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Francesco Locatelli Dipartimento di Nefrologia, Dialisi e Trapianto di Rene Ospedale “Alessandro Manzoni” di Lecco Bari, 19-20 Marzo 2010 XV Convegno del.

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Presentation on theme: "Francesco Locatelli Dipartimento di Nefrologia, Dialisi e Trapianto di Rene Ospedale “Alessandro Manzoni” di Lecco Bari, 19-20 Marzo 2010 XV Convegno del."— Presentation transcript:

1 Francesco Locatelli Dipartimento di Nefrologia, Dialisi e Trapianto di Rene Ospedale “Alessandro Manzoni” di Lecco Bari, 19-20 Marzo 2010 XV Convegno del gruppo di studio di Dialisi Peritoneale

2 EPO receptor Elliott S, et al. Blood 89: 493-502, 1997 Syed RS, et al. Nature 395: 511-516, 1998 Erythropoietin has two erythropoietin receptor binding sites

3 EPO receptor Erythropoietin has two erythropoietin receptor binding sites EPO receptor rHuEPO Elliott S, et al. Blood 89: 493-502, 1997 Syed RS, et al. Nature 395: 511-516, 1998

4 The ideal ESA  Effective  Safe  Flexible administration route  Less frequent administration schedule  Cheap

5 Currently available ESAs  Recombinant human erythropoietin (rHuEPO) –Epoetin alfa –Epoetin beta  Long-acting ESAs –Darbepoetin alfa Different molecular structure Increased biological activity - CERA Different mechanism of action Different molecular structure Increased biological activity

6 rHuEPO 3 N-linked carbohydrate chains Up to 14 sialic acids 30,400 daltons ~40% carbohydrate Egrie JC, Browne JK. Nephrol Dial Transplant. 2001;16(suppl 3):3-13 4 N-linked carbohydrate chains Up to 18 sialic acids 33,750 daltons ~46% carbohydrate NESP 5 N-linked carbohydrate chains Up to 22 sialic acids 37,100 daltons ~51% carbohydrate Biological activitySerum half-life Receptor binding Biochemical and biological properties of rHuEPO and glycosylation analogs

7 Hb concentrations at 4-week intervals 7 8 9 10 11 12 13 14 15 Study week 251591317213749 Hb (g/dL) 37 129 35 128 35 127 33 127 34 123 33 121 31 1067751 rHuEPO NESP rHuEPO NESP Patient numbers: Locatelli F et al. Kidney Int 2001; 60: 741-747

8

9 Weeks since withheld dose 9 10 11 12 13 14 15 16 –5–4–3–2–101234567891011–6 Hb (g/dL) Time for Hb to return to  12 g/dL after dose withheld due to Hb >14 g/dL rHuEPO (n = 13) NESP (n = 31) Locatelli F et al. Kidney Int 2001; 60: 741-747

10 DA administration Q2W was not associated with an increased frequency of Hb >14 g/dL Percentage of Hb values >14 g/dL 543210543210 Q2W (n=153) QW (n=153) Mean % of Hb values > 14 g/dL 1.3 2.6 Locatelli F et al. Nephrol Dial Transplant 2005;20 S.5:MP181

11 16 (10) 2007

12 Serum half life of ESAs 3. Dougherty et al. ASCO 2004 4. Macdougall et al. ASN 2005 AgentPopulationMean (± SE) half-life (h) IVSC Epoetin alfa Healthy volunteers 1 6.8 ± 0.619.4 ± 2.5 Epoetin beta Healthy volunteers 1 8.8 ± 0.524.2 ± 2.6 Darbepoetin alfa Peritoneal dialysis patients 2 25.3 ± 2.248.8 ± 5.2 C.E.R.A. Healthy volunteers 3 133 ± 9.8137 ± 21.9 Peritoneal dialysis patients 4 134 ± 19139 ± 20 1. Halstenson et al. Clin Pharmacol Ther. 1991:50:702-712 2. Macdougall et al. J Am Soc Nephrol. 1999;10:2392-2395

13 Understanding how C.E.R.A. is different Receptor binding properties Pharmacokinetic properties Different pharmacologic profile

14

15 C.E.R.A: Dose independent of schedule Core study, PP population, n=124 (BA16286) Mean (SE) change in Hb (g/dL) at 6 wk Locatelli et al. Curr Med Res Opin 2007;23:969–979 n.s. Administration schedule QWQ3WQ4W -1.5 -0.5 0.0 0.5 1.0 1.5

16 -0.75-0.50-0.250.000.250.500.751.00 Difference in adjusted group mean Hb (g/dL) change between baseline and evaluation (97.5% CI) P<0.0001 for all comparisons PP 0.004 -0.2150.223 C.E.R.A. Q2W -0.1730.275 0.051 C.E.R.A. Q4W Non-inferiority limit: C.E.R.A. groups vs epoetin Primary efficacy analysis C.E.R.A. up to once-monthly as effective as epoetin TIW-QW Levin NW et al. Lancet 2007, 370 (9596): 1415-1421 ITT -0.213 0.031 0.276 0.025 0.270-0.220 C.E.R.A. Q2W C.E.R.A. Q4W

17 IV C.E.R.A. once- and twice-monthly maintains stable Hb over one year 481216202428323640444852 C.E.R.A. Q2W IV C.E.R.A. Q4W IV Epoetin TIW-QW IV Mean (SD) Hb (g/dL) Months Weeks Levin NW et al. Lancet 2007, 370 (9596): 1415-1421

18 - 1.00- 0.75- 0.50- 0.250.000.250.500.751.00 Non-inferiority lower 97.5% CI limit Difference in mean adjusted Hb versus epoetin (g/dL) SC C.E.R.A. once-monthly and twice- monthly as effective as epoetin 3x/wk PROTOS: primary efficacy analysis (PP population) P < 0.0001 for all comparisons 0.141 - 0.0980.380 C.E.R.A. 1x/2wk - 0.2620.217 - 0.022 C.E.R.A. 1x/4wk Sulowicz, Locatelli Clin J Am Soc Nephrol. 2007 Jul;2(4):637-46

19 Mean (SD) Hb (g/dL) 481216202428323640444852 Months Weeks C.E.R.A. 1x/2wk C.E.R.A. 1x/4wk Epoetin 1-3x/wk Stable Hb maintenance with once-monthly SC C.E.R.A. PROTOS: ITT population Sulowicz, Locatelli Clin J Am Soc Nephrol. 2007 Jul;2(4):637-46

20 0.180 -0.0490.408 0.180 - 0.0490.408 - 1.00- 0.75- 0.50- 0.250.000.250.500.751.00 Non-inferiority lower 95.0% CI limit Difference in mean adjusted Hb (g/dL) P < 0.0001 IV C.E.R.A. twice-monthly as effective as darbepoetin 1x/wk STRIATA: primary efficacy analysis (PP population) Canaud….Locatelli et al. ERA - EDTA 2006 Canaud….Locatelli et al. Advance Access Published Nephrol Dial Transplant. 2008 Jul 31

21 Mean (SD) Hb (g/dL) 481216202428323640444852 Months Weeks C.E.R.A. 1x/2wk Darbepoetin 1x/wk Stable Hb maintenance with twice-monthly IV C.E.R.A. STRIATA: ITT Population Canaud….Locatelli et al. ERA - EDTA 2006 Canaud….Locatelli et al. Advance Access Published Nephrol Dial Transplant. 2008 Jul 31

22 SC C.E.R.A.: Smooth and steady Hb increase with a high response rate ARCTOS: ITT population Response rate (%) 95% CI C.E.R.A. 1x/2wk97.593.8-99.3 Darbepoetin alfa 1x/wk 96.392.1-98.6 Mean (SD) Hb (g/dL) C.E.R.A. 1x/2wk Darbepoetin alfa 1x/wk Macdougall, … Locatelli et al. Clin J Am Soc Nephrol. 2008 Mar;3(2):337-47 BL123456 7 8 9 10 11 12 13 14 15 16 Final visit Months Weeks 4 812162024

23 Mean (SD) Hb (g/dL) BL123456 7 8 9 10 11 12 13 14 15 16 Final visit Months Weeks 4 812162024 C.E.R.A. 1x/2wk Darbepoetin alfa 1x/wk rHuEPO Locatelli F et al. Kidney Int 2001; 60: 741- 747 Hb concentrations during 24-week intervals Macdougall, … Locatelli et al. Clin J Am Soc Nephrol. 2008 Mar;3(2):337-47

24 P < 0.0001 Patients (%)* Fewer patients exceed Hb 13 g/dL with C.E.R.A. than with darbepoetin alfa ARCTOS: ITT population *Patients with ≥1 Hb value >13 g/dL during first 8 weeks C.E.R.A. 1x/2wkDarbepoetin alfa 1x/wk 0 10 20 30 40 Macdougall, … Locatelli et al. Clin J Am Soc Nephrol. 2008 Mar;3(2):337-47

25 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 studies Mean (SD) Hb (g/dL) Safety populations Epoetin (QW to TIW) or darbepoetin alfa (QW or Q2W) (n=126) C.E.R.A. Q4W (n=59) Weeks since treatment interruption (time 0) Locatelli F. et al Kidney Intern. S. 2008 : Heifets & Dougherty. WCN 2007 -3-20123456 10 11 12 13 14 15 16

26 alfabeta alfa 0 20 40 60 80 100 120 140 Hours Epoetin Darbepoetin SC IV Half life comparison Halstenson. Clin Pharmacol Ther. 1991;50:702 Macdougall. J Am Soc Nephrol. 1999;10:23925 Reigner. Nephrol Dial Transplant. 2003;18(suppl 4):167 Abstract M527 Methoxy polyethylene glycol-epoetin beta’s half-life is much longer than that of darbepoetin alfa  137 h vs 38 h when given SC  133 h vs 25 h when given IV Methoxy polyethlene glycol-epoetin beta

27 Half life of epoetins Halstenson. Clin Pharmacol Ther. 1991;50:702 Macdougall. J Am Soc Nephrol. 1999;10:2392 Reigner. Nephrol Dial Transplant. 2003;18(suppl 4):167. Abstract M527 Woodburn. Blood. 2004;104:2904 *Healthy volunteers † Peritoneal dialysis patients t ½ (hours) Intravenous Subcutaneous Epoetin alfa 6.8* 19.4* Epoetin beta 8.8* 24.2* Darbepoetin alfa † 25.3 48.8 3:1 2:1 Methoxy polyethylene glycol-epoetin beta 130 133 1:1 Hematide 75~80 1:1

28 Nissenson AR et al. J Am Soc Nephrol 5:1517-1529, 1995 Ht response to EPO or placebo in PD patients

29 * ERI: EPO resistance index Wei M, et al. Int Urol Nephrol. 2007;39(3):935-40. Cosa può influenzare la scarsa risposta agli ESAs in DP?

30 Sono stati condotti pochi trials sull'uso degli ESA's nei pazienti in dialisi peritoneale La via di somministrazione di ESAs in dialisi peritoneale deve, per ragioni pratiche, essere SC Le 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 ESAs in dialisi peritoneale

31 1 Ling B et al. Clin Nephrol 2005;63:327-34; 2 Agarwal AK et al. J Intern Med 2006;260:577-85; 3 Disney A et al. Nephrology (Carlton) 2007;12:95-101; 4 Sousa American Society of Nephrology 2006; Abstract SA-PO218; 5 Hoggard J et al. Curr Med Res Opin 2006;22:2023-30. Once monthly (QM) dosing of darbepoetin alfa was effective in CKD patients not on dialysis Reference Open-label study description* Treatment + evaluation period Hb study target range Primary endpoint Ling 1 n=98 Q2W DA → QM DA 29 weeks10-12 g/dl % of patients within Hb study target range Agarwal 2 n=152 Q2W DA → QM DA 33 weeks11-13 g/dl % of patients with Hb ≥11 g/dl Disney 3 n=66 Q2W DA → QM DA 33 weeks10-13 g/dl Maintaining mean Hb ≥10 g/dl Sousa 4 n=71 Q2W DA → QM DA 18 months11-13 g/dl Effectiveness and safety of DA QM Hoggard 5 n=442 QW/Q2W rHuEPO → QM DA 28 weeks10-12 g/dl % of patients converting from EA QW who preferred DA QM at week 21

32 Limited evidence with once-monthly dosing Drug Administration interval (route of administration) Target Hb (g/dL) Population (no. patients enrolled) Trial designReference Epoetin alfaQW, Q2W Q3W, Q4W (SC) ≥11CKD not on dialysis (n=519) RandomisedProvenzano et al 2005 Darbepoetin alfa Q4W (SC)10-12CKD not on dialysis (n=97) Single arm, non-randomised Ling et al 2005 Darbepoetin alfa Q4W (SC)≥10CKD not on dialysis (n=66) Single arm, non-randomised Disney et al 2007 Darbepoetin alfa Q4W (SC)≥11CKD not on dialysis (n=152) Single arm, non-randomised Agarwal et al 2006 Darbepoetin alfa Q3W, Q4W a (IV and SC) 10-13Dialysis patients (n=54) Single arm, non-randomised Jadoul et al 2004 a Dosing once a month is not indicated for darbepoetin alfa in dialysis, except in Switzerland ESAs, erythropoiesis-stimulating agents; Hb, haemoglobin; IV, intravenous; SC, subcutaneous

33 Limited evidence of efficacy in HD patients for once-monthly darbepoetin alfa a Patients on darbepoetin alfa Q2W converted to Q3W dosing and, if Hb stable (10- 13 g/dL), to Q4W dosing a 522 patients originally recruited Limited conversion to Q4W dosing a : Of 54 patients entering the study, 36 patients were converted to Q4W dosing Limited maintenance on Q4W dosing a : Of 36 patients converting to Q4W dosing, 30 patients maintained Hb >10 g/dL over 20 weeks Jadoul et al. Nephrol Dial Transplant 2004;19:898-903 13.0 12.5 12.0 11.5 11.0 10.5 10.0 9.5 9.0 100 80 60 40 20 0 –20481216202630344238 Hb (g/dL) Dose (  g/wk) Study week Q3W dosing (n=44)Q4W dosing a (n=30) Hb Dose a Dosing once a month is not indicated for darbepoetin alfa in dialysis, except in Switzerland

34 Labelled dosing information on maintenance therapy dosing interval MIRCERA –Once-monthly maintenance dosing in CKD patients on dialysis and not on dialysis Darbepoetin alfa –In HD patients Once weekly or once every 2 weeks maintenance dosing In Switzerland in selected HD patients, also once monthly –In CKD patients not on dialysis Stepwise expansion from QW over Q2W to QM for those patients stable on previous dose interval and by doubling the dose ARANESP, Summary of Product Characteristics, 2006; MIRCERA, Summary of Product Characteristics, 2007 CKD, chronic kidney disease; HD, haemodialysis; QW, weekly; Q2W, every 2 weeks; QM, once monthly

35 The PATRONUS study: a randomised comparison of the efficacy and safety of MIRCERA ® with darbepoetin alfa using once- monthly dosing in haemodialysis patients

36 PATRONUS study objectives Primary –To 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 therapy Secondary –To 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.

37 Evaluation (wk 50-53) 4 weeks26 weeks Screening period Darbepoetin alfa 1x/2 weeks (n=245) Darbepoetin alfa 1x/week Darbepoetin alfa* 1x/month Primary end point MIRCERA ® 1x/month (n=245) MIRCERA ® 1x/month R PATRONUS compared once-monthly MIRCERA ® and darbepoetin alfa maintenance treatment R, randomisation * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

38 Primary end point: superiority assessment of the difference in the proportion of responders between groups –Responders are patients with an average Hb decrease from baseline of 10.5 g/dL during evaluation Study was powered to detect an absolute difference of 15% in the primary end point between the 2 treatment groups –Assumed 60% of patients would respond to MIRCERA ® vs 45% to darbepoetin alfa Target Hb range: 11–13 g/dL PATRONUS primary end point * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

39 Analysis population Primary efficacy analysis used the intent-to-treat population, defined as all randomised patients –In 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 transfusion Safety population included all patients who received >1 dose of MIRCERA ® or darbepoetin alfa RBC, red blood cell * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

40 Darbepoetin alfa to MIRCERA ® dose conversion schedule Weekly darbepoetin alfa dose (  g/week) MIRCERA ® starting dose (  g/month) <40120 40–80200 >80360 * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

41 Darbepoetin alfa starting doses 4 week baseline period Two changes needed: Week 1 Week 27 26 weeks Double Week 25 dose Double Week – 1 dose * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

42 PATRONUS: A multicentre, multinational trial CountryPatients enrolled France95 Italy86 Spain80 Canada65 Germany33 Belgium31 UK22 Portugal21 Australia15 Austria15 Switzerland11 Finland9 Denmark7 Total490 * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

43 Baseline patient characteristics MIRCERA ® n=245 Darbepoetin alfa n=245 Male, n (%)148 (60)156 (64) Race, n (%) Caucasian 233 (95)225 (92) Black 5 (2)12 (5) Other 7 (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) Dosing Median 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 (120-200)100 (60-160) SD = standard deviation; IQR = Interquartile Range

44 Once-monthly MIRCERA ® exhibited a superior response rate compared with once-monthly darbepoetin alfa* CI, confidence interval Response rate (%) 64.1% 40.4% * Primary end point *P<0.0001 ® 64.1% 40.4% * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

45 Once-monthly MIRCERA ® shows a 59% higher likelihood of response compared with once-monthly darbepoetin alfa* Primary end point −0.751.001.251.501.752.0 Relative risk of response at evaluation for MIRCERA ® vs darbepoetin alfa 1.59* 1.901.33 Superiority limit: MIRCERA ® vs darbepoetin alfa *P<0.0001 * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

46 Median Hb value (g/dL) 14.0 12.0 10.0 8.0 7.0 MIRCERA ® (median, IQR) Darbepoetin alfa (median, IQR) Baseline481216202428323640444852 Weeks (of trial treatment) 16.0 Evaluation (wk 50-53) 15.0 9.0 13.0 11.0 Only once-monthly MIRCERA ® maintained Hb levels during the second 26-week treatment period

47 Darbepoetin alfa dose increased by >30% during the second 26-week treatment period The median MIRCERA ® dose was virtually unchanged during the second 26-week treatment period whereas darbepoetin alfa substantially increased by 35% Median (IQR) treatment dose,  g/month MIRCERA ® n=211 Darbepoetin alfa n=219 Week 27200 (120-313)150 (80-280) Months 11 and 12196 (120-351)225 (106-400) Secondary end point 0% +35% * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

48 150 125 100 75 50 25 0 −25 −50 Trial treatment dose change (%) 789101112 MIRCERA (median, IQR) Darbepoetin alfa (median, IQR) Months (of trial treatment) MIRCERA ® dose was unchanged during the second 26-week treatment period Secondary end point * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

49 Most safety parameters were similar between the two PATRONUS study groups Similar incidence of AEs in both study arms –higher 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 MIRCERA ®, n (%) n=245 Darbepoetin alfa, n (%) n=244 AEs222 (90.6)217 (88.9) SAEs 99 (40.4) 94 (38.5) AEs leading to withdrawals3 (1.2)7 (2.9) Withdrawals58 (23.7)96 (39.3) Withdrawals due to insufficient response 10 (4.1)48 (19.7) Deaths*14 (5.7) AEs, adverse event; SAEs, serious adverse events *includes 3 patients who died after withdrawal due to other events * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

50 SAEs (>5% in either group) were comparable between study groups in PATRONUS MIRCERA ® n=245 n (%) Darbepoetin alfa n=244 n (%) All body systems 99 (40.4)94 (38.5) Infections and infestations 29 (11.8)27 (11.1) Injury, poisoning and procedural complications 26 (10.6)18 (7.4) Cardiac 16 (6.5)16 (6.6) Vascular 14 (5.7)16 (6.6) Gastrointestinal 11 (4.5)16 (6.6) Nervous system 7 (2.9)13 (5.3) Neoplasms 10 (4.1)5 (2.0) Metabolism and nutrition 10 (4.1)4 (1.6) Respiratory, thoracic and mediastinal 4 (1.6)7 (2.9) * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

51 Clinical Nephrology, Vol 73 – n 2/2010 (94-103)

52 Conclusions MIRCERA ® was shown to be superior to darbepoetin alfa as once-monthly treatment in the dialysis setting –Significantly more patients responded with MIRCERA ® compared with darbepoetin alfa –MIRCERA ® maintained Hb levels within a tight target range during the second 26-week treatment period –Mean 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 increases This is the first large, randomised, prospective head-to-head study that has shown one ESA to offer superior efficacy compared with another Carrera F et al. WCN 2009 Milano, poster M558 * Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

53 Hb (or at least high levels) vs ESA (or at least high levels) ESA Hb


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