Elagolix (Orilissa™)

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  1. Indications & Dosing
  2. Pharmacology
  3. Safety
  4. EBM & Historical Context
  5. Drug Cost

Elagolix Visual Summary

~ Indications and Dosing ~

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Endometriosis

  • Moderate-Severe Pain: 150 mg PO QD for up to 24 months; alternatively, 200 mg PO BID for 6 months; use shorter course if hepatic impairment

Link to FDA Label

~ Pharmacology ~

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Physiology

Elagolix is a gonadotropin releasing hormone (GnRH) antagonist. It competitively inhibits GnRH receptors in the pituitary gland, resulting in suppression of gonadotropin secretion. Decreased serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) lead to attenuated production of estradiol and progesterone in ovarian tissue. Lower levels of circulating estrogen inhibits the growth of both uterine and ectopic endometrial tissue and can thereby reduce endometriosis-associated pain.

Metabolism

Elagolix is hepatically metabolized. It is a major substrate (and weak-moderate inducer) of CYP3A4 and a minor substrate of CYP2D6/CYP2C8 and the UGTs. Elagolix is also a substrate of P-gp and OATP1B1 transporters.

Pharmacokinetics

Elagolix has a half-life of 4-6 hours and is eliminated fecally. Individuals with some organic anion transporter polypeptide (OATP) 1B1 polymorphisms experience decreased elagolix metabolic efficiency and increased serum drug levels. Renal impairment does not affect elagolix exposure, but hepatic impairment significantly increases peak serum elagolix concentrations.

Elagolix Mechanism of Action

Link to FDA Label

~ Safety ~

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Adverse Events

  • Bone Loss (2-7% in clinical trials experienced >8% bone mineral density loss, label warning)
  • Amenorrhea or Changes in Menstrual Bleeding Pattern [May Affect Ability to Recognize Pregnancy] (4-7% in clinical trials, label warning)
  • Reduced Efficacy of Estrogen-Containing Contraceptives (mechanistic inference, label warning)
  • Mood Alteration and Suicide (5-6% mood changes in clinical trials, 1 completed suicide in 952 patients receiving treatment, label warning)
  • Hepatotoxicity [Elevated Liver Transaminases] – (0.2 – 1.1% in clinical trials, label warning)
  • Night sweats/Hot Flush (24-46% in clinical trials)
  • Insomnia/Irritability (6-9% in clinical trials)
  • Headache (17-20% in clinical trials)
  • GI Distress/Nausea (11-16% in clinical trials)
  • Anxiety (3-5% in clinical trials)
  • Arthralgia (3-5% in clinical trials)
  • Dizziness (3-5% in clinical trials)
  • Weight gain (3-5% in clinical trials)
  • Decreased libido (3-5% in clinical trials)
Contraindications

  • Pregnancy
  • Osteoporosis
  • Severe Hepatic Impairment
  • Co-administration of strong OATP1B1 inhibitors (e.g., gemfibrozil, cyclosporine)
Drug Interactions

  • Reduced efficacy of estrogen-containing contraceptives
  • CYP3A4 substrates and modulators
  • P-glycoprotein substrates and modulators
  • OATP1B1 substrates and modulators (e.g., gemfibrozil, cyclosporine)
Pregnancy

Elagolix is contraindicated in pregnancy. Animal data suggests an increased rate of pregnancy loss at very high doses of elagolix.

Link to FDA Label

~ EBM & Historical Context ~

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Elagolix Development Summary

Elagolix was developed in the late 2000’s for the treatment of endometriosis and uterine fibroids. In July 2018, it was approved by the FDA for the treatment of moderate-severe pain associated with endometriosis.

 

History and Foundational Studies

  • 2008: Novel GnRH antagonist 10b (elagolix) is synthesized, characterized, and tested in macaques by Neurocrine Biosciences.

    Link to ACS Article

  • 2009: Phase I clinical trial (double-blind RCT, 55 participants) of elagolix in healthy premenoupausal women. Drug administration appears to be safe and results in pituitary-gonadal suppression and decreased circulating estradiol, FSH, and LH.

    Link to JCEM Article

  • 2008-2009 (published 2013): Phase II clinical trial (155 women, double-blind, RCT) of elagolix for endometriosis pain. Efficacy did not reach statistical significance over placebo in primary endpoint, but dysmenorrhea and other nonmenstrual pelvic pain symptoms improved on elagolix.

    Link to Reproductive Science Article

  • 2012-2014 (Published 2017)– Phase III clinical trials, Elaris Endometriosis I (EM I)-I & Elaris Endometriosis II (EM II), double-blind RCTs with 1285 total participants, demonstrate elagolix efficacy in endometriosis. Dysmenorrhea symptoms improved in significantly more women (46-72%) in the treatment group compared to those who received placebo (23%).

    Link to NEJM Article

  • 2011-2014 (Published 2017): Phase II randomized, double-blind clinical trial of elagolix in 271 women with heavy menstrual bleeding associated with uterine fibroids. Treatment-branch participants experienced mean blood volume reductions between 72 and 98%.

    Link to Fertility and Sterility Article

  • 2012-2014 (Published 2018) Phase III extension studies of EM-I/EM-II, Elaris Endometriosis (EM III) & Elaris Endometriosis IV (EM IV) demonstrate sustained improvement in endometriosis pain associated with elagolix therapy, with no additional safety concerns arising in the treatment arm.

    Link to Obstetrics and Gynecology

  • 2018 (July 23rd)Elagolix is approved by the FDA for the treatment of moderate-severe pain associated with endometriosis.

Link to FDA Website

~ Drug Cost ~

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The estimated cost of Orilissa in 2018 is $844/month.

Link to Business Insider Article

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