Treatment of Anaemia in CKD journal club

Treatment of Anaemia in CKD journal club

1. JOURNAL CLUB Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients A Randomized Clinical Trial The Journal of the American Medical Association Internal Medicine Published on April 4, 2022 MODERATOR : DR SURESH C PRESENTER : DR BHAGYASHREE S

2. CONTENT Introduction Materials & Methods Inclusion criteria Exclusion criteria Trial Design Outcomes Results Adverse events Discussion Limitations of the study References

3. INTRODUCTION CHRONIC KIDNEY DISEASE Definition : CKD is defined as abnormalities of kidney structure or function, present for a minimum of 3 months, with implications for health. Criteria for CKD : Presense of either of the following for a minimum of 3 months Markers of kidney damage (1 or more) ✓Albuminuria (ACR $30 mg/g [$3 mg/mmol]) ✓Urine sediment abnormalities ✓Persistent hematuria ✓Electrolyte and other abnormalities due to tubular disorders ✓Abnormalities detected by histology ✓Structural abnormalities detected by imaging ✓History of kidney transplantation Decreased GFR GFR <60 ml/min per 1.73 m2 (GFR categories G3a–G5)

4. Classification of CKD

5. Risk factors and leading causes of CKD

6. Burden of the disease Global Burden : In 2017, a systematic analysis from the all-age GBD project found 697.5 million cases of all-stage CKD, for a global prevalence of 9.1% (8.5%–9.8%). CKD was estimated to account for 35.8 million DALYs 1.2 million people deaths from CKD. CKD has risen from 19th to 11th in rank among leading causes of death between 1990 and 2019 due to aging and an increasing burden of risk factors for CKD (including diabetes and hypertension) India : Prevalence in India is 16.8 %, as reported Ene-lordache et al. (2016).

7. Anaemia in CKD According to KDIGO , anaemia in CKD is considered when the haemoglobin level is < 13 g/dl in men and < 12 g/dl in women. A normocytic, normochromic anemia is observed as early as stage 3 CKD and is almost universal by stage 4. The primary cause is insufficient production of erythropoietin (EPO) by the diseased kidneys. Clinical manifestations include fatigue and diminished exercise tolerance, angina, heart failure, decreased cognition and mental acuity, and impaired host defense against infection.

8. Causes of Anaemia in CKD

9. TREATMENT OF ANAEMIA IN CKD IRON AGENTS : Adequate bone marrow iron stores should be available before treatment with ESA is initiated. For adult CKD patients with anemia who are not on iron or ESA therapy, it is suggested to try intravenous (IV) iron or, for those with CKD not on dialysis, a 1–3 month trial of oral iron therapy under the following conditions: 1. An increase in hemoglobin (Hb) concentration without starting ESA treatment is desired. 2. Transferrin saturation (TSAT) is ≥30% and ferritin is ≥500 ng/mL. For adult CKD patients on ESA therapy who are not receiving iron supplementation, it is suggested to try IV iron or, for those with CKD not on dialysis, a 1–3 month trial of oral iron therapy under the following conditions: 1. An increase in hemoglobin concentration or a decrease in ESA dose is desired. 2. Transferrin saturation (TSAT) is ≥30% and ferritin is ≥500 ng/mL.

10. Two main strategies in treating Anaemia in CKD Erythropoietin analogues. Compounds that induce the synthesis and secretion of endogenous erythropoietin : HIF- PHI compounds ( hypoxia inducible factor- prolyl hydroxylase inhibitor ) ✓HIF-PHI compounds stimulate erythropoiesis via the inhibition of HIF-PH domain enzymes. ✓This inhibition stabilizes HIF-α transcription factors and induces HIF-responsive genes involved in adaptation to hypoxia, including ✓Endogenous erythropoietin, vascular endothelial growth factor, and certain genes that regulate iron uptake, mobilization, and transport, resulting in decreased hepcidin production. TREATMENT OF ANAEMIA IN CKD

11. B. ERYTHROPOIETIN STIMULATING AGENTS : Erythropoietin (EPO) is a glycoprotein hormone produced by the peritubular cells of the renal cortex. This hormone stimulates RBC production in response to low partial pressure of oxygen. Erythropoiesis stimulating agents (ESAs) are recombinant forms of EPO produced synthetically via recombinant DNA technology in cell cultures. Examples of erythropoiesis-stimulating agents include epoetin alfa, darbepoetin, and methoxy polyethylene glycol-epoetin β. Endogenous erythropoietin and erythropoiesis-stimulating agents induce the division and differentiation of erythroid progenitor cells by acting on EPO receptors present on surface of CD34+ haemotopoietic stem cells. Target Hb levels maintained while on ESA s are 10.0 to 11.5 g/dL , with the targets > 13 g/dL are associated with adverse outcomes. TREATMENT OF ANAEMIA IN CKD

12. C. HIF PH INHIBITORS : Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a novel class of medications for treating anemia in (CKD). These drugs work by stabilizing the HIF complex, which promotes the production of endogenous erythropoietin. HIF-PH inhibitors enhance iron mobilization to the bone marrow and are administered orally. They induce lower but more stable erythropoietin levels compared to (ESAs), potentially leading to fewer adverse cardiovascular effects while maintaining similar hemoglobin levels. Some of the examples are roxadustat, daprodustat, vadadustat, molidustat, and enarodustat, where Daprodustat is the only FDA approved drug for Anemia in CKD. TREATMENT OF ANAEMIA IN CKD

13. The potential advantages of HIF-PHI agents compared with ESA physiologic endogenous erythropoietin levels, oral dosing greater iron availability for erythropoiesis correction of anemia in patients who are hyporesponsive to ESA

14. D. BLOOD TRANSFUSION: Recommendations: For chronic conditions: Erythropoiesis-stimulating agent (ESA) therapy is ineffective due to conditions like hemoglobinopathies, bone marrow failure, or ESA resistance. The risks associated with ESA therapy outweigh its benefits, such as in patients with a history of malignancy or stroke . For acute conditions : Rapid correction of anemia to stabilize the patient's condition, like in cases of acute hemorrhage or unstable coronary artery disease. Rapid pre-operative hemoglobin correction to prepare for surgery. TREATMENT OF ANAEMIA IN CKD

15. Daprodustat Mechanism of action : Reversible inhibition of HIF-PH1, PH2 and PH3 Stabilization & nuclear accumulation of HIF-1α & HIF-2α TF T ranscription of HIF -responsive genes (including EPO)

16. Pharmacokinetics : Onest : ✓ increase in endogenous erythropoietin: 6 to 8 hours. ✓ peak increase in reticulocyte count : u to 15 days . More than 99% protein bound . Metabolism primarily by Cyp2C8. Bioavailability : 65 % Half life : 1 to 4 hours Time to peak: 1 to 4 hours Excretion: Feces: 74% (primarily metabolites); Urine: 21% (primarily metabolites).

17. Indication : Anaemia in CKD Dosing : ✓ In patients not on ESAs Pretreatment hemoglobin level Initial dose <9 g/dL 4 mg OD ≥9 to ≤10 g/dL 2 mg OD >10 g/dL 1 mg OD

18. Current dosing of ESA Intial dose of Daprodustat Epoetin alfa Darbepoetin alfa Methoxy PEG-epoetin beta ≤2K U/week 20 to 30 mcg per 4 weeks 30 to 40 mcg per month 4 mg OD >2K to <10K U/week >30 to 150 mcg per 4 weeks >40 to 180 mcg per month 6 mg OD ≥10K to <20K U/week >150 to 300 mcg per 4 weeks >180 to 360 mcg per month 8 mg OD ≥20K U/week >300 units per 4 weeks >360 mcg per month 12 mg OD ✓ In patients already on ESAs

19. Dose adjustments : ✓ If Hb >11 g/dL: Decrease dose. ✓ If Hb >12 g/dL: Treatment is interrupted , once the Hb falls within treatment range, treatment restarted at 1 dose level lower. ✓ Lack of Hb response: Treatment discontinued after 24 weeks (or sooner) if no Hb increase is achieved. ✓ In liver impairment : * Child-Pugh class A : No dosage adjustment * Child-Pugh class B : 50% of usual recommended dose * Child-Pugh class C : Not recommended

20. Adverse events : Exacerbation of hypertension ( 24 % ) Abdominal pain (11%) Gastrointestinal erosion (≤6 %) Malignant neoplasm (4%) Hypersensitivity reaction (7%) Dizziness (7%) Others : Acute myocardial infarction, deep vein thrombosis, heart failure, pulmonary embolism, thrombosis (vascular access), venous thromboembolism , CVA. Contraindications : Uncontrolled Hypertension Concomitant use with strong CYP2C8 inhibitors (eg, gemfibrozil)

21. Journal proper Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients A Randomized Clinical Trial Ajay K. Singh, BorutCizman, KevinCarroll, JohnJ.V.McMurray et al.

22. Introduction Incident dialysis(ID) is arbitrarily defined as dialysis initiated within 90 to 120 days The first 90 days of initiating dialysis is a period of high risk for patients, with mortality twice as high as the mortality in the subsequent 9 months. Because Incident dialysis patients undergo abrupt physiological and psychological changes, including metabolic flux from clearances of uremic mediators correction of anemia changes in parameters of metabolic bone disease, changes in blood pressure and extracellular volume. patients also have evidence of heightened inflammation and protein-calorie malnutrition.

23. Materials and Methods Study design : ASCEND ID trial. It is a global, randomized, open-label, active-control-group, phase 3 clinical trial. Efficacy and safety of daprodustat and darbepoetin alfa in patients recently initiating hemodialysis (HD) or peritoneal dialysis (PD). Study duration : May 11, 2017 to September 24, 2020. Consisted of 4 periods: screening stabilization period (day 1 to week 28) evaluation period (week 28 to52) follow-up (week 56 to 58)

24. ASCEND ID Study Design

25. INCLUSION CRITERIA Between 18 and 99 years of age Planning to start chronic dialysis with the next 6 weeks from the date of the screening visit OR have started and received dialysis (as specific below) for end-stage renal disease for a maximum of ≤90 days. Not expected to stop dialysis during the duration of the trial Hemoglobin concentration of 8-10.5 g/dL at screening and 8-11.0 g/dL at randomization Informed consent at screening

26. Planned for kidney transplant during the study. Ferritin ≤100 ng/mL (≤100 µg/L) at screening or after IV iron supplementation Transferrin saturation ≤20% at screening or after IV iron supplementation Vitamin B12 below the lower limit of the reference range at screening or after vitamin B12 supplementation Folate <2.0 ng/mL (<4.5 nmol/L) at screening History of bone marrow aplasia or pure red cell aplasia Untreated pernicious anemia, thalassemia major, sickle cell disease, or myelodysplastic syndrome Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR clinically significant gastrointestinal bleeding ≤10 weeks prior to screening through to randomization (Day 1) Use of any ESA treatment within 8 weeks prior to screening except for limited use as part of dialysis initiation EXCLUSION CRITERIA

27. Myocardial infarction or acute coronary syndrome ≤10 weeks prior to screening through to randomization (Day 1) Stroke or transient ischemic attack ≤10 weeks prior to screening through to randomization (Day 1) Chronic Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system Current uncontrolled hypertension as determined by the Investigator that would contraindicate the use of rhEPO Liver disease History of malignancy within 2 years prior to screening through to randomization (Day 1), or currently receiving treatment for cancer or complex kidney cyst >3cm History of severe allergic reactions of anaphylactic reactions to excipients in the investigational product or darbepoetin alfa EXCLUSION CRITERIA : Continued

28. Initially patients were stratified based on ✓ Dialysis type : Hemo Dialysis vs Peritoneal Dialysis. ✓ Dialysis manner : Planned Dialysis vs Unplanned or Urgent Dialysis ( Unplanned dialysis or urgent dialysis was defined as no nephrology care or referral within the previous 4 months and/or an HD start with temporary vascular access with no previous planning for chronic dialysis or recent (<2 weeks) PD catheter insertion ) Following stratification, patients were randomized 1:1 to daprodustat or darbepoetin alfa. RANDOMIZATION

29. The starting doses of daprodustat and darbepoetin alfa, based on the Hb concentration at randomization on day 1 is given. Protocol-specified dose adjustment algorithm to achieve and maintain Hb concentrations within 10.0 to11.0 g/dL was applied for both treatments. Iron management criteria were implemented to ensure patients remained iron replete and not iron overloaded. A rescue algorithm was used to minimize inadequate Hb response to the assigned anemia treatment. INTERVENTION

30. Starting doses of daprodustat and Darbepoetin alfa

31. Primary Outcome : ✓ To demonstrate the non-inferiority of daprodustat compared with darbepoetin alfa in increasing and maintaining the Hb concentration assessed as the mean change in Hb concentration from baseline during this period. Secondary Outcome : ✓ The mean monthly intravenous (IV) iron dose during the study period (baseline to week 52) ✓ Safety and tolerability comparison between two groups. OUTCOMES OF THE STUDY

32. Study population ✓ Overall, 518 patients were screened worldwide, with 206 (40%)not meeting eligibility criteria . ✓ The remaining 312 patients were randomized at 90 centers in 14 countries to either daprodustat (157) or darbepoetin alfa. ✓ Randomized treatment was prematurely discontinued in 45 patients (29%) receiving daprodustat and 39 (25%) receiving darbepoetin alfa; ✓ 306 patients (98%) completed the study. ✓ The mean(SD) baseline Hb concentration was 9.46(1.00) g/dL in the daprodustat group and 9.49 (0.97)g/dL in the darbepoetin alfa group. ✓Baseline IV iron use was similar between groups (daprodustat,67%;darbepoetinalfa,70%),although the median (IQR) standardized IV iron dose at baseline was lower in the daprodustat group (87mg/mo[0-230mg/mo]) than in the darbepoetin alfa group (130mg/mo[0-280mg/mo]) RESULTS OF THE STUDY

33. Treatment exposure and dosing : The exposure to randomized treatment was comparable between the two groups: ✓ In the daprodustat arm, 135 patients (86%) received treatment for over 6 months. ✓ In the darbepoetin arm, 139 patients (90%) received treatment for over 6 months. Dosing: ✓ The median daily dose for daprodustat was 2 mg and that of darbepoetin alfa was 60 μg administered every 4 weeks. Duration of Exposure: ✓The median total duration of exposure was 12.0 months (IQR: 9.6-12.0 months) for the daprodustat arm. ✓The median total duration of exposure was 12 months (IQR: 11.8-12.1 months) for the darbepoetin arm. RESULTS OF THE STUDY

34. B. Haemoglobin efficacy : ✓During the evaluation period, the mean (SD) Hb concentration was 10.5 (1.0) g/dL in the daprodustat arm and 10.6 (0.9)g/dL in the darbepoetin alfa arm, which remained in the analysis range of 10.0 to 11.5 g/dL . ✓The adjusted mean (SE) change from baseline in the daprodustat vs darbepoetin alfa groups was 1.02 (0.09) g/dLvs 1.12 (0.09) g/dL, giving a treatment difference of −0.10 g/dL (95% CI, −0.34 to 0.14 g/dL). ✓Thus achieving noninferiority of daprodustat compared with darbepoetin alfa at the prespecified noninferioritymargin of −0.75 g/dL. RESULTS OF THE STUDY

35. Daprodustat: ✓Total Iron-Binding Capacity (TIBC): Increased. ✓Ferritin Level: Decreased. ✓Transferrin Saturation: Remained relatively stable. ✓Total Iron Level: Remained relatively stable. ✓Hepcidin Level: Reduced by 26%, from a mean of 112.6 ng/mL to 82.8 ng/mL. Darbepoetin Alfa: ✓Total Iron-Binding Capacity (TIBC): Remained similar to baseline. ✓Ferritin Level: No specific data provided. ✓Hepcidin Level: Reduced by 10%, from a mean of 111.6 ng/mL to 100.2 ng/mL (In summary, daprodustat led to significant changes in iron metabolism markers, notably increasing TIBC and decreasing ferritin, while also markedly reducing hepcidin levels. On the other hand, darbepoetin alfa had a more modest effect on hepcidin and didnot affect TIBC significantly. RESULTS OF THE STUDY

36. Markers of Iron metabolism and use : Reduction in Monthly IV Iron Use: Both treatment groups experienced a decrease in mean monthly IV iron use from baseline to week 52. Comparison of Treatments: Daprodustat was not superior to darbepoetin alfa in terms of reducing monthly IV iron use. The adjusted mean treatment difference was 19.4 mg/month, with a 95% confidence interval of –11.0 to 49.9 mg/month, indicating that the difference could be either a reduction or an increase. Mean Monthly IV Iron Use: Daprodustat: 142 mg (SD 161 mg)Darbepoetin Alfa: 128 mg (SD 137 mg) RESULTS OF THE STUDY

37. Three percent of patients in both treatment groups (5 in daprodustat and 5 in darbepoetin alfa) met the rescue criteria, resulting in permanent discontinuation of randomized treatment. The rate of a first occurrence of redbloodcell or whole blood transfusion during the on-treatment period was similar between the groups. RESCUE AND TRANSFUSIONS

38. The proportion of patients experiencing treatment-emergent AEs ands serious AEs was generally similar between the treatment arms. Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa. The incidence of potential AEs of special interest was generally similar between treatment groups for each category of AEs of special interest. Adverse Events and safety outcomes

39. This randomized clinical trial demonstrated that daprodustat was non inferior to darbepoetin alfa for increasing and maintaining Hb concentration for 52 weeks in patients receiving both incident HD and PD . The difference in Hb change from baseline was 0.10g/dL between the treatment arms. The response to daprodustat was comparable with the response to darbepoetin alfa across several sub groups and was robust for both treatments ,even among patients with higher levels of inflammatory markers such as high-sensitivity C reactive protein. The daprodustat - induced Hb response was independent of baseline levels of high-sensitivity C-reactive protein, further supporting its efficacy among ID patients who have increased levels of inflammation. DISCUSSION

40. Iron use , a key secondary outcome,was similar between patients treated with daprodustat and darbepoetin alfa , and there was not a significant reduction in iron use in the daprodustat-treated patients compared with patients treated with darbepoetin alfa. Overall , daprodustat’s safety profile appeared to be similar to that of darbepoetin alfa , and no unexpected safety concerns were identified. DISCUSSION

41. Study showed non inferiority of daprodustat to darbepoetin alfa in the treatment of anemia in ID patients. Daprodustat was effective in maintaining Hb concentrations in a subgroup of patients with an unplanned dialysis start , in patients receiving PD, and in patients with inflammation. Monthly IV iron use was similar in both study arms, and although changes in iron kinetics with daprodustat were observed, the significance of these findings is not clear. Based on the efficacy and short term safety data in this study, daprodustat may represent a potential oral alternative to one of the conventional ESAs for patients with CKD whoare starting dialysis. CONCLUSION

42. a relatively short 52 weeks study treatment length and a small sample size, limited the evaluation of MACE safety outcomes. The openlabel design may have contributed to biased AE reporting. As darbepoetin alfa was used in this trial , conclusions about noninferiority to other ESAs are limited. LIMITATION

43. A study Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis , concluded that, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. Study of the efficacy of Roxadustat for the treatment of anemia in dialysis dependent CKD patients: an updated systematic review and meta-analysis of randomized clinical trials showed , ROX increased Hb level and improved iron utilization parameters in DD-CKD patients, RELATED STUDIES

44. A study of Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis concluded that among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. RELATED STUDIES

45. Harrison's Principles Of Internal Medicine KDIGO 2024 Clinical Practice Guideline for the evaluation and management of CKD KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease - 2012 Hasan M, Sutradhar I, Gupta RD, Sarker M. Prevalence of chronic kidney disease in South Asia: a systematic review. BMC Nephrol. 2018 Oct 23;19(1):291. doi: 10.1186/s12882-018-1072-5. PMID: 30352554; PMCID: PMC6199753. https://www-uptodate-com.rguhs.remotlog.com/contents/daprodustat-dru g-information REFERENCES

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