Efficacy and safety of increasing doses of the cyclophilin inhibitor Debio 025 in combination with...

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. Flisiak1, S.V. Feinman2, M. Jablkowski3, A. Horban4, W. Kryczka5, W. Halota6, J.E. Heathcote7, G. Mazzella8, C. Vandelli9, J.S. Liz10, P. Scalfaro10, H. Porchet10 and R. Crabbé10

1Medical University, Bialystok, Poland; 2Mount Sinai Hospital, Toronto, Canada; 3Medical University, Lodz, Poland; 4Hospital for Infectious Diseases, Warsaw, Poland; 5Regional Hospital, Kielce, Poland; 6Medical University, Bydgoszcz, Poland; 7University of Toronto, Toronto, Canada; 8University of Bologna, Bologna, Italy; 9University of Modena and Reggio Emilia, Modena, Italy; 10Debiopharm SA, Lausanne, Switzerland

43rd Annual Meeting of EASL, April 23-27, 2008J Hepatol 2008, vol. 48, suppl. 2: s62 [143]

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, 20054. Nakagawa et al.Gastroenterology 2005; 129:1031-10415. Watashi K et al. Hepatology 2003; 38: 1282-1288.

Debio 025

position 4 - N-Ethyl Valine instead of N-Methyl Leucine (prevent CaN binding)

position 3 - methyl group (stronger Cyp binding)

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 log10 copies/mL

-28

1

2

3

4

5

6

7

8

DEBIO-025

Placebo

0 5 10 15 20 25 30 35 40 45 50

Treatment

Time (Days)

Log 1

0 co

pies

/ml

(n=3)

(n=16)

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 CommitteePeg = PegIFN2a

DMCPeg + Placebo: n= 6Peg + Debio 025 200 mg: n=18



Debio 025 1000 mg: n=18

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&4n=60

gen 2&3n=30

PegIFN2a - 180 g/week + placebo

Debio 025 - 1000 mg/day

PegIFN2a - 180 g/week






-5

-4

-3

-2

-1

0

day 1 day 8 day 15 day 22 day 29

Me

an

HC

V R

NA

re

du

ctio

n [lo

g1

0 IU

/mL

]

Peg + Placebo

Debio 025 1000 mg

Peg + Debio 025 200 mg



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

-6

-5

-4

-3

-2

-1

0

day 1 day 8 day 15 day 22 day 29

Me

an

HC

V R

NA

re

du

ctio

n [lo

g1

0 IU

/mL

]

Peg + Placebo

Debio 025 1000 mg




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

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

Genotype 1&4 Genotype 2&30

10

20

30

40

50

60

70

80

90

100

%

Peg + Placebo

Debio 025 1000 mg




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)

PegIFN2a PegIFN2a PegIFN2a PegIFN2a

placeboDebio 025

200 mgDebio 025

600 mgDebio 025 1000 mg

Debio 025 1000 mg

N=18 N=18 N=18 N=18 N=18

Headache 12 12 11 10 8

Myalgia 8 4 4 5 1

Pyrexia 13 6 10 5 0

Chills 6 5 4 3 0

Fatigue 6 1 2 9 7

Nausea 8 2 3 7 8

Leukopenia 2 3 0 2 0

Neutropenia 6 6 2 3 0

Hyperbiliru-binaemia

0 0 0 5 8

The most frequently reported Adverse Events

0

2

4

6

8

10

12

14

16

18

screen day 1 day 8 day 15 day 22 day 29 day 50

Peg + Placebo

Debio 025 1000mg

Peg + Debio 025 200mg



2

3

1 1

1

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

Pla

tele

ts (G

iga/

L)

0

50

100

150

200

250

300

day 1 day 8 day 15 day 22 day 29 day 50

Peg + Placebo

Debio 025 1000 mg




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

Neu

troph

ils (G

iga/

L)

0

1

2

3

4

5

day 1 day 8 day 15 day 22 day 29 day 50

Peg + Placebo

Debio 025 1000 mg




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

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.

Acknowledgements

Study sites - PolandR. 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 - ItalyG. Mazzella, D. Festi, F. Lodato (Bologna)C. Vandelli, E. Tesini (Modena)

Study sites - CanadaSV. Feinman, S. Bojarski, M. Jong Hsiao (Toronto)JE. Heathcote, D. Kaznowski (Toronto)F. Anderson (Vancouver)S. Erb (Vancouver)

Debiopharm SA - SwitzerlandR. Crabbé, JS. Liz, H. Porchet, P. Scalfaro, V. Nicolas, A. Ménétrey, G. Vuagniaux

Efficacy and safety of increasing doses of the cyclophilin inhibitor Debio 025 in combination with...

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