Interferon free therapy Are we getting there? Graham R Foster Queen Marys University of London

Interferon free therapy Are we getting there? Graham R Foster Queen Marys University of London

IFN free therapy Disclosures I have received personal and institutional funding from companies that sell drug to treat hepatitis C including Roche, Novartis, Janssen, Gilead, Merck, BI, BMS and GSK

IFN free therapy IFN free therapy means ALL patients are going to receive IFN free treatment We are a long way from this

Clinical Trials Clinical trials are designed to show a drug at its best

Clinical Trials How many trials have you seen in: Patients with portal hypertension Patients with immunosuppression Injection drug users

Clinical Trials How many trials have you seen in: Patients with portal hypertension Patients with immunosuppression Injection drug users People who are likely to fail

Clinical Trials Clinical trials show a drug at its best...

GS 7977 + RBV in Genotype 1 HCV GS 7977 400 mg QD + RBV SVR4 (%) n=25 n=19 n=19 n=9 1 2 2 New Zealand Cirrhotics excluded 56% non CC USA Cirrhotics (fibrosis stage 2) not excluded 84% non CC USA Mainly African Americans RBV, ribavirin; SVR4, sustained virological response at 4 weeks; TN, treatment naïve; QD, once daily 1. EASL, Barcelona, Spain, 18 22 April 2012; Abstract 1113; 2. Press release, Gilead Sciences, 19 July 2012

Daclatasvir + GS 7977 ± RBV in Tx Naive GT1, 2/3 Pts Wk 1 Wk 24 Wk 48 Treatment naive patients with GT1a or 1b HCV infection (n = 44) A B C GS 7977 (n = 15) Daclatasvir + GS 7977 Daclatasvir + GS 7977 (n = 14) Daclatasvir + GS 7977 + Ribavirin (n = 15) Follow up Follow up Follow up Treatment naive patients with GT2 or 3 HCV infection (n = 44) D E F GS 7977 (n = 16) Daclatasvir + GS 7977 Daclatasvir + GS 7977 (n = 14) Daclatasvir + GS 7977 + Ribavirin (n = 14) Follow up Follow up Follow up GS 7977 dosed 400 mg QD. Daclatasvir dosed 60 mg QD. RBV dosed by body weight for GT1 pts (1000 1200 mg/day); 800 mg/day for GT 2/3 pts. Sulkowski M, et al. EASL 2012. Abstract 1422.

Daclatasvir + GS 7977 ± RBV: Efficacy Analysis According to Genotype Genotype 1a/1b HCV Genotype 2/3 HCV Patients (%) 100 80 60 40 20 n = 0 100 100 100 87 93 73 100 100 100 93 100 100 100 87 86 87 86 93 15 14 15 15 14 15 15 14 15 Wk 4 Wk 24 (EOT) SVR4 Group A Group B Group C Light: < LOD Dark: < LLOQ and detectable Patients (%) 100 80 60 40 20 n = 0 100 100 100 88 79 64 100 94 93 93 86 86 100 100 88* 86 88 79 16 14 14 16 14 14 16 14 14 Wk 4 Wk 24 (EOT) SVR4 Group D Group E Group F Light: < LOD Dark: < LLOQ and detectable mitt analysis, bars not reaching 100% after Wk 4 reflect missing values. mitt analysis, bars not reaching 100% after Wk 4 reflect missing values. *1 patient required addition of pegifn alfa/rbv (tx intensification), 1 patient with relapse at posttreatment Wk 4 2 patients lost to follow up (following Wk 12 and 24 visits). Sulkowski M, et al. EASL 2012. Abstract 1422.

Co Pilot: 12 Wk ABT 450/r + ABT 333 + RBV in Tx Naive and Exp d GT1 Patients Interim analysis of nonrandomized, prospective, open label phase II trial Wk 12 Treatment naive patients infected with genotype 1 HCV (n = 33) Treatment experienced* patients infected with genotype 1 HCV (n = 17) ABT 450/Ritonavir 250/100 mg QD + ABT 333 400 mg BID + RBV 1000 1200 mg QD (n = 19) ABT 450/Ritonavir 150/100 mg QD + ABT 333 400 mg BID + RBV 1000 1200 mg QD (n = 14) ABT 450/Ritonavir 150/100 mg QD + ABT 333 400 mg BID + RBV 1000 1200 mg QD (n = 17) 48 wks of follow up *Previous null response (< 2 log 10 decrease in HCV RNA by Wk 12) or partial response (HCV RNA above limit of detection during treatment) Poordad F, et al. EASL 2012. Abstract 1399.

Co Pilot: Virologic Outcomes SVR12 in 94% of treatment naive and 47% of treatment experienced patients Responses independent of IL28B genotype 100 80 90 90 95 95 79 79 93 93 77 RVR ervr SVR4 SVR12 Patients (%) 60 40 59 47 47 20 0 ABT 450/r 250/100 mg QD + ABT 333 + RBV Treatment naive (n = 19) ABT 450/r 150/100 mg QD + ABT 333 + RBV Treatment naive (n = 14) ABT 450/r 150/100 mg QD + ABT 333 + RBV Nonresponders (n = 17) Poordad F, et al. EASL 2012. Abstract 1399.

Interferon Free Trials Encouraging results BUT

Interferon Free Trials Encouraging results BUT Easy to treat populations Motivated, closely monitored patients

Interferon Free How will these drugs work in the real world? Compliance PegIFN has a long half life Ribavirin lasts for ever A few missed doses does not matter

Cumulative ribavirin exposure week 13 48 after full exposure week 1 12: SVR 90 80 70 60 50 40 30 20 10 0 n=325 ETR SVR >97% >80 97% >60 80% 0 60 % Cumulative Ribavirin Exposure P= 0.0107 Reddy KR et al Clin Gastroenterol Hepatol 2007

Compliance with new drugs Unstudied Unknown (How many of your HBV patients are fully compliant?)

Costs The new drugs won t be cheap Everyone is broke

Costs 2015 choice of therapy PegIFN + Riba G2/3 non cirrhotic E6,000 Oral combo G2/3 non cirrhotic E30,000 PegIFN + Riba G1 IL 28 CC E6,000 Oral combo G1 IL 28 CC E60,000

Costs The new drugs won t be cheap Everyone is broke Who will pay for the new drugs?

Madame Sosotris, famous clairvoyant

HCV patients cheap oral drugs Everyone gets IFN free Failures (20%) go on to IFN plus regimes

HCV patients expensive oral drugs Poor people with easy to cure disease IFN REGIMES Rich people with easy to cure disease ALL ORAL REGIMES Poor people with challenging disease Viral specific therapy

All Oral Therapy for HCV Are we nearly there? Success with IFN free regimes depends upon: Virological success Economic success Successful delivery

All Oral Therapy for HCV Are we nearly there? Success with IFN free regimes depends upon: Virological success Economic success Successful delivery (easy cases)

IFN free regimes Are we nearly there? NO