Desidustat

Last updated
Desidustat
Desidustat.svg
Clinical data
Other namesZYAN1
Identifiers
  • 2-[[1-(Cyclopropylmethoxy)-4-hydroxy-2-oxoquinoline-3-carbonyl]amino]acetic acid
CAS Number
UNII
Chemical and physical data
Formula C16H16N2O6
Molar mass 332.312 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]

Related Research Articles

Darbepoetin alfa (INN) is a re-engineered form of erythropoietin containing 5 amino acid changes resulting in the creation of 2 new sites for N-linked carbohydrate addition. It has a 3-fold longer serum half-life compared to epoetin alpha and epoetin beta. It stimulates erythropoiesis by the same mechanism as rHuEpo and is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy. Darbepoetin is marketed by Amgen under the trade name Aranesp.

<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 and mouth 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 renal disease (ESRD), 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, hyperkalemia, and volume overload. Complications of chronic failure also include heart disease, high blood pressure, and anaemia.

<span class="mw-page-title-main">Hemolytic–uremic syndrome</span> Group of blood disorders related to bacterial infection

Hemolytic–uremic syndrome (HUS) is a group of blood disorders characterized by low red blood cells, acute kidney injury, and low platelets. Initial symptoms typically include bloody diarrhea, fever, vomiting, and weakness. Kidney problems and low platelets then occur as the diarrhea progresses. Children are more commonly affected, but most children recover without permanent damage to their health, although some children may have serious and sometimes life-threatening complications. Adults, especially the elderly, may present a more complicated presentation. Complications may include neurological problems and heart failure.

<span class="mw-page-title-main">Chronic kidney disease</span> Abnormal kidney structure or gradual loss of kidney function

Chronic kidney disease (CKD) is a type of long-term kidney disease, in which either there is a gradual loss of kidney function which occurs over a period of months to years, or an abnormal kidney structure. 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. CKD can lead to kidney failure requiring kidney dialysis or kidney transplantation.

Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver. Hepcidin production and release shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells. As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, or anemia of inflammatory response.

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.

Epoetin alfa, sold under the brand name Epogen among others, is a human erythropoietin produced in cell culture using recombinant DNA technology. Epoetin alfa is an erythropoiesis-stimulating agent. It stimulates erythropoiesis and is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy. Epoetin alfa is developed by Amgen.

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> Drug class

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a novel class of oral medications developed for the treatment of anemia in chronic kidney disease (CKD). These drugs work by inhibiting hypoxia-inducible factor-proline dioxygenase, which are responsible for the degradation of hypoxia-inducible factor (HIF) under normal oxygen conditions. By stabilizing HIF, these inhibitors mimic the body's natural response to hypoxia, leading to increased endogenous erythropoietin production and improved iron metabolism. HIF-PHIs have shown efficacy in correcting and maintaining hemoglobin levels in both dialysis-dependent and non-dialysis-dependent CKD patients, offering an alternative to traditional erythropoiesis-stimulating agents (ESAs).

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">Saroglitazar</span> Chemical compound

Saroglitazar is a drug for the treatment of type 2 diabetes mellitus, dyslipidemia, NASH and NAFLD It is approved for use in India by the Drug Controller General of India. Saroglitazar is indicated for the treatment of diabetic dyslipidemia and hypertriglyceridemia with type 2 diabetes mellitus not controlled by statin therapy. In clinical studies, saroglitazar has demonstrated reduction of triglycerides (TG), LDL cholesterol, VLDL cholesterol, non-HDL cholesterol and an increase in HDL cholesterol a characteristic hallmark of atherogenic diabetic dyslipidemia (ADD). It has also shown anti-diabetic medication properties by reducing the fasting plasma glucose and HBA1c in diabetes patients.

<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. Vadadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor.

<span class="mw-page-title-main">Roxadustat</span> Anti-anemia medication

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). It is taken by mouth. The drug was developed by FibroGen, in partnership with AstraZeneca.

<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">ZyCoV-D</span> Vaccine candidate against COVID-19

ZyCoV-D is a DNA plasmid-based COVID-19 vaccine developed by Indian pharmaceutical company Cadila Healthcare, with support from the Biotechnology Industry Research Assistance Council. It is approved for emergency use in India.

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

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. It is taken by mouth. Belzutifan is an hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor.

<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. ↑ 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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