Presentation on theme: "XV Convegno del gruppo di studio di Dialisi Peritoneale"— Presentation transcript:
1XV Convegno del gruppo di studio di Dialisi Peritoneale Bari, Marzo 2010XV Convegno del gruppo di studio di Dialisi PeritonealeUpdate sulla terapiadell'anemia in PDFrancesco LocatelliDipartimento di Nefrologia, Dialisi e Trapianto di ReneOspedale “Alessandro Manzoni” di Lecco
2Erythropoietin has two erythropoietin receptor binding sites EPO receptorEPO receptorMain Points• This slide shows an X-ray crystallography image of rHuEPO and the EPO receptor.1• rHuEPO activates RBC progenitor cells by binding and activating the erythropoietin receptor on the cell surface, which is made up of a dimer of erythropoietin receptor moleculesBackground Information• The Erythropoietin receptor is a member of the superfamily of cytokine receptors. The unique crystal structure that is formed when erythropoietin is complexed to the extracellular ligand-binding domains of the erythropoietin receptor is responsible for optimal signaling through intracellular kinase pathways.1,2• The complex formed by erythropoietin and the extracellular ligand-binding domain of the erythropoietin receptor is held together by two regions located on opposite faces of erythropoietin. These erythropoietin-receptor interfaces on erythropoietin have been identified as high-affinity and low-affinity binding sites.1ReferencesSyed RS, Reid SW, Culwel Li, et al. Efficiency of signaling through cytokine receptors depends critically on receptor orientation. Nature. 1998;395:Cheung JY, Miller BA. Molecular mechanisms of erythropoietin signaling. Nephron. 2001;87:Elliott S, Lorenzini T, Barzilay J, Chang D, Delorme E. Mapping of the active site of recombinant human erythropoietin. Blood. 1997;89:Elliott S, et al. Blood 89: , 1997Syed RS, et al. Nature 395: , 19982
3Erythropoietin has two erythropoietin receptor binding sites EPO receptorEPO receptorrHuEPOMain Points• This slide shows an X-ray crystallography image of rHuEPO and the EPO receptor.1• rHuEPO activates RBC progenitor cells by binding and activating the erythropoietin receptor on the cell surface, which is made up of a dimer of erythropoietin receptor moleculesBackground Information• The Erythropoietin receptor is a member of the superfamily of cytokine receptors. The unique crystal structure that is formed when erythropoietin is complexed to the extracellular ligand-binding domains of the erythropoietin receptor is responsible for optimal signaling through intracellular kinase pathways.1,2• The complex formed by erythropoietin and the extracellular ligand-binding domain of the erythropoietin receptor is held together by two regions located on opposite faces of erythropoietin. These erythropoietin-receptor interfaces on erythropoietin have been identified as high-affinity and low-affinity binding sites.1ReferencesSyed RS, Reid SW, Culwel Li, et al. Efficiency of signaling through cytokine receptors depends critically on receptor orientation. Nature. 1998;395:Cheung JY, Miller BA. Molecular mechanisms of erythropoietin signaling. Nephron. 2001;87:Elliott S, Lorenzini T, Barzilay J, Chang D, Delorme E. Mapping of the active site of recombinant human erythropoietin. Blood. 1997;89:Elliott S, et al. Blood 89: , 1997Syed RS, et al. Nature 395: , 19983
4The ideal ESA Effective Safe Flexible administration route Less frequent administration scheduleCheapKey pointsDespite years of using erythropoiesis-stimulating agents (ESAs) there is still room to improve the pattern of practice in the treatment of anaemiaIt is possible to optimize the use of ESAs by careful selection of the type of ESA used, the best route of administration and the frequency of administrationIt is also posssible to consider potential cost-savings associated with the use of the different ESAs available in the market
5Currently available ESAs Recombinant human erythropoietin (rHuEPO)Epoetin alfaEpoetin betaLong-acting ESAsDarbepoetin alfaDifferent molecular structureIncreased biological activityKey pointsCurrently available erythropoiesis-stimulating agents (ESAs): epoetin alfa, epoetin beta, epoetin delta and darbepoetin alfaDarbepoetin alfa has been engineered to contain five N-linked carbohydrate chains (two more than recombinant human erythropoietin [rHuEPO])Compared with rHuEPO, darbepoetin alfa has a longer serum half-life (approximately three-fold) and greater in vivo potency, even though it has a lower affinity for the erythropoietin receptorDarbepoetin alfa can, therefore, be administered less frequently to obtain the same biological responseBackgroundThere is a direct relationship between the ESA molecule's sialic acid-containing carbohydrate content and its serum half-life and in vivo biological activity, but an inverse relationship with its receptor-binding affinityIncreasing the carbohydrate content should, therefore, lead to a molecule with enhanced biological activityHyperglycosylated rHuEPO analogues such as darbepoetin alfa, were, therefore, developedReferenceEgrie JC et al. Br J Cancer 2001;84(1):3–10CERADifferent mechanism of actionDifferent molecular structureIncreased biological activity
6Biochemical and biological properties of rHuEPO and glycosylation analogs Receptor bindingrHuEPO3 N-linked carbohydrate chainsUp to 14 sialic acids30,400 daltons~40% carbohydrate4 N-linked carbohydrate chainsUp to 18 sialic acids33,750 daltons~46% carbohydrateBiological activitySerum half-lifeNESP5 N-linked carbohydrate chainsUp to 22 sialic acids37,100 daltons~51% carbohydrateThe 4- and 5-N linked chain glycosylation analogs of rHuEPO are biochemically distinct from rHuEPO. They have increased molecular weight, sialic acid content and negative charge. The two extra carbohydrate chains on Aranesp® increase the molecular weight by about 22% and the maximum number of sialic acid residues from 14 to 22.In tests of in vivo efficacy, the magnitude of the hematocrit rise correlated with the number of carbohydrate chains and the sialic acid content of the molecules.Egrie JC, Browne JK. Nephrol Dial Transplant. 2001;16(suppl 3):3-13
7Hb concentrations at 4-week intervals 789101112131415rHuEPONESPHb (g/dL)Patient numbers:37353533343331rHuEPONESP1291281271271231211067751251591317213749Study weekLocatelli F et al. Kidney Int 2001; 60:
9Weeks since withheld dose Time for Hb to return to £12 g/dL after dose withheld due to Hb >14 g/dL16rHuEPO (n = 13)NESP (n = 31)151413Hb (g/dL)1211109–6–5–4–3–2–11234567891011Weeks since withheld doseLocatelli F et al. Kidney Int 2001; 60:
10Percentage of Hb values >14 g/dL Mean % of Hb values > 14 g/dL DA administration Q2W was not associated with an increased frequency of Hb >14 g/dLPercentage of Hb values >14 g/dL543212.6Mean % of Hb values > 14 g/dL1.3Key pointsPatients who switched to the darbepoetin alfa once-every-2-week (Q2W) regimen were less likely to experience haemoglobin (Hb) levels above 14 g/dL, compared with the once-weekly (QW) patients:Proportion of patients (95% CI) with Hb levels >14 g/dL was 1.3% (0.28, 2.22) for Q2W patients and 2.6% (1.33, 3.86) for QW patientsReferenceLocatelli F et al. Nephrol Dial Transplant 2006;21(Suppl 4):SP411 abstract and posterQ2W (n=153)QW (n=153)Locatelli F et al. Nephrol Dial Transplant 2005;20 S.5:MP181
12Serum half life of ESAs IV SC Agent Population Mean (± SE) half-life (h)IVSCEpoetin alfaHealthy volunteers16.8 ± 0.619.4 ± 2.5Epoetin beta8.8 ± 0.524.2 ± 2.6Darbepoetin alfaPeritoneal dialysis patients225.3 ± 2.248.8 ± 5.2C.E.R.A.Healthy volunteers3133 ± 9.8137 ± 21.9Peritoneal dialysis patients4134 ± 19139 ± 20Pharmacokinetic properties of ESAs in healthy volunteers and peritoneal dialysis patientsIn healthy volunteers and patients with chronic kidney disease (CKD) receiving peritoneal dialysis, C.E.R.A. has a prolonged and comparable half-life of approximately 130 h following IV and SC administration.This is considerably longer than the half-lives reported for epoetin (alfa and beta) and darbepoetin alfa. C.E.R.A’.s prolonged serum half-life suggests that it can be administered at extended intervals.1. Halstenson et al. Clin Pharmacol Ther. 1991:50:2. Macdougall et al. J Am Soc Nephrol. 1999;10:3. Dougherty et al. ASCO Macdougall et al. ASN 2005Halstenson CE et al. Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta. Clin Pharmacol Ther. 1991;50:Macdougall IC et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999;10:Dougherty FC et al. C.E.R.A. (Continuous Erythropoiesis Receptor Activator): dose-response, pharmacokinetics and tolerability in phase I multiple ascending dose studies. J Clin Oncol 2004, 22:(Suppl 15)14S (abstract 6692).Macdougall IC et al. Pharmacologic profile of C.E.R.A. (Continuous Erythropoietin Receptor Activator) in chronic kidney disease (CKD) patients (pts) following intravenous (IV) and subcutaneous (SC) administration. Poster presented at 38th Annual Meeting of the American Society of Nephrology, November 8-13, 2005 (J Am Soc Nephrol. 2005;16:[abstract SA-PO926]).
13Understanding how C.E.R.A. is different Receptor bindingpropertiesPharmacokineticpropertiesCERA is different to other erythropoietic stimulating agents (ESAs), having different receptor binding properties.Different pharmacologic profile
15Administration schedule C.E.R.A: Dose independent of schedule Core study, PP population, n=124 (BA16286)Mean (SE) change in Hb (g/dL) at 6 wkn.s.QWQ3WQ4W-1.5-1.0-0.50.00.51.01.5Administration scheduleLocatelli et al. Curr Med Res Opin 2007;23:969–979
16Primary efficacy analysis C. E. R. A Primary efficacy analysis C.E.R.A. up to once-monthly as effective as epoetin TIW-QWNon-inferiority limit: C.E.R.A. groups vs epoetin0.004-0.2150.223C.E.R.A. Q2WITT-0.2130.0310.2760.0250.270-0.220C.E.R.A. Q2WC.E.R.A. Q4WPP-0.1730.2750.051C.E.R.A. Q4Weheanc11_1001 Table 20 page 84 CSReheanc11_4001 Table 21 page 85 CSRFor the non-inferiority test, the mean change in Hb between the baseline and evaluation periods was assessed for C.E.R.A. 1x/2 weeks and 1x/4 weeks and adjusted relative to the mean change in Hb between the baseline and evaluation periods for epoetin. The lower limits of 97.5% confidence interval for the mean difference in Hb between baseline and evaluation periods between the treatment groups for the C.E.R.A. 1x/2 weeks and 1x/4 weeks were both greater than ‑0.75 g/dL, indicating that both C.E.R.A. 1x/2 weeks and 1x/4 were clinically non-inferior to the epoetin reference group.-1.00-0.75-0.50-0.250.000.250.500.751.00Difference in adjusted group mean Hb (g/dL) change between baseline and evaluation (97.5% CI)P< for all comparisonsLevin NW et al. Lancet 2007, 370 (9596):16
17IV C.E.R.A. once- and twice-monthly maintains stable Hb over one year 481216202428323640444852C.E.R.A. Q2W IVC.E.R.A. Q4W IVEpoetin TIW-QW IVMean (SD) Hb (g/dL)MonthsWeeksehe11p_4170Stable Hb levels continued to be maintained with C.E.R.A. throughout the year-long study. Results are shown for the ITT population.ReferenceLevin NW, Fishbane S, Zeig S, Nassar G, Moran J, Villa G, Dougherty FC. Intravenous (IV) C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered once every 2 weeks or once monthly maintains haemoglobin (Hb) levels in patients with chronic kidney disease (CKD) on dialysis. Nephrol Dial Transplant. 2006;21(Suppl 4):iv11 (abstract SO023).Levin NW et al. Lancet 2007, 370 (9596):17
18SC C.E.R.A. once-monthly and twice-monthly as effective as epoetin 3x/wk PROTOS: primary efficacy analysis (PP population)Non-inferiority lower 97.5% CI limit0.1410.380C.E.R.A. 1x/2wk0.217C.E.R.A. 1x/4wkeheanc11_1001 Table 20 BA16740 section efficacy CEeheanc11_4001 Table 21 BA16740 section efficacy CE- 1.00- 0.75- 0.50- 0.250.000.250.500.751.00Difference in mean adjusted Hb versus epoetin (g/dL)P < for all comparisonsSulowicz, Locatelli Clin J Am Soc Nephrol Jul;2(4):637-46
19Stable Hb maintenance with once-monthly SC C. E. R. A Stable Hb maintenance with once-monthly SC C.E.R.A. PROTOS: ITT populationMean (SD) Hb (g/dL)C.E.R.A. 1x/2wkC.E.R.A. 1x/4wkEpoetin 1-3x/wkConversion to IV C.E.R.A. once monthly maintains steady Hb levelsehe11p_4170MonthsWeeks481216202428323640444852Sulowicz, Locatelli Clin J Am Soc Nephrol Jul;2(4):637-46
20IV C.E.R.A. twice-monthly as effective as darbepoetin 1x/wk STRIATA: primary efficacy analysis (PP population)Non-inferiority lower 95.0% CI limit0.180-0.0490.4080.180P <0.408eheanc11_1001eheanc11_4001<<Slide to be animated>>- 1.00- 0.75- 0.50- 0.250.000.250.500.751.00Difference in mean adjusted Hb (g/dL)Canaud….Locatelli et al. ERA - EDTA 2006Canaud….Locatelli et al. Advance Access Published Nephrol Dial Transplant Jul 31
21Stable Hb maintenance with twice-monthly IV C. E. R. A Stable Hb maintenance with twice-monthly IV C.E.R.A. STRIATA: ITT PopulationMean (SD) Hb (g/dL)C.E.R.A. 1x/2wkDarbepoetin 1x/wkConversion to IV C.E.R.A. once monthly maintains steady Hb levelsehe11p_4170MonthsWeeks481216202428323640444852Canaud….Locatelli et al. ERA - EDTA 2006Canaud….Locatelli et al. Advance Access Published Nephrol Dial Transplant Jul 31
22SC C.E.R.A.: Smooth and steady Hb increase with a high response rate ARCTOS: ITT population Mean (SD) Hb (g/dL)Response rate (%)95% CIC.E.R.A. 1x/2wk97.5Darbepoetin alfa 1x/wk96.316C.E.R.A. 1x/2wkDarbepoetin alfa 1x/wk151413121110987MonthsBL123456Final visitWeeks4812162024Macdougall, … Locatelli et al. Clin J Am Soc Nephrol Mar;3(2):337-47
23Hb concentrations during 24-week intervals Locatelli F et al. Kidney Int 2001; 60:Macdougall, … Locatelli et al. Clin J Am Soc Nephrol Mar;3(2):337-47Mean (SD) Hb (g/dL)1615C.E.R.A. 1x/2wk14Darbepoetin alfa 1x/wk13rHuEPO121110987MonthsBL123456Final visitWeeks4812162024
24Fewer patients exceed Hb 13 g/dL with C. E. R. A Fewer patients exceed Hb 13 g/dL with C.E.R.A. than with darbepoetin alfa ARCTOS: ITT population40P <30Patients (%)*2010C.E.R.A. 1x/2wkDarbepoetin alfa 1x/wk*Patients with ≥1 Hb value >13 g/dL during first 8 weeksMacdougall, … Locatelli et al. Clin J Am Soc Nephrol Mar;3(2):337-47
25Weeks since treatment interruption Decline in Hb after withholding treatment Long C.E.R.A. half-life does not affect Hb decline following dose interruption – pooled analysis of maintenance studiesMean (SD) Hb (g/dL)C.E.R.A. Q4W (n=59)16Epoetin (QW to TIW) or darbepoetin alfa (QW or Q2W) (n=126)151413121110-3-2-1123456Weeks since treatment interruption(time 0)Safety populationsLocatelli F. et al Kidney Intern. S : Heifets & Dougherty. WCN 2007
26Half life comparison 140 120 SC IV 100 Hours 80 60 40 20 Methoxy polyethylene glycol-epoetin beta’s half-life is much longer than that of darbepoetin alfa137 h vs 38 h when given SC133 h vs 25 h when given IV140120SC100IV80Hours6040CERA’s half-life is much greater than that of darbepoetin alpha (Aranesp®):137 hours compared to 38 hours when injected SC133 hours compared to 25 hours when dosed IV20EpoetinEpoetinDarbepoetinMethoxy polyethlene glycol-epoetin betaalfabetaalfaHalstenson. Clin Pharmacol Ther. 1991;50:702Macdougall. J Am Soc Nephrol. 1999;10:23925Reigner. Nephrol Dial Transplant. 2003;18(suppl 4):167 Abstract M527
27Half life of epoetins t (hours) Intravenous Subcutaneous 6.8* 19.4* *Healthy volunteers†Peritoneal dialysis patientst(hours)IntravenousSubcutaneousEpoetin alfa6.8*19.4*Epoetin beta8.8*24.2*Darbepoetin alfa†25.348.83:12:1Methoxy polyethylene glycol-epoetin beta1301331:1Hematide75~80Halstenson. Clin Pharmacol Ther. 1991;50:702Macdougall. J Am Soc Nephrol. 1999;10:2392Reigner. Nephrol Dial Transplant. 2003;18(suppl 4):167. Abstract M527Woodburn. Blood. 2004;104:2904
28Ht response to EPO or placebo in PD patients Nissenson AR et al. J Am Soc Nephrol 5: , 1995
29Cosa può influenzare la scarsa risposta agli ESAs in DP? * ERI: EPO resistance indexWei M, et al. Int Urol Nephrol. 2007;39(3):
30ESAs in dialisi peritoneale Sono stati condotti pochi trials sull'uso degli ESA's nei pazienti in dialisi peritonealeLa via di somministrazione di ESAs in dialisi peritoneale deve, per ragioni pratiche, essere SCLe dosi di ESAs necessarie per mantenere livelli di Hb nel range suggerito dalle linee guida in dialisi peritoneale sono ridotte rispetto ai pazienti in emodialisi
31Open-label study description* Treatment + evaluation period Once monthly (QM) dosing of darbepoetin alfa was effective in CKD patients not on dialysisReferenceOpen-label study description*Treatment + evaluation periodHb study target rangePrimary endpointLing1n=98Q2W DA → QM DA29 weeks10-12 g/dl% of patients within Hb study target rangeAgarwal2n=15233 weeks11-13 g/dl% of patients with Hb ≥11 g/dlDisney3n=6610-13 g/dlMaintaining mean Hb ≥10 g/dlSousa4n=7118 monthsEffectiveness and safety of DA QMHoggard5n=442QW/Q2W rHuEPO → QM DA28 weeks% of patients converting from EA QW who preferred DA QM at week 21Ling B, Walczyk M, Agarwal A, Carroll W, Liu W, Brenner R. Darbepoetin alfa administered once monthly maintains hemoglobin concentrations in patients with chronic kidney disease. Clin Nephrol 2005;63:Agarwal AK, Silver MR, Reed JE, et al. An open-label study of darbepoetin alfa administered once monthly for the maintenance of haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis. J Intern Med 2006;260:Disney A, Jersey PD, Kirkland G, et al. Darbepoetin alfa administered monthly maintains haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis: a multicentre, open-label, Australian study. Nephrology (Carlton) 2007;12:Sousa American Society of Nephrology 2006; Abstract SA-PO218.Hoggard J, Crouch T, McMurray S, et al. Preference for monthly darbepoetin alfa dosing in patients with chronic kidney disease not receiving dialysis. Curr Med Res Opin 2006;22:1Ling B et al. Clin Nephrol 2005;63:327-34; 2Agarwal AK et al. J Intern Med 2006;260:577-85; 3Disney A et al. Nephrology (Carlton) 2007;12:95-101; 4Sousa American Society of Nephrology 2006; Abstract SA-PO218; 5Hoggard J et al. Curr Med Res Opin 2006;22:
32Limited evidence with once-monthly dosing DrugAdministration interval (route of administration)Target Hb (g/dL)Population (no. patients enrolled)Trial designReferenceEpoetin alfaQW, Q2W Q3W, Q4W (SC)≥11CKD not on dialysis (n=519)RandomisedProvenzano et al 2005Darbepoetin alfaQ4W (SC)10-12CKD not on dialysis (n=97)Single arm, non-randomisedLing et al 2005≥10CKD not on dialysis (n=66)Disney et al 2007CKD not on dialysis (n=152)Agarwal et al 2006Q3W, Q4Wa (IV and SC)10-13Dialysis patients (n=54)Jadoul et al 2004ESAs, erythropoiesis-stimulating agents; Hb, haemoglobin; IV, intravenous; SC, subcutaneousaDosing once a month is not indicated for darbepoetin alfa in dialysis, except in Switzerland32
33Limited evidence of efficacy in HD patients for once-monthly darbepoetin alfaa Hb (g/dL)Dose (g/wk)Patients on darbepoetin alfa Q2W converted to Q3W dosing and, if Hb stable (10-13 g/dL), to Q4W dosinga522 patients originally recruitedLimited conversion to Q4W dosinga: Of 54 patients entering the study, 36 patients were converted to Q4W dosingLimited maintenance on Q4W dosinga: Of 36 patients converting to Q4W dosing, 30 patients maintained Hb >10 g/dL over 20 weeksHb13.0100Dose12.5Q3W dosing (n=44)Q4W dosinga (n=30)8012.011.56011.04010.510.0209.59.0–2481216202630343842Study weekaDosing once a month is not indicated for darbepoetin alfa in dialysis, except in SwitzerlandJadoul et al. Nephrol Dial Transplant 2004;19:
34Labelled dosing information on maintenance therapy dosing interval MIRCERAOnce-monthly maintenance dosing in CKD patients on dialysis and not on dialysisDarbepoetin alfaIn HD patientsOnce weekly or once every 2 weeks maintenance dosingIn Switzerland in selected HD patients, also once monthlyIn CKD patients not on dialysisStepwise expansion from QW over Q2W to QM for those patients stable on previous dose interval and by doubling the doseCKD, chronic kidney disease; HD, haemodialysis; QW, weekly; Q2W, every 2 weeks; QM, once monthlyARANESP, Summary of Product Characteristics, 2006; MIRCERA, Summary of Product Characteristics, 2007
35The PATRONUS study: a randomised comparison of the efficacy and safety of MIRCERA® with darbepoetin alfa using once-monthly dosing in haemodialysis patients35
36PATRONUS study objectives PrimaryTo compare the efficacy of once-monthly IV MIRCERA® with that of darbepoetin alfa* in the maintenance of Hb levels in HD patients with chronic renal anaemia previously receiving IV darbepoetin alfa maintenance therapySecondaryTo assess the safety and tolerability of IV MIRCERA® in HD patients with chronic renal anaemia previously receiving IV darbepoetin alfa maintenance treatment* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.36
37PATRONUS compared once-monthly MIRCERA® and darbepoetin alfa maintenance treatment Evaluation (wk 50-53)Screening periodMIRCERA® 1x/month (n=245)MIRCERA® 1x/monthPrimary end pointDarbepoetin alfa 1x/weekRDarbepoetin alfa 1x/2 weeks (n=245)Darbepoetin alfa* 1x/month4 weeks26 weeks26 weeksR, randomisation* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
38PATRONUS primary end point Primary end point: superiority assessment of the difference in the proportion of responders between groupsResponders are patients with an average Hb decrease from baseline of <1.0 g/dL and an average Hb >10.5 g/dL during evaluationStudy was powered to detect an absolute difference of 15% in the primary end point between the 2 treatment groupsAssumed 60% of patients would respond to MIRCERA® vs 45% to darbepoetin alfaTarget Hb range: 11–13 g/dL* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
39Analysis populationPrimary efficacy analysis used the intent-to-treat population, defined as all randomised patientsIn case of withdrawals, the last Hb value in the second treatment period was used for the Hb assessment (last value carried forward)To correct for any increase in Hb caused by RBC transfusion, the Hb values measured within 3 weeks after a transfusion were replaced by the Hb value measured immediately before the transfusionSafety population included all patients who received >1 dose of MIRCERA® or darbepoetin alfaRBC, red blood cell* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
40Darbepoetin alfa to MIRCERA® dose conversion schedule Weekly darbepoetin alfa dose (g/week)MIRCERA® starting dose (g/month)<4012040–80200>80360* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.40
41Darbepoetin alfa starting doses Two changes needed:Double Week – 1 doseDouble Week 25 doseWeek 1Week 274 week baseline period26 weeks26 weeks* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
42PATRONUS: A multicentre, multinational trial CountryPatients enrolledFrance95Italy86Spain80Canada65Germany33Belgium31UK22Portugal21Australia15AustriaSwitzerland11Finland9Denmark7Total490* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
43Baseline patient characteristics MIRCERA®n=245Darbepoetin alfaMale, n (%)148 (60)156 (64)Race, n (%)Caucasian233 (95)225 (92)Black5 (2)12 (5)Other7 (3)8 (3)Mean age, years (SD)66.2 (13.6)65.5 (13.9)Mean weight, kg (SD)72.3 (15.1)73.8 (16.9)Mean baseline Hb, g/dL (SD)12.09 (0.56)12.07 (0.55)Mean time since first dialysis, years (SD)4.20 (5.92)4.15 (5.55)DosingMedian darbepoetin alfa dose at week before randomisation, g (IQR)30.0 (20-40)20.0 (15-40)Median study drug dose in month 1, g/month (IQR)120.0 ( )100 (60-160)SD = standard deviation; IQR = Interquartile Range
44Once-monthly MIRCERA® exhibited a superior response rate compared with once-monthly darbepoetin alfa*Primary end point**P<0.000164.1%64.1%Response rate (%)40.4%40.4%CI, confidence interval* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.44
45Superiority limit: MIRCERA® vs darbepoetin alfa Once-monthly MIRCERA® shows a 59% higher likelihood of response compared with once-monthly darbepoetin alfa*Primary end pointSuperiority limit: MIRCERA® vs darbepoetin alfa1.59*1.331.90−0.751.001.251.501.752.0Relative risk of response at evaluation for MIRCERA® vs darbepoetin alfa*P<0.0001* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.45
46Weeks (of trial treatment) Only once-monthly MIRCERA® maintained Hb levels during the second 26-week treatment periodEvaluation (wk 50-53)16.0MIRCERA® (median, IQR)Darbepoetin alfa (median, IQR)15.014.013.012.0Median Hb value (g/dL)11.010.09.08.07.0Baseline481216202428323640444852Weeks (of trial treatment)
47Darbepoetin alfa dose increased by >30% during the second 26-week treatment period Secondary end pointMedian (IQR) treatment dose, g/monthMIRCERA®n=211Darbepoetin alfan=219Week 27200 ( )150 (80-280)Months 11 and 12196 ( )225 ( )0%+35%The median MIRCERA® dose was virtually unchanged during the second 26-week treatment period whereas darbepoetin alfa substantially increased by 35%* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.47
48MIRCERA® dose was unchanged during the second 26-week treatment period 150MIRCERA (median, IQR)Darbepoetin alfa (median, IQR)Secondary end point12510075Trial treatment dose change (%)5025−25−50789101112Months (of trial treatment)* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
49Most safety parameters were similar between the two PATRONUS study groups MIRCERA®, n (%)n=245Darbepoetin alfa, n (%)n=244AEs222 (90.6)217 (88.9)SAEs99 (40.4)94 (38.5)AEs leading to withdrawals3 (1.2)7 (2.9)Withdrawals58 (23.7)96 (39.3)Withdrawals due to insufficient response10 (4.1)48 (19.7)Deaths*14 (5.7)*includes 3 patients who died after withdrawal due to other eventsAEs, adverse event; SAEs, serious adverse eventsSimilar incidence of AEs in both study armshigher rate of constipation with MIRCERA®Most common AEs in both arms were hypertension (14.7 vs 10.7%), procedural hypotension (8.6 vs 11.1%) and nasopharyngitis (10.2 vs 8.2%)Fewer withdrawals with MIRCERA® than with darbepoetin alfa* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.49
50SAEs (>5% in either group) were comparable between study groups in PATRONUS MIRCERA®n=245 n (%)Darbepoetin alfan=244 n (%)All body systems99 (40.4)94 (38.5)Infections and infestations29 (11.8)27 (11.1)Injury, poisoning and procedural complications26 (10.6)18 (7.4)Cardiac16 (6.5)16 (6.6)Vascular14 (5.7)Gastrointestinal11 (4.5)Nervous system7 (2.9)13 (5.3)Neoplasms10 (4.1)5 (2.0)Metabolism and nutrition4 (1.6)Respiratory, thoracic and mediastinal* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.50
52ConclusionsMIRCERA® was shown to be superior to darbepoetin alfa as once-monthly treatment in the dialysis settingSignificantly more patients responded with MIRCERA® compared with darbepoetin alfaMIRCERA® maintained Hb levels within a tight target range during the second 26-week treatment periodMean Hb levels for patients receiving darbepoetin alfa fell to below the lower target (11 g/dL) over the same 26-week period, despite substantial dose increasesThis is the first large, randomised, prospective head-to-head study that has shown one ESA to offer superior efficacy compared with anotherCarrera F et al. WCN 2009 Milano, poster M558* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
53Hb (or at least high levels) vs ESA (or at least high levels)