Peginesatide for Anaemia in Chronic Kidney Disease – First and Second Line

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%.

Trial PEARL 1, NCT00598273, AFX-01-11; PEARL 2, NCT00598442, AFX-01-013; non-dialysis patients; peginesatide (SC) non-dialysis patients; peginesatide (SC) or darbepoetin alpha; phase III. or darbepoetin alpha; phase III. Sponsor Affymax. Affymax. Status Complete, unpublished. Complete, unpublished. Source of Abstract22,23, Trial registry 24, Abstract23,25, Trial registry26, information manufacturer18. manufacturer18. Location USA. USA, EU (inc UK). Design Randomised, open-label, active- Randomised, open-label, active- controlled. controlled. Participants n=490; adults; CKD; not expected to n=493; adults; CKD; not expected to and schedule begin dialysis ≥12 weeks; no ESA begin dialysis ≥12 weeks; Hb ≥8.0g/dL treatment ≥12 weeks; Hb values ≥8.0g/dL and <11.0g/dL. and ≤11.0g/dL. Randomised to peginesatide starting dose Randomised to peginesatide starting dose 0.025mg/kg or 0.04mg/kg monthly, or 0.025mg/kg or 0.04mg/kg monthly, or darbepoetin alpha starting dose 0.75µg/kg darbepoetin alpha starting dose 0.75µg/kg every two weeks, titrated to maintain Hb every two weeks, titrated to maintain Hb of 11-12g/dL. of 11-12g/dL. All administered SC. All administered SC. Follow-up Screening period within 4 weeks of Screening period within 4 weeks of randomisation; active treatment period randomisation; active treatment period include 24 week correction period, 12 include 24 week correction period, 12 week evaluation period); and then ≥16 week evaluation period); and then ≥16 week long-term safety and efficacy week long-term safety and efficacy period. period. Primary Mean change in Hb (evaluation period, Mean change in Hb (evaluation period, outcome weeks 25-36). weeks 25-36). Secondary RBC transfusions, Hb response. RBC transfusions, Hb response. outcome Key results Peginesatide 0.025mg/kg (n=161) and Peginesatide 0.025mg/kg (n=167) and 0.04mg/kg (n=165) vs darbepoetin 0.04mg/kg (n=163) vs darbepoetin (n=164), respectively: mean change in Hb (n=163), respectively: mean change in Hb (g/dL) 1.39 (97.5% CI, -0.19 to 0.26) and (g/dL) 1.50 (97.5% CI, -0.09 to 0.36) and 1.64 (97.5% CI, 0.04 to 0.48) vs 1.37; 1.68 (97.5% CI, 0.08 to 0.54) vs 1.35; RBC transfusions, 6.2% (p>0.05) and RBC transfusions, 11.4% and 10.4% vs 7.3% (p>0.05) vs 4.9%; mean Hb level 4.9% (p<0.05 between peginesatide maintained at 11.0-12.0g/dL during 0.04mg/kg and darbepoetin groups); evaluation period, 93% and 94% vs 94%; mean Hb level maintained at 11.0- mean Hb during evaluation period (g/dL), 12.0g/dL during evaluation period, 91% 11.5 and 11.6 vs 11.5. and 93% vs 95%; mean Hb during evaluation period (g/dL), 11.6 and 11.7 vs 11.4. Pooled For peginesatide vs darbepoetin, respectively: at least one CSE; 21.6% vs 17.1%, HR results 1.34 (90% CI, 1.03 to 1.73). Significantly increased risk for sudden death. Peginesatide statistically non-inferior in correcting anaemia and maintaining target Hb levels. 5 June 2012

Adverse AEs peginesatide 0.025mg/kg vs AEs peginesatide 0.025mg/kg vs events 0.04mg/kg vs darbepoetin, respectively: 0.04mg/kg vs darbepoetin, respectively: 48% vs 46% vs 43%. 52% vs 49% vs 43%.

Pooled analysis of all phase III studies (EMERALD 1 and 2, PEARL 1 and 2) – experience of at least one CSE18: peginesatide 22.4% vs epoetin or darbepoetin 21.6%, hazard ratio (HR) 1.06b (90% CI 0.91 to 1.22).

Trial DIAMOND, NCT01478971, AFX01-18; CKD; dialysis patients; peginesatide (IV or SC); phase III. Sponsor Affymax. Status Ongoing. Source of Trial registry27, manufacturer. information Location USA. Design Non-randomised, single arm. Participants n=240; adults; CKD; anaemia; haemodialysis for ≥12 weeks; epoetin therapy. and schedule The company are currently unable to advise on the dose or schedule to be used. Follow-up Active treatment period 6 months; then 7 months follow up. Primary Conversion to peginesatide. outcome Secondary Peginesatide dosing; dose deviations; Hb range of 10-11g/dL; total intravenous iron outcomes dose; red blood cell transfusions. Expected December 2012. reporting date

Trial NCT00680043, AFX-01- NCT00752609, AFX-01- NCT00434330, AFX-01- 15; haemodialysis; 202; peginesatide IV or 07; haemodialysis; peginesatide IV or epoetin SC; phase II. peginesatide IV or SC; alpha IV; phase II. phase II. Sponsor Affymax. Takeda; Affymax. Affymax. Status Complete, unpublished. Complete, unpublished. Complete, unpublished. Source of Abstract28, trial registry29, Abstract24, trial registry30, Trial registry31, information manufacturer. manufacturer. manufacturer. Location Russian Federation. USA. EU (inc UK). Design Randomised, open-label, Non-randomised, open Non-randomised, open active-controlled. label. label. Participants n=114; adults; CKD; n=101; adults; CKD; n=91; adults; CKD; and schedule haemodialysis for ≥2 haemodialysis for ≥6 haemodialysis for ≥ 3 weeks; Hb values ≥8.0g/dL months or not yet on months; epoetin and <11.0g/dL; no ESA dialysis; stable darbepoetin maintenance therapy; Hb treatment in ≥12 weeks. alfa maintenance therapy; values ≥10.0 and Randomised to mean Hb values ≥10.0 and ≤12.5g/dL; ferritin peginesatide 0.04mg/kg or ≤12.0g/dL. ≥100µg/l; transferrin 0.08mg/kg once every 4 Received peginesatide saturation (TSAT) ≥20%. weeks, or epoetin starting 0.04mg/kg-0.16mg/kg SC Received tiered dose 50U/kg once every 2 or IV every 4 weeks, for peginesatide, weight-based weeks, all titrated to 24 weeks. dosing, all administered maintain Hb of 11-12g/dL. once every 4 weeks for a All administered IV. total of 7 doses as IV or SC, with or without transition period between b Non-inferiority defined as the hazard ratio upper limit 90% CI ≤1.3. 6 June 2012

epoetin and peginesatide treatment. Dose adjustments allowed. Follow-up 28 weeks treatment. 24 weeks treatment. 28 weeks treatment. Primary Mean change in Hb. Mean change in Hb. Average weekly change in outcomes Hb; change in Hb. Secondary RBC transfusions, Hb Mean Hb within 10 to Hb ±1.0g/dL of baseline; outcomes response. 12g/dL; change in Hb of maintenance of Hb values ≤1g/dL; RBC 9.5-13.0g/dL. transfusions; mean Hb during 4-week intervals; maintenance of target Hb during 4-week intervals; dose adjustments. Key results Interim analysis (12 70.7% maintained Hb Mean peginesatide starting weeks): for all 3 groups within 10 to 12g/dL. dose was 0.053mg/kg; mean Hb increased from mean dose during study mean overall baseline of 0.055mg/kg; mean Hb 9.2 g/dL, and was levels maintained between maintained in target range -0.6g/dL and +1.4g/dL of of 10-12g/dL. baseline (10.75g/dL and 12.5g/dL). Adverse AEs reported as related to Common AE: diarrhoea, Injection related AEs events peginesatide were: 13.9%. occurring ≥2 patients: hypertension, 4.5%; SAEs: arteriovenous increased blood pressure catheter-related fistula; thrombosis; chest (3.3%); headache (3.3%); complication, 0.9%; and pain; congestive cardiac and infusion site procedural hypertension, failure; pleural effusion. thrombosis (2.2%). 0.9%. The company to advise on 16 patients experienced 27 the proportion of patients. SAEs, including 6 Four patients withdrew arteriovenous fistula from the study because of thromboses and 2 vitreous AEs. haemorrhages.

Trial NCT00109291, AFX-01- NCT00228449, AFX-01- NCT00228436, AFX-01- 02; peginesatide vs 03; haemodialysis; 04; peginesatide IV or SC; placebo IV; phase II. peginesatide IV; phase II. phase II. Sponsor Affymax. Affymax. Affymax. Status Complete, unpublished. Complete, unpublished. Complete, published. Source of Trial registry32, Abstract33, trial registry34, Publication35, trial information manufacturer. manufacturer. registry36, manufacturer. Location UK. USA. EU (inc UK). Design Randomised, placebo Non-randomised, open Non-randomised, open controlled. label. label. Participants n=17; adults; CKD; Hb n=165; adults; CKD; n=139; adults; CKD; not and schedule ≥9g/dL and ≤11g/dL; haemodialysis ≥6 months; expected to begin dialysis glomerular filtration rate epoetin alfa maintenance ≥12 weeks; no treatment (GFR) ≤60mL/min; no therapy for ≥8 weeks; Hb with ESAs ≥12 weeks; Hb previous treatment with ≥10.0 and ≤12.5g/dL; ≥9.0 and <11.0g/dL; ESAs; not on dialysis. ferritin ≥100µg/l; TSAT ferritin >100µg/l; TSAT Randomised to single dose ≥20%. >20%. of peginesatide Received peginesatide Received peginesatide; 0.025mg/kg, 0.05mg/kg, monthly based on once every 4 weeks for 6 0.10mg/kg, or placebo. conversion factor, weight- doses, or once every 2 based or tiered fixed dose weeks for 12 doses; 7 June 2012

strategy for 6 doses. Dose weight-based dose adjustments allowed. (0.05mg/kg, 0.075 mg/kg, 0.0375mg/kg or 0.025mg/kg) or fixed dose (3.0mg or 4.0mg) regimens; IV or SC. Dose adjustments allowed. Follow-up 29 days. 24 weeks. 24 weeks. Primary Safety. Average weekly Hb; Dose range. outcomes change in Hb. Secondary Pharmacodynamics; Hb within ±1.0g/dL of - outcomes pharmacokinetics; baseline; maintainance of pharmacologically active Hb within 9.5-13.0g/dL. dose (PAD). Key results Hb response from baseline In cohorts using a weight- Starting doses of showed dose-dependent based strategy and no 0.05mg/kg monthly, and clinically significant transition period (1 week 0.075mg/kg monthly, and increases with increasing without ESA 4.0mg fixed dose monthly peginesatide dose. treatment), mean Hb resulted in mean Hb exceeded 12.0g/dL shortly increase ≥1g/dL within 2 following conversion. In weeks, sustained to week cohorts using a transition 25. Mean Hb maintained period, mean Hb level did between 11.0g/dL and not exceed 12.0g/dL. 13.0g/dL from weeks 3 to 25. Starting doses of 0.025mg/kg monthly and 3.0mg fixed dose monthly required longer to achieve Hb increase ≥1g/dL, though mean Hb levels maintained between 11 and 13g/dL from weeks 7 to 25. Adverse Common AEs included: AEs reported as related to AEs reported as related to events headache (23.1%) and peginesatide in ≥2 subjects peginesatide in ≥2 patients back pain (15.4%). were fatigue (1.8%), were hypertension (6.5%), All AEs considered decreased Hb (1.8%), arthritis (1.4%) and unrelated to study asthenia (1.2%) and rash headache (1.4%). treatment. No SAEs or (1.2%). 47 patients deaths reported. experienced 81 SAEs, including an infusion related reaction related to peginesatide injection.

Estimated cost and cost impact The cost of peginesatide is not yet known. The company state that peginesatide will be priced at similar levels to current ESA agents.

The costs for the starting dose of other selected treatments for anaemia in CKD are as follows37:

8 June 2012

Drug Dosec Cost per 28 days Darbepoetin alfa (Aranesp) 750ng/kg SC once every 2 weeks. £176 (SC) 450ng/kg IV once weekly. £235 (IV) Epoetin alpha (Binocrit) 50U/kg IV 3 times weekly. £244 (IV) Epoetin alpha (Eprex) 50U/kg SC or IV 3 times weekly. £266 (SC) Epoetin beta (NeoRecormon) 20U/kg SC 3 times weekly. £180 (SC) 40U/kg IV 3 times weekly. £360 (IV) Epoetin theta (Eporatio) 20U/kg SC 3 times weekly. £144 (SC) 40U/kg IV 3 times weekly. £288 (IV) Epoetin zeta (Retacrit) 50U/kg SC or IV 3 times weekly. £272 Methoxy polyethylene glycol- 600ng/kg SC or IV once every 2 weeks. £147 epoetin beta (Mircera)

Claimed or potential impact – speculative

Patients Reduced mortality or increased  Reduction in associated morbidity Quicker, earlier or more accurate length of survival or improved quality of life for diagnosis or identification of patients and/or carers disease Other: None identified

Services Increased use Service organisation Staff requirements

 Decreased use: once monthly Other: None identified administration.

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: Savings:  Other: uncertain unit cost compared to existing treatment options.

Other issues Clinical uncertainty or other research question identified:  None identified

References

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8 National Collaborating Centre for Chronic Conditions. Anaemia management in chronic kidney disease. National clinical guideline for management in adults and children. London (UK): Royal College of Physicians; 2006. 9 KDOQI; National Kidney Foundation Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease in adults. American Journal of Kidney Diseases. 2006; 47(5 suppl 3):S16-85. 10Stevens PE, O'Donoghue DJ, de Lusignan S et al. Chronic kidney disease management in the United Kingdom: NEOERICA project results. Kidney International 2007;72:92–99. 11National Institute for Health and Clinical Excellence. Anaemia management in chronic kidney disease. Clinical guideline. CG39. London: NICE; September 2006. 12Hayat A, Haria D and Salifu M. Erythropoietin stimulating agents in the management of anemia of chronic kidney disease. Patient Preference and Adherence 2008:2;195–200. 13MHRA Public Assessment Report. Epoetins for the management of anaemia in patients with chronic renal disease: mortality and cardiovascular morbidity. November 2007. http://www.mhra.gov.uk/ Accessed 30 March 2012. 14British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 63. London: BMJ Group and RPS Publishing, March 2012. 15Schiller, et al. Safety and Efficacy of Peginesatide for Treatment of Anemia in Hemodialysis Patients Previously on Epoetin Alfa. National Kidney Foundation Spring Clinical Meetings (NKF) 2011, Las Vegas. April 2011. Poster 191. 16Schiller B, Locatelli F, Covic AC et al. Primary results from two phase 3 randomized, active-controlled, open- label studies (EMERALD 1 and EMERALD 2) of the safety and efficacy of Hematide/Peginesatide for the maintenance treatment of anemia in patients with chronic renal failure who were receiving hemodialysis and were previously treated with epoetin alfa or epoetin beta. Late-breaking clinical trials. Journal of the American Society of Nephrology 2010;21:2B. 17ClinicalTrials.gov. Hematide injection for anemia in chronic hemodialysis (HD) patients (EMERALD 1) http://www.clinicaltrials.gov/ct2/show/NCT00597753 Accessed 29 March 2012. 18Affymax. Affymax and Takeda announce phase 3 trials meet primary endpoints for investigational drug, hematide/peginesatide, to treat anemia in chronic renal failure with some differences noted in secondary analyses. Press release. 21 June 2010. http://www.investors.affymax.com/releasedetail.cfm?ReleaseID=481068 19Takeda. Affymax and takeda report additional phase 3 clinical trial data for peginesatide in dialysis patients at the national kidney foundation spring clinical meetings. Press release. 28 April 2011. http://www.takeda.com/press/article_40784.html 20Besarab A et al. Safety and efficacy of peginesatide for treatment of anemia in hemodialysis patients previously on epoetin alfa or beta. National Kidney Foundation Spring Clinical Meetings (NKF) 2011, Las Vegas. April 2011. Poster 183. 21ClinicalTrials.gov. Hematide injection for anemia in chronic hemodialysis (HD) patients (EMERALD 2) http://www.clinicaltrials.gov/ct2/show/NCT00597584 Accessed 29 March 2012. 22Fishbane S et al. Primary safety and efficacy results from four phase 3 randomized, active-controlled, open-label studies of hematide/peginesatide among CKD dialysis and non-dialysis patients. American Society of Nephrology (ASN) Renal week, 43rd Annual Meeting and Scientific Exposition, Denver, CO. November 2010. Abstract LB-FC3 23Macdougall IC, Provenzano R, Pergola PE et al. Primary results from two phase 3 randomized, active- controlled, open-label studies (PEARL 1 and PEARL 2) of the safety and efficacy of Hematide™/Peginesatide for the correction of anemia in patients with chronic renal failure not on dialysis and not receiving treatment with erythropoiesis-stimulating agents. 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Conversion study from epoetin alfa to monthly peginesatide injection in patients with chronic kidney disease on dialysis (DIAMOND) http://clinicaltrials.gov/ct2/show/NCT01478971 Accessed 29 March 2012. 28Gurevich A, Yampolskiy A, Timokhovskaya G et al. Interim analysis of once-monthly hematide efficacy and safety in HD patients not on ESA treatment. Renal Week 2009: American Society of Nephrology (ASN) Annual Meeting, San Diego, CA. October 2009. Poster F-PO1094. 10 June 2012

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