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Desidustat

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Desidustat
Clinical data
Other namesZYAN1
Identifiers
  • 2-[[1-(Cyclopropylmethoxy)-4-hydroxy-2-oxoquinoline-3-carbonyl]amino]acetic acid
CAS Number
UNII
Chemical and physical data
FormulaC16H16N2O6
Molar mass332.312 g·mol−1
3D model (JSmol)
  • C1CC1CON2C3=CC=CC=C3C(=C(C2=O)C(=O)NCC(=O)O)O
  • InChI=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)
  • Key:IKRKQQLJYBAPQT-UHFFFAOYSA-N

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] Desidustat was successfully introduced as an alternative treatment in patient of endogenous erythropoietin (EPO)-induced pure red cell aplasia (PRCA) due to anti-EPO antibodies. This led to a substantial and sustained improvement in hemoglobin levels, emphasizing the crucial role of desidustat intervention in EPO-induced PRCA cases.[16] 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.[17] Zydus Lifesciences is launching a proof-of-concept Phase 2a clinical trial to evaluate the safety and efficacy of desidustat in people with sickle cell disease (SCD). The study is the result of a collaboration with the Indian Council of Medical Research (ICMR)[18]

References

[edit]
  1. ^ Joharapurkar A, Pandya V, Patel H, Jain M and Desai R (2024) Desidustat: a novel PHD inhibitor for the treatment of CKD-induced anemia. Front. Nephrol. 4:1459425. doi: 10.3389/fneph.2024.1459425.
  2. ^ Joharapurkar AA, Patel VJ, Kshirsagar SG, Patel MS, Savsani HH, Kajavadara C, Valani D, Jain MR (2022). "Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state". Curr Res Pharmacol Drug Discov. 3: 100102. doi:10.1016/j.crphar.2022.100102. PMC 9096675. PMID 35570856.
  3. ^ CDSCO, SEC Committee. "SEC meeting to examine IND proposals, dated 29.12.2021". CDSCO website Govt of India. CDSCO. Retrieved 19 January 2022.
  4. ^ Kansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, et al. (January 2018). "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. doi:10.1007/s40262-017-0551-3. PMC 5766731. PMID 28508936.
  5. ^ Parmar DV, Kansagra KA, Patel JC, Joshi SN, Sharma NS, Shelat AD, Patel NB, Nakrani VB, Shaikh FA, Patel HV (2019). "Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study". Am J Nephrol. 49 (6): 470–8. doi:10.1159/000500232. PMID 31112954.
  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 (2022). "Desidustat in Anemia due to Non-Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-ND)". Am J Nephrol. 53 (5): 352–360. doi:10.1159/000523961. PMID 35462372.
  7. ^ Gang S, Khetan P, Varade D, Chinta VR, Mavani S, Gupta U, Reddy SV, Rajanna S, Jeloka T, Ruhela V, Kansagra K, Kanani P, Bhatt J, Zala K (2022). "Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-D)". Am J Nephrol. 53 (5): 343–351. doi:10.1159/000523949. PMC 9254304. PMID 35462369.
  8. ^ Jain MR, Joharapurkar AA, Pandya V, Patel V, Joshi J, Kshirsagar S, et al. (February 2016). "Pharmacological Characterization of ZYAN1, a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia". Drug Research. 66 (2): 107–112. doi:10.1055/s-0035-1554630. PMID 26367279. S2CID 21764674.
  9. ^ Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR (August 2018). "Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases". Journal of Medicinal Chemistry. 61 (16): 6964–82. doi:10.1021/acs.jmedchem.7b01686. PMID 29712435.
  10. ^ Jain M, Joharapurkar A, Patel V, Kshirsagar S, Sutariya B, Patel M, et al. (January 2019). "Pharmacological inhibition of prolyl hydroxylase protects against inflammation-induced anemia via efficient erythropoiesis and hepcidin downregulation". European Journal of Pharmacology. 843: 113–120. doi:10.1016/j.ejphar.2018.11.023. PMID 30458168. S2CID 53943666.
  11. ^ Patel VJ, Joharapurkar AA, Kshirsagar SG, Patel MS, Savsani HH, Dodiya HS, Rakhasiya MH, Patel AK, Sundar R, Jain MR (September 2024). "HIF Stabilizer Desidustat Protects against Complement-Mediated Diseases". Drug Res (Stuttg). 74 (7): 325–334. doi:10.1055/a-2347-9919. PMID 38991528.
  12. ^ "Zydus enters into licensing agreement with China Medical System Holdings". Business Standard India. 20 January 2020. Retrieved 20 January 2020 – via Business Standard.
  13. ^ Joharapurkar AA, Patel VJ, Kshirsagar SG, Patel MS, Savsani HH, Jain MR (September 2021). "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. doi:10.1002/ddr.21792. PMID 33480036. S2CID 231680317.
  14. ^ "Zydus' trials of Desidustat shows positive results for Covid-19 management". The Hindu Business Line. The Hindu. 25 January 2021. Retrieved 25 January 2021.
  15. ^ "Zydus receives approval from USFDA to initiate clinical trials of Desidustat in cancer patients receiving chemotherapy". PipelineReview.com. La Merie Publishing. 23 July 2020. Retrieved 22 January 2021.
  16. ^ Kashiv P, Malde S, Dubey S, Gupta S, Pawar T, Sejpal KN, Gurjar P, Pasari A, Balwani M, Bhawane A, Tolani P, Bawankule CP (June 2024). "A Case of Erythropoietin (EPO)-Induced Pure Red Cell Aplasia and Its Treatment Efficacy With Desidustat". Cureus. 16 (6): e62022. doi:10.7759/cureus.62022. PMC 11235398. PMID 38989377.
  17. ^ "Sun Pharma, Zydus to co-market drug for CKD-induced anaemia". The Times of India. 31 October 2023.
  18. ^ https://sicklecellanemianews.com/news/oral-desidustat-tested-sickle-cell-disease-phase-2a-clinical-trial/?cn-reloaded=1
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