HCV Treatment : SOTA : where are we today ? Robert G. Gish MD San - PowerPoint PPT Presentation

HCV Treatment : SOTA : where are we today ? Robert G. Gish MD San Diego ACCP 2012

Concepts in HCV • HCV is curable • 20-30% of HCV infected patient develop cirrhosis • HCV is a systemic disease: – note cyroglobulinemia – HCV increases overall mortality rates • Liver biopsy or indirect fibrosis assessment is required to triage patients in 2012 2

To Treat or not to Treat: A Constellation of Considerations Histologic stage Duration of Genotype virus 20%+ life time risk Genotype Patient (IL28) infection Of cirrhosis Personal plans Family and other (marriage, Age support pregnancy) Patient ALT Occupation "mindset" Extrahepatic Contraindications Features HIV coinfection & comorbidities (Fatigue, EMC, PCT) Insulin Resistance PinK AALSD CME 2009

HCV Subtype Distribution: A Mosaic of Overlapping Sub-Epidemics Mandell, 6th Edition, 2005

2 Protease Inhibitors Approved for Genotype 1 HCV Infection Protease Inhibitor Additional Regimen Considerations Components  Naive to previous therapy Boceprevir 800 mg TID PegIFN alfa  Previous treatment failure (q7-9hrs) [1,2] +  Compensated cirrhosis weight-based RBV  RGT  Naive to previous therapy Telaprevir 750 mg TID PegIFN alfa  Previous treatment failure (q7-9hrs) [2,3] +  Compensated cirrhosis weight-based RBV  RGT For patients with genotype 2/3 infection, HCV therapy with pegIFN/RBV remains the standard of care 1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. 2011.

What can we tell our patients? Significantly Higher SVR rates in Telaprevir-Treated Patients Compared to Peg IFN/Ribavirin Alone T12PR PR P <0.0001 100 Percent of patients with 90 75 80 70 60 44 50 40 30 SVR 20 10 0 n/N = 271/363 158/361 SVR Jacobson IM, et al. Hepatology 2010;52(Suppl 1):Abstract 211.

Telaprevir + PegIFN/RBV: Genotype 1 Treatment-Naive Patients Dosage and Administration 750 mg (two 375-mg tablets) TID (every 7-9 hrs) with food (standard fat meal 20  g,)eg, ½ cup nuts or 2 oz cheddar cheese) Must be administered with both pegIFN and RBV  Telaprevir dose must not be reduced or interrupted  F/u eRVR; stop at Wk 24/ f/u TVR + PegIFN + RBV PegIFN + RBV 24 No eRVR; PegIFN + RBV wks 4 12 24 0 48 Wks Week 24 HCV RNA Week 12 HCV RNA Week 4 HCV RNA Futility detectable > 1000 IU/ml > 1000 IU/ml Treatment duration Patients with extended RVR (eRVR, undetectable* HCV RNA at Week 4 and 12)  receive 24 wks of therapy  Patients without eRVR continue on pegIFN + RBV for a total of 48 wks Treatment-naive patients with compensated cirrhosis and eRVR may benefit from  Telaprevir package insert. May 2011. *Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL. additional 36 wks of pegIFN + RBV (ie, to Week 48)

Boceprevir for genotype 1 naïve HCV Milestones: Weeks 8, 12, 24 Week 48 Week 28 Week 4 Week 72 TW 8-24 HCV-RNA Undetectable* Follow-up PR PR + BOC (24 weeks) Non-cirrhotic lead-in Week 36 PR+BOC Follow-up PR (32 weeks) Week 12 Week 24 TW 8 HCV-RNA Detectable/ TW 24 undetectable PR PR + BOC (44) weeks for cirrhotic patients/ Follow-up poorly responsive pts lead-in Week 12 Futility Week 24 Futility HCV > 100 IU/ml Detectable HCV RNA *assay should have a lower limit of HCV-RNA quantification < 25 IU/mL, and limit of HCV- RNA detection of approximately 10-15 IU/mL

SPRINT 2: SVR* and Relapse Rates SVR Relapse Rate p <0.0001 p =0.004 p < 0.0001 p = 0.044 100 100 80 68 67 80 53 60 211 213 60 Percent Percent 316 311 42 40 29 40 40 23 55 23 125 22 17 311 52 14 12 9 20 8 20 37 12 6 162 21 18 52 2 3 35 0 232 230 14 25 0 48 P/R BOC RGT BOC/PR48 48 P/R BOC RGT BOC/PR48 Non-Black Patients Black Patients *SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24- week post-treatment level was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA documented at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39%, 66% and 68%, respectively and in Cohort 2 were 21%, 42% and 51%, respectively.

Use of Predictors to Decide to Treat Now or Wait for INF free regimens – Current Issues Treatment duration • At least 24 weeks for HCV GT1 ? • Studies in Asia should be for 12 week triple therapy total or less with TVR or 12 +12 with BCP for IL28 CC ? • Suboptimal results for non-RVR patients after 48 weeks of treatment Safety profile • Several IFN-related AEs • Current PIs: anemia, rash, etc • DDI Low efficacy in certain patients • History of null response • IL28B : TT • Liver cirrhosis

Clinical Pharmacology and Drug Interactions  Boceprevir  Strong inhibitor of CYP3A4/5  Partly metabolized by CYP3A4/5  Potential inhibitor of and substrate for P-gp  Telaprevir  Substrate of CYP3A  Inhibitor of CYP3A  Substrate of P-gp  Must perform DDI survey or work with clinic pharmacology  http://www.hep-druginteractions.org/ P-gp = p-glycoprotein Boceprevir capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2011. Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

There is a paucity of data in Asians there is a dearth of ethnicity reporting in all trials 90% Pre-2005 Post-2005 80% 70% 60% % Race Reported 50% 40% 30% 20% 10% 0% Only US Partially US Only EU Partially EU AASLD 2012: Saraswuthala/Muir

A Polymorphism on Chromosome 19 Predicts SVR 60 Mb IL28B gene IFN Lambda-3 gene 3 kb 19q13.13 Polymorphism rs12979860 Chromosome 19 Ge D, et al. Nature. 2009;461:399-401. Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. Available at: http://www.ornl.gov/sci/techresources/meetings/ecr2/olsen.gif. Accessed on: October 21, 2009.

SVR Rates in ADVANCE Patients Genotyped for IL28B 100 90 T12PR 84 Patients with SVR (%) T8PR 73 80 71 64 PR 59 57 60 40 25 23 20 0 16/22 19/32 6/26 45/50 38/45 35/55 48/68 43/76 20/80 n/N= CC CT TT Jacobson IM, et al. Poster presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin, Germany. Poster LB1369.

SPRINT-2 Boceprevir: IL28B CC Polymorphism Predicts Week 8 Response Poordad F, et al. EASL 2011. Abstract 12.

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ATOMIC Trial: Virologic Response Virologic Response SVR4 • Rapid reduction in HCV RNA in SVR12 first 2 weeks of therapy 94% 92% 92% regardless of IL28B status 90% • SVR4 rates were comparable between GS-7977 regimens of 12 and 24 week duration Patients (%) • Virologic relapse was rare to date, 4 patients sequenced – No S282T mutation (population sequencing) – Deep sequencing results are pending for all patients with NR NR relapse 12 24 12+12 GS-7977 + pegIFN + RBV (weeks) Kowdley KV, et al. J Hepatol. 2012;56(suppl 2):S1. Abstract 1. NR: not reported.

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ZENITH Study Vertex Pol VX 222, TVR and Ribavirin: SVR12 Outcomes CC SVR12 CT TT • There was an 100% 100% 88% association between 83% 73% IL28B genotype and 67% undetectable HCV RNA Patients (%) at week 2 – This association disappeared at week 4 due to high RVR rates across all IL28B VX-222 (100 mg bid) VX-222 (400 mg bid) genotypes (83% to (n=12/11/6) (n=8/16/6) 100%) All patients received telaprevir (1125 mg bid) + PegIFN + RBV Penney MS, et al. J Hepatol. 2012;56(supp 2):S476-S477. Abstract 1203.

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Interferon-Free: PILOT and Co-PILOT Pilot : G1, treatment naïve, IL28B CC, non-cirrhotic Co-Pilot 2 ABT-450/r + ABT-072 + RBV Pilot 1 95 100 91 93 Co-Pilot : G1, non-cirrhotic 80 ABT-450 250mg/r SVR12 (%) 60 47 + ABT-333 + RBV Naive 40 ABT-450 150mg/r + ABT-333 + RBV 20 9/10 ABT-450 250 mg/r 0 Treatment n=11 n=17 n=19 n=14 Experienced + ABT-333 + RBV ABT-450: NS3 inhibitor weeks 0 12 ABT-072 and -333: non-nucleoside inhibitor r: ritonavir 1. Lawitz E, et al. EASL 2012. Abstract 1187 2. Poordad F, et al. EASL 2012. Abstract 1399

BMS: INF Free, Riba Free, triple therapy PI, NS5A, Pol Inh

Towards a Future for the Asian Patient Treatment Personalized Medicine for HCV Therapy Direct Acting Antivirals 8-12 weeks therapy or shorter NNI + PI Nuc + NS5A PEG-IFN + RBV Nuc + RBV ± RBV ± RBV ± PI + DAA (s) To shorten Rx Nuc: nucleotide polymerase inhibitor time to ?4 weeks NNI: non-nucleotide polymerase inhibitor PI: protease inhibitor NS5A: NS5A replication complex inhibitor

Treat now ? Yes DAAs provisional “yes” with current Pis as part of triple therapy INF + Riba • Advanced fibrosis by – Liver biopsy – Fibroscan – Imaging • Cryoglobulinemia • Patient demand • 1 st Gen PIs in Asian patients, off label: – Shorten Rx with TVR to 8 weeks if 2 week vRVR – Shorten Rx with BCP to 12 to 18 weeks if 2 week vRVR

Will week 1 or2 become the new assessment of seRVR or vRVR? • For Asia • Ready for DAA s now – Qualified yes – Cost: estimates will be the cost of 50 000 $ use for a 12 week course, dual triple or quad – Use of INF as back bone to save cost? Shorten Rx to 4-6 weeks for some favorable> • G 1b • No metabolic Syndrome • IL28 CC