C.E.R.A. alkalmazása renális anaemiában – a klinikai vizsgálatok eredményeinek áttekintése Dr. Ladányi Erzsébet orvos-igazgató FMC Miskolci Nefrológiai Központ

CERA Epoetin methoxy-polyethylene glycol polymer 30.000 + 30.400 Da ~ 60.400 Da 30.400 Da

Erythroid progenitor sejt proliferáció és apoptosis gátlás  EPO receptor kötődés (50x) CERA CERA CERA foszforiláció Gén aktiváció Erythroid progenitor sejt proliferáció és apoptosis gátlás

Farmakokinetikai különbségek 137 48,8 24,2 19,4 Macdougall IC. Curr Hemat Rep 2005;4:436-440

C.E.R.A. III. fázisú klinikai vizsgálatok 2004-2006. / 29 ország / 2400 összes / 1450 CERA beteg ARCTOS AMICUS MAXIMA PROTOS STRIATA RUBRA Dialízis IV BA16736 CKD† SC BA16738 Dialízis IV BA16739 Dialízis SC BA16740 Dialízis IV BA17283 Dialízsis IV/SC PFS BA17284 1x/2hét 1x/2hét C.E.R.A. adagolási gyakoriság 1x/2hét 1x/4hét 1x/2hét 1x/4hét 1x/2hét 1x/4hét 1x/2hét 1x/4hét 1x/2hét 1x/2hét The C.E.R.A. Phase III study program The C.E.R.A. clinical program is the largest ever undertaken in anemia management and has been an outstanding success in terms of recruitment and data quality. Enrolment into the six Phase III studies began in March 2004, and the studies were complete by January 2006. The Phase III program involved 2400 patients from 29 countries in Europe, Africa, Australasia, North America, and Central and South America, of whom 1450 received C.E.R.A. Two correction studies (shown in blue) have investigated the efficacy of C.E.R.A. in ESA-naïve patients. Four maintenance studies (shown in orange) in which patients previously maintained on epoetin or darbepoetin alfa were converted directly to C.E.R.A. have also been conducted. The studies have been conducted in patients with CKD on dialysis and not on dialysis (CKD Stages 3-5), and have compared C.E.R.A. with traditional ESAs. In addition to the Phase III program, which was the largest of its kind in renal anemia, Roche is undertaking Phase IIIb studies, and additional Phase IV studies are planned. Komparátor adagolási gyakoriság Epoetin 3x/hét Darbepoetin 1x/hét Epoetin 3x-1x/hét Epoetin 3x-1x/hét Darbepoetin 1x/hét; 1x/2hét Epoetin 3x-1x/hét Korrekciós vizsgálatok Fenntartó vizsgálatok † nem dializált CKD betegek

Célkitűzések és elsődleges végpontok A havonta kétszer, IV vagy SC alkalmazott C.E.R.A. alkalmas az anémia korrekciójára A C.E.R.A. biztonságossága és tolerálhatósága Célkitűzések: Korrekciós vizsgálatok Hb reagálási ráta a korrekciós és értékelési periódus alatt (a Hb ≥11 g/dL és ≥1 g/dL növekedése a kiindulási értékhez képest) Átl. Hb változás a kiindulási és az értékelés között Végpontok: Korrekciós vizsgálatok Az 2x vagy 1x/hónap, IV vagy SC adott C.E.R.A. fenntartja a dializált betegek Hb-szintjét a 3x-1x/hét adagolt epoetinről vagy 1x/hét illetve 1x/2hét adott darbepoetin alfáról történt direkt konverzió után A C.E.R.A. biztonságossága és tolerálhatósága Célkitűzések: Fenntartó vizsgálatok The C.E.R.A. Phase III study program The C.E.R.A. clinical development program is the largest ever undertaken in anemia management. Two correction studies investigated the efficacy of C.E.R.A. in erythropoiesis-stimulating agent (ESA)-naïve patients with renal anemia. Four maintenance studies have been conducted in which patients previously maintained on epoetin or darbepoetin alfa were converted directly to C.E.R.A. The studies have been conducted in both patients on dialysis and not on dialysis (chronic kidney disease [CKD] Stages 3-5), and have compared C.E.R.A. with approved ESAs. The primary objective of the correction studies was to demonstrate that intravenous (IV) or subcutaneous (SC) C.E.R.A. administered twice monthly effectively corrects anemia in ESA-naïve patients with CKD, both on dialysis and not on dialysis (Klinger et al 2006; Macdougall et al 2006). The primary efficacy endpoint of the correction studies was the Hb response rate, defined as an increase of ≥1 g/dL from baseline and a single measurement ≥11 g/dL without the need for transfusion. The primary objective of the maintenance studies was to demonstrate that IV or SC C.E.R.A. administered once or twice monthly effectively maintains Hb levels following direct conversion from either epoetin administered one to three times weekly, or darbepoetin administered twice monthly or once weekly (Levin et al 2006; Sulowicz et al 2006; Canaud et al 2006; Spinowitz et al 2006). The primary efficacy endpoint of the maintenance studies was the mean change in Hb between baseline and the evaluation period. The secondary objective of all studies was to evaluate safety and tolerability of C.E.R.A. References Canaud B et al. Intravenous (IV) C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered once every 2 weeks maintains stable haemoglobin (Hb) levels in patients with chronic kidney disease (CKD) on dialysis. Nephrol Dial Transplant. 2006;21(Suppl 4):iv157 (abstract SP425). Klinger M et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered at extended intervals corrects Hb levels in patients with CKD on dialysis. J Am Soc Nephrol. 2006;17:620A (abstract SA-PO212). Levin NW et al. 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). Macdougall IC et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered at extended intervals corrects anemia and maintains stable Hb levels in patients with CKD not on dialysis. J Am Soc Nephrol. 2006;17:619A (abstract SA-PO208). Spinowitz B et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered once every 2 weeks via pre-filled syringe (PFS) maintains stable Hb levels in patients with CKD on dialysis. J Am Soc Nephrol. 2006;17:895A (abstract PUB376). Sulowicz W, Locatelli F, Balla J, Csiky B, Rikker C, Aldigier J-C, Dougherty FC. Subcutaneous (SC) 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):iv156-iv157 (abstract SP424). Végpontok: Fenntartó vizsgálatok Átl. Hb változás a kiindulási és az értékelés között Klinger et al. ASN 2006; Macdougall et al. ASN 2006; Levin et al. EDTA 2006; Sulowicz et al. EDTA 2006; Canaud et al. EDTA 2006; Spinowicz et al. ASN 2006

Bevonási és kizárási kritériumok Korrekciós vizsgálatok Fő bevonási kritériumok Felnőtt korú ( ≥18 év ) CKD betegek ( 3 – 5 stádium) Kiindulási Hb érték 8-11 g/dl Se ferritin ≥100 ng/mLvagy TSAT ≥20% vagy hypochrom VVT <10% Fő kizárási kritériumok ESA kezelés a megelőző 12 hétben VVT transzfúzió vagy GI vérzés a megelőző 8 hétben Fenntartó vizsgálatok Fő bevonási kritériumok ≥12 hét óta rendszersen HD vagy PD kezelést kapó felnőtt korú ( ≥18 év ) betegek Stabil kiindulási Hb: 10.5-13.0 g/dl ≥8 hét óta változatlan epoetin alfa v. beta v. darbepoetin alfa fenntartó kezelés Se ferritin ≥100 ng/mL vagy TSAT ≥20% vagy hypochrom VVT <10% Fő kizárási kritériumok Súlyos betegség a megelőző 12 hétben VVT transzfúzió vagy GI vérzés a megelőző 8 hétben CRP >30 mg/L Várható élettartam <12 hónap The C.E.R.A. Phase III study program inclusion and exclusion criteria Major inclusion and exclusion criteria are shown. In all studies, patients were aged ≥18 year with chronic renal anemia and were required to have adequate iron status defined as serum ferritin ≥100ng/mL or transferrin saturation (TSAT) ≥20% or hypochromic red blood cells <10%. Inclusion criteria for the correction studies required patients to have received no previous ESA treatment, to have baseline hemoglobin (Hb) of 8-11 g/dL Exclusion criteria for the correction studies included ESA treatment in the previous 12 weeks and overt gastrointestinal bleeding or blood transfusion within the previous 8 weeks. For the ARCTOS study, which was carried out in patients not on dialysis, those with expected rapid progression of CKD (eg, creatinine clearance decrease of >20% within 12 weeks) or need for dialysis within the next 6 months were also excluded (Klinger et al 2006; Macdougall et al 2006). Inclusion criteria for the maintenance studies required patients to have stable baseline Hb of 10.5-13.0 g/dL (max-min variation ≤1.0 g/dL during the 4-week baseline run-in period), stable maintenance with either epoetin alfa or beta or darbepoetin alfa at the same administration level for ≥8 weeks. Exclusion criteria for the maintenance studies included any severe diseases within 12 weeks preceding the study, blood transfusion or gastrointestinal bleed within the last 8 weeks, C-reactive protein >30mg/L, thrombocytes >500 000/L, or life expectancy <12 months (Levin et al 2006; Sulowicz et al 2006; Canaud et al 2006; Spinowitz et al 2006). References Canaud B et al. Intravenous (IV) C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered once every 2 weeks maintains stable haemoglobin (Hb) levels in patients with chronic kidney disease (CKD) on dialysis. Nephrol Dial Transplant. 2006;21(Suppl 4):iv157 (abstract SP425). Klinger M et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered at extended intervals corrects Hb levels in patients with CKD on dialysis. J Am Soc Nephrol. 2006;17:620A (abstract SA-PO212). Levin NW et al. 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). Macdougall IC et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered at extended intervals corrects anemia and maintains stable Hb levels in patients with CKD not on dialysis. J Am Soc Nephrol. 2006;17:619A (abstract SA-PO208). Spinowitz B et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered once every 2 weeks via pre-filled syringe (PFS) maintains stable Hb levels in patients with CKD on dialysis. J Am Soc Nephrol. 2006;17:895A (abstract PUB376). Sulowicz W et al. Subcutaneous (SC) 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):iv156-iv157 (abstract SP424). Klinger et al. ASN 2006; Macdougall et al. ASN 2006; Levin et al. EDTA 2006 Sulowicz et al. EDTA 2006; Canaud et al. EDTA 2006; Spinowicz et al. ASN 2006

A C.E.R.A. kezelés hatásosságát és biztonságát igazoló eredmények

Korrekciós vizsgálatok: magas reagálási ráta a C. E. R. A Korrekciós vizsgálatok: magas reagálási ráta a C.E.R.A. IV vagy SC alkalmazásakor 93.3 C.E.R.A. 1x/2hét (n=135) 87.7 96.9 91.3 AMICUS Epoetin 3x/hét (n=46) 79.2 97.6 10 20 30 40 50 60 70 80 90 100 Reagálási ráta (%) 97.5 C.E.R.A. 1x/2hét (n=162) 93.8 99.3 ARCTOS 96.3 Darbepoetin alfa 1x/hét (n=162) 92.1 98.6 AMICUS (BA16736) and ARCTOS (BA16738) correction studies The AMICUS and ARCTOS studies demonstrate that C.E.R.A. effectively corrects anemia when administered twice monthly. The primary efficacy parameter in the correction studies AMICUS and ARCTOS was the Hb response rate defined as an increase of ≥1 g/dL from baseline and a single measurement ≥11 g/dL without the need for transfusion in the intent-to-treat (ITT) population. If the lower limit of the 95% CI for response was >60% it could be concluded that C.E.R.A. administered twice monthly corrected anemia effectively. In the AMICUS study, the Hb response rate in the C.E.R.A. group was 93.3%, and 91.3% in the epoetin group (ITT population). The lower limit of the 95% CI for C.E.R.A. was 87.7%, well above the pre-defined 60% level required for statistical significance (Klinger et al 2006). In the ARCTOS study, the Hb response rate in the C.E.R.A. group was 97.5%, and 96.3% in the darbepoetin alfa group (ITT population). The lower limit of the 95% CI for C.E.R.A. was 93.8%, also well above the pre-defined 60% level required for statistical significance (Macdougall et al 2006). It can therefore be concluded that the primary endpoint was achieved in both of these studies. References Klinger M et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered at extended intervals corrects Hb levels in patients with CKD on dialysis. J Am Soc Nephrol. 2006;17;620A (abstract SA-PO212). Macdougall IC et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered at extended intervals corrects anemia and maintains stable Hb levels in patients with CKD not on dialysis. J Am Soc Nephrol. 2006;17:619A (abstract SA-PO208). 10 20 30 40 50 60 70 80 90 100 Reagálási ráta (%) Reagálás kritériuma: a kiinduláshoz képest ≥1 g/dL Hb emelkedés valamint Hb ≥11 g/dL a korrekció során VVT transzfúzió nélkül ITT populáció Klinger et al. ASN 2006; Macdougall et al. ASN 2006

Egyenletes és folyamatos Hb emelkedés C.E.R.A. IV és SC adásakor Átl. (SD) Hb (g/dL) Átl. (SD) Hb (g/dL) 16 C.E.R.A. 1x/2hét IV (n=135) C.E.R.A. 1x/2hét SC (n=162) Darbepoetin alfa 1x/hét SC (n=162) 15 Epoetin 3x/hét IV (n=46) 14 13 12 11 10 9 8 7 AMICUS (BA16736) and ARCTOS (BA16738) correction studies The AMICUS and ARCTOS studies demonstrate that IV or SC C.E.R.A. provides a smooth and steady increase in Hb in accordance with EBPG guidelines. In the AMICUS study, mean Hb levels increased from baseline in both epoetin and C.E.R.A groups, with mean (SD) values at the end of the correction period of 12.0 ± 1.11 and 12.1 ± 1.35 g/dL respectively. The initial rate of increase with epoetin was greater than with C.E.R.A., and Hb levels with epoetin treatment rose to their maximum by week 16. Mean (SD) change in Hb levels from baseline to the end of the correction period were 2.70 ± 1.45 and 2.56 ± 1.31 g/dL with C.E.R.A. and epoetin, respectively. In the ARCTOS study, mean Hb levels increased from baseline in both darbepoetin alfa and C.E.R.A. treatment groups, with mean (SD) values at the end of the correction period of 12.17 ± 0.9 and 12.33 ± 0.97 g/dL respectively. The rate of increase with darbepoetin alfa was greater than with C.E.R.A., and Hb levels with darbepoetin alfa treatment were greatest by week 12. Mean (SD) change in Hb levels from baseline to the end of the correction period were 2.12 ± 1.06 and 2.02 ± 1.05 g/dL with C.E.R.A. and darbepoetin, respectively. In both studies, due to the controlled rise in Hb levels, fewer patients in the C.E.R.A. treatment arm exceeded an Hb level of 13 g/dL in the first 8 weeks of treatment. In both studies there was no significant difference between the treatment groups. Results of the ITT populations are shown in the slide. References Klinger M et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered at extended intervals corrects Hb levels in patients with CKD on dialysis. J Am Soc Nephrol. 2006;17;620A (abstract SA-PO212). Locatelli F et al; European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19(Suppl 2): ii1–ii47. Macdougall IC et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered at extended intervals corrects anemia and maintains stable Hb levels in patients with CKD not on dialysis. J Am Soc Nephrol. 2006;17:619A (abstract SA-PO208). BL 1 2 3 4 5 6 Final visit Hó Hét Final visit Hó hét 4 8 12 16 20 24 4 8 12 16 20 24 AMICUS ARCTOS ITT populáció Klinger et al. ASN 2006; Macdougall et al. ASN 2006

Korrekció: C.E.R.A. esetén kevesebb betegben alakul ki Hb >13 g/dl P = 0.0953 P < 0.0001 Betegek (%) Betegek (%) 33.5 17.4 12.4 8.2 AMICUS (BA16736) and ARCTOS (BA16738) correction studies In post-hoc analyses of the first 8 weeks of therapy, maximum Hb values >13 g/dL were experienced by 8.2% of patients on C.E.R.A. and 17.4% on epoetin (P=0.0953) in the AMICUS study and by 12.4% of patients on C.E.R.A. and 33.5% on darbepoetin alfa in ARCTOS (P<0.0001). These results support a steady and controlled rise in Hb in patients treated with C.E.R.A. References Klinger M et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered at extended intervals corrects Hb levels in patients with CKD on dialysis. J Am Soc Nephrol. 2006;17;620A (abstract SA-PO212). Macdougall IC et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered at extended intervals corrects anemia and maintains stable Hb levels in patients with CKD not on dialysis. J Am Soc Nephrol. 2006;17:619A (abstract SA-PO208). C.E.R.A. IV 1x/2hét Epoetin IV 3x/hét C.E.R.A. SC 1x/2hét Darbepoetin alfa SC 1x/hét (n=135) (n=46) (n=162) (n=162) AMICUS ARCTOS ITT populáció Adatok a vizsgálatok első 8 hetéből Klinger et al. ASN 2006; Macdougall et al. ASN 2006

Fenntartó kezelés: C.E.R.A. más ESA-kal azonos hatásosságú Non-inferiority határ: C.E.R.A. csoportok vs komparátor Non-inferiority határ: C.E.R.A. csoportok vs komparátor 0.004 -0.215 0.223 0.141 C.E.R.A. 1x/2hét IV C.E.R.A. 1x/2hét SC -0.098 0.380 0.051 -0.022 C.E.R.A. 1x/4hét IV C.E.R.A. 1x/4hét SC -0.173 0.275 -0.262 0.217 -1.00 -0.75 -0.50 -0.25 0.00 0.25 0.50 0.75 1.00 -1.00 -0.75 -0.50 -0.25 0.00 0.25 0.50 0.75 1.00 MAXIMA (BA16739), PROTOS (BA16740), STRIATA (BA17283) and RUBRA (BA17284) maintenance studies The C.E.R.A. maintenance studies demonstrate that IV or SC C.E.R.A. twice monthly is as effective as epoetin once to three-times weekly or darbepoetin alfa once or twice monthly, and that IV or SC C.E.R.A. once monthly is as effective as epoetin once to three-times weekly at maintaining stable Hb levels. The primary efficacy parameter in these studies was the mean change in Hb between baseline and the evaluation period. A non-inferiority test was applied to determine whether C.E.R.A. was as effective as the comparator. In this test, separate comparisons were performed for C.E.R.A. twice monthly versus comparator, and C.E.R.A. once monthly versus comparator as appropriate. The non-inferiority test compared the mean change in Hb during study between the agents. It looked at whether the patients’ Hb could be maintained after patients switched to C.E.R.A. It compared the change in Hb levels in patients who continued their original ESA treatment with that in patients who converted to C.E.R.A. The non-inferiority test assumed that a lower limit of the difference between the mean changes in Hb between C.E.R.A. and epoetin or darbepoetin alfa of more than 0.75 g/dL of Hb was significant. In the studies, the mean and two-sided 97.5% confidence interval (CI) (MAXIMA and PROTOS) or 95% CI (STRIATA and RUBRA) for the difference between the C.E.R.A. group and the comparator group in the change in Hb level between baseline and the evaluation period was calculated using an ANCOVA (analysis of covariance). To conclude that C.E.R.A. was as effective as comparator, the lower limit of the CI had to be ≥-0.75 g/dL in all cases. This test was conducted in the per-protocol (PP) population. Results are comparable in the ITT population. In all four studies the lower limit of the CI was well above the pre-specified limit of -0.75 g/dL, therefore the primary endpoint of all studies was achieved. Data are shown from PROTOS and MAXIMA. References Canaud B et al. Intravenous (IV) C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered once every 2 weeks maintains stable haemoglobin (Hb) levels in patients with chronic kidney disease (CKD) on dialysis. Nephrol Dial Transplant. 2006;21(Suppl 4):iv157 (abstract SP425). Levin NW et al. 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). Spinowitz B et al. C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered once every 2 weeks via pre-filled syringe (PFS) maintains stable Hb levels in patients with CKD on dialysis. J Am Soc Nephrol. 2006;17:895A (abstract PUB376). Sulowicz W et al. Subcutaneous (SC) 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):iv156-iv157 (abstract SP424). A Hb kiindulási és értékelési periódosok között mért csoportonkénti átlagolt különbsége a komparátorhoz képest (g/dL) A Hb kiindulási és értékelési periódosok között mért csoportonkénti átlagolt különbsége a komparátorhoz képest (g/dL) MAXIMA PROTOS P<0.0001 minden összehasonlításban PP betegek; Hasonló eredmény az ITT populációban is Levin et al. EDTA 2006; Sulowicz et al. EDTA 2006 Canaud et al. EDTA 2006; Spinowitz et al. ASN 2006

Sikeres átállítás C.E.R.A.-ra konzisztens Hb stabilitással MAXIMA vizsgálat: az értékelési periódusban a betegek >66%-a tartotta meg a kiindulási Hb ±1 g/dL szintjét Betegek (%) Felette Megtartott Alatta 80 60 40 MAXIMA (BA16739): direct conversion from epoetin TIW-QW The Phase III maintenance studies show that patients can be converted directly from epoetin one to three times weekly to C.E.R.A. once monthly. One of the secondary efficacy parameters in these studies (MAXIMA, PROTOS, STRIATA and RUBRA) was the number of patients maintaining average Hb concentration within ±1 g/dL of their average baseline concentration. The main analysis for secondary endpoints was carried out with the ITT population. Results from the MAXIMA study are shown. The results show that >66% of patients maintained consistent Hb stability. Reference Levin NW et al. 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). 20 C.E.R.A. 1x/2hét IV (n=223) C.E.R.A. 1x/4hét IV (n=224) Epoetin 3x-1x/hét IV (n=226) ITT populáció Levin EDTA 2006

C.E.R.A. IV és SC: stabil és folyamatos Hb kontroll PROTOS és MAXIMA vizsgálatok: epoetin alfa vagy beta kezelés mellett stabil Hb-szintű betegek bevonásával Átl. (SD) Hb (g/dL) Átl. (SD) Hb (g/dL) C.E.R.A. 1x/2hét IV (n=223) C.E.R.A. 1x/2hét SC (n=190) C.E.R.A. 1x/4hét IV (n=224) C.E.R.A. 1x/4hét SC (n=191) Epoetin 3x-1x/hét IV (n=226) Epoetin 3x-1x/hét SC (n=191) Hosszú távú biztonság Hosszú távú biztonság Titrálás Értékelés Titrálás Értékelés MAXIMA (BA16739) and PROTOS (BA16740): maintenance of stable Hb levels Throughout the year-long study, C.E.R.A. administered up to once monthly continued to maintain stable Hb levels. Patients included in these studies were stable on comparator drug (epoetin alfa or epoetin beta) prior to the start of the study. Importantly, the patients who converted directly from comparator to C.E.R.A. either twice or once monthly had subsequent Hb stability comparable to those who were already stable on and continued to receive comparator drug. Results are shown for the ITT population of PROTOS and MAXIMA. References Levin NW et al. 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). Sulowicz W et al. Subcutaneous (SC) 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):iv156-iv157 (abstract SP424). Hó Hét Hó 4 8 12 16 20 24 28 32 36 40 44 48 52 4 8 12 16 20 24 28 32 36 40 44 48 52 Hét MAXIMA PROTOS ITT populáció Sulowicz et al. EDTA 2006; Levin et al. EDTA 2006

MAXIMA és PROTOS: a C.E.R.A. valamennyi dializált CKD betegben hatásos Kezelt csoportok A betegek kora, neme, diabetes statusa hasonló volt a kezelt csoportokban Hb stabilitás Valamennyi Hb érték a protokol által meghatározott tartományban maradt MAXIMA (BA16739) and PROTOS (BA16740) in all CKD patients IV or SC C.E.R.A. given at extended administration intervals of once monthly, maintains Hb levels within target range in hemodialysis patients, irrespective of age, gender or diabetic status. Subgroup analyses of the MAXIMA and PROTOS studies have been carried out to examine the impact of age, gender or diabetic status on mean Hb levels in patients receiving C.E.R.A. once monthly. Mean Hb levels at baseline (ranges, 11.85-11.97 g/dL [MAXIMA] and 11.65-11.70 g/dL [PROTOS]) were similar across groups. During the evaluation period (weeks 29-36), mean Hb levels in the C.E.R.A. once monthly groups in both studies were similar for ages <65, 65-74 and ≥75 years. Consistent mean Hb levels were also found in subgroup analyses by gender and diabetic status. References Levin NW et al. Adequate Hb levels are maintained with IV C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered up to once monthly in dialysis patients irrespective of age, gender or diabetic status. J Am Soc Nephrol. 2006;17:619A (abstract SA-PO206). Ryckelynck JP et al. SC C.E.R.A. (Continuous Erythropoietin Receprot Activator) administered up to once monthly in patients with CKD on dialysis maintains adequate Hb levels regardless of age, gender or diabetic status. J Am Soc Nephrol. 2006;17:620A (abstract SA-PO210). A max. havonta 1x adagolt C.E.R.A. hatékonyan tartja meg a dializált CKD betegek Hb-szintjét, a betegek korától, nemétől és diabetes statusától függetlenül Valamennyi beteg Ryckelynck et al. ASN 2006; Levin et al. ASN 2006

C.E.R.A.: jó tolerálhatóság Az AE-k jellemzők a beteg csoportra és hasonlóak a rövidebb hatású ESA-k esetén észleltekhez MAXIMA Leggyakoribb AE-k C.E.R.A. 1x/4 hét IV (n=220) Epoetin 3x-1x/hét IV (n=225) Diarrhea 12% 13% Nasopharyngitis 18% 11% Hypertensio 16% Arteriovenous graft thrombosis 14% Felsőlégúti infekció Fejfájás 8% Folyadék visszatartás 10% Izomgörcs 9% PROTOS C.E.R.A. 1x/4hét SC (n=190) Epoetin 3x-1x/hét SC (n=191) Beadást követő hypotensio 15% MAXIMA (BA16739) and PROTOS (BA16740) adverse events IV and SC C.E.R.A. once monthly was generally well tolerated during all studies, and AEs were typical of those associated with this patient population and with approved ESAs. This slide shows adverse events (AEs) occurring in ≥10% of patients in the safety population in the MAXIMA and PROTOS studies. The most frequently reported AEs were diarrhea (MAXIMA only), nasopharyngitis and hypertension. References Levin NW et al. Adequate Hb levels are maintained with IV C.E.R.A. (Continuous Erythropoietin Receprot Activator) administered up to once monthly in dialysis patients irrespective of age, gender or diabetic status. J Am Soc Nephrol. 2006;17:619A (abstract SA-PO206). Ryckelynck JP et al. SC C.E.R.A. (Continuous Erythropoietin Receprot Activator) administered up to once monthly in patients with CKD on dialysis maintains adequate Hb levels regardless of age, gender or diabetic status. J Am Soc Nephrol. 2006;17:620A (abstract SA-PO210). Locatelli F et al; European/Australian NESP 980202 Study Group. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int. 2001;60:741-747. A MAXIMA és PROTOS vizsgálatokban ≥10% gyakorisággal jelzett AE-k Ryckelynck et al. ASN 2006; Levin et al. ASN 2006

Egészséges önkéntesek1 Egészséges önkéntesek3 A C.E.R.A. hosszú félélet ideje havonta 1x-i adagolást is lehetővé tesz Hatóanyag Betegek Átl. (± SE) T 1/2 (h) Adagolás frekvencia IV SC Epoetin alfa Egészséges önkéntesek1 6.8 ± 0.6 19.4 ± 2.5 3x-1x/hét Epoetin beta 8.8 ± 0.5 24.2 ± 2.6 Darbepoetin alfa PD kezelt betegek2 25.3 ± 2.2 48.8 ± 5.2 1x/1-2hét C.E.R.A. Egészséges önkéntesek3 133 ± 9.8 137 ± 21.9 Max. havi 1x PD kezelt betegek4 134 ± 19 139 ± 20 Long half life of C.E.R.A. suggests dosing intervals of up to once monthly In healthy volunteers and patients with 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 long serum half-life suggests that it can be administered at extended dosing intervals. References Halstenson CE et al. Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta. Clin Pharmacol Ther. 1991;50:702-712. Macdougall IC et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999;10:2392-2395. 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. Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous Continuous Erythropoietin Receptor Activator (C.E.R.A.) in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:1211-1215. 1. Halstenson et al. 1991; 2. Macdougall et al. 1999; 3. Dougherty et al. ASCO 2004; 4. Macdougall et al. 2006

C.E.R.A.: új osztály az eritropoietikus hatású gyógyszerek között A C.E.R.A. eltérő receptor kötődése és hosszú félélet ideje akár havonta 1x-i adagolást is lehetővé tesz Új hatásmód Havi 2x-i adagolásban is hatékony Egyenletes és folyamatos Hb növekedés Kevesebb beteg lépi túl a javasolt Hb célértéket Anémia korrekció Sikeres direkt konverzió 3x-1x/hét epoetinről és 1x/1-2hét darbepoetin alfáról havonta 1x-i C.E.R.A. alkalmazásra Konverzió Hb kontroll Hosszútávú és stabil Hb kontroll havi 1x-i C.E.R.A. adagolással C.E.R.A.: A new class of erythropoietic agent C.E.R.A. is a new class of erythropoietic agent with a novel pharmacological profile. Through its different interaction with the erythropoietin receptor, it provides continuous receptor activation and steady, predictable erythropoiesis. This, together with the longest half-life of all currently available erythropoietic agents, allows administration intervals up to once monthly. Although some shorter-acting erythropoietic agents have tested administration intervals up to once monthly, evidence suggests that they may be effective at longer intervals only in a subgroup of highly selected patients after stepwise increases in intervals (Jadoul et al 2004; Provenzano et al 2005; Grzeszczak et al 2005). Two Phase III studies of anemia correction (ARCTOS and AMICUS) have shown that C.E.R.A. administered twice monthly corrects anemia as effectively as epoetin one to three times weekly and darbepoetin alfa once weekly. C.E.R.A. achieves a smooth and steady increase in Hb in accordance with current treatment guidelines, and fewer patients exceed recommended Hb targets than with epoetin or darbepoetin alfa during correction. Four Phase III studies (MAXIMA, PROTOS, STRIATA and RUBRA) have investigated direct conversion to C.E.R.A. up to once monthly from epoetin one to three times weekly and darbepoetin alfa once weekly and twice monthly. In contrast to other studies investigating extended administration intervals, the design of the C.E.R.A. studies did not involve sequential lengthening of the administration interval only in patients already stably maintained on a shorter interval. Patients successfully converted to C.E.R.A., and maintained stable and sustained Hb control for up to 1 year with once-monthly administration. In all studies, C.E.R.A. was well tolerated with a safety profile characteristic of the patient population and similar to short-acting ESAs. Study drug-related immunogenicity was not detected in any patient. References Grzeszczak W et al. The efficacy and safety of once-weekly and once-fortnightly subcutaneous epoetin  in peritoneal dialysis patients with chronic renal anaemia. Nephrol Dial Transplant. 2005;20:936-944. Jadoul M et al; on behalf of the Darbepoetin Alfa 20000144 Study Group. Darbepoetin alfa administered once monthly maintains haemoglobin levels in stable dialysis patients. Nephrol Dial Transplant. 2004;19:898-903. Locatelli F, et al; European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19(Suppl 2): ii1-ii47. Provenzano R et al; for the PROMPT Study Group. Extended epoetin alfa dosing as maintenance treatment for the anemia of chronic kidney disease: the PROMPT study. Clin Nephrol. 2005;64:113-123. A ritkább adagolási frekvencia és stabil Hb-szint jobb eü. forrás gazdálkodást és potenciális egészség nyereséget jelenthet Gazdaságosság C.E.R.A. a kezelt betegcsoport biztonságossági profiljának megfelelően és más ESA-khoz hasonlóan jól tolerálható Biztonság

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