Desidustat Explained

Iupac Name:2-1-(Cyclopropylmethoxy)-4-hydroxy-2-oxoquinoline-3-carbonylamino]acetic acid
Cas Number:1616690-16-4
Unii:Y962PQA4KS
Synonyms:ZYAN1
C:16
H:16
N:2
O:6
Stdinchi:1S/C16H16N2O6/c19-12(20)7-17-15(22)13-14(21)10-3-1-2-4-11(10)18(16(13)23)24-8-9-5-6-9/h1-4,9,21H,5-8H2,(H,17,22)(H,19,20)
Stdinchikey:IKRKQQLJYBAPQT-UHFFFAOYSA-N
Smiles:C1CC1CON2C3=CC=CC=C3C(=C(C2=O)C(=O)NCC(=O)O)O

Desidustat (INN, also known as ZYAN1) 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.[1] Desidustat reduces the requirement of recombinant erythropoietin (EPO) in anemia, and decreases EPO-resistance, by reducing IL-6, IL-1β, and anti-EPO antibodies.[2] 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.[3] Clinical trials on desidustat have been done in India and Australia.[4] 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.[5] The Phase 3 clinical trials were conducted in chronic kidney disease patients which were not on dialysis [6] as well as on dialysis.[7] 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.[8] [9] Desidustat can also be useful in treatment of anemia of inflammation since it causes efficient erythropoiesis and hepcidin downregulation.[10] Desidustat has been shown to have significant effect in the treatment of complement-mediated diseases. Complement activation-induced membrane attack complex (MAC) formation and Factor B activity were also reduced by desidustat treatment. Owing to this mechanism, desidustat can be an effective therapy against membranous nephropathy and retinal degeneration, since it specifically inhibited alternative complement system, without affecting the lectin-, or classical complement pathway[11] .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. National Medical Products Administration of China (NMPA) accepted the new drug application for desidustat on 23 April 2024.[12] It has been observed that desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines like IL-6 and oxidative stress.[13] 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.[14] Zydus has also received approval from the US FDA to initiate clinical trials of desidustat in chemotherapy Induced anemia (CIA).[15] Zydus Lifesciences and Sun Pharmaceuticals have entered an agreement in October 2023 to co-market Desidustat. Sun Pharma will sell the drug as Rytstat, while Zydus will continue to sell it as Oxemia.[16]

Notes and References

  1. Web site: Zydus receives DCGI approval for new drug Oxemia; what you need to know.
  2. Joharapurkar A.A., Patel V.J., Kshirsagar S.G., Patel M.S., Savsani H.H., Kajavadara C., Valani D., Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state, Current Research in Pharmacology and Drug Discovery, Available online 30 April 2022, 100102, https://doi.org/10.1016/j.crphar.2022.100102
  3. Web site: CDSCO . SEC Committee . SEC meeting to examine IND proposals, dated 29.12.2021 . CDSCO website Govt of India . CDSCO . 19 January 2022.
  4. Kansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, Parikh DP, Heading H, Patel HB, Gupta RJ, Shah CY, Patel MR, Dholakia VN, Sukhadiya R, Jain MR, Parmar KV, Barot K . 6 . Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers . Clinical Pharmacokinetics . 57 . 1 . 87–102 . January 2018 . 28508936 . 5766731 . 10.1007/s40262-017-0551-3 .
  5. Parmar DV, Kansagra KA, Patel JC, Joshi SN, Sharma NS, Shelat AD, Patel NB, Nakrani VB, Shaikh FA, Patel HV; on behalf of the ZYAN1 Trial Investigators. Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study. Am J Nephrol. 2019 May 21;49(6):470-478. doi: 10.1159/000500232.
  6. Agrawal D, Varade D, Shah H, Nazar A, Krishnan J, Shukla V, Ramakrishna C, Bandara Galahitiyawa MC, Mavani SB, Rajanna S, Jikki P, De Silva S, Ruhela V, Koradia P, Kansagra K, Kanani P, Sharma N, Zala K, Parmar D; Study Investigator Group. Desidustat in Anemia due to Non-Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-ND). Am J Nephrol. 2022 Apr 22:1-9. doi: 10.1159/000523961. Epub ahead of print. PMID 35462372.
  7. Gang S, Khetan P, Varade D, Chinta VR, Mavani S, Gupta U, Reddy SVK, Rajanna S, Jeloka T, Ruhela V, Kansagra K, Kanani P, Bhatt J, Zala K; Study Investigator Group. Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-D). Am J Nephrol. 2022 Apr 22:1-9. doi: 10.1159/000523949. Epub ahead of print. PMID 35462369.
  8. Jain MR, Joharapurkar AA, Pandya V, Patel V, Joshi J, Kshirsagar S, Patel K, Patel PR, Desai RC . 6 . Pharmacological Characterization of ZYAN1, a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia . Drug Research . 66 . 2 . 107–12 . February 2016 . 26367279 . 10.1055/s-0035-1554630 . 21764674 .
  9. Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR . Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases . Journal of Medicinal Chemistry . 61 . 16 . 6964–6982 . August 2018 . 29712435 . 10.1021/acs.jmedchem.7b01686 .
  10. Jain M, Joharapurkar A, Patel V, Kshirsagar S, Sutariya B, Patel M, Patel H, Patel PR . 53943666 . 6 . Pharmacological inhibition of prolyl hydroxylase protects against inflammation-induced anemia via efficient erythropoiesis and hepcidin downregulation . European Journal of Pharmacology . 843 . 113–120 . January 2019 . 30458168 . 10.1016/j.ejphar.2018.11.023 .
  11. Patel VJ, Joharapurkar AA, Kshirsagar SG, Patel MS, Savsani HH, Dodiya HS, Rakhasiya MH, Patel AK, Sundar R, Jain MR. HIF Stabilizer Desidustat Protects against Complement-Mediated Diseases. Drug Res (Stuttg). 2024 Jul 11. doi: 10.1055/a-2347-9919. Epub ahead of print. PMID: 38991528.
  12. News: Zydus enters into licensing agreement with China Medical System Holdings. Business Standard India. 20 January 2020. 20 January 2020. Business Standard .
  13. Joharapurkar AA, Patel VJ, Kshirsagar SG, Patel MS, Savsani HH, Jain MR . Prolyl hydroxylase inhibitor desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines and oxidative stress . Drug Development Research . 82 . 6 . 852–860 . September 2021 . 33480036 . 10.1002/ddr.21792 . 231680317 .
  14. Web site: Zydus' trials of Desidustat shows positive results for Covid-19 management . The Hindu Business Line . The Hindu . 25 January 2021.
  15. Web site: Zydus receives approval from USFDA to initiate clinical trials of Desidustat in cancer patients receiving chemotherapy . PipelineReview.com . La Merie Publishing . 22 January 2021.
  16. https://timesofindia.indiatimes.com/city/ahmedabad/sun-pharma-zydus-to-co-market-drug-for-ckd-induced-anaemia/articleshow/104839743.cms

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