Relugolix

Relugolix
Clinical data
Pronunciation/ˌrɛlʊˈɡoʊlɪks/
RE-luu-GOH-liks
Trade namesOrgovyx, Relumina
Other namesRGX; RVT-601; TAK-385
AHFS/Drugs.comMonograph
MedlinePlusa621006
License data
Routes of
administration		By mouth[1]
Drug classGnRH antagonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding68–71%[1]
Elimination half-life36 to 65 hours[1]
ExcretionFeces: 82%[1]
Urine: 4%[1]
Identifiers
  • 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC29H27F2N7O5S
Molar mass623.64 g·mol−1
3D model (JSmol)
  • CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)C)c(=O)n(-c2ccc(OC)nn2)c(=O)n3Cc2c(F)cccc2F)cc1
  • InChI=1S/C29H27F2N7O5S/c1-36(2)14-19-24-26(39)38(22-12-13-23(42-3)34-33-22)29(41)37(15-18-20(30)6-5-7-21(18)31)27(24)44-25(19)16-8-10-17(11-9-16)32-28(40)35-43-4/h5-13H,14-15H2,1-4H3,(H2,32,35,40)
  • Key:AOMXMOCNKJTRQP-UHFFFAOYSA-N

Relugolix, sold under the brand names Orgovyx and Relumina among others, is a gonadotropin-releasing hormone antagonist (GnRH receptor antagonist) medication which is used in the treatment of prostate cancer in men and uterine fibroids in women.[5][1][7] It is taken by mouth.[1][7]

Side effects of relugolix include menstrual abnormalities, hot flashes, excessive sweating, headache, and decreased bone mineral density.[7][1] Relugolix is a GnRH antagonist, or an antagonist of the gonadotropin-releasing hormone receptor.[1] Unlike most other GnRH modulators, but similarly to elagolix (brand name Orilissa), relugolix is a non-peptide, small-molecule compound and is orally active.[8][9][10] It suppresses sex hormone levels to the postmenopausal or castrate range in both women and men.[1][11][5]

Relugolix was approved for use for the treatment of uterine fibroids in Japan in January 2019, and for the treatment of prostate cancer in the United States in December 2020.[12][13]

Medical uses

Relugolix is approved in the United States, Canada and the United Kingdom for the treatment of prostate cancer in men and in Japan for the treatment of uterine fibroids (uterine leiomyoma) in women.[12][7][5]

Available forms

Relugolix is available in the form of 40 and 120 mg oral tablets.[5][13][7]

Side effects

The main side effects of relugolix for uterine fibroids include abnormal uterine bleeding (24.6–48.6% vs. 6.3% for placebo), hot flashes (42.8–45.5% vs. 0% for placebo), heavy menstrual bleeding (12.1–49.3% vs. 9.4% for placebo), headache (12.3–15.2%), and excessive sweating (9.4–15.2% vs. 0% for placebo).[1][7] In addition, decreased bone mineral density occurs with relugolix (21.7% decrease by week 12, 24.4% decrease by week 24).[1]

Pharmacology

Pharmacodynamics

Estradiol levels with 40 mg relugolix once per day in premenopausal women relative to untreated premenopausal women.[7]

Relugolix is a selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR), with a half-maximal inhibitory concentration (IC50) of 0.12 nM.[1][8][9]

A dosage of relugolix of 40 mg once per day has been found to suppress estradiol levels to postmenopausal levels (<20 pg/mL) within 24 hours in premenopausal women.[1] In the control group of women, estradiol levels fluctuated between 50 and 250 pg/mL.[1] Estradiol levels have been found to return to normal concentrations within 4 weeks of discontinuation of relugolix in premenopausal women.[1] The medication additionally suppresses levels of progesterone, luteinizing hormone, and follicle-stimulating hormone in premenopausal women.[1] Relugolix at a dosage of 40 mg or more once per day has been found to reduce testosterone levels to sustained castrate levels (<20 ng/dL) in men.[11] It additionally suppresses luteinizing hormone and follicle-stimulating hormone levels in men.[11]

Lower doses of relugolix (<40 mg/day) are under investigation for achieving partial sex hormone suppression in the treatment of endometriosis and uterine fibroids.[14] This is intended to reduce the incidence and severity of menopausal symptoms such as hot flushes and decreased bone mineral density that are secondary to estrogen deficiency.[14][15]

Pharmacokinetics

A single 40-mg oral dose of relugolix has been found to result in peak levels of relugolix of 29 ng/mL (47 nmol/L) after 1.5 hours.[1] Steady-state levels are reached within 7 days with 40 mg/day relugolix administration.[1] There is an approximate 2-fold accumulation of relugolix by 2 weeks of continuous administration.[1] Food diminishes the oral bioavailability of relugolix by about 50%.[1]

Relugolix is a substrate for P-glycoprotein, which may have a limiting effect on its absorption and distribution.[1] The plasma protein binding of relugolix is approximately 68 to 71% over a concentration range of 0.05 to 5 μg/mL.[1]

Relugolix is not a substrate for CYP3A4.[1] The elimination half-life of relugolix is 36 to 65 hours across a dosage range of 20 to 180 mg/day.[1] There is moderate to high interindividual variability in systemic exposure to relugolix.[1]

Relugolix is excreted mainly in feces (83%) and to a small degree in urine (4%).[1] Only about 6% of a dose of relugolix is excreted unchanged.[1]

Chemistry

Relugolix is a non-peptide, small-molecule compound, and is structurally distinct from GnRH analogues.[10] It is an N-phenyl urea derivative.[1]

History

Relugolix was first described in 2004.[16][8] It superseded sufugolix (developmental code name TAK-013), which was developed by the same researchers.[8] Relugolix was approved for the treatment of uterine fibroids in Japan in January 2019.[12][13] It was the second orally active GnRH antagonist to be introduced for medical use, following elagolix (brand name Orilissa) in July 2018.[12][17] Relugolix was approved for the treatment of prostate cancer in the United States on 18 December 2020.[12][5]

The FDA approved relugolix based on evidence from a clinical trial (NCT03085095) of 930 participants 48 to 97 years old with advanced prostate cancer.[18] The trial was conducted at 155 sites in the United States, Canada, and countries in South America, Europe and the Asia Pacific region.[18] All participants in the trial had advanced prostate cancer.[18] Participants were randomly assigned to receive either one relugolix tablet daily (on the first day they received three tables) or an active control (leuprolide acetate) which was given as an injection under the skin every three months.[18] The participants and healthcare providers were aware of which treatment was being given.[18] The treatment lasted for 48 weeks.[18] The efficacy of relugolix was assessed by the percentage of participants who achieved and maintained low testosterone level equal to castration.[18]

Society and culture

Names

Relugolix is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and JANTooltip Japanese Accepted Name.[19][20] It is also known by its former developmental code names RVT-601 and TAK-385.[12][19]

Relugolix is sold under the brand name Orgovyx for the treatment of prostate cancer and under the brand name Relumina for the treatment of uterine fibroids.[12][13][7][5] Relugolix compounded with ethinyl estradiol and norethindrone is sold under the brand name Myfembree for the treatment of uterine fibroids.[21]

Availability

Relugolix is available in the United States and in Japan.[5][13][7]

In February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Orgovyx, intended for the treatment of prostate cancer.[22] The applicant for this medicinal product is Myovant Sciences Ireland Limited.[22] Relugolix was approved for medical use in the European Union in April 2022,[6][23] and in the United Kingdom in July 2022[24] (although not available in NHS England until August 2024[25]).

Research

Relugolix is under development for use in the treatment of endometriosis.[26][27][14][28][8][9]

References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac Barra F, Seca M, Della Corte L, Giampaolino P, Ferrero S (August 2019). "Relugolix for the treatment of uterine fibroids". Drugs of Today. 55 (8): 503–512. doi:10.1358/dot.2019.55.8.3020179. PMID 31461087. S2CID 201654739.
  2. ^ "Therapeutic Goods (Poisons Standard—June 2024) Instrument 2024". Federal Register of Legislation. 30 May 2024. Retrieved 10 June 2024.
  3. ^ "Notice: Multiple additions to the Prescription Drug List (PDL) [2023-12-22]". Health Canada. 22 December 2023. Retrieved 3 January 2024.
  4. ^ "Summary Basis of Decision (SBD) for Orgovyx". Health Canada. 16 February 2024. Retrieved 24 February 2024.
  5. ^ a b c d e f g h "Orgovyx- relugolix tablet, film coated". DailyMed. Retrieved 25 May 2021.
  6. ^ a b "Orgovyx EPAR". European Medicines Agency. 22 February 2022. Retrieved 3 March 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. ^ a b c d e f g h i "Relumina (relugolix) Information" (PDF). ASKA Pharmaceutical (in Japanese). January 2019. Archived from the original (PDF) on 16 February 2019. Retrieved 16 February 2019.
  8. ^ a b c d e Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, et al. (July 2011). "Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor". Journal of Medicinal Chemistry. 54 (14): 4998–5012. doi:10.1021/jm200216q. PMID 21657270.
  9. ^ a b c Nakata D, Masaki T, Tanaka A, Yoshimatsu M, Akinaga Y, Asada M, et al. (January 2014). "Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice". European Journal of Pharmacology. 723: 167–174. doi:10.1016/j.ejphar.2013.12.001. PMID 24333551.
  10. ^ a b Tukun FL, Olberg DE, Riss PJ, Haraldsen I, Kaass A, Klaveness J (December 2017). "Recent Development of Non-Peptide GnRH Antagonists". Molecules. 22 (12): 2188. doi:10.3390/molecules22122188. PMC 6149776. PMID 29232843.
  11. ^ a b c MacLean DB, Shi H, Faessel HM, Saad F (December 2015). "Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males". The Journal of Clinical Endocrinology and Metabolism. 100 (12): 4579–4587. doi:10.1210/jc.2015-2770. PMC 4667159. PMID 26502357.
  12. ^ a b c d e f g "Relugolix - Myovant/Takeda". AdisInsight. Springer Nature Switzerland AG.
  13. ^ a b c d e "Myovant Provides Corporate Updates and Reports Financial Results for Third Fiscal Quarter Ended December 31, 2018" (Press release).
  14. ^ a b c Streuli I, de Ziegler D, Borghese B, Santulli P, Batteux F, Chapron C (March 2012). "New treatment strategies and emerging drugs in endometriosis". Expert Opinion on Emerging Drugs. 17: 83–104. doi:10.1517/14728214.2012.668885. PMID 22439891. S2CID 27472695.
  15. ^ Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP (February 2009). "Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix". The Journal of Clinical Endocrinology and Metabolism. 94 (2): 545–551. doi:10.1210/jc.2008-1695. PMC 2646513. PMID 19033369.
  16. ^ US 7300935, Cho N, Imada T, Hitaka T, Miwa K, Kusaka M, Suzuki N, "Thienopyrimidine compounds and use thereof", issued 27 November 2007, assigned to Takeda Pharmaceutical Co Ltd. 
  17. ^ "Elagolix - Abbvie/Neurocrine Biosciences". AdisInsight. Springer Nature Switzerland AG.
  18. ^ a b c d e f g "Drug Trial Snapshot: Orgovyx". U.S. Food and Drug Administration (FDA). 18 December 2020. Retrieved 6 January 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  19. ^ a b "Relugolix". ChemIDplus. U.S. National Library of Medicine.
  20. ^ "Relugolix". KEGG DRUG Database. Kyoto Encyclopedia of Genes and Genomes.
  21. ^ "Myfembree- relugolix, estradiol hemihydrate, and norethindrone acetate tablet, film coated". DailyMed. 18 January 2024. Retrieved 24 February 2024.
  22. ^ a b "Orgovyx: Pending EC decision". European Medicines Agency. 24 February 2022. Archived from the original on 27 February 2022. Retrieved 27 February 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  23. ^ "Orgovyx Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  24. ^ "ORGOVYX FILM-COATED TABLETS RELUGOLIX - PLGB 00142/1272". Retrieved 20 September 2024.
  25. ^ "Relugolix for treating hormone-sensitive prostate cancer". Retrieved 20 September 2024.
  26. ^ Goenka L, George M, Sen M (June 2017). "A peek into the drug development scenario of endometriosis - A systematic review". Biomedicine & Pharmacotherapy. 90: 575–585. doi:10.1016/j.biopha.2017.03.092. PMID 28407578.
  27. ^ Dellis A, Papatsoris A (October 2017). "Therapeutic outcomes of the LHRH antagonists". Expert Review of Pharmacoeconomics & Outcomes Research. 17 (5): 481–488. doi:10.1080/14737167.2017.1375855. PMID 28870102. S2CID 38014222.
  28. ^ Elancheran R, Maruthanila VL, Ramanathan M, Kabilan S, Devi R, Kunnumakara A, Kotoky J (2015). "Recent discoveries and developments of androgen receptor based therapy for prostate cancer". Med. Chem. Commun. 6 (5): 746–768. doi:10.1039/C4MD00416G. ISSN 2040-2503. S2CID 72654573.

Further reading

  • Clinical trial number NCT03085095 for "A Study to Evaluate the Safety and Efficacy of Relugolix in Men With Advanced Prostate Cancer (HERO)" at ClinicalTrials.gov

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