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Hypoxia-inducible Factors Inhibitors: Drugs, Side Effects, Interactions & List

How Do Hypoxia-inducible factors inhibitors Work?

Reviewed on 2/28/2023

How do hypoxia-inducible factors inhibitors work?

Hypoxia-inducible factors inhibitors are a new class of drugs used for the treatment of certain tumors and cancers associated with von Hippel-Lindau (VHL) disease. Currently, belzutifan, with the brand name of Welireg, is the only drug available in this class, which was approved by the FDA in August 2021.

Von Hippel-Lindau disease is a rare inherited condition caused by deletion or mutation in the VHL gene. VHL gene encodes VHL protein which helps regulate cellular functions including cell growth and division. Impairment or lack of functional VHL protein results in growth of mostly benign tumors but also malignant cancers in the brain, spinal cord, eye, ear, adrenal glands, pancreas, or other parts of the body.

Hypoxia-inducible factors inhibitors work by inhibiting the activity of hypoxia-inducible factor 2A (HIF-2A), a transcription factor that regulates genes which promote adaptation to low oxygen (hypoxia) environment leading to cell proliferation, new blood vessel formation (angiogenesis) and tumor growth.

Under normal oxygen levels VHL protein degrades HIF-2A. Lack of VHL protein leads to stabilization and accumulation of HIF-2A, which enters the cell nucleus and interacts with HIF-2B, forming a complex that activates genes that drive cell growth and proliferation in hypoxic state. Hypoxia-inducible factors inhibitors bind to HIF-2A and prevent interaction between HIF-2A and HIF-2B and consequent tumor growth.

How are hypoxia-inducible factors inhibitors used?

Hypoxia-inducible factors inhibitors are oral tablets approved by the FDA for treatment of adult patients with von Hippel-Lindau disease who do not need immediate surgery but require therapy for associated tumors and cancers including:

What are the side effects of hypoxia-inducible factors inhibitors?

Side effects of hypoxia-inducible factors inhibitors may include the following:

  • Low red blood cell count (anemia)
  • Reduced hemoglobin
  • Reduced leukocytes
  • Fatigue
  • Weakness (asthenia)
  • Headache
  • Migraine
  • Dizziness
  • Vertigo
  • Nausea
  • Vomiting
  • Constipation
  • Abdominal pain and/or discomfort
  • Diarrhea
  • Dehydration
  • Increase in creatinine
  • Increase in blood glucose level
  • Increase in liver enzymes ALT and AST
  • Reduced calcium levels
  • Reduced phosphate levels
  • Upper respiratory tract infection
  • Viral upper respiratory tract infection
  • Sinus inflammation (sinusitis)
  • Bronchial inflammation (bronchitis)
  • Shortness of breath (dyspnea)
  • Cough
  • Muscle pain (myalgia)
  • Joint pain (arthralgia)
  • Musculoskeletal pain
  • Visual impairment
  • Blurred vision
  • Block in the central retinal vein
  • Retinal detachment
  • High blood pressure (hypertension)
  • Increased weight

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

What are names of some hypoxia-inducible factors inhibitors?

Generic and brand names of hypoxia-inducible factors inhibitors include:

  • belzutifan
  • Welireg
References
https://reference.medscape.com/drugs/hypoxia-inducible-factors-inhibitors

https://www.uptodate.com/contents/belzutifan-drug-information

https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf

https://go.drugbank.com/drugs/DB15463

https://www.cancer.net/cancer-types/von-hippel-lindau-syndrome