Antiviral agents in HCV

Transcription

1 Antiviral agents in HCV : Upcoming Therapeutic Options Su Jong Yu, M.D., Ph.D. Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine

2 Estimated 170 Million Persons With HCV Infection Worldwide 3-4 million newly infected each year worldwide Prevalence of infection > 10% 2.5% to 10.0% 1.0% to 2.5% NA World Health Organization Available at:

3 Spectrum of HCV infection Acute HCV Infection 15%-30% 55%-85% Recovery Chronic HCV Infection ~ 30% Normal ALT Chronic Hepatitis C Mild Moderate Severe Cirrhosis 20% End-Stage Liver Disease Hepatocellular Carcinoma Liver Transplantation Death

4 Liver Transplantation & CHC Cirrhosis secondary to HCV is the leading cause of LT Infection of the allograft by HCV is inevitable after LT 20 30% of recipients have fibrosis/cirrhosis at 5 years after transplantation Fibrosing cholestatic hepatitis occurs in up to 10% of patients post-transplant, and leads to accelerated allograft failure and death Decompensation: around 40% at 1 yr

5 Goals of Antiviral Therapy in CHC Viral clearance Prevention of cirrhosis Delay decompensation Prevention of HCC Prevention of HCV recurrence after LT

6 SVR (%) The Evolution of HCV Therapy IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12m Strader DB, et al. Hepatology 2004;39: PEG-IFN 12m PEG-IFN /RBV 12m

7 Patterns of Virologic Responses (SOC) SVR McHutchison JG, et al. N Engl J Med. 2009;361:

8 HCV Standard Tx duration & outcomes SVR: 80-90% Curable disease SVR: 40-60%?

9 SVR rates of Post-LT recurrent HCV Regimen SVR (%) Discontinuations (%) IFN IFN + RBV PEG-IFN PEF-IFN + RBV Arjal RR, et al. Aliment Pharmacol Ther 2007;26:127

10 Listed Potential intervening time points Transplant Chronic hepatitis Graft loss Prevent graft infection Prevent infection or Reduce risk of disease progression Prevent Cirrhosis & graft failure Pre- Transplant Antiviral Therapy Prophylactic or Preemptive Therapies Antiviral therapy for recurrent disease Biggins SW, et al. Infect Dis Clin N Am 2006;20:155.

11 Pts with undetectable HCV RNA (%) Prophylactic Tx (SOC) after LT 50 Prophylactic arm Observation arm switched to treatment RVR cevr 24 weeks 48 weeks undetectable undetectable SVR Bzowej N. Liver Transpl 2011;17:528

12 Mechanisms of IFN & RBV IFN RBV Nature 2005;436:939 Nature 2005;436:967

13 Clinical AEs & Lab Abn in PEG-IFN/RBV therapy Most common clinical AEs Influenza like (fatigue, HA, fever & rigors) : > 50% Psychiatric (depression, insomnia): 22-31% Lab Abn Neutropenia (ANC < 1500/mm3): 18-20% Anemia (Hb < 12 g/dl): ~ 30%

14 What Will Be the Standard of Care for Genotype 1 HCV Patients?

15 Gastroenterology 2012;142:1340 HCV Life Cycle

16 Schematic representation of the HCV genome Nature 2005;436:933

17 NS3/4A Protease Inhibitors

18 Mechanism of Protease Inhibitors Protein Processing Role of NS3/4A Serine Protease Polyprotein Precursor Signal Peptidase NS2/3 Protease NS3/4A Serine Protease C E1 E2 p7 NS2 NS3 A NS4 B A NS5 B Proteins Protein Processing C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

19 Mechanism of Protease Inhibitors Hepatitis C Virus NS3/4A Serine Protease Inhibitors NS3/4A Serine Protease Inhibitors Polyprotein Precursor Signal Peptidase NS2/3 Protease NS3/4A Serine Protease C E1 E2 p7 NS2 NS3 A NS4 B A NS5 B Proteins C E1 E2 p7 NS2 NS3 A NS4 B A NS5 B

20 NS3/4A Serine Protease Inhibitors Products FDA-Approved - Boceprevir (Victrelis) 800 mg (four 200-mg capsules) 3 times daily with food Boceprevir given for weeks Treat with PR for weeks based on HCV RNA results (week 8 & 24) - Telaprevir (Incivek) Helicase 750 mg (two 375-mg tablets) three times daily with food (not low fat) Treat with PR for 12 weeks NS3 Protease Protease Inhibitor Protease Active Site NS4A (followed by additional 12 or 36 weeks PR)

21 Overall SVR Rates: PI + SOC in Tx-naïve GT1 BOC TVR Hepatology 2011;54:1433.

22 First-line Treatment for Genotype 1 HCV Boceprevir or Telaprevir PegIFN-α Ribavirin

23 Boceprevir: Adverse Events Anemia and dysgeusia reported more frequently in BOC arms vs control in SPRINT-2 Poordad F, et al. AASLD Abstract LB-4.

24 Telaprevir: Adverse Events Pruritus, rash, and anemia reported more frequently in TVR arms vs control in ADVANCE Jacobson IM, et al. AASLD Abstract 211.

25 Virologic response (%) Efficacy of protease inhibitors for severe hepatitis C recurrence after liver transplantation 80 BOC/PR TVR/PR crvr cevr J Hepatol 2012; 56 (Suppl. 2): s21.

26 Drug interactions btw PI and CI BOC TVR 1. Hepatology 2012;56: Liver Transpl 2012;18:

27 NS5B RNA-dependent RNA polymerase (RdRp)

28 NS5B structure and drug targets Poordad F, et al. AASLD Abstract LB-4.

29 NS5B NIs

30 NS5B NNIs

31 NS5A Inhibitors Integral component of viral replication complex Impair innate immune response Daclatasvir (BMS )

32 Characteristics of HCV DAA Classes Characteristic Protease Inhibitors Nucleos(t)ide Polymerase Inhibitors Nonnucleoside Polymerase Inhibitors NS5A Inhibitors Potency High; variable among HCV genotypes Moderate-high; consistent across genotype, subtype Variable; variable among HCV genotypes High; multiple HCV genotypes Barrier to resistance Drug interaction potential Toxicity Pharmacokinetics Comments Low 1a < 1b High 1a = 1b Very low 1a < 1b Low 1a < 1b High Low Variable Low to moderate Rash; anemia; bilirubin Variable; QD to TID 2nd-generation PIs: better barrier, pangenotypic Mitochondrial; nuc interactions (ART) QD Single target; good tolerability in agents progressing in PhIII Variable Variable; QD to TID Many targets Variable QD Multiple antiviral MOA

33 Host-Targeted Agents and IFNs Alternative IFNs Cyclophilin Inhibitors SR-B1 inhibitor

34 Expected benefit of IFN λ (IL-29) Similar signaling pathway as IFN-α Unique receptor No cross- reactivity with IFN-α receptor Expressed on hepatocytes Limited expression on hematopoietic and neuronal cells Pharmacologic activity without typical IFN-α S/E Nature Genetics. 2009;41:

35 Cyclophilin inhibitor

36 Antiviral Efficacy of Alisporivir

37 Nature. 2009;457:797 Entry inhibition of HCV

38 New HCV therapy Novel Interferons Alternative Ribavirin Investigational agents Other Drugs Direct acting antiviral agents (DAA) Host target NS3/4A protease inhibitors NS5B polymerase inhibitors NS5A replication complex inhibitors Cyclophilin Entry

39 Investigational HCV Regimens in Phase III Clinical Trials Regimens With 1 DAA + PegIFN alfa/rbv Regimens With 2 DAAs + PegIFN alfa/rbv IFN-Free Regimens Faldaprevir (BI , PI) Daclatasvir (BMS , NS5A) Sofosbuvir (GS-7977, NI) Simeprevir (TMC-435, PI) Alisporivir (CYP) Vaniprevir (MK-7009, PI) Alternative Dosing TVR BID (approved PI) ClinicalTrials.gov. November 27, Daclatasvir + asunaprevir New IFNs PegIFN lambda-1a + RBV PegIFN lambda-1a + daclatasvir + RBV PegIFN lambda-1a + RBV + TVR Sofosbuvir + RBV Sofosbuvir + GS-5885 (NS5A) (FDC) ± RBV Asunaprevir (PI) + daclatasvir ABT-450 (PI)/RTV/ABT- 267 (NS5A) (FDC) + ABT-333 (NNI) + RBV Faldaprevir (PI) + BI (NNI) + RBV

40 Thank you for your attention