Disclosures 29/09/2014. Genetic determinants of. HCV treatment outcome. IDEAL: IL28B-type is the strongest pre-treatment predictor of SVR

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1 29/9/214 Genetic determinants of ᴧ HCV treatment outcome Disclosures Advisory board member - Gilead, Abbvie, Bristol-Myers Squibb (BMS), Janssen, Merck, and oche Speaker - Gilead, Janssen, Merck, BMS, Abbvie Prof. Alex Thompson St. Vincent s Hospital Melbourne, Australia The University of Melbourne, Australia Alice Springs, September, 214 PI - Gilead, Merck, oche, BMS, Janssen, Achillion, Springbank esearch / grant support Gilead, Merck, BMS, Abbvie My presentation includes discussion of genetic tests and drugs which are not approved for clinical use Genome-wide association studies identify an association b/w IL28B polymorphism and SV Genome-wide association studies identify an association b/w IL28B polymorphism and SV IDEAL study pharmacogenomics cohort, n = 164 rs rs99917 rs rs rs43223 rs12962 IL28B IL28B = IFN-lambda-3 Ge*, Fellay*, Thompson* et al, Nature, 29 C/C genotype predicts SV IDEAL: IL28B-type is the strongest pre-treatment predictor of SV Odds atio 95% Confidence Interval p-value IL28B-type vs non <.1 VL 6, IU/mL <.1 Caucasian vs AA ethnicity <.1 Hispanic vs AA ethnicity METAVI F <.1 Fasting Blood Sugar < 5.6 mmol/l <.1 Co-variates - rs (2-level), ethnicity (4-level), age ( 4), gender, BMI (< 3), VL ( 6,), ALT ( ULN), fasting glucose (< 5.6), hepatic steatosis (N/Y[>%]), fibrosis (METAVI F12), BV (>13 mg/kg/d) Ge*, Fellay*, Thompson* et al, Nature, 29 Thompson, Gastro, 21 1

2 Median HCV NA Change From Baseline (Log1 IU/mL) SV (%) 29/9/214 IL28B genotype is associated with phase 1 viral kinetics The global prevalence of C/T alleles at rs may explain the recognized geographical variation in SV rates Genotype 1 HCV, IL28B rs TT CT Day 1, P <.1 Neumann, EASL, 21 Thomas, Thio, Martin et al. Nature, 29 IL28B variation is associated with spontaneous clearance of HCV Multi-national IDU cohort, n = 388 (cleared) vs 62 (chornic) Case-control candidate gene study, SNP = rs O for clearance ( vs non-) = 3., P = 1-13 Summary In genotype 1(/4) HCV patients, IL28B genotype: strongly associated with cure of HCV strongest baseline predictor explains much of the ethnic difference in response rates profoundly influences viral kinetics In genotype 2/3/6 HCV, the association between IL28B genotype and P response is attenuated IL28B polymorphism is also strongly associated with spontaneous clearance of HCV IL28B genotype Thomas, Thio, Martin et al. Nature, 29 PIs attenuate the association between IL28B genotype and SV Direct acting antiviral agents (DAAs) Boceprevir, treatment naive Telaprevir, treatment naive DAA + peginterferon and ribavirin PI - Telaprevir, boceprevir, simeprevir NI - sofosbuvir P BOC/GT BOC/P48 TT CT P T8P T12P Poordad, Gastroenterology, 212 Pol, J Hepatology, 213 2

3 SV (%) SV12 (%) 29/9/214 PIs attenuate the association between IL28B genotype and SV IL28B genotype predicts for short duration therapy Boceprevir, treatment naive P BOC/GT BOC/P48 TT CT Telaprevir, treatment naive P T8P T12P Week 8 HCV NA Undetectable* (%) Boceprevir + P 52 Non- 89 ev* (%) 1 *Decision point for short vs. long treatment duration with GT Telaprevir + P TT CT Poordad, Gastroenterology, 212 Pol, J Hepatology, 213 Jacobson, EASL, 211 Poordad, Gastro, 212; Jacobson, EASL, 211 Simeprevir + P: IL28B genotype predicts SV Clinical utility similar to the setting of TV / BOC + P QUEST-1 Simeprevir + P, Phase 3, n=394 Sofosbuvir + P: IL28B genotype is less relevant NEUTINO (n=327) BV +SIMEPEVI 5 +BV +PLACEBO F-F2 F3-F4 1a 1b/other TT CT Predicts short duration therapy (note 85% of patients overall were eligible) 78 Jacobson, EASL, no- 12 week fixed duration (no GT) 98 Lawitz, NEJM, 213 Summary PI + P regimens: Naïve patients - association b/w IL28B and SV is attenuated patients: small absolute increase in SV goal = short duration therapy Non- patients: 2-fold increase in SV with DAA P experienced patients - IL28B less useful Sofosbuvir + P: As SV rates approach 1%, IL28B is less clinically useful Direct acting antiviral agents (DAAs) IFN-free regimens 3

4 SV12 (%) 29/9/214 IL28B genotype is associated with viral kinetics during IFN-free therapy 2 nd phase more important? Lessons from SOUND-C2: IL28B genotype predicted SV for HCV-1a INFOM-1 : Mericitabine (NS5B NI) + danoprevir ( PI), 14 days IL28B genotype is important for HCV-subtype 1a BI BI BV, 28 weeks Non- Chu, Gastro, 212 Zeuzem S, EASL, 212: A IFN-free treatment for Gt IFN-free treatment for Gt 2/3 W W8 W12 W24 SV genotype 1 (n=1556) W W12 W24 SV genotype 2 Sofosbuvir + ledipasvir +/- BV 1 Sofosbuvir + BV 1 +BV +BV +BV +BV 24w 8w Naïve (TN) Treatment experienced (TE) TN SV genotype 3 SV genotype 1 (n=238) ABT-45/rb + ABT ABT-333 +/- BV 2 Sofosbuvir + BV 2 1 Gilead press release, Dec 18, Abbvie press release, Dec Jacobson, NEJM, 213; 2 Zeuzem AASLD, 213 Summary: IFN-free therapy Predictors of response: 215+ IL28B genotype was relevant to early IFN-free DAA regimens patients were easy to cure, esp HCV-1a As SV rates increase with more potent combination DAA regimens, IL28B no longer predicts for SV One Size Fits All? There may not be any baseline variables that predict for outcome Cirrhotic null responders? Adherence may remain an issue? Perfectovir 4

5 29/9/214 But does everyone need perfectovir? Can IL28B genotype individualize treatment: Shorter? Cheaper? Ultra-short duration for C/C IL28B patients is possible $$$ Quad SV12 (%) 98 vv = 92% weeks 12 weeks 1 Thompson A, et al. EASL, 213 The future of HCV therapy 212 TV/BOC IL28B Beyond IL28B? IL28B NI Cost minimization Peg backbone 214+ BV NI BV NI NNI $$$ Simpler/shorter DAA regimens estricted access We have the technology Conclusion ITPA polymorphism predicts BV-associated anemia Fibrosis progression Cirrhosis isk Score - 7-snp signature (AZIN1, TL4, TPM5, AQP2, Chr 1(rs229351), Chr 3 (rs42929), and Chr 5 (rs177466)) NF7, METK polymorphisms Hepatic steatosis PNPLA3 on 22q13.31 (rs73849 C>G encoding I148M) Has also been associated with HCV-related fibrosis progression Fellay, Nature, 21; Thompson, Gastro, 21; Holmes, Hepatology, 214 Huang, Hepatology. 27; Marcolongo, Hepatology, 29; Trepo, J Hepatol., 211 Patin, Gastro, 212 Trepo, Hepatology, 211; Cai, J Hep, 211; Valenti, Hepatology, 211; Clark, Dig Dis Sci. 212 H MICA on 6p21.33 (rs ) ecent data suggests this signal may be due to linked variation in HCP5 Kumar, Nature genetics, 211; Lange, EASL, 213 (Late-breaker) The discovery of the association between IL28B genotype and peginterferon-response was a success story for pharmacogenomics Personalized medicine became reality for HCV IL28B genotype informed pre-treatment counselling IL28B genotype predicts for short duration treatment with first generation protease inhibitors (TV/BOC) DEPDC5 on 22q12 (rs11268) Miki, Nature genetics, 211 5

6 29/9/214 Conclusion The field is now moving away from personalized therapy for HCV Multiple optimized treatment regimens from 215+ IL28B genotype will not directly predict SV One size will fit all BUT not all patients will be able to pay for perfectovir ($$$) IL28B genotyping will remain useful to personalize regimens: Cheaper Simpler (less drugs) Shorter 6