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Guidelines 4.4 – 4.6 Treatment of Anaemia – HIF-PHI dose and frequency

Guidelines 4.4 – 4.6 Treatment of Anaemia – HIF-PHI dose and frequency

Guideline 4.4 – Treatment of Anaemia – Initial HFP-PHI dose

We recommend that the initial HIF-PHI dose should be based on the person’s weight and Hb level and the observed rate of increase in Hb level and clinical circumstances. The appropriate dose should follow label recommendations until further data is available. (1B)

Guideline 4.4.1

We suggest that the starting HIF PHI dose should be lower for those who are ESA-naïve versus those who are not. (2B)

Guideline 4.5 – Treatment of Anaemia with HIF-PHI therapy – Frequency of Administration:

We suggest that the frequency of administration should be determined by the response to therapy to maintain the desired Hb target range of 100-120g/L. (2B)

Guideline 4.6 – Treatment of Anaemia with HIF-PHI Therapy – Dose Adjustments:

We suggest that adjustments to HIF-PHI doses should be considered when Hb is <105 or >115 g/L in adults to balance the benefit and safety to people given the current evidence base. (2B)

Rationale

Currently only 1 HIF-PHI has been recommended in the UK by NICE for people who have stage 3 to 5 CKD with no iron deficiency and are not on dialysis at the start of HIF-PHI treatment. Compared with ESA these drugs work as well for anaemia management (1, 2). NICE has therefore recommended that HIF-PHI can be used as an alternative to ESA for people with NDD-CKD stages 3 to 5, especially if they find self-injecting difficult or painful or rely on others to give them their injections. Starting doses are based on weight, and dose changes are based on response to treatment and changes in Hb levels. The correction phase lasts up to approximately 3 months from starting treatment or until a stable Hb level of 100-120 g/L is achieved and stabilised. The maintenance phase starts immediately after the correction phase. Clinicians with expertise in this field have indicated that the decision whether to stop treatment depends on how well anaemia is managed. They stated that they would titrate the dose down if Hb levels reached approximately 125 g/L so that Hb levels stay within a “presumed safe range” (that is, between 100 g/L and 120 g/L) rather than stopping treatment completely.

Adjustments to HIF-PHI doses should be considered when Hb is <105 or >115 g/L in adults to balance the benefit and safety to people given the current evidence base. These thresholds for intervention should achieve a population distribution centred on a mean of 110 g/L with a range of 100-120 g/L, similar to ESA based therapy.

The intermittent dosing strategy with HIF-PHI for the treatment of anaemia in people with chronic kidney disease was developed to maintain its effectiveness. This is the case for Roxadustat with a half life of 15 hours administered three times per week, enabling HIF transcriptional activity to return to baseline between doses, which results in the intermittent induction of hypoxia-inducible target genes involved in erythropoiesis. However, for vadadustat which has a half-life of approximately 4.5 – 9.2 hours it is given daily.

The appropriate dose should follow label recommendations. We would suggest that starting HIF

PHI dose should be lower for those who are ESA-naïve versus those who are not. Based on the current Hb and the achieved change in Hb (typically over a 4-week period), the dosing in phase 3 trials was maintained or changed in stepwise fashion. Treatment was temporarily discontinued when Hb exceeded 120 or 130 g/L in most studies (3-20). It should be noted that Roxadustat is more than 90% protein bound so caution should be used when the drug is used in patients with nephrotic syndrome due to the potentially higher levels of free drug which may lead to adverse events and more rapid rise in haemoglobin.

References

  1. NICE. Final appraisal document – Roxadustat for treating anaemia in people with chronic kidney disease. Issue date: June 2022 Available at: https://www.nice.org.uk/guidance/ta807/documents/final-appraisal-determination-document Accessed 12.10.23
  2. Evrenzo- SMpC, Available at: Evrenzo (roxadustat) film coated tablets (Great Britain) – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) Accessed 12.10.23
  3. 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.
  4. Agrawal D, Varade D, Shah H, et al. Desidustat in anemia due to nondialysis-dependent chronic kidney disease: a phase 3 study (DREAMND). Am J Nephrol. 2022;53:352–360.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Chertow GM, Pergola PE, Farag YMK, et al. Vadadustat in patients with anemia and non-dialysis-dependent CKD. N Engl J Med. 20
  10. 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 kidney Disease
  11. 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.
  12. Gang S, Khetan P, Varade D, et al. Desidustat in anemia due to dialysisdependent chronic kidney disease: a phase 3 study (DREAM-D). Am J Nephrol. 2022;53:343–351.
  13. 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.
  14. 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;36:1717–1730.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. Nangaku M, Kondo K, Takabe S, et al. Vadadustat for anemia in chronic kidney disease patients on peritoneal dialysis: a phase 3 open-label study in Japan. Ther Apher Dial. 2021;25:642–653.
  20. Nangaku M, Kondo K, Takabe S, et al. A phase 3, open-label, single-arm study of vadadustat for anemia in chronic kidney disease for Japanese patients on hemodialysis not receiving erythropoiesis-stimulating agents. Ther Apher Dial. 2022;26:45–54.