Innovazione farmacologica e farmacologia clinica

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1 Innovazione farmacologica e farmacologia clinica Francesco Scaglione, MD, PhD Department of Medical Biotechnology and Translational Medicine School of medicine Postgradute School of clinical pharmacology University of Milan,Italy PostGraduate School Clinical Pharmacology

2 Milestones Achieved, Miles to Go SVR (%) % 42% 39% 54-56% 56% 20 6% 16% 0 IFN 6 m IFN 12 m IFN/RBV 6 m IFN/RBV 12 m PEG-IFN 12 m PEG-IFN /RBV 12 m Strader et al. Hepatology; 39:

3 Sustained Viral Response Rates with PEG-IFN /RBV 76%-82% 42%-46% 46% Genotype 1 Genotype Non-1 Strader et al. Hepatology; ; 39:

4 The importance of viral kinetics 8 7 Therapy Log (10) HCV RNA Non-response (NR) Slow response with relapse Early virologic response (EVR) Rapid virologic response (RVR) Time (wks) Scott J and Gretch DR. JAMA 2007.

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6 Mechanism of Action: Interferon Biologic response modifier HCV Interferon alfa HCV virions IFN receptors JAK STAT STAT1 Assembly HCV replicative Viral RNA complex Protein Adenosine kinase R IRF9 deaminase 2',5'oligoadenylate synthetase OAS: activates antiviral RNAses PKR: inactivates viral ptn translation ADA: edits viral RNA ISG mrna ISGF3 ISRE Adapted from Hoofnagle J. NEJM 2006

7 Effect of IFN-α Average HCV RNA level reduction (log IU/ml) Group A: untreated Group C: IFN-α 3 MU tiw (Pawlotsky et al., Gastroenterology 2004;126:703-14) Days

8 inosinemonophospatedehydrogenase (IMPDH),

9 Effect of IFN-α/Ribavirin Average HCV RNA level reduction (log IU/ml) Group A: untreated Group C: IFN-α 3 MU tiw Group D: IFN-α 3 MU tiw + ribavirin g qd Days (Pawlotsky et al., Gastroenterology 2004;126:703-14) slide courtesy of JM Pawlotsky

10 e il futuro? HIV protease HIV! Abbiamo imparato tutto da qui!

11 ..il futuro è cominciato!!

12 Direct Acting Antivirals (DAAs) Specifically Targeted Antiviral Therapy for Hepatitis C (STAT-C) Telaprevir Boceprevir

13 The Hepatitis C Genome HCV Polyprotein C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B NS3 Protease domain NS3 Helicase domain NS3 Bifunctional protease / helicase NS5B RNA-dependent RNA polymerase

14 The protease cleaves the HCV polyprotein chain, initiating replication E1 E2 P7 NS2 NS3/4A Protease NS4B NS5A C NS5B Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No

15 Protease inhibitors prevents cleavage of the polyprotein chain, preventing viral replication Boceprevir and Telaprevir Protease inhibitor binds to protease Downstream cleavage is halted Protease Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No

16 Zhang J et al.hepatology 2005;42:535A. Farmacocinetica Il cuore dall azione dei farmaci BOCEPREVIR T max T 1/2 1-2,5 h 7-15 h

17 Pharmacokinetic parameters of plasma telaprevir BOCEPREVIR T max T 1/2 1-2,5 h 7-15 h Journal of Viral Hepatitis, 2012, 19, e112 e119

18 Attenzione alle interazioni!

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22 Drug Boceprevir Telaprevir cyclosporine Tacrolimus Midazolam iv 9 os Atorvastatin !!!

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34 Specifically Targeted Antiviral Therapies for HCV (STAT-C) Protease Inhibition Polymerase Inhibition Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No

35 The final enzyme cleaved from the HCV polyprotein, the polymerase is critical to RNA replication NS5B Replicated RNA HCV replicase RNA template Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No

36 Inhibition of the polymerase halts viral replication downstream NS5B Polymerase inhibitor HCV replicase RNA template Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No

37 Evolution of HCV genotype 1 treatment 100 SVR rate (%) % IFN % IFN + RBV % Peg-IFN + RBV % DAA + Peg- IFN + RBV IFN: interferon; RBV: ribavirin Peg-IFN: peginterferon DAA: direct-acting antiviral SVR: sustained virologic response 1. McHutchison JG, et al. N Engl J Med 1998;339: ; 2. Fried M, et al. N Engl J Med 2002;347: Manns MP, et al. Lancet 2001;358:958 65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140: Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A 7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14

38 The importance of viral kinetics 8 7 Therapy Log (10) HCV RNA Non-response (NR) Slow response with relapse Early virologic response (EVR) Rapid virologic response (RVR) Time (wks) Scott J and Gretch DR. JAMA 2007.

39 4 3 2 telaprevir PK Pharmacokinetic parameters telaprevir PK of Cmax 30 Cmin plasma telaprevir 20 AUC Days Days Journal of Viral Hepatitis, 2012, 19, e112 e119

40 No Correlation of SVR With Plasma PK No SVR (n=29) SVR (n=87) No SVR (n=29) SVR (n=87) Tx-Experienced Tx-Naive Median, Quartiles Data from RESPOND-2 and SPRINT-2. AUC=area under the concentration-time curve; Cmin=minimum observed plasma concentration; PK=pharmacokinetic; SVR=sustained virologic response.

41 Paradigm of HCV Diagnosis and Treatment Treated 1 Treated but failed 1 Diagnosed but not treated 1 Not diagnosed 2 1. Evon DM, et al. Dig Dis Sci. 2007;52(11): McHutchison JG, Bacon BR. Am J Manag Care. 2005;11(10 suppl):s286-s295.

42 Grazie per l attenzione!