Innovazione farmacologica e farmacologia clinica Francesco - PowerPoint PPT Presentation

PostGraduate School Clinical Pharmacology 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

Milestones Achieved, Miles to Go Milestones Achieved, Miles to Go 100 1986 1986 1998 1998 2001 2001 2002 2002 80 54 54- -56% 56% %) %) SVR (% SVR (% 60 42% 42% 39% 39% 34% 34% 40 16% 16% 20 6% 6% 0 IFN/RBV IFN/RBV PEG PEG- -IFN IFN IFN IFN IFN IFN IFN/RBV IFN/RBV PEG PEG- -IFN IFN 12 m 12 m /RBV /RBV 6 m 6 m 12 m 12 m 6 m 6 m 12 m 12 m 12 m 12 m Strader et al. Hepatology ; 39:1147-1171

Sustained Viral Response Rates with Sustained Viral Response Rates with PEG PEG- -IFN /RBV IFN /RBV 76%- 76% 76%- 76% -82% -82% 82% 82% 42% 42%- 42% 42%- -46% -46% 46% 46% Genotype 1 Genotype 1 Genotype Non- Genotype Non -1 1 Strader et al. Hepatology Strader et al. Hepatology ; 39:1147 ; 39:1147- -1171 1171

The importance of viral kinetics 8 Therapy 7 6 Non-response (NR) CV RNA 5 Slow response with relapse Log (10) HC 4 Early virologic response (EVR) 3 Rapid virologic response (RVR) 2 1 0 0 1 2 3 4 12 24 48 72 Time (wks) Scott J and Gretch DR. JAMA 2007.

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

Effect of IFN- α Average HCV RNA level reduction (log IU/ml) Average HCV RNA level reduction (log IU/ml) +0.5 +0.5 0.0 0.0 - -0.5 0.5 - -1.0 1.0 -1.5 - 1.5 -2.0 - 2.0 -2.5 - 2.5 - -3.0 3.0 - -3.5 3.5 Group A: untreated Group A: untreated Group C: IFN- Group C: IFN - α α 3 MU tiw 3 MU tiw -4.0 - 4.0 -4.5 - 4.5 -5.0 - 5.0 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 18 18 20 20 22 22 24 24 26 26 28 28 Days Days (Pawlotsky et al., Gastroenterology 2004;126:703-14)

inosine- monophospate- dehydrogenase (IMPDH),

Effect of IFN- α /Ribavirin Average HCV RNA level reduction (log IU/ml) Average HCV RNA level reduction (log IU/ml) +0.5 +0.5 0.0 0.0 - -0.5 0.5 - -1.0 1.0 -1.5 - 1.5 -2.0 - 2.0 -2.5 - 2.5 - -3.0 3.0 - -3.5 3.5 Group A: untreated Group A: untreated Group C: IFN Group C: IFN- - α α 3 MU tiw 3 MU tiw -4.0 - 4.0 Group D: IFN Group D: IFN- - α α 3 MU tiw + ribavirin 1.0 3 MU tiw + ribavirin 1.0- -1.2 g qd 1.2 g qd -4.5 - 4.5 - -5.0 5.0 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 16 16 18 18 20 20 22 22 24 24 26 26 28 28 Days Days (Pawlotsky et al., Gastroenterology 2004;126:703-14) slide courtesy of JM Pawlotsky

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

…..il futuro è cominciato!!

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

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

The protease cleaves the HCV polyprotein The protease cleaves the HCV polyprotein chain, initiating replication chain, initiating replication NS3/4A NS2 P7 Protease NS4B E2 NS5A E1 NS5B C Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No. 2 2006

Protease inhibitors prevents cleavage of the Protease inhibitors prevents cleavage of the polyprotein chain, preventing viral replication polyprotein chain, preventing viral replication Boceprevir and Telaprevir Downstream Protease inhibitor cleavage binds to protease is halted Protease Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No. 2 2006

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

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

Attenzione alle interazioni!

Drug Boceprevir Telaprevir cyclosporine 2.7 4.6 ! Tacrolimus 17 70 ! Midazolam 6.3 3.4 iv 9 os Atorvastatin 2.3 7.9 !

Specifically pecifically T Targeted argeted A Antiviral ntiviral T Therapies herapies for H for HC CV (STAT V (STAT- -C) C) Protease Protease Inhibition Inhibition Polymerase Polymerase Inhibition Inhibition Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No. 2 2006

The final enzyme cleaved from the HCV polyprotein, The final enzyme cleaved from the HCV polyprotein, the polymerase is critical to RNA replication the polymerase is critical to RNA replication Replicated RNA NS5B HCV replicase RNA template Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No. 2 2006

Inhibition of the polymerase halts viral replication Inhibition of the polymerase halts viral replication downstream downstream Polymerase inhibitor NS5B HCV replicase RNA template Kwong et al. Drug Discovery Today: Therapeutic Strategies, Vol. 3, No. 2 2006

Evolution of HCV genotype 1 treatment 100 59– ate (%) 75% 80 42– 60 54% SVR ra DAA DAA + 16– 4 Peg- 28% IFN + Peg-IFN RBV 5–8 + 0 RBV 2–4 2– IFN 20 + 7% RBV 1 IFN 1 1990 2000 2020 2010 IFN: interferon; RBV: ribavirin 1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–82 Peg-IFN: peginterferon 3. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–55 DAA: direct-acting antiviral 5. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A SVR: sustained virologic response 7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14

The importance of viral kinetics 8 Therapy 7 6 Non-response (NR) CV RNA 5 Slow response with relapse Log (10) HC 4 Early virologic response (EVR) 3 Rapid virologic response (RVR) 2 1 0 0 1 2 3 4 12 24 48 72 Time (wks) Scott J and Gretch DR. JAMA 2007.

telaprevir PK telaprevir PK 4 Pharmacokinetic parameters of Cmax 30 Cmin AUC 3 plasma telaprevir 20 2 1 10 0 0 20 40 60 80 100 0 Days 0 20 40 60 80 100 Days Journal of Viral Hepatitis, 2012, 19, e112–e119

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.

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):3251-3258. 2. McHutchison JG, Bacon BR. Am J Manag Care . 2005;11(10 suppl):S286-S295.

Grazie per l’attenzione !