymes and excreted in the feces. The half-life is 4 to 6 hours with minimal accumulation after multiple doses. A dose-dependent suppression of luteinizing hormone, follicle-stimulation hormone, estradiol, progesterone, and ovulation was observed with elagolix, which was readily reversible upon discontinuation of the drug.

Elagolix exposure is not altered by renal impairment. Increased elagolix exposure was observed with increasing severity of hepatic impairment; dosage adjustment is recommended for patients with moderate or severe hepatic impairment. Elagolix is a substrate for CYP3A enzymes, P-glycoprotein (P-gp), and organic anion transporting polypeptide (OATP)1B1. Elagolix is an inhibitor of efflux transporter P-gp and an inducer of CYP3A enzymes. Drug interactions have been studied between elagolix and ketoconazole, rifampin, digoxin, rosuvastatin, midazolam, sertraline, fluconazole, estradiol, norgestimate, and norethindrone. Concomitant use of Orilissa with strong OATP1B1 inhibitors is contraindicated. Additional recommendations for dosing adjustment or clinical monitoring when taken concomitantly with other drugs are provided in the Orilissa Product Monograph. No dose adjustment of Orilissa is required based on age, body weight, body mass index, race, ethnicity, OATP1B1 genotype status, or food effect. No clinically significant QTc prolongation was observed with a single dose of elagolix resulting in 17-fold the maximum recommended human dose.

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

Clinical Efficacy

The efficacy of Orilissa 150 mg once daily (QD) and 200mg twice daily (BID) for the treatment of moderate to severe pain associated with endometriosis was demonstrated in two pivotal Phase III studies, M12-665 and M12-671. The corresponding uncontrolled blinded extension studies, M12-667 and M12-821, were also used as added reference.

Studies M12-665 and M12-671 were Phase III, randomized, double-blind, placebo-controlled, multicentre studies conducted in premenopausal women 18 to 49 years of age with moderate to severe endometriosis-associated pain. The primary objective of these Phase III studies was to evaluate the safety and efficacy of two doses of Orilissa (150 mg QD and 200 mg BID) compared to a placebo in the management of moderate to severe pain associated with endometriosis over a 6-month treatment period. Secondary efficacy objectives included evaluation of persistence of efficacy at 6 months, and assessments of other endometriosis-associated symptoms, rescue analgesic use, as well as quality of life endpoints.

A total of 872 patients were randomized in Study M12-665, and 817 patients in Study M12-671. In both studies, patients enrolled were randomly assigned to receive either a placebo, or Orilissa 150 mg QD, or Orilissa 200 mg BID for a 6-month treatment period. Eligible patients who completed the 6-month treatment period were then permitted to enter a separate continuous-use extension study for 6 additional months of treatment in which all patients received active Orilissa therapy. Patients who chose not to enter the extension study had a post-treatment follow-up period of up to 12 months.

For both pivotal studies, M12-665 and M12-671, the co-primary efficacy endpoints were:

• the proportion of responders at Month 3 on the daily assessment of dysmenorrhea (DYS), and
• the proportion of responders at Month 3 on the daily assessment of non-menstrual pelvic pain (NMPP).

Pain data were collected daily by the patients via an electronic diary based on the Endometriosis Daily Pain Impact Scale. Use of rescue analgesic and uterine bleeding were also recorded. Patients were considered as responders if they experienced a clinically meaningful reduction in DYS and/or NMPP with no increased analgesic use. A clinically meaningful reduction consisted of a patient's assessment of pain as 'much improved' or 'very much improved'.

Results from both pivotal studies demonstrated a greater proportion of patients treated with either dose (150 mg QD or 200 mg BID) of Orilissa were responders for DYS and NMPP compared to placebo at Month 3. The proportion of responders for DYS at Month 3 was 46.4% for Orilissa 150 mg QD (p<0.001), 75.8% for Orilissa 200 mg BID (p<0.001), and 19.6% for placebo. The proportion of responders for NMPP at Month 3 was 50.4% for Orilissa 150 mg QD (p<0.001), and 54.5% for Orilissa 200 mg BID (p<0.001), and 36.5 for placebo.

The reduction in dyspareunia (DYSP), a secondary endpoint, were superior to placebo for Orilissa 200 mg BID by Month 3 and this was maintained through Month 6. However, no statistically significant effect on DYSP was seen with Orilissa 150 mg QD.

In the two extension studies, participants maintained on their same dosage of Orilissa reported durability of improvement in DYS, NMPP, and DYSP for up to 12 months. The improvements disappeared promptly upon discontinuation of treatment.

For other secondary endpoints, there was a statistically significant (p<0.001) reduction in the percentage of days per month of use of the opioid or nonsteroidal anti-inflammatory drugs (NSAID) rescue medication among patients taking Orilissa 200 mg BID compared to patients receiving a placebo.

Indication

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

• Orilissa (elagolix) is indicated for the management of endometriosis with associated moderate to severe pain.

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Orilissa (elagolix) is indicated for the treatment of moderate to severe pain associated with endometriosis.

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

Clinical Safety

The clinical safety of Orilissa was evaluated primarily based on data from the two Phase III studies, M12-665 and M12-671 previously described in the Clinical Efficacy section, in addition to their corresponding open label extensions.

The main safety concerns associated with Orilissa therapy are chiefly due to Orilissa's hypoestrogenic effects. The most frequent (≥10%) adverse reactions reported in clinical studies with Orilissa include hot flushes (placebo 8.6%, Orilissa 150 mg QD 23.2%, Orilissa 200 mg BID 44.9%), headache (placebo 12.0%, Orilissa 150 mg QD 16.8%, Orilissa 200 mg BID 19.9%), and nausea (placebo 12.5%, Orilissa 150 mg QD 10.7%, Orilissa 200 mg BID 15.9%). The severity of each event was noted as dose-dependent and the majority were assessed as mild to moderate. Other reactions observed with use of Orilissa include night sweats, mood changes, changes in menstrual flow, as well as increases in serum lipids.

Of particular concern, one hypoestrogenic effect noted with the use of Orilissa is a dose-proportional decrease in mean bone mineral density from baseline to Month 6, compared with increases in the placebo group. Anatomic sites (i.e., lumbar spine, total hip, and femoral neck) assessed by dual-energy X-ray absorptiometry in Orilissa-treated patients all showed a loss in bone mineral density. This loss was consistent with a hypoestrogenic pattern of bone loss. Greatest bone mineral density decreases were observed in the lumbar spine, with mean changes in lumbar spine bone mineral density from baseline to Month 6 of +0.47% for placebo compared to -0.32 for Orilissa 150 mg QD and -2.61% for Orilissa 200 mg BID. Among patients who continued on their original dose of Orilissa to Month 12, mean bone mineral density changes at the lumbar spine declined further, to -0.63% for Orilissa 150 mg QD and -3.61% for Orilissa 200 mg BID. Progressive but incomplete improvement of bone mineral density was documented at 6 months and 12 months at all three anatomic locations following discontinuation of treatment. Given the observed loss in bone mineral density, this concern has been addressed by limiting Orilissa treatment to 12 months for the 150 mg OD, and 6 months for the 200 mg BID. Use of Orilissa is also not recommended in woman at increased risk for osteoporosis.

A dose-dependent, asymptomatic elevations of serum alanine aminotransferase to at least 3 times the upper limit of the reference range were reported: 1 patient out of 450 (0.2%) with Orilissa 150 mg daily, 5 patients out of 443 (1.1%) with Orilissa 200 mg twice daily and 1 patient out 696 (0.1%) in the placebo group. Similar increases were seen in the extension studies. No cases meeting the criteria for Hy's Law were observed. However, warnings are included in the Orilissa Product Monograph to monitor patients for signs of liver injury and to promptly investigate elevations in liver function tests.

Dose-dependent increases in total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides were noted during Orilissa treatment.

Lipid increases typically occurred within 1 to 2 months after the start of Orilissa therapy and remained stable thereafter over 12 months. Elevated levels of lipids returned to baseline one month after stopping treatment.

The mean increase from pre-treatment baseline in LDL-C was 0.136 mmol/L for 150 mg once daily and 0.339 mmol/L for 200 mg twice daily. The mean increase from pre-treatment baseline in HDL-C was 0.058 mmol/L for 150 mg once daily and 0.108 mmol/L for 200 mg twice daily. The mean increase from pre-treatment baseline in triglycerides was 0.005 mmol/L for 150 mg once daily and 0.125 mmol/L for 200 mg twice daily following 6-month treatment of Orilissa. Among patients with mildly elevated lipid levels at baseline, further increases in lipid levels occurred more frequently in patients receiving Orilissa than those in patients receiving placebo. Changes in lipid ratios were minimal due to increases in both LDL-C and HDL-C.

One death was reported in a patient who had received Orilissa 150 mg daily for 31 days, who committed suicide 2 days after her last dose of Orilissa. The patient had no relevant past history involving depression, but was experiencing life stressors. Among 2,090 patients exposed to Orilissa during the Phase II/III studies, there were 4 reports of suicidal ideation. In 3 of the cases there was a history of depression. Among the 4 patients, 2 discontinued Orilissa and 2 completed the clinical study. In the placebo-controlled studies, reports of adverse mood changes (depressed mood, depression, tearfulness) were numerically more frequent in patients receiving Orilissa, particularly in those with a history of depression.

Orilissa was associated with a dose-dependent increase in the proportion of patients developing amenorrhea. However, within two months of discontinuing the drug more than 85% of patients reported at least one episode of menstrual flow.

Orilissa is not a contraceptive and its safety during pregnancy has not been established, therefore patients treated with Orilissa must use an effective contraceptive method not containing estrogen, which might compromise the efficacy of Orilissa. The Orilissa Product Monograph also advises that Orilissa frequently causes alterations in menstrual bleeding patterns, including amenorrhea, and recommends prompt pregnancy testing if pregnancy is suspected, with prompt discontinuation of Orilissa therapy until pregnancy is excluded.

Overall, the results from Orilissa clinical studies demonstrate an acceptable and manageable adverse event profile for the treatment of moderate to severe pain associated with endometriosis. The identified safety issues noted with Orilissa can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Orilissa Product Monograph to address the identified safety concerns. In addition, clinical studies with Orilissa have been limited to a 12-month exposure to the drug, therefore safety and efficacy of Orilissa beyond 12 months have not been established. Because of the dose-dependent loss of bone mineral density associated with Orilissa treatment, the use of Orilissa 200 mg twice daily is limited to 6 months duration.

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