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Efficacy and safety of increasing doses of the cyclophilin inhibitor Debio 025 in combination with pegylated Interferon alpha-2a in treatment naïve chronic.

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Presentation on theme: "Efficacy and safety of increasing doses of the cyclophilin inhibitor Debio 025 in combination with pegylated Interferon alpha-2a in treatment naïve chronic."— Presentation transcript:

1 Efficacy and safety of increasing doses of the cyclophilin inhibitor Debio 025 in combination with pegylated Interferon alpha-2a in treatment naïve chronic HCV patients R. Flisiak 1, S.V. Feinman 2, M. Jablkowski 3, A. Horban 4, W. Kryczka 5, W. Halota 6, J.E. Heathcote 7, G. Mazzella 8, C. Vandelli 9, J.S. Liz 10, P. Scalfaro 10, H. Porchet 10 and R. Crabbé 10 1 Medical University, Bialystok, Poland; 2 Mount Sinai Hospital, Toronto, Canada; 3 Medical University, Lodz, Poland; 4 Hospital for Infectious Diseases, Warsaw, Poland; 5 Regional Hospital, Kielce, Poland; 6 Medical University, Bydgoszcz, Poland; 7 University of Toronto, Toronto, Canada; 8 University of Bologna, Bologna, Italy; 9 University of Modena and Reggio Emilia, Modena, Italy; 10 Debiopharm SA, Lausanne, Switzerland 43rd Annual Meeting of EASL, April 23-27, 2008 J Hepatol 2008, vol. 48, suppl. 2: s62 [143]

2 Cyclophilins Expressed in every organ ( ~ 1 µg/mg cellular protein). 1 Peptidyl-Prolyl cis-trans isomerase (de novo folding of intracellular proteins). 2 Functional regulator of the NS5B - RNA dependent RNA Polymerase (the most likely CypB). 3 Cyclophilins inhibition with Cyclosporin A reduces HCV replication (associated with immunosuppression). 4,5 1.Ryffel B et al. Immunology 1991; 72: 399-404. 2.Edlich F, Fischer G. Handb Exp Pharmacol 2006; 172: 359-404. 3.Watashi K et al: Molecular Cell, Vol 19, 111-122, July 1, 2005 4.Nakagawa et al.Gastroenterology 2005; 129:1031-1041 5.Watashi K et al. Hepatology 2003; 38: 1282-1288.

3 Debio 025 position 4 - N-Ethyl Valine instead of N-Methyl Leucine (prevent CaN binding) position 3 - methyl group (stronger Cyp binding)

4 DEBIO 025 1200mg (n=16) or placebo (n=3), bid p.o. for 14 days Flisiak R et al. Hepatology 2008; 47(3): 817-826 Anti-HCV effect of Debio 025 in HCV/HIV coinfected patients (double-blind, randomized, placebo controlled, phase 1) mean HCV RNA decrease: 3.6 log 10 copies/mL (n=3) (n=16)

5 Design of the study DEB-025-HCV-203 (double-blind, randomised, placebo-controlled, phase 2a) DMC selected the next higher dose in function of safety, PK and VL reduction DMC = Data Monitoring Committee Peg = PegIFN 2a DMC Peg + Placebo: n= 6 Peg + Debio 025 200 mg: n=18 DMC Peg + Placebo: n= 6 Peg + Debio 025 600 mg: n=18 DMC Peg + Placebo: n= 6 Peg + Debio 025 1000 mg: n=18 Debio 025 1000 mg: n=18

6 Design of the study DEB-025-HCV-203 (double-blind, randomised, placebo-controlled, phase 2a) 29 days 21 days Treatment naive, HCV mono-infected, with compensated liver function N=90 gen 1&4 n=60 gen 2&3 n=30 PegIFN 2a - 180 g/week + placebo Debio 025 - 1000 mg/day PegIFN 2a - 180 g/week Debio 025 - 200 mg/day PegIFN 2a - 180 g/week Debio 025 - 600 mg/day PegIFN 2a - 180 g/week Debio 025 - 1000 mg/day

7 Mean HCV RNA reduction during the treatment genotypes 1 and 4 (n=12 per group)

8 Mean HCV RNA reduction during the treatment genotypes 2 and 3 (n=6 per group)

9 Proportion of patients with undetectable HCV RNA at day 29 limit of quantification = 15 IU/mL

10 Safety No Serious Adverse Events Discontinuation due to mild to moderate AE: 4 –PegIFN - 2a + Debio 025 600 mg: 1 Dental abscess at day 11 (recovered) –PegIFN - 2a + Debio 025 1000 mg: 2 Hypertension at day 15 (recovered) Abnormal feeling, pain, nausea at day 3 (recovered) –Debio 025 1000 mg: 1 Hyperbilirubinaemia at day 15 (recovered)

11 PegIFN 2a placebo Debio 025 200 mg Debio 025 600 mg Debio 025 1000 mg N=18 Headache 12 11108 Myalgia 84451 Pyrexia 1361050 Chills 65430 Fatigue 61297 Nausea 82378 Leukopenia 23020 Neutropenia 66230 Hyperbiliru- binaemia 00058 The most frequently reported Adverse Events

12 2 3 11 1 Number of patients with total bilirubin >3 mg/dL (n=18 per group)

13 Mean Platelet count during treatment and follow-up (n=18 per group)

14 Mean Neutrophil count during treatment and follow-up (n=18 per group)

15 Conclusions 1.Debio 025 at daily doses of 1000 or 600 mg demonstrates an additive anti-HCV effect in combination with PegIFN -2a. This effect was more evident in patients with genotype 1 & 4. 2.Debio 025 in daily doses of 200 or 600 mg in combination with PegIFN -2a was well tolerated and the majority of reported adverse events were known side effects of alpha interferons. 3.Isolated hyperbilirubinaemia, was the most important dose-limiting adverse event, which occurred only during treatment with 1000 mg of Debio 025. 4.Debio 025 in daily dose 600 mg in combination with 180 µg of PegIFN -2a per week, shows the best balance between antiviral effect and safety.

16 Acknowledgements Study sites - Poland R. Flisiak, A. Czauz-Andrzejuk, J. Jaroszewicz, I. Wierzbicka (Bialystok) M. Jablkowski, J. Bialkowska, D. Dworniak (Lodz) A. Horban, H. Berak, A. Kolakowska-Rzadzka, M. Wasilewski (Warsaw) W. Kryczka, P. Pabian, D. Zarebska-Michaluk (Kielce) W. Halota, D. Dybowska, D. Kozilewicz, M. Pawlowska (Bydgoszcz) Study sites - Italy G. Mazzella, D. Festi, F. Lodato (Bologna) C. Vandelli, E. Tesini (Modena) Study sites - Canada SV. Feinman, S. Bojarski, M. Jong Hsiao (Toronto) JE. Heathcote, D. Kaznowski (Toronto) F. Anderson (Vancouver) S. Erb (Vancouver) Debiopharm SA - Switzerland R. Crabbé, JS. Liz, H. Porchet, P. Scalfaro, V. Nicolas, A. Ménétrey, G. Vuagniaux


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