Peginesatide for anaemia in chronic kidney disease – first and second line June 2012 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The NIHR Horizon Scanning Centre Research Programme is part of the National Institute for Health Research www.nhsc-healthhorizons.org.uk June 2012 Peginesatide for anaemia in chronic kidney disease – first and second line Target group • Symptomatic anaemia: patients on dialysis with chronic kidney disease (CKD) – first and second line. Background Human erythropoietin (EPO) is a protein produced by the kidneys that stimulates the production of red blood cells. Because the kidney is the sole source of EPO synthesis in adults, the reduction in kidney mass that occurs in progressive CKD often causes impairment of EPO production, resulting in anaemia. Technology description Peginesatide (AF-37702) is a synthetic peptide mimetic of EPO that binds directly to the erythropoietin receptor on red blood cell precursors to stimulate red cell formation. Peginesatide is intended as a substitute for currently available erythropoiesis stimulating agents (ESAs) in the treatment of anaemia in CKD dialysis patients. It is administered intravenously (IV) or subcutaneously (SC) at 0.04 mg/kg once monthly. After the initial dose, doses may be titrated to achieve a haemoglobin (Hb) level in the range of 10 to 12g/dL. Peginesatide is also in phase II clinical trials for pure red cell aplasia. Innovation and/or advantages If licensed, peginesatide may offer another treatment option for this patient group. It is administered less frequently than most currently available treatments and can be stored at room temperature for up to three months once dispensed. Developer Takeda Pharmaceuticals Ltd. Availability, launch or marketing dates, and licensing plans Completed phase III clinical trials. NHS or Government Priority Area This topic is relevant to the National Service Framework for Renal Services Part Two: Chronic Kidney Disease, Acute Renal Failure and End of Life Care (2005). Relevant guidance • NICE technology appraisal. Guidance on home compared with hospital haemodialysis for patients with end-stage renal failure. 20021. 2 • NICE clinical guideline. Anaemia management in chronic kidney disease. 2011 . • NICE clinical guideline. Early identification and management of chronic kidney disease in adults in primary and secondary care. 20083. • Kidney Disease: Improving Global Outcomes (KDIGO). Clinical Practice Guideline on Anaemia in CKD in development. Expected 20124. 5 • UK Renal Association. Anaemia of CKD. Clinical practice guidelines. 2010 . 6 • SIGN. Diagnosis and management of chronic kidney disease. 2008 . 2 June 2012 • National Collaborating Centre for Chronic Conditions. Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care. 20087. • National Collaborating Centre for Chronic Conditions. Anaemia management in chronic kidney disease. 20068. • Kidney Disease Outcomes Quality Initiative (KDOQI). National Kidney Foundation clinical practice guidelines and clinical practice recommendations for anaemia in chronic kidney disease in adults. 20069. Clinical need and burden of disease The UK whole population prevalence of stage 3-5 CKD is 4.9%, with an estimated age- standardised prevalence of 8.5% (10.6% in females and 5.8% in males)10. Prevalence of CKD rises dramatically with age and is higher amongst women, and black and minority ethnic groups. Other risk factors for CKD include obesity, diabetes and hypertension1. The prevalence of anaemia in people with CKD depends on the stage of kidney disease, and ranges from 1% in people with moderate decreases in glomerular filtration rate (GFR) to 33% in people with established renal failure11. An estimated 90,000-108,000 of the population in England and Wales have anaemia associated with CKD11. Anaemia is a contributing factor in many of the symptoms associated with reduced kidney function, including fatigue, depression, reduced exercise tolerance and shortness of breath. In addition, anaemia has direct adverse cardiovascular disease (CVD) consequences, such as left ventricular hypertrophy and systolic dysfunction, coronary artery disease, and stroke. As a result, patients with anaemia due to CKD are at increased risk of hospitalisation, increased length of hospital stay, reduced quality of life and 12 increased mortality . Existing comparators and treatments Guidelines suggest that management of anaemia should be considered in people with CKD when their Hb level is≤11g/dL or, if they develop symptoms attributable to anaemia (such as tiredness, shortness of breath, lethargy and palpitations)2. Treatment with ESAs should be offered to patients with anaemia of CKD who are likely to benefit in terms of quality of life and physical function2. Treatment should maintain stable Hb levels between 10 and 12g/dL2. To keep the Hb level within the aspirational range, treatment should be adjusted when Hb levels are within 0.5g/dL of the range’s limits2. The MHRA advise that overcorrection of haemoglobin concentration in patients with CKD may increase the risk of death and serious cardiovascular events13. People receiving ESA maintenance therapy should also be given iron supplements2. Current treatment options include2,14: • Blood transfusion (not indicated for people with anaemia of CKD in whom kidney transplant is a treatment option). • Correction of iron or folate deficiency. • Epoetins - recombinant human erythropoietin. • Darbepoetin (Aranesp) - a hyperglycosylated derivative of epoetin. • Methoxy polyethylene glycol-epoetin beta (Mircera) - a continuous erythropoietin receptor activator. 3 June 2012 Efficacy and safety Trial EMERALD 1, NCT00597753, AFX-01- EMERALD 2, NCT00597584, AFX-01- 12; haemodialysis; peginesatide (IV) or 014; haemodialysis; peginesatide (IV or epoetin alfa; phase III. SC) or epoetin alfa (IV); phase III. Sponsor Affymax. Affymax. Status Complete, unpublished. Complete, unpublished. Source of Abstract15,16, trial registry17, Abstract20,16, trial registry21, information manufacturer18,19. manufacturer18,19. Location USA. USA, EU (inc UK). Design Randomised, active-controlled. Randomised, open-label, active- controlled. Participants n=803; adults; CKD; haemodialysis ≥3 n=823; adults; CKD; haemodialysis ≥3 and schedule months; IV epoetin alfa therapy; Hb months; IV epoetin alfa therapy; Hb values ≥10g/dL and ≤12g/dL. values ≥10g/dL and ≤12g/dL. Randomised to peginesatide, weight- Randomised to peginesatide, weight- based dosing (based on screening epoetin based dosing (based on screening epoetin dose) starting dose 0.04-0.16mg/kg, IV or dose) starting dose 0.04-0.16mg/kg, IV SC every 4 weeks ; or epoetin alpha, or SC every 4 weeks; or epoetin alpha or weight-based dosing, IV or SC 1-3 times beta, weight-based dosing, IV or SC 1-3 weekly. times weekly. Follow-up Up to 6 week screening period, 28 week Up to 6 week screening period, 28 week titration period, 8 week evaluation titration period, 8 week evaluation period); and then ≥16 week long-term period); and then ≥16 week long-term safety and efficacy period. safety and efficacy period. Primary Mean change in Hb. Mean change in Hb. outcome Secondary Red blood cell (RBC) transfusions, Hb RBC transfusions, Hb level 10.0- outcomes level 10.0-12.0g/dL. 12.0g/dL. Key results Peginesatide (n=524) vs epoetin (n=269) Peginesatide (n=542) vs epoetin (n=273) respectively: mean change in Hb (g/dL), - respectively: mean change in Hb (g/dL), - 0.24 vs -0.09 (95% CI -0.29 to -0.01); 0.07 vs -0.17 (95% CI -0.05 to 0.26); RBC transfusions 10.3% vs 8.6%; mean RBC transfusions 7.6% vs 9.9%; mean Hb level maintained at 10-12g/dL during Hb level maintained at 10-12g/dL during evaluation period, 63.0% vs 71.7% evaluation period, 63.5% vs 65.9%; mean (p<0.05); mean Hb during evaluation Hb during evaluation period (g/dL) 11.1 period (g/dL) 11.1 vs 11.3; Hb level vs 11.1; Hb level maintained weeks 1-28 maintained weeks 1-28 (initial titration (initial titration period), 58-68% vs 67- period), 60-69% vs 65-74%; Hb level 78%; Hb level maintained weeks 29-36, maintained weeks 29-36, 63% vs 72%; 64 vs 66%; Hb level maintained weeks Hb level maintained weeks 29-52 29-52 (evaluation and long-term follow (evaluation and long-term follow up up periods), 64-70% vs 65-74%; Hb periods), 67-75% vs 68-75%; Hb levels levels maintained without increasing maintained without increasing RBC RBC transfusion, 8% vs 10%. transfusion, 10% vs 9%. Pooled For peginesatide vs epoetin, respectively: at least one cardiovascular composite results endpointa(CSE); 22.8% vs 24.4%, HR 0.95 (90% CI 0.79 to 1.13). Adverse Peginesatide vs epoetin, respectively: Peginesatide vs epoetin, respectively: effects common AEs: diarrhoea, 20% vs 14%; common AEs: muscle spasm, 20% vs a Composite safety endpoint (CSE) defined as time to first event consisting of death from any cause or a cardiovascular event (myocardial infarction, stroke, or a serious adverse event of congestive heart failure, unstable angina, or arrhythmia). 4 June 2012 cough, 19% vs 20%; dyspnoea, 19% vs 19%; dyspnoea, 18 % vs 18%; nausea, 20%; and nausea,17% vs 19%. 18% vs 20%; and diarrhoea, 17 % vs Serious AEs (SAEs), 58% vs 63%: death, 18%. 11.1% vs 11.2%; stroke, 2.3% vs 4.5 %; SAEs, 49% vs 52%: death, 10.5% vs myocardial infarction, 4.8 % vs 5.9 %; 12.5%; stroke, 2.6% vs 2.9%; myocardial unstable angina, 2.7 % vs 2.6 %; infarction, 4.4% vs 4.8%; unstable congestive heart failure, 11.3 % vs 9.7 %; angina, 1.8% vs 1.8%; congestive heart and arrhythmia, 6.9 % vs 6.7 %. failure, 8.1% vs 8.4%; and arrhythmia, 5.0% vs 6.2%.