Patients with Cirrhosis: Managing the HCV Peri-Transplant Patient

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2 Patients with Cirrhosis: Managing the HCV Peri-Transplant Patient Fred Poordad, MD Professor of Medicine University of Texas Health Science Center VP, Academic and Clinical Affairs The Texas Liver Institute San Antonio, TX

3 Disclosures Grant/Research support: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol- Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, ZymoGenetics Speaker: Gilead, Kadmon, Janssen, Merck, Onyx/Bayer, Genentech, Salix and Vertex Consultant/Advisor: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol- Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix, Merck, Novartis, Tibotec/Janssen, Theravance and Vertex.

4 Hepatitis C is the Leading Cause for Liver Transplant in the US Berg et al. Am J Transplant. 2009;9(part 2):907.

5 Number of Cases Numbers of HCV Patients With Decompensated Cirrhosis and HCC Are Expected to Peak in 2020 in the US Increasing prevalence of decompensated cirrhosis and HCC could increase number of patients on liver transplant waiting list 160, ,000 Hepatocellular cancer Decompensated cirrhosis 120, ,000 80,000 60,000 40,000 20,000 Curves indicate gender and age at time of initial HCV infection. Data are for the United States. Davis et al. Gastroenterology. 2010;138: Year

6 Base 2010 cost ($/patient/year) Costs of Liver Transplant Much Higher Than Costs of Less Advanced Sequelae for Hepatitis C Summary of Studies Reporting Incremental Cost by Sequela (In 2010 US $) a a Studies use a patient cohort model to estimate total cost using cost and transition probability for each sequela. El Khoury et al. J Viral Hepat. 2012;19:153.

7 Costs of Liver Transplants Vary Around the World Canada $113,280 ($61,490-$165,070) United States $201,110 ($173,760- $223,460) Brazil $64,170 UK $97,040 ($52,490-$164,390) Spain $253,460 ($132,260-$443,700) Japan $163,140 ($74,920-$299,690) Taiwan $23,150 ($15,430-$30,860) Australia $132,040 ($127,920-$136,170) New Zealand $82,530 The lowest transplantation costs have been reported in Taiwan and the highest in Western Europe El Khoury et al. J Med Econ. 2012;15:887.

8 Widespread Use of Effective Therapy Could Significantly Reduce Need for Transplants Number of Persons Potential Transplant Need 180, , , , , , ,000 91,310 80,000 60,000 49,013 40,000 20, , Year in Model 162, ,747 25,573 27,175 26,207 24,258 21,994 No treatment 25% 50% 75% treated All treated Desai et al. The Liver Meeting Abstract 1427.

9 Adjusted a IR per 100,000 Numbers of HCV Patients on Liver Transplant: HCC Numbers Have Nearly Doubled Since Incidence rate ratio a for HCC: (95% CI, ); P<0.001 HCC ESLD a Adjusted for age and sex. Fleming et al. The Liver Meeting Abstract The number of HCV patients wait-listed for HCC has risen by 12% per year on average (from 623 in 2003 to 1379 in 2010, or from 2.1 to 4.6 per 100,000) In contrast, wait-listing due to end-stage liver disease (ESLD) has remained relatively stable over the study period (0.7% rise, from 1451 to 1674, or from 4.8 to 5.6 per 100,000)

10 Pre-Transplant Therapy

11 SOF + RBV to Prevent HCV Recurrence Post-LT SOF 400 mg + RBV mg (n=61) ptvr12 N=61 DDLT candidates with MELD exception for HCC Genotypes 1-4 CPT 7 (43% CP=5) Median MELD =8 (8-14) CrCl 60 ml/min Rx-naïve (25%) or experienced (75%) Absence of HIV or HBV Curry MP, et al. APASL Brisbane, Australia. Oral presentation

12 Viral Response Rate (%) Virological Response SOF + RBV to Prevent HCV Recurrence Post-Transplant On-treatment HCV RNA suppression was rapid and similar to other patient populations on SOF regimens Treatment with SOF + RBV was generally safe and well tolerated *3 subjects were >LLOQ at transplant 1 subject has not reached ptvr12, 1 subject lost to follow up at Week 8 post transplant Curry MP, et al. APASL Brisbane, Australia. Oral presentation

13 Analysis of Post-Transplant Recurrence in GT 1 4 Days HCV RNA Continuously TND Prior to Transplant No Recurrence (n=29) Recurrence (n=10) No recurrence in 24/25 (96%) of patients who maintained HCV RNA TND >28 days Median days TND No recurrence: 99 Recurrence: 5.5 p <0.001* 28 *Wilcoxon rank sum test. Curry MP, et al. APASL Brisbane, Australia. Oral presentation

14 SOF+RBV for Chronic HCV with Cirrhosis and Portal HTN ± Decompensation Randomized, open-label, safety and efficacy study of SOF+RBV for 48 weeks compared to observation for 6 months in patients with HCV cirrhosis and portal HTN (CTP 5 9) SOF + RBV n=25 Observation n=25 Arm 1 n=25 Arm 2 n=25 Wk 0 Wk 24 Wk 48 Wk 72 Wk 96 SOF 400 mg + RBV mg Observation Preliminary results Afdhal N, EASL, 2014, O68 SOF 400 mg + RBV mg SVR12 SVR12 Male, n (%) 18 (72) 20 (80) Median age, y (range) 56 (43 69) 55 (44 69) BMI 30 kg/m 2, n (%) 8 (32) 7 (28) Mean HCV RNA, log 10 IU/mL (range) 6.1 ( ) 6.1 ( ) GT, n (%) 1a 10 (40) 9 (36) 1b 9 (36) 6 (24) 2 2 (8) 1 (4) 3 2 (8) 8 (32) 4 2 (8) 1 (4) IL28B non-cc, n (%) 22 (88) 18 (72) Prior HCV treatment, n (%) 17 (68) 23 (92) Mean HVPG mmhg, n (range) 16.9 (9 29) 16.2 (7 27) HVPG >12 mmhg, n (%) 19 (76) 20 (80)

15 HCV RNA < LLOQ (%) Virologic Response *1 patient was a non-responder at Week 8. Afdhal N, EASL, 2014, O68 Week

16 Laboratory and Clinical Event Changes Platelets (10 3 /µl) p=0.003 p=ns SOF+RBV Observation 24 weeks p=0.001 Albumin (g/dl) p=0.001 ALT (U/L) CTP A CTP B Patients, n SOF + RBV n=25 Ascites Observation n=25 SOF + RBV n=25 Hepatic Encephalopathy Observation n=25 Baseline Week Week Afdhal N, EASL, 2014, O68

17 Post Transplant Therapy

18 Sofosbuvir Compassionate Use Program: Patient Disposition Severe acute hepatitis/early recurrence (<12 months from liver transplant with typical biochemical and histological findings) n=48 Post transplant compensated and decompensated cirrhosis [liver biopsy (F4) or clinical decompensation] n=56 Forns, et al. EASL 2014 Discon due to AE n=7 Liver transplant n=12 Death N=13 SOF Compassionate Use Program SOF+RBV±PEG n=104 Completed weeks treatment N=72

19 Results: Baseline Characteristics Forns, et al. EASL 2014 Demographics Overall (n=104) Male, n (%) 76 (73) Median age, y (range) 55 (16-76) Median HCV RNA, log 10 IU/mL (range) 8.4 ( ) GT, n 1/1a/1b 8/29/51 2/3/4 1/7/8 Median bilirubin, mg/dl (range) 3.1 (0.4-45) Median albumin, g/dl (range) 3.1 ( ) Median INR (range) 1.3 ( ) Median ALT, IU/L (range) 71 (8-1162) Median platelets, x10 3 /µl (range) 78 (19-340) Median MELD (range) 15 (6-43) Median months from LT to treatment (range) 17 (1-262)

20 Results: Overall Virologic Response 81/93 53/85 Patients were excluded from this analysis if received a liver transplant (n=8 at EOT; n=12 at SVR12) Forns, et al. EASL 2014

21 Patients (%) Results: Overall Virologic Response 100 8/93 4/ /93 13/85 15/85 Lost to follow-up Death HCV RNA>LLOQ HCV RNA <LLOQ Forns, et al. EASL /93 EOT 53/85 SVR12

22 Patients (%) Results: Clinical Outcomes /104 22/104 22/104 Improved* Stable Worsened/Deceased All patients who received 1 dose of SOF are included *Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in liverrelated laboratory values. Forns, et al. EASL 2014

23 INR MELD Bilirubin (mg/dl) Albumin (g/l) Forns, et al. EASL 2014 Results: Laboratory Tests (Median and Interquartile Ranges) Baseline EOT FU Wk12 Baseline EOT FU Wk Baseline EOT FU Wk12 Baseline EOT FU Wk12

24 SOF+RBV for Established Recurrent HCV Post-Liver Transplant TN & TE with recurrent HCV N=40 SOF 400 mg + RBV mg SVR 12 Study Week 0 24 Low, ascending-dose RBV regimen starting at 400 mg/day, escalated based on hemoglobin levels Study inclusion criteria Liver transplant 6 months and 150 months CTP 7 and MELD 17 Exclusion: Prednisone >5 mg/day Key baseline characteristics 55% GT1a, 28% GT1b, 15% GT3, 3% GT4 88% treatment experienced (23% PI/PEG/RBV failures) 40% F4 cirrhotic Samuel D, EASL, 2014, P1232

25 Virologic Response 40/40 40/40 29/40 28/40 28/40 Relapse was not influenced by RBV dose or exposure No TAC or CsA toxicities or drug interactions were observed - 4 patients increased TAC dosing due to improved liver function Samuel D, EASL, 2014, P1232

26 Adverse Events and Lab Abnormalities Adverse Events, n (%) SOF + RBV, N=40 SAEs* 6 (15) AEs that led to D/C of study treatment 2 (5) AEs in 15% of patients Fatigue 12 (30) Diarrhea 11 (28) Headache 10 (25) Arthralgia 9 (23) Nausea 8 (20) Anemia 8 (20) Cough 7 (18) Grade 3 and 4 Lab Abnormalities, n (%) SOF + RBV, N=40 Overall Grade 3 11 (28) Overall Grade 4 11 (28) Lymphocytes (5 G3; 9 G4) 13 (33) Hemoglobin (G3) 8 (20) Hyperglycemia (3 G3; 1 G4) 4 (10) White blood cell count (G3) 3 (8) Hyperbilirubinemia (G4) 1 (3) Lipase (G4) 1 (3) Neutrophils (G3) 1 (3) AST (G3) 1 (3) *All SAEs assessed as unrelated to SOF: ascites, pyrexia (2 cases), jaundice, pneumonia, urinary tract infection, hemarthrosis, osteoporotic fracture, confusion, hallucination; Recurrence of hepatocellular carcinoma and pneumonia. AST, aspartate aminotransferase; DC, discontinuation; G, grade; SAE, serious adverse event. Samuel D, EASL, 2014, P1232

27 ABT-450/r/ABT ABT Ribavirin in Liver Transplant Recipients With Recurrent HCV 3D + RBV (N=34) SVR12 Day 0 Week 24 To Week 72 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID RBV: dosing was managed at the discretion of the investigator and closely monitored per protocol Kwo, et al. EASL 2014

28 Calcineurin Inhibitor (CNI) Dosing With 3D Regimen A phase 1 drug-drug interaction study demonstrated that dosing tacrolimus (TAC) or cyclosporine (CYA) with the 3D regimen compared to either alone resulted in a 7-fold increase in TAC half-life 3-fold increase in CYA half-life Based on these findings, recommended dosing during 3D treatment was TAC 0.5 mg once weekly or 0.2 mg every 3 days CYA 1/5 of the daily pre-3d treatment dose given once daily Kwo, et al. EASL 2014

29 Eligibility Criteria 18 to 70 years of age, inclusive HCV GT1 infection Liver transplantation due to HCV infection >12 months before screening Treatment-naïve after transplantation PegIFN/RBV treatment prior to transplantation was permitted Screening liver biopsy-confirmed Metavir score <F2 No history of steroid-resistant rejection Receiving a stable TAC- or CYA-based immunosuppressant regimen Prednisone use permitted at doses 5 mg/day Use of mtor inhibitors not permitted Kwo, et al. EASL 2014

30 Baseline Patient Characteristics 3D + RBV (N=34) Mean time since transplantation, months 47.9 Male (%) 79.4 Black/white race (%) 11.8 / 85.3 Hispanic or Latino ethnicity (%) 17.6 Mean age (years) 59.6 Mean BMI (kg/m 2 ) 29.7 Fibrosis stage (%) F0-F1/F2 53 / 47 IL28B non-cc (%) 76.5 HCV subtype (%) GT1a/GT1b 85.3 / 14.7 Mean HCV RNA (log 10 IU/mL) 6.6 Immunosuppressive medication (%) Tacrolimus/cyclosporine 85.3 / 14.7 Mean creatinine clearance (ml/min) 90.5 Mean creatinine (mg/dl) 1.1 Mean ALT/AST/GGT (U/L) 78.9 / 63.9 / Kwo, et al. EASL 2014

31 % Patients Preliminary Efficacy Results 100% 100% 97.0% 96.2% 34/34 RVR 34/34 EOTR (Week 4) (Week 24) No patient had breakthrough; One patient had a relapse (post-treatment day 3) Kwo, et al. EASL /33 25/26 SVR4 SVR12

32 Adverse Events Occurring in >15% of Patients Event, n (%) 3D + RBV (N=34) Any AE 33 (97.1) Headache 15 (44.1) Fatigue 14 (41.2) Cough 10 (29.4) Insomnia 9 (26.5) Asthenia 8 (23.5) Diarrhea 8 (23.5) Nausea 8 (23.5) Rash 7 (20.6) Anemia 6 (17.6) Dizziness 6 (17.6) Muscle spasms 6 (17.6) Pyrexia 6 (17.6) No episodes of acute or chronic rejection 1 patient discontinued study drug due to AEs (moderate rash, memory impairment, and anxiety) after week 18 Patient achieved SVR12 2 patients had serious AEs Hypotension and tachycardia associated with initiation of tamsulosin after elective surgery Moderate peripheral edema and pain in extremity in a diabetic patient with history of peripheral edema Kwo, et al. EASL 2014

33 Hemoglobin Effect Event, n (%) 3D + RBV (N=34) <LLN-10.0 g/dl (Grade 1) 12 (35.3) < g/dl (Grade 2) 8 (23.5) < g/dl (Grade 3) 1 (2.9) <6.5 g/dl (Grade 4) 0 5 patients received erythropoietin at investigator discretion No patient underwent transfusion No patient discontinued study drugs due to anemia Kwo, et al. EASL 2014

34 Ribavirin Dose Modifications RBV total daily dose (mg), n (%) Baseline (N=34) 3D + RBV End of Treatment (N=34) (8.8) 4 (11.8) 600 to (55.9) 25 (73.5) 1000 to (35.3) 5 (14.7) 600 to 800 mg daily was the most frequent RBV dosage both at baseline and end of treatment Kwo, et al. EASL 2014

35 Tacrolimus Concentration (ng/ml) Pre-Treatment and On-Treatment Tacrolimus C trough Concentrations Kwo, et al. EASL 2014 Pre-Treatment On-Treatment (Treatment Weeks 1-4) C trough levels were comparable pretreatment and on-treatment TAC dose was 0.5 to 1.0 mg at 1-2 week intervals for most patients 4 patients experienced a TAC level >15 ng/ml ( ng/ml) All 4 patients had TAC dosing errors 2 patients had associated creatinine increases (1.8 and 1.4 mg/dl), which normalized when dosing was corrected

36 Cyclosporine Concentration (ng/ml) Pre-Treatment and On-Treatment Cyclosporine C trough Concentrations CYA levels were maintained within the desired range with the recommended dosing regimen (N=5 patients) 50 Pre-Treatment On-Treatment On-treatment CYA dose was 1/5 of the pretreatment dose in these patients Kwo, et al. EASL 2014

37 Future Therapies

38 HCV RNA <LLOQ Patients, % DCV+SOF: A Study Shows High SVR Rates in Multiple Genotypes GT2/3 Patients Achieving SVR12 GT1a/1b LI SOF +DCV DCV +SOF DCV +SOF +RBV LI SOF +DCV DCV +SOF DCV +SOF +RBV DCV +SOF DCV +SOF +RBV DCV +SOF DCV +SOF +RBV Safety Highlights Treatment-naive; 24 wk of treatment Treatment-naive; 12 wk of treatment Prior PI failures; 24 wk of treatment DCV + SOF has an acceptable tolerability profile Only 2/211 (<1%) patients receiving SOF + DCV with and without RBV discontinued therapy due to adverse events The most common adverse events were fatigue (29%-50%), headache (16%-38%), and nausea (10%-32%), which were mild-to- moderate Sulkowski et al. N Engl J Med. 2014;370:211.

39 DCV + SOF: ALLY 1 Cirrhosis and Post-Transplant Study Design Objective: Assess the efficacy and safety of DCV 60 mg QD + SOF 400 mg QD in treatment-naive or -experienced GT1 6 patients with advanced liver disease awaiting liver transplantation, or with recurrent HCV post-transplant Primary end point: SVR12 Study Week Pre-transplant (n=60) 3 mo 12 y Post-transplant (n=50) DCV 60 mg QD + SOF 400 mg QD Therapy up to 12 wk DCV 60 mg QD + SOF 400 mg QD 24-wk follow-up 24-wk follow-up OR Transplant 24-wk follow-up AI SVR12

40 Study Design of DCV + SMV + RBV Objective: Assess the effect of DCV + SMV on the pharmacokinetics of cyclosporine and tacrolimus and the efficacy and safety of DCV + SMV + RBV in post orthotopic liver transplantation participants with recurrent HCV genotype 1b infection Primary end point: SVR12 Recurrent HCV GT 1b (n=40) Metavir Score F1-F2 F1-F4 Part 1: DCV + SMV + RBV Part 2: DCV + SMV + RBV Week 24 Follow-up Follow-up SVR12 Inclusion criteria Liver transplant between 6 months and 10 years prior to screening visit Screening HCV RNA level >10,000 IU/mL No post orthotopic liver transplant anti-hcv treatment Receiving stable immunosuppressant therapy with cyclosporine or tacrolimus for >3 months prior to the screening visit SMV = simeprevir. NCT ;

41 Conclusion Peri-transplant patients are an important group of HCV patients, although small in numbers overall Eradication in this population will free up organs for other liver indications IFN no longer has an indication in this population Multiple all oral therapies appear effective