The HCV Pipeline Ira M. Jacobson, MD, FACP, FACG, AGAF. Slide Presentation. IFN-free DAA combinations (G1)

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1 Slide Presentation The HCV Pipeline Vincent Astor Distinguished Professor of Medicine Chief, Division of Gastroenterology and Hepatology Medical Director, Center for the Study of Hepatitis C Weill Cornell Medical College New York-Presbyterian Hospital New York, New York HCV Therapy: Past, Present, and Future Interferon Ribavirin Proof of concept for DAA (PI) Suppression of HCV with DAA combination (PI + NI) Telaprevir and boceprevir Frequent curability of diverse populations without IFN Potential approval of other DAAs with IFN (eg, faldaprevir) IFN-free DAA combinations (G1) Pegylated interferons Courtesy of Ira Jacobson, MD Curability of HCV without interferon Approval of simeprevir and sofosbuvir w/ IFN (G1) First approved IFN-free therapy: SOF+RBV for GT 2,3 HOST Mir122 inhibitors Miravirsen Multiple Validated Drug Targets 5 UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B Protease HCV PIs inhibitors Viral Enzyme Active Site Protease Telaprevir Boceprevir Simeprevir Faldaprevir Asunaprevir Danoprevir ABT-45 MK-5172 Sovaprevir ACH-2684 None p7 NS5A Inhibitors BIT225 Nonenzyme Replication Complex Daclatasvir Ledipasvir ABT-267 GS-5816 ACH-312 PPI-668 GSK23365 Samatasvir (IDX-719) MK-8742 Helicase None 4A HOST Cyclophilin Inhibitors Alisporivir SCY-635 and entry inhibitors Membranous web (Preclin) NS5B Nucs Viral Enzyme Active Site Polymerase Sofosbuvir Meracitabine VX-135 IDX963 ACH UTR NS5B Non-nucs Viral Enzyme Allosteric Site ABT-333 Deleobuvir BMS PPI-383 GS-9669 TMC64755 Not all-inclusive. Adapted from Dr John Link, adapted with permission Courtesy of Ira Jacobson, MD 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

2 Compressing the Accordion of Treatment Duration in HCV Drug Development THEN Entry EOT SVR24 48 weeks 24 weeks Treatment Follow-up NOW Treatment Follow-up EOT 1 Moving to next phase Submission of NDA 1. Chen J et al. Gastroenterol 13;114: EOT: end of treatment; NDA: new drug application; /24: sustained virologic response 12/24 weeks after end of treatment DAA + PegIFN/RBV: A New Plateau or the Last Gasp (or Both) for IFN Therapy? Treatment-Naïve GT1: Phase 3 Trials QUEST-1 and QUEST-2: Pooled analysis, PR + SMV 15 mg for weeks 1 NEUTRINO: PR + SOF mg for 12 weeks 2 1. Jacobson IM et al. Hepatol 13; 58(Supp):756-7A 2. Lawitz E et al. NEJM 13; 368: All Yes No GT1 GT5/6 Cirrhosis GT4 PBO, placebo; PegIFN, pegylated interferon; PR, pegylated interferon + ribavirin Successful Retreatment With SOF of G1 Patients Who Failed Prior Therapy With PR + 1 or 2 Additional DAAs patients who received PR + PR ± NS5A ± NNI HCV RNA < LLOQ Pol S et al, EASL 14, #O /67 66/67 37/5 Wk 4 EOT SVR independent of number of prior drugs SVR independent of number of RAVs Supports use of PR+SOF in PR failures 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

3 Hurdles Overcome on the Road to IFN-Free Therapy for Genotype 1 HCV Impact of G1 subtype Impact of prior nonresponse to interferon Oral Regimens With 9% SVR for GT1 Patients No nucleotide Nucleotide ± RBV ± RBV PI* NS5A* ± RBV NNI, nonnucleoside inhibitor; Nuc, nucleotide inhibitor; PI, protease inhibitor * second generation Highly Effective DAA Regimens for Genotype 1 No Nucleotide 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

4 ABT-45/r (PI), ABT-267 (NS5A), ABT-333 (non-nuc) ± RBV: AVIATOR GT 1, Noncirrhotic n= Wk Wk 8 Wk 12 Wk RBV RBV RBV RBV RBV Under study Pivotal Phase 3 Treatment naïve Null responders RBV RBV Pivotal Phase RBV 45: ABT-45/r; 267: ABT-267; 333: ABT-333 all investigational agents not approved by the EMA for use in HCV / 34/ 7/ 7/ 76/ 73/ Kowdley K et al. NEJM 14;37: SVR 24 rates IJ / 45 42/ 45 41/ 43 ABT-45/r Ombitasvir + Dasabuvir + RBV: SAPPHIRE-1 Genotype 1, treatment naïve, 12 weeks, n= /473 37/ /151 Overall G1a G1b Feld JJ et al, NEJM 14;37: ABT-45/r Ombitasvir + Dasabuvir + RBV: SAPPHIRE-1 Genotype 1, treatment naïve, 12 weeks, n= Non- Male Female Black black <55 >55 <3 >3 F-2 F3 CC CC <K >K Yes No Gender Race Age BMI Fibrosis IL28B HCV RNA RBV dose Feld JJ et al, NEJM 14;37: reduction Non- 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

5 SAPPHIRE-1: Safety and Tolerability Viral breakthrough or relapse = 1.7% Adverse events included fatigue, headache, and nausea Discontinuations for adverse events =.6% ABT-45/r Ombitasvir + Dasabuvir + RBV: SAPPHIRE-2 Genotype 1, treatment experienced, 12 weeks, n=394 Zeuzem S et al, NEJM Overall G1a G1b SAPPHIRE-2: Safety and Tolerability 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

6 ABT-45/r Ombitasvir + Dasabuvir ± RBV Genotype 1 Patients With Compensated Cirrhosis: Treatment Naïve and Treatment Experienced 92 P= % DC for AEs in both arms (fatigue, HA, nausea most common) Relapse/viral breakthrough in 6% (12 weeks) and 2% (24 weeks) Weeks 24 Weeks AbbVie press release, Jan 31, 14 Which Population Drove the Difference Between 12 and 24 Weeks in TURQUOISE-II? Arm A: 12-week regimen 85.7 Arm B: 24-week regimen n N Naive Relapser Partial Null Naive Relapser Partial Null GT1b Poordad F et al. NEJM; epub, April 12, GT1a TURQUOISE-II: Safety and Tolerability 12-week group 24-week group AE leading to d/c SAE Death.5 Fatigue Headache Nausea 18 Pruritus Diarrhea Rash Anemia 8 11 Dyspnea 6 12 List of AEs not all-inclusive 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

7 TURQUOISE-II: Lab Abnormalities 12-week group 24-week group ALT, grade Total bilirubin, grade Hemoglobin grade 1* 5 56 grade grade grade patients with grade 3-4 ALT elevations: 4 completed treatment, 1 stopped, 1 occurred after d/c of study drugs. *34 RBV dose reduction: SVR % SAPPHIRE-1 Resistance Data From the 3D+RBV Pivotal Trials 473 patients - 1 (.2%) with breakthrough - 7/463 (1.5%) had relapse - All 8 had 1 class-resistant variant(s) SAPPHIRE-2 TURQUOISE-II 297 patients - 7/293 (2.4%) had relapse - 5/7 had 1 class RAVs 12 weeks 24 weeks 13/8 (6.2%) virologic failure - 1/8 (.5%) on treatment - 12/3 (5.9%) relapse 4/172 (2.3%) virologic failure - 3/172 (1.7%) on treatment - 1/164 (.6%) relapse 15/17 virologic failures had >2 class RAVs ABT-45/r Ombitasvir + Dasabuvir ± RBV Genotype 1a, Treatment Naïve, 12 Weeks (PEARL-4) RBV No RBV AbbVie press release, Jan 31, by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

8 ABT-45/r Ombitasvir + Dasabuvir ± RBV Genotype 1b Naïve, 12 Weeks (PEARL-3) Genotype 1b Experienced, 12 Weeks (PEARL-2) RBV No RBV RBV No RBV AbbVie press release, Jan 31, 14 Asunaprevir (PI), Daclatasvir (NS5A), BMS (NNI) G1, Treatment Naïve, 12 Wks Response (% patients) 82% genotype 1a (9% cirrhotic), BID dosing mitt = 89% 9% / 81/86 73/79 77/84 71/77 77/84 End of Treatment SVR4 Discontinuation for AEs 1.2% SVR in cirrhotics 13/15 (88%); CC 96%, non-cc 9%; GT1a 91%, GT1b 96% DCV + ASV mg bid DCV + ASV mg bid Viral breakthrough 5/166 (3%) (all GT1a) Viral relapse 6/166 (3.6%) (all GT1a) 13/17 with baseline NS3 or NS5A RAVs had SVR Hallmark Study: Dual Asunaprevir and Daclatasvir in GT1b Patients Tx naïve 9 182/ 3 Nonresponder / / 84 Ineligible/intolerant 57/ / / 77 Null Partial Manns M et al, EASL 14, #O by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

9 % Pts HCV RNA < 25 IU/mL C-WORTHY Study: MK-5172 ( mg) and MK-8742 (5 mg) ± RBV G1 Patients With Cirrhosis or Previous Null Response Treatment naïve, cirrhosis, n=123 PR nulls + cirrhosis, n=13 12 wk, + RBV 12 wk, no RBV 18 wk, + RBV 18 wk, no RBV wk, + RBV 12 wk, no RBV 18 wk, + RBV 18 wk, no RBV TW4 TW12 f/u wk 4/8 TW4 TW12 f/u wk 4/8 F/u 8 for 12-wk arms and f/u 4 for 18 wk arms Lawitz E et al, EASL 14, #O61 Highly Effective Regimens for Genotype 1 Nucleotide Containing Daclatasvir + Sofosbuvir ± RBV DCV mg, SOF mg, RBV -1 mg G1 naïve, noncirrhotic, 12 wks 95* 41/41 39/41 DCV+SOF DCV+SOF+RBV *1 missing at f/u week, had SVR 24, 1 lost to f/u G1 PI failure, noncirrhotic, 24 wks 95* 21/21 19/ DCV+SOF DCV+SOF+RBV *1 missing at f/u wk 12; had SVR 24 Sulkowski M et al, NEJM Jan 16, 14, 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

10 ION-1: Ledipasvir (NS5A Inhibitor) + Sofosbuvir Genotype 1 Treatment Naïve, n=865, Cirrhosis in 16% / / / /217 SOF/LDV SOF/LDV+RBV SOF/LDV SOF/LDV+RBV 12 weeks 24 weeks Afdhal N et al. NEJM; epub April 12, 14 On-treatment failure + RBV + RBV 1* Relapse 1 1 Lost to f/u Withdrew consent ION-1: Ledipasvir + Sofosbuvir Reasons for Failure to Attain SVR 12 weeks 24 weeks 2 1 *Undetectable drug levels Afdhal N et al. NEJM; epub April 12, 14 ION-1: Ledipasvir + Sofosbuvir Safety and Tolerability 12 weeks 24 weeks + RBV + RBV D/C for AEs 2 3 SAEs < Fatigue Insomnia Cough Pruritus Anemia 12 1 Hgb<1 gm/dl 9 7 List of AEs is not all-inclusive Afdhal N et al. NEJM; epub April 12, by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

11 ION-2: Ledipasvir + Sofosbuvir ± RBV Genotype 1 Treatment Experienced /19 17/111 18/ SOF/LDV SOF/LDV+RBV SOF/LDV SOF/LDV+RBV 12 weeks 24 weeks Afdhal N et al. NEJM; epub April 12, 14 ION-2: Ledipasvir + Sofosbuvir ± RBV Genotype 1 Treatment Experienced Protease Inhibitor Failures SOF/LDV SOF/LDV+RBV SOF/LDV SOF/LDV+RBV 12 weeks 24 weeks Afdhal N et al. NEJM; epub April 12, 14 ION-2: Ledipasvir + Sofosbuvir ± RBV Genotype 1 Treatment Experienced 86 Patients With Cirrhosis 82 19/22 18/22 22/22 22/22 SOF/LDV SOF/LDV+RBV SOF/LDV SOF/LDV+RBV 12 weeks 24 weeks Afdhal N et al. NEJM; epub April 12, by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

12 ION-2: Ledipasvir + Sofosbuvir Virologic Failures On-treatment failure 12 weeks 24 weeks + RBV + RBV 1 (1)* Relapse 7 (6%) 4 (4%) *Undetectable drug levels Afdhal N et al. NEJM; epub April 12, 14 ION-3: SOF + LDV + RBV Genotype 1, Treatment Naïve, Noncirrhotic: 8 vs 12 Weeks /215 1/216 SOF/LDV SOF/LDV+RBV SOF/LDV 95 6/216 8 weeks 12 weeks Kowdley K et al. NEJM, epub April 11, 14 ION-3: Ledipasvir + Sofosbuvir Reasons for Failure to Attain SVR On-treatment failure (N=215) + RBV (N=216) (N=216) Relapse, n 11 (5) 9 (4) 3 (1) Lost to f/u Withdrew consent 8 weeks 8 weeks 12 weeks 1 1 Kowdley K et al. NEJM, epub April 11, by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

13 ION-3: Ledipasvir + Sofosbuvir Safety and Tolerability 8 weeks 8 weeks 12 weeks + RBV D/C for AEs <1 1 SAEs 2 <1 2 Fatigue Insomnia Cough Pruritus Anemia Hgb < 1 g/dl 5 <1 List of AEs not all-inclusive Kowdley K et al. NEJM, epub April 11, 14 Resistance Data From the ION Studies ION-1 ION-2 Baseline NS5A variants in 1/861 (16%) by deep sequencing 96% had SVR 2 relapsers, 1 BT: all 3 had NS5A RAVs at relapse Both relapsers had NS5A RAVs at baseline Viral breakthrough: no NS5A RAVs at baseline Baseline NS5A variants in 62/439 (14%) by deep sequencing 89% had SVR 11 relapsers (all in the 12-week treatment group) All 11 patients had NS5A RAVs at relapse 6/11 had NS5A variants at baseline In ION-2, baseline PI RAVs had no impact ION-3 Baseline NS5A variants in 116/647 (18%) by deep sequencing 9% had SVR 23 relapsers: 15 had NS5A RAVs at relapse 9 had NS5A RAVs at baseline No clear role for baseline testing What Happens When SVR Does Not Occur After SOF-Based Therapy? Potential routes to failure Failure to suppress Viral breakthrough Posttreatment relapse IJ2 1 SOF Failure = Relapse No SOF resistance left behind Signature mutation (S282T) has very low replicative fitness 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

14 Retreatment of Relapsers to SOF/RBV With SOF/LDV ± RBV Pts With HCV RNA < LLOQ NIH SPARE trial, n=14 Wk 4 Wk 8 EOT SVR4 SVR8 LDV/SOF ELECTRON-2, n=19 14/14 14/14 14/14 LDV/SOF/RBV OsinusiA et al. EASL 14, #O11 Gane EJ et al, EASL 14, #O6 COSMOS: Simeprevir + Sofosbuvir + RBV for Prior Null Responders and Naïve Patients Week Arm 1 Arm 2 SMV + SOF + RBV SMV + SOF Posttreatment follow-up Posttreatment follow-up Arm 3 Arm 4 SMV + SOF + RBV SMV + SOF Posttreatment follow-up Posttreatment follow-up Enrollment ratio 2:1:2:1 Cohort 1: Prior null responders (METAVIR F-2) Final for all arms Cohort 2: Treatment naïve and prior null responders (METAVIR F3-4) Interim SVR4 for arms 3 and 4 Total n=167 COSMOS: Final Results in Cohort 2 Non-VF Relapse 2/27 7% 7% 7% 2/3 1/14 3% 2% 3/87 2/87 % Patients 93% % 93% 93% 94% 28/3 16/16 13/14 25/27 82/87 SMV/SOF + RBV SMV/SOF SMV/SOF + RBV SMV/SOF SMV/SOF ± RBV 24 weeks 12 weeks Overall Lawitz E et al, EASL by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

15 COSMOS: Final Results in Cohort 2 GT 1b GT 1a without QK 93 GT 1a with QK 93% % 93% 93% 94% 6/6 11/11 11/11 4/4 7/7 4/4 5/5 13/14 7/8 3/3 7/8 3/3 18/18 38/ 25/26 SMV/SOF + RBV SMV/SOF SMV/SOF + RBV SMV/SOF SMV/SOF ± RBV 24 weeks 12 weeks Overall Simeprevir and Sofosbuvir: Clinical Considerations The first prescribable DAA combination regimen Compelling option for patients Advanced fibrosis Prior null responders Interferon unable Safety cannot be extrapolated to Childs-Pugh B and C at this time Access is a challenge Full disclosure to patients if regimen is contemplated (off-label, modest study size, interim analysis, PI resistance possible) Ribavirin does not appear to be necessary Slight hint that 24 weeks better than 12 weeks for cirrhotics Theoretical access issues if regimen fails (speculative) AASLD/IDSA Guidelines: Recommended Role for Simeprevir + Sofosbuvir Genotype 1, interferon eligible Genotype 1, treatment experienced (PR failure) Interferon eligible Interferon ineligible hcvguidelines.org 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

16 Factors That Will Drive Regimen Choices in Genotype 1 Patients Differences in efficacy: real or perceived Safety/tolerability of DAAs Need for ribavirin Duration of treatment: any SVR price to pay to shorten? Genotype 1 subtype (esp. areas of high 1b prevalence) Baseline resistant variants (if shown to be relevant) Virologic price of failure Comorbidities and drug-drug interactions Simplicity of regimen (pills, dosing frequency) Complexity of diagnostics (GT1 subtyping, documentation of prior treatment history, accurate fibrosis assessment) Cost Oral Therapy for Genotype 2: Sofosbuvir + Ribavirin Sofosbuvir + Ribavirin (Phase 3) 97 in Genotype 2 Patients % SOF mg RBV -1 mg weeks 12 or 16 weeks Naïve IFN-unable Treatment experienced >9% naïve Lawitz E et al, NEJM 13;368: ; Jacobson I et al, NEJM 13;368: by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

17 VALENCE: SOF + RBV for 12 Weeks 29/3 2/2 3/33 7/8 Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Naïve Treatment experienced Zeuzem S et al, AASLD 13, #185 Oral Therapy for Genotype 3: Sofosbuvir + Ribavirin % Sofosbuvir + Ribavirin (Phase 3) 61 in Genotype 3 Patients 12 weeks 12 or 16 weeks SOF mg RBV -1 mg Naïve IFN-ineligible Treatment experienced >9% naïve Lawitz E et al, NEJM 13;368: ; Jacobson I et al, NEJM 13;368: by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

18 Sofosbuvir + Ribavirin for Genotype 3 VALENCE: 24 weeks SOF+RBV LONESTAR-2: 12 weeks PEG IFN + SOF + RBV /92 12/13 87/ 27/45 Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Naïve Treatment experienced Zeuzem S et al, AASLD 13, # /12 1/12 No cirrhosis Cirrhosis Treatment experienced Lawitz E et al. AASLD 13, #LB-4 Historically Difficult-to-Cure Populations Cirrhosis Compensated: Will regimens be different for cirrrhotics? Decompensated: preliminary results promising First demonstration of prevention of recurrence with oral regimen 1 Post-liver transplant Significant SVR rates with SOF+RBV in posttransplant study 2 SOF+RBV yields viral suppression and clinical improvement in severe recurrent disease, including fibrosing cholestatic hepatitis 3 Renal disease African Americans Minimal to no decrement in efficacy with DAA regimens so far HIV coinfected PR/SMV, PR/FDV, PR/SOF, SOF+RBV results similar to monoinfected patients 1. Curry M et al, AASLD 13; 2. Charlton M et al, AASLD 13; 3. Forns X et al, AASLD 13 Treatment of Hepatitis C: A Fundamental Change in Mindset Watch and wait No reason to wait 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART

19 Treatment of Hepatitis C: A Medical and Moral Imperative All Patients Are At Risk Liver Portal hypertension Liver failure HCC Systemic Public Health Diabetes Cryoglobulinemia Lymphoma Fatigue Depression Cognition Infectivity/transmission The democratization of HCV therapy 14 by individual slide author(s). All rights reserved. HEPATITIS C MANAGEMENT 14: STATE OF THE ART