Belzutifan
Clinical data
Pronunciation/bɛlˈzuːtɪfæn/
bel-ZOO-ti-fan
Trade namesWelireg
Other namesMK-6482, PT2977
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classAntineoplastic
ATC code
Legal status
Legal status
Identifiers
  • 3-{[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl]oxy}-5-fluorobenzonitrile
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
FormulaC17H12F3NO4S
Molar mass383.34 g·mol−1
3D model (JSmol)
  • CS(=O)(=O)c1ccc(Oc2cc(F)cc(C#N)c2)c2c1[C@H](O)[C@H](F)[C@@H]2F
  • InChI=1S/C17H12F3NO4S/c1-26(23,24)12-3-2-11(13-14(12)17(22)16(20)15(13)19)25-10-5-8(7-21)4-9(18)6-10/h2-6,15-17,22H,1H3/t15-,16-,17+/m1/s1
  • Key:LOMMPXLFBTZENJ-ZACQAIPSSA-N

Belzutifan, sold under the brand name Welireg, is an anti-cancer medication used for the treatment of von Hippel–Lindau disease-associated renal cell carcinoma.[7][8][9][10][11][12] It is taken by mouth.[7] Belzutifan is an hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor.[7][8][13]

Belzutifan's capacity to reduce serum erythropoietin verified its clinically useful for the treatment of malignancies linked to von Hippel-Lindau (VHL), such as renal cell carcinoma (RCC) with clear cell histology (ccRCC), pancreatic lesions, neuroendocrine tumors, and CNS hemangioblastomas or pancreatic neuroendocrine tumors (pNET) but do not require immediate surgery. Belzutifan obtained a disease control rate of 80% in pretreated ccRCC during a phase I trial[14]

The most common side effects include decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea.[8]

Belzutifan is the first drug to be awarded an "innovation passport" from the UK Medicines and Healthcare products Regulatory Agency (MHRA).[15][10] Belzutifan was approved for medical use in the United States in August 2021.[8][16] Belzutifan is the first hypoxia-inducible factor-2 alpha inhibitor therapy approved in the US.[16] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[17]

Medical uses

Belzutifan is indicated for treatment of adults with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.[8] Belzutifan was also found to be efficacious in an adolescent who had Pacak–Zhuang syndrome with polycythemia and paragangliomas.[18]

Adverse effects

Belzutifan was well tolerated, according to the previously available data, and its adverse effect profile was acceptable. Anemia, tiredness, headaches, vertigo, nausea, and dyspnea were the most typical side effects. All participants in the phase II trial reported a hemoglobin reduction of at least 1.9 g/dL; however, only a small number of individuals needed transfusions or erythropoietin-stimulating medications. Because of the downstream effect of HIF-2 inhibition, anemia was a predicted negative outcome of inhibiting the EPO gene. The majority of negative outcomes were grade 1 or 2, while 33% of patients experienced grade 3 to 5 occurrences. In 43% of patients, the course of treatment was discontinued, and in 15% of patients, the dosage had to be adjusted. 2% of patients stopped receiving therapy as a result of a treatment-related. fatigue, increased creatinine, headache, dizziness, elevated hyperglycemia, and nausea were the most frequent side effects, including laboratory abnormalities, recorded in 20% or less of patients. Belzutifan has the potential to harm fetuses and embryos during pregnancy and can render some hormonal contraceptives ineffective Belzutifan had a good safety profile and was well tolerated throughout the three-year follow-up following the phase I trial. There were no new substantial safety concerns or grade 4 or 5 adverse events.[19][20]

History

The FDA granted the application for belzutifan orphan drug designation.[17]

Merck announced in May 2019, that it had acquired Peloton Therapeutics for the development of novel small-molecule therapeutic candidates targeting HIF-2, with belzutifan as the lead candidate. The purchase was completed in July 2019. Merck has patent protection for belzutifan in the United States that is valid until 2034, as of May 2021.[21]

References

  1. 1 2 "Welireg". Therapeutic Goods Administration (TGA). 4 January 2023. Archived from the original on 5 January 2023. Retrieved 6 January 2023.
  2. ↑ "Welireg (Merck Sharp & Dohme (Australia) Pty Ltd)". Therapeutic Goods Administration (TGA). 13 January 2023. Retrieved 8 April 2023.
  3. ↑ "Welireg belzutifan 40 mg film-coated tablet bottle (355338)". Therapeutic Goods Administration (TGA). 23 December 2022. Retrieved 8 April 2023.
  4. ↑ "Product monograph. Belzutifan tablets" (PDF). Archived (PDF) from the original on 28 October 2022. Retrieved 1 October 2022.
  5. ↑ "Summary Basis of Decision - Welireg". Health Canada. 23 October 2014. Retrieved 23 February 2023.
  6. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  7. 1 2 3 4 "Welireg- belzutifan tablet, film coated". DailyMed. Retrieved 12 September 2021.
  8. 1 2 3 4 5 6 "FDA approves belzutifan for cancers associated with von Hippel-Lindau". U.S. Food and Drug Administration (FDA). 13 August 2021. Retrieved 13 August 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  9. ↑ "Belzutifan". SPS - Specialist Pharmacy Service. 18 March 2021. Archived from the original on 26 April 2021. Retrieved 25 April 2021.
  10. 1 2 "MHRA awards first 'innovation passport' under new pathway". RAPS (Press release). Retrieved 25 April 2021.
  11. ↑ "Merck Receives Priority Review From FDA for New Drug Application for HIF-2α Inhibitor Belzutifan (MK-6482)" (Press release). Merck. 16 March 2016. Retrieved 25 April 2021 – via Business Wire.
  12. ↑ "FDA Grants Priority Review to Belzutifan for von Hippel-Lindau Disease–Associated RCC". Cancer Network. 16 March 2021. Retrieved 26 April 2021.
  13. ↑ Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, et al. (May 2021). "Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis". Nature Medicine. 27 (5): 802–805. doi:10.1038/s41591-021-01324-7. PMC 9128828. PMID 33888901. S2CID 233371559.{{cite journal}}: CS1 maint: overridden setting (link)
  14. ↑ Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, et al. (May 2021). "Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis". Nature Medicine. 27 (5): 802–805. doi:10.1038/s41591-021-01324-7. PMC 9128828. PMID 33888901.{{cite journal}}: CS1 maint: overridden setting (link)
  15. ↑ "First Innovation Passport awarded to help support development and access to cutting-edge medicines". Medicines and Healthcare products Regulatory Agency (MHRA) (Press release). 26 February 2021. Retrieved 14 August 2021.
  16. 1 2 "FDA Approves Merck's Hypoxia-Inducible Factor-2 Alpha (HIF-2α) Inhibitor Welireg (belzutifan) for the Treatment of Patients With Certain Types of Von Hippel-Lindau (VHL) Disease-Associated Tumors" (Press release). Merck. 13 August 2021. Retrieved 13 August 2021 – via Business Wire.
  17. 1 2 Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  18. ↑ Kamihara J, Hamilton KV, Pollard JA, Clinton CM, Madden JA, Lin J, et al. (November 2021). "Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome". The New England Journal of Medicine. 385 (22): 2059–2065. doi:10.1056/NEJMoa2110051. PMID 34818480. S2CID 244651726.{{cite journal}}: CS1 maint: overridden setting (link)
  19. ↑ Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, et al. (November 2021). "Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease". The New England Journal of Medicine. 385 (22): 2036–2046. doi:10.1056/NEJMoa2103425. PMC 9275515. PMID 34818478.{{cite journal}}: CS1 maint: overridden setting (link)
  20. ↑ Fallah J, Brave MH, Weinstock C, Mehta GU, Bradford D, Gittleman H, et al. (November 2022). "FDA Approval Summary: Belzutifan for von Hippel-Lindau Disease-Associated Tumors". Clinical Cancer Research. 28 (22): 4843–4848. doi:10.1158/1078-0432.CCR-22-1054. PMC 9669093. PMID 35727604.{{cite journal}}: CS1 maint: overridden setting (link)
  21. ↑ Deeks ED (November 2021). "Belzutifan: First Approval". Drugs. 81 (16): 1921–1927. doi:10.1007/s40265-021-01606-x. PMID 34613603. S2CID 238360443.
  • Clinical trial number NCT04195750 for "A Study of Belzutifan (MK-6482) Versus Everolimus in Participants With Advanced Renal Cell Carcinoma (MK-6482-005)" at ClinicalTrials.gov
  • Clinical trial number NCT03401788 for "A Phase 2 Study of Belzutifan (PT2977, MK-6482) for the Treatment of Von Hippel Lindau (VHL) Disease-Associated Renal Cell Carcinoma (RCC) (MK-6482-004)" at ClinicalTrials.gov
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