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Rationale for Treatment with HIF-PHI Agents (Guidelines 4.1 – 4.9)

Rationale for Treatment with HIF-PHI Agents (Guidelines 4.1 – 4.9)

Published trials confirm that the six HIF-PHI agents with data are superior to placebo and non-inferior to ESAs in increasing and maintaining haemoglobin (Hb) concentration among people with NDD-CKD and DD-CKD (1-33). Large, randomised trials have demonstrated that Roxadustat (8-19), Vadadustat (20-23), and Daprodustat (1-7) are superior to placebo and/or non-inferior to ESAs in correcting and/or maintaining Hb at target levels in NDD-CKD and incident and prevalent people with DD-CKD. These findings have also been seen with Molidustat, Enarodustat, and Desidustat (24-33). The Hb response when using HIF-PHI therapy is dose-dependent and there are variations depending on the molecule used and trial protocol. Some molecules depending on the starting doses used, increased the Hb more rapidly than others. Rates of blood transfusion are similar among patients receiving HIF-PHI therapy versus ESA therapy and lower than among those receiving placebo in randomised trials.

Several meta-analyses have confirmed the clinical findings from these RCTs (34-40). A recent meta-analysis of the phase 3 RCTS comparing HIF-PHI therapy to active comparator has confirmed the efficacy of this class of drug in both people on dialysis (both peritoneal and haemodialysis) and not on dialysis (41). A total of 26 trials were included in this recent analysis with over 24, 000 participants. The average length of follow-up was 16.5 months (range 6-42 months) and the mean baseline eGFR ranged from 15.9-22.1 ml/min/1,73m2. The mean age was 67.1 years (range 48-72 years). The authors found a statistically higher change in Hb levels from baseline between HIF-PHI therapy at the dose selected compared to ESA of 1.0 g/L (95% CI 0.2-1.7) favouring HIF-PHI use but perhaps not clinically significant. There was no difference in those reaching the pre-specified Hb target (OR 1.04; 95% CI 0.88-1.22) (41).

Roxadustat, the first in class HIF-PHI to receive NICE guidance and SmPC recommendation has a half-life of around 15 hours in people with CKD, is orally bioavailable, leads to an increase in EPO levels after oral administration and lasts for up to 48 hours post-dose administration. Its efficacy and safety have been examined in eight randomised controlled trials involving 9600 patients (8-19).

The results of trials that included people treated with haemodialysis (HD) and peritoneal dialysis (PD) and single-arm trials among patients treated with PD (19) have shown that HIF-PHI therapy is at least as effective among those receiving PD versus HD.

References

  1. Nangaku M, Hamano T, Akizawa T, et al. Daprodustat compared with epoetin beta pegol for anemia in Japanese patients not on dialysis: a 52-week randomized open-label phase 3 trial. Am J Nephrol. 2021;52: 26–35.
  2. Singh AK, Carroll K, McMurray JJV, et al. Daprodustat for the treatment of anemia in patients not undergoing dialysis. N Engl J Med. 2021;385: 2313–2324.
  3. Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med. 2021;385: 2325–2335.
  4. Kanai H, Nangaku M, Nagai R, et al. Efficacy and safety of daprodustat in Japanese peritoneal dialysis patients. Ther Apher Dial. 2021;25: 979–987.
  5. Singh AK, Cizman B, Carroll K et al. Efficacy and safety of daprodustat for treatment of anemia of chronic kidney dis- ease in incident dialysis patients: a randomized clinical trial. JAMA Intern Med 2022; 182 :592–602.
  6. Akizawa T, Nangaku M, Yonekawa T et al. Efficacy and safety of daprodustat compared with darbepoetin alfa in Japanese hemodialysis patients with anemia: a randomized, double-blind, phase 3 trial. Clin J Am Soc Nephrol 2020; 15 :1155–65.
  7. Coyne DW, Singh AK, Lopes RD et al. Three times weekly dosing of daprodustat versus conventional epoetin for treatment of anemia in hemodialysis patients: ASCEND-TD: a phase 3 randomized, double-blind, noninferiority trial. Clin J Am Soc Nephrol 2022; 17 :1325–36.
  8. Chen N, Hao C, Peng X, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med. 2019;381: 1001–1010.
  9. Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for treating anemia in patients with CKD not on dialysis: results from a randomized phase 3 study. J Am Soc Nephrol. 2021;32:737– 755.
  10. Chen N, Hao C, Liu BC, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med. 2019;381: 1011–1022.
  11. Barratt J, Andric B, Tataradze A et al. Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES). Nephrol Dial Transplant 2021; 36 :1616–28.
  12. Akizawa T, Iwasaki M, Otsuka T et al. Phase 3 Study of roxadustat to treat anemia in non-dialysis-dependant CKD. Kidney Int Rep 2021; 6 :1810–28.
  13. Provenzano R, Shutov E, Eremeeva L et al. Roxadustat for anemia in patients with end-stage renal disease incident to dialysis. Nephrol Dial Transplant 2021; 36 :1717–30.
  14. Charytan C, Manllo-Karim R, Martin ER et al. A randomized trial of roxadustat in anemia of kidney failure: SIERRAS Study. Kidney Int Rep 2021; 6 :1829–39.
  15. Csiky B, Schömig M, Esposito C et al. Roxadustat for the maintenance treatment of anemia in patients with end-stage kidney disease on stable dialysis: a European phase 3, randomized, open-label, active-controlled study (PYRENEES). Adv Ther 2021; 38 :5361–80.
  16. Fishbane S, Pollock CA, El-Shahawy M et al. Roxadustat versus epoetin alfa for treating anemia in patients with chronic kidney disease on dialysis: results from the randomized phase 3 ROCKIES study. J Am Soc Nephrol 2022; 33 :850–66.
  17. Akizawa T, Iwasaki M, Yamaguchi Y et al. Phase 3, randomized, double-blind, active-comparator (darbepoetin alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan. J Am Soc Nephrol 2020; 31 :1628–39.
  18. Chen N, Hao C, Liu BC et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med 2019; 381 :1011–22.
  19. Hou YP, Mao XY, Wang C et al. Roxadustat treatment for anemia in peritoneal dialysis patients: a randomized controlled trial. J Formos Med Assoc 2022; 121 :529–38.
  20. Eckardt KU, Agarwal R, Aswad A, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med. 2021;384: 1601–1612.
  21. Nangaku M, Kondo K, Ueta K et al. Efficacy and safety of vadadustat compared with darbepoetin alfa in Japanese anemic patients on hemodialysis: a Phase 3, multicenter, randomized, double-blind study. Nephrol Dial Transplant 2021; 36 :1731–41.
  22. Nangaku M, Kondo K, Kokado Y et al. Phase 3 randomized study comparing vadadustat with darbepoetin alfa for anemia in Japanese patients with nondialysis-dependent CKD. J Am Soc Nephrol 2021; 32 :1779–90.
  23. Chertow GM, Pergola PE, Farag YMK et al. Vadadustat in patients with anemia and non-dialysis-dependent CKD. N Engl J Med 2021; 384 :1589–600.
  24. Agrawal D, Varade D, Shah H et al. Desidustat in Anemia due to Non-Dialysis-Dependent Chronic Kidney Disease: a Phase 3 Study (DREAM-ND). Am J Nephrol 2022; 53 :352–360.
  25. Gang S, Khetan P, Varade D et al. Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: a Phase 3 Study (DREAM-D). Am J Nephrol 2022; 53 :343–51.
  26. Akizawa T, Nangaku M, Yamaguchi T, et al. A phase 3 study of enarodustat in anemic patients with CKD not requiring dialysis: the SYMPHONY ND study. Kidney Int Rep. 2021;6:1840–1849.
  27. Akizawa T, Nangaku M, Yamaguchi T, et al. A phase 3 study of enarodustat (JTZ-951) in Japanese hemodialysis patients for treatment of anemia in chronic kidney disease: SYMPHONY HD study. Kidney Dis (Basel). 2021;7:494–502.
  28. Akizawa T, Nangaku M, Yamaguchi T, et al. A placebo-controlled, randomized trial of enarodustat in patients with chronic kidney disease followed by long-term trial. Am J Nephrol . 2019;49:165– 174.
  29. Yamamoto H, Nobori K, Matsuda Y, et al. Efficacy and safety of molidustat for anemia in ESA-naive nondialysis patients: a randomized, phase 3 trial. Am J Nephrol. 2021;52:871–883.
  30. Yamamoto H, Nobori K, Matsuda Y, et al. Molidustat for renal anemia in nondialysis patients previously treated with erythropoiesis-stimulating agents: a randomized, open-label, phase 3 study. Am J Nephrol. 2021;52: 884–893.
  31. Akizawa T, Nobori K, Matsuda Y, et al. Molidustat for anemia correction in Japanese patients undergoing hemodialysis: a single-arm, phase 3 study. Ther Apher Dial. 2021;25:917–925.
  32. Macdougall IC, Akizawa T, Berns JS, et al. Effects of molidustat in the treatment of anemia in CKD. Clin J Am Soc Nephrol. 2019;14:28–39.
  33. Akizawa T, Yamada T, Nobori K et al. Molidustat for Japanese patients with renal anemia receiving dialysis. Kidney Int Rep 2021; 6 :2604–16.
  34. Natale P, Palmer SC, Jaure A et al. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev 2022; 8: CD013751.
  35. Zheng Q, Wang Y, Yang H et al. Cardiac and kidney adverse effects of HIF prolyl-hydroxylase inhibitors for anemia in patients with CKD not receiving dialysis: a systematic re- view and meta-analysis. Am J Kidney Dis 2023; 81 :434–45.e1.
  36. Takkavatakarn K, Thammathiwat T, Phannajit J et al. The impacts of hypoxia-inducible factor stabilizers on labora- tory parameters and clinical outcomes in chronic kidney disease patients with renal anemia: a systematic review and meta-analysis. Clin Kidney J 2023; 16 :845–58.
  37. Chen H, Cheng Q, Wang J et al. Long-term efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: a meta-analysis including 13,146 patients. J Clin Pharm Ther 2021; 46 :999–1009.
  38. Abdelazeem B, Abbas KS, Shehata J et al. The efficacy of roxadustat for the treatment of anemia in dialysis de- pendent chronic kidney disease patients: an updated sys- tematic review and meta-analysis of randomized clinical trials. Ann Transl Med 2021; 9 :1714.
  39. Li J, Xie QH, You L et al. Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors on iron regulation in non- dialysis-dependent chronic kidney disease patients with anemia: a systematic review and meta-analysis. Pharma- col Res 2021; 163 :105256.
  40. Zheng Q, Yang H, Sun L et al. Efficacy and safety of HIF prolyl-hydroxylase inhibitor vs epoetin and darbepoetin for anemia in chronic kidney disease patients not undergoing dialysis: a network meta-analysis. Pharmacol Res 2020; 159 :105020.
  41. Minutolo R, Liberti ME, Simeon V, Sasso FC, Borrelli S, De Nicola L, Garofalo C, CKJ 2023).