Roxadustat

Last updated

Roxadustat
Roxadustat.svg
Clinical data
Trade names Evrenzo
Other namesFG-4592, ASP1517, AZD9941
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • EU:Rx-only [1]
  • In general: ℞ (Prescription only)
Identifiers
  • 2-[(4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard 100.245.356 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H16N2O5
Molar mass 352.346 g·mol−1
3D model (JSmol)
  • CC1=NC(=C(C2=C1C=C(C=C2)OC3=CC=CC=C3)O)C(=O)NCC(=O)O
  • InChI=1S/C19H16N2O5/c1-11-15-9-13(26-12-5-3-2-4-6-12)7-8-14(15)18(24)17(21-11)19(25)20-10-16(22)23/h2-9,24H,10H2,1H3,(H,20,25)(H,22,23)
  • Key:YOZBGTLTNGAVFU-UHFFFAOYSA-N

Roxadustat, sold under the brand name Evrenzo, is an anti-anemia medication. Roxadustat is a HIF prolyl-hydroxylase inhibitor that increases endogenous production of erythropoietin and stimulates production of hemoglobin and red blood cells. It was investigated in clinical trials for the treatment of anemia caused by chronic kidney disease (CKD). [2] [3] It is taken by mouth. [1] The drug was developed by FibroGen, in partnership with AstraZeneca.

Contents

The most common side effects include hypertension (high blood pressure), vascular access thrombosis (formation of blood clots in the blood vessels associated with dialysis), diarrhea, peripheral edema (swelling especially of the ankles and feet), hyperkalemia (high blood potassium levels) and nausea (feeling sick). [1]

Roxadustat received its first global approval in China on 17 December 2018, [4] for the treatment of anemia caused by CKD in patients who are dialysis-dependent. [5] It was approved in Japan in 2019, for the treatment of anemia caused by CKD in patients on dialysis, and in 2020 for patients not on dialysis. [6] Roxadustat was approved for medical use in the European Union in August 2021. [1] [7]

Medical uses

Roxadustat is indicated for treatment of adults with symptomatic anemia associated with chronic kidney disease (CKD). [1]

Adverse effects

Roxadustat is reported to increase VEGF, a signal protein that can activate tumor growth [8] and also is considered to cause pulmonary hypertension. [9] In phase 3 trial conducted at 29 sites in China, roxadustat treatment was found to cause hyperkalemia, i.e., increase in serum potassium, and metabolic acidosis in patients. [10]

Society and culture

In July 2021, the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted against the use of roxadustat in people with anemia in chronic kidney disease, both for those that are non-dialysis-dependent and those that are on dialysis. [11] Significant safety concerns were raised that the panelists believed could not be addressed without further study. [12] Notably, prior to the vote of the FDA committee, FibroGen and AstraZeneca announced that the company had changed parameters used to analyze cardiovascular safety data, which made the drug appear safer than it is. [13]

Usage as a doping product

Due to the potential applications of roxadustat in athletic doping, such as raising haemoglobin levels and stimulating the production of red blood cells, [14] it has been incorporated into screens for performance-enhancing drugs, as it has already been detected being used illicitly by athletes. [15] [16] [17] In October 2022, it was announced that Romanian former world No. 1 tennis player Simona Halep had tested positive for roxadustat at the 2022 US Open. [18] In September 2023, she was banned from the game for four years by the International Tennis Integrity Agency (ITIA) for two anti-doping violations: taking roxadustat, and anomalies in her athlete biological passport, [14] although the Court of Arbitration for Sport reduced the ban to nine months in March 2024, on the grounds that roxadustat was in Keto MCT, a contaminated supplement, and the doping was unintentional. [19]

Related Research Articles

<span class="mw-page-title-main">Erythropoietin</span> Protein that stimulates red blood cell production

Erythropoietin, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO include any anemia, and hypoxemia due to chronic lung disease.

<span class="mw-page-title-main">Kidney failure</span> Disease where the kidneys fail to adequately filter waste products from the blood

Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as either acute kidney failure, which develops rapidly and may resolve; and chronic kidney failure, which develops slowly and can often be irreversible. Symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications of acute and chronic failure include uremia, hyperkalaemia, and volume overload. Complications of chronic failure also include heart disease, high blood pressure, and anaemia.

<span class="mw-page-title-main">Chronic kidney disease</span> Medical condition

Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications can relate to hormonal dysfunction of the kidneys and include high blood pressure, bone disease, and anemia. Additionally CKD patients have markedly increased cardiovascular complications with increased risks of death and hospitalization.

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They also respond to instances of pseudohypoxia, such as thiamine deficiency. Both hypoxia and pseudohypoxia leads to impairment of adenosine triphosphate (ATP) production by the mitochondria.

<span class="mw-page-title-main">Sevelamer</span> Chemical compound

Sevelamer (rINN) is a phosphate binding medication used to treat hyperphosphatemia in patients with chronic kidney disease. When taken with meals, it binds to dietary phosphate and prevents its absorption. Sevelamer was invented and developed by GelTex Pharmaceuticals. Sevelamer is marketed by Sanofi under the brand names Renagel and Renvela.

Epoetin alfa is a human erythropoietin produced in cell culture using recombinant DNA technology. Authorised by the European Medicines Agency on 28 August 2007, it stimulates erythropoiesis and is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy.

<span class="mw-page-title-main">Procollagen-proline dioxygenase</span> Enzyme

Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha-Ketoglutaric acid, Fe2+, and ascorbate. This particular enzyme catalyzes the formation of (2S, 4R)-4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome.

<span class="mw-page-title-main">Robert Provenzano</span> American physician

Robert Provenzano is an American nephrologist. He is also an Associate Clinical Professor of Medicine at Wayne State University School of Medicine.

Continuous erythropoietin receptor activator (CERA) is the generic term for drugs in a new class of third-generation erythropoiesis-stimulating agents (ESAs). In the media, these agents are commonly referred to as 'EPO', short for erythropoietin. CERAs have an extended half-life and a mechanism of action that promotes increased stimulation of erythropoietin receptors compared with other ESAs.

<span class="mw-page-title-main">HIF prolyl-hydroxylase inhibitor</span>

Not to be confused with Factor Inhibiting HIF Asparaginyl Hydroxylase Inhibitors

Peginesatide, developed by Affymax and Takeda, is an erythropoietic agent, a functional analog of erythropoietin.

Hypoxia-inducible factor-proline dioxygenase (EC 1.14.11.29, HIF hydroxylase) is an enzyme with systematic name hypoxia-inducible factor-L-proline, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating). This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Rockwell Medical</span>

Rockwell Medical Inc. is a company based in Wixom, Michigan and founded in 1996 that focuses on development and commercialization of treatments against diseases such as end-stage renal disease (ESRD) and chronic kidney disease (CKD).

Sucroferric oxyhydroxide, sold under the brand name Velphoro, is a non-calcium, iron-based phosphate binder used for the control of serum phosphorus levels in adults with chronic kidney disease (CKD) on haemodialysis (HD) or peritoneal dialysis (PD). It is used in form of chewable tablets.

<span class="mw-page-title-main">Etelcalcetide</span> Chemical compound

Etelcalcetide is a calcimimetic drug for the treatment of secondary hyperparathyroidism in patients undergoing hemodialysis. It is administered intravenously at the end of each dialysis session. Etelcalcetide functions by binding to and activating the calcium-sensing receptor in the parathyroid gland. Parsabiv is currently owned by Amgen and Ono Pharmaceuticals in Japan.

<span class="mw-page-title-main">Vadadustat</span> Chemical compound

Vadadustat, sold under the brand name Vafseo is a medication used for the treatment of symptomatic anemia associated with chronic kidney disease.

<span class="mw-page-title-main">Daprodustat</span> Chemical compound

Daprodustat, sold under the brand name Duvroq among others, is a medication that is used for the treatment of anemia due to chronic kidney disease. It is a hypoxia-inducible factor prolyl hydroxylase inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Molidustat</span> Chemical compound

Molidustat is a drug which acts as an HIF prolyl-hydroxylase inhibitor and thereby increases endogenous production of erythropoietin, which stimulates production of hemoglobin and red blood cells. It is in Phase III clinical trials for the treatment of anemia caused by chronic kidney disease. Due to its potential applications in athletic doping, it has also been incorporated into screens for performance-enhancing drugs.

<span class="mw-page-title-main">Desidustat</span> Chemical compound

Desidustat is a drug for the treatment of anemia of chronic kidney disease. This drug with the brand name Oxemia is discovered and developed by Zydus Life Sciences. Desidustat reduces the requirement of recombinant erythropoietin requirement in anemia, and decreases EPO-resistance, by reducing IL-6, IL-1β, and anti-EPO antibodies. The subject expert committee of CDSCO has recommended the grant of permission for manufacturing and marketing of Desidustat 25 mg and 50 mg tablets in India,based on some conditions related to package insert, phase 4 protocols, prescription details, and GCP. Clinical trials on desidustat have been done in India and Australia. In a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study, a mean hemoglobin increase of 1.57, 2.22, and 2.92 g/dL in desidustat 100, 150, and 200 mg arms, respectively, was observed. The Phase 3 clinical trials were conducted in chronic kidney disease patients which were not on dialysis as well as on dialysis. Desidustat is developed for the treatment of anemia as an oral tablet, where currently injections of erythropoietin and its analogues are drugs of choice. Desidustat is a HIF prolyl-hydroxylase inhibitor. In preclinical studies, effects of desidustat was assessed in normal and nephrectomized rats, and in chemotherapy-induced anemia. Desidustat demonstrated hematinic potential by combined effects on endogenous erythropoietin release and efficient iron utilization. Desidustat can also be useful in treatment of anemia of inflammation since it causes efficient erythropoiesis and hepcidin downregulation. In January 2020, Zydus entered into licensing agreement with China Medical System (CMS) Holdings for development and commercialization of desidustat in Greater China. Under the license agreement, CMS will pay Zydus an initial upfront payment, regulatory milestones, sales milestones and royalties on net sales of the product. CMS will be responsible for development, registration and commercialization of desidustat in Greater China. It has been observed that desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines like IL-6 and oxidative stress. A clinical trial to evaluate the efficacy and safety of desidustat tablet for the management of COVID-19 patients is ongoing in Mexico, wherein desidustat has shown to prevent acute respiratory distress syndrome (ARDS) by inhibiting IL-6. Zydus has also received approval from the US FDA to initiate clinical trials of desidustat in chemotherapy Induced anemia (CIA).

<span class="mw-page-title-main">Enarodustat</span> Chemical compound

Enarodustat is a drug used for the treatment of anemia, especially when associated with chronic kidney disease (CKD). Enarodustat functions as a inhibitor of hypoxia inducible factor-proly hydroxylase (HIF-PH).

References

  1. 1 2 3 4 5 "Evrenzo EPAR". European Medicines Agency (EMA). 23 June 2021. Retrieved 24 August 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. ↑ Provenzano R, Besarab A, Sun CH, Diamond SA, Durham JH, Cangiano JL, et al. (June 2016). "Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD". Clinical Journal of the American Society of Nephrology. 11 (6): 982–991. doi:10.2215/CJN.06890615. PMC   4891748 . PMID   27094610.
  3. ↑ Becker K, Saad M (April 2017). "A New Approach to the Management of Anemia in CKD Patients: A Review on Roxadustat". Advances in Therapy. 34 (4): 848–853. doi: 10.1007/s12325-017-0508-9 . PMID   28290095.
  4. ↑ Dhillon S (April 2019). "Roxadustat: First Global Approval". Drugs. 79 (5): 563–572. doi: 10.1007/s40265-019-01077-1 . PMID   30805897. S2CID   71147333.
  5. ↑ Dhillon S (April 2019). "Roxadustat: First Global Approval". Drugs. 79 (5): 563–572. doi: 10.1007/s40265-019-01077-1 . PMID   30805897. S2CID   71147333.
  6. ↑ "Astellas Receives Approval of Evrenzo (roxadustat) in Japan for the Treatment of Anemia of Chronic Kidney Disease in Adult Patients Not on Dialysis". Astellas. 27 November 2020.
  7. ↑ "Evrenzo Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  8. ↑ Zhou M, Hou J, Li Y, Mou S, Wang Z, Horch RE, et al. (April 2019). "The pro-angiogenic role of hypoxia inducible factor stabilizer FG-4592 and its application in an in vivo tissue engineering chamber model". Scientific Reports. 9 (1): 6035. Bibcode:2019NatSR...9.6035Z. doi:10.1038/s41598-019-41924-5. PMC   6465281 . PMID   30988335.
  9. ↑ Cygulska K, Wejner-Mik P, Plewka M, Figiel Ł, Chrzanowski Ł, Kasprzak JD (May 2019). "Roxadustat: another drug that causes pulmonary hypertension? Report of first human case". Polish Archives of Internal Medicine. 129 (5): 344–345. doi: 10.20452/pamw.4445 . PMID   30758318.
  10. ↑ Chen N, Hao C, Peng X, Lin H, Yin A, Hao L, et al. (September 2019). "Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis". The New England Journal of Medicine. 381 (11): 1001–1010. doi: 10.1056/NEJMoa1813599 . PMID   31340089.
  11. ↑ "FibroGen Announces Outcome of FDA Advisory Committee Review of Roxadustat for Treatment of Anemia of Chronic Kidney Disease". FibroGen (Press release). Retrieved 15 July 2021.
  12. ↑ Sagonowsky E (15 July 2021). "AstraZeneca, FibroGen hit another roxadustat setback as FDA panel calls for more safety data". FiercePharma. Retrieved 16 July 2021.
  13. ↑ Liu A (7 April 2021). "FibroGen admits to messing with roxadustat safety data, upending hopes for the AZ-partnered anemia drug". Fierce Pharma. Retrieved 30 October 2022.
  14. 1 2 Ingle S (12 September 2023). "Simona Halep given four-year ban from tennis for anti-doping violations". The Guardian. Retrieved 12 September 2023.
  15. ↑ Beuck S, Schänzer W, Thevis M (November 2012). "Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis". Drug Testing and Analysis. 4 (11): 830–845. doi: 10.1002/dta.390 . PMID   22362605.
  16. ↑ Buisson C, Marchand A, Bailloux I, Lahaussois A, Martin L, Molina A (March 2016). "Detection by LC-MS/MS of HIF stabilizer FG-4592 used as a new doping agent: Investigation on a positive case". Journal of Pharmaceutical and Biomedical Analysis. 121: 181–187. doi:10.1016/j.jpba.2016.01.029. PMID   26808067.
  17. ↑ Eichner D, Van Wagoner RM, Brenner M, Chou J, Leigh S, Wright LR, et al. (November 2017). "lmplementation of the prolyl hydroxylase inhibitor Roxadustat (FG-4592) and its main metabolites into routine doping controls". Drug Testing and Analysis. 9 (11–12): 1768–1778. doi: 10.1002/dta.2202 . PMID   28378453.
  18. ↑ MacInnes P (21 October 2022). "Simona Halep vows to 'fight for the truth' after positive doping test". The Guardian. Retrieved 21 October 2022.
  19. ↑ Carayol T (5 March 2024). "Simona Halep's 'triumph of truth' after doping ban significantly reduced". The Guardian. Retrieved 6 March 2024.

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