Session. Viral Hepatitis B & D: Clinical. Saturday April 25, Cihan Yurdaydin, MD

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1 Session Viral Hepatitis B & D: Clinical Saturday April 25, 2015 Cihan Yurdaydin, MD 1

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3 Optimizing the prenylation inhibitor lonafarnib using ritonavir boosting in patients with chronic delta hepatitis Cihan Yurdaydin, Ramazan Idilman, Ingrid Choong, Cagdas Kalkan, Onur Keskin, M Fatih Karakaya, E Ali Tuzun, Ersin Karatayli, Mithat Bozdayi, David Cory, Jeffrey S Glenn 3

4 Hepatitis D Virus HBsAg HDV is always associated with HBV Infection HDV worldwide prevalence is 15 million HDV is the most severe form of viral hepatitis - More rapid progression to liver cirrhosis and liver cancer No FDA approved Rx for HDV - In absence of an approved therapy, HDV screening is limited 4

5 Classic Antivirals Ineffective Against HDV IFN-α effective in ~ 25% of chronic HDV patients HBV nucleos(t)ide analogs (NAs) are ineffective IFN-α + NAs (HIDIT 1 / HIDIT 2) no better than IFN No direct acting agents have been studied for HDV Yurdaydin et al, Sem Liver Dis

6 Prenylation is Key to HDV Life Cycle Farnesyl Transferase Inhibitors Target Prenylation Entry Inhibitors e.g. Farnesyl transferase inhibitors Ciancio et al; Nature Reviews Gastroenterology & Hepatology 11, (2014) 6

7 Prenylation Inhibitors as Antivirals Compelling Preclinical Rationale Proof of Concept Virus Like Particle (VLP) Infectious Virus In-Vivo Animal Model l Jeffrey S. Glenn 7

8 Well-Characterized Clinical Stage Lead Compound Small molecule, oral, inhibitor of farnesyl transferase Br Inhibits farnesylation of large delta antigen - Blocks assembly and packing of viral particles N Br N O N NH 2 O - High theoretical barrier to resistance Cl Phase 2a POC in HDV infected patients completed - NIH study presented at 2014 AASLD (Boston) 8

9 PEG IFN-α 2a* versus in HDV % Patients Achieving 1 Log Decline in HDV-RNA NIH NIH LNF LNF 100 mg 200 mg BID BID 100 % Patients Achieving 1 Log VL Decline % 100% 0 Wöbse et al, AASLD 2014, # 1613; Koh et al, AASLD 2014, #

10 PEG IFN-α 2a* versus in HDV % Patients Achieving 1 Log Decline in HDV-RNA HIDIT - 2 NIH NIH PEG IFN α 2a 180 mcg QW + Tenofovir QD LNF 100 mg BID LNF 200 mg BID 100 % Patients Achieving 1 Log VL Decline % 68% 79% 33% 100% 0 Wöbse et al, AASLD 2014, # 1613; Koh et al, AASLD 2014, #

11 PEG IFN-α 2a* versus in HDV % Patients Achieving 1 Log Decline in HDV-RNA HIDIT - 2 NIH NIH PEG IFN α 2a 180 mcg QW + Tenofovir QD LNF 100 mg BID LNF 200 mg BID? 100 % Patients Achieving 1 Log VL Decline % 68% 79% 33% 100% 0 Wöbse et al, AASLD 2014, # 1613; Koh et al, AASLD 2014, #

12 Aims of Study Explore if efficacy can be optimized by: increasing lonafarnib dose increasing lonafarnib intake frequency combination therapy with peg-interferon combination therapy with ritonavir 12

13 LOWR HDV 1 Study LOnafarnib With and without Ritonavir Patients and Methods Treatment duration 4-8 weeks 72 hour PK and PD evaluation on day 1 and day 28 Testing frequency: days 1, 2, 3, 7, 14, 28 and then Q2W Biochemical parameters HDV RNA (by in-house quantitative real-time PCR) HBV DNA (by Cobas, Taqman, Amplicor) 13

14 LOWR HDV 1 Study LOnafarnib With and without Ritonavir in HDV Month 1 n=3 n=3 n=3 n=3 n=3 200 mg BID 300 mg BID 100 mg TID 100 mg BID + Ritonavir 100 mg QD 100 mg BID + PEG IFN-α 180 mcg QW Assess: Efficacy, Tolerability, PK, Viral Load 14

15 Day 28 Reduction in Serum HDV RNA LOWR mg TID 200 mg BID 300 mg BID 100 mg BID + Ritonavir 100 mg QD 100 mg BID + PEG IFN α 2a 180 mcg QW Change in Log HDV RNA copies/ml Log Log Log Log Log N = 3 N = 3 N = 3 N = 3 N = 3 15

16 Day 28 Reduction in Serum HDV RNA NIH (AASLD 2014) LOWR Placebo 100 mg BID 200 mg BID 100 mg TID 200 mg BID 300 mg BID 100 mg BID + Ritonavir 100 mg QD 100 mg BID + PEG IFN α 2a 180 mcg QW Change in Log HDV RNA copies/ml Log Log Log Log Log Log Log Log N = 4 N = 6 N = 6 N = 3 N = 3 N = 3 N = 3 N = 3 16

17 Day 28 Reduction in Serum HDV RNA NIH (AASLD 2014) LOWR Placebo 100 mg BID 200 mg BID 100 mg TID 200 mg BID 300 mg BID 100 mg BID + Ritonavir 100 mg QD 100 mg BID + PEG IFN α 2a 180 mcg QW Change in Log HDV RNA copies/ml Log Log Log Log Log Log Log Log N = 4 N = 6 N = 6 N = 3 N = 3 N = 3 N = 3 N = 3 17

18 LOWR HDV 1 LOnafarnib With and without Ritonavir Month 1 Month 2 Boost with Ritonavir N=3 LNF + RTN 100 mg BID N=10 + Ritonavir 100 mg QD LNF + RTN 100 mg BID N=10 + Ritonavir 100 mg QD Complement with PEG IFN N=3 LNF + RTN 100 mg BID N=10 + PEG IFN α 2a 180 mcg QW LNF RTN mg BID N=10 + PEG IFN α 2a 180 mcg QW Assessments: Safety, Tolerability, HDV-RNA, PK 18

19 Viral Load Declines on + Ritonavir Week 4 Mean Change in HDV-RNA Viral Load -2.2 Log Week 8 Mean Change in HDV-RNA Viral Load -3.2 Log mg BID + Ritonavir 100 mg QD Post-treatment 0.0 Change in Log HDV RNA copies/ml PaBent 1 PaBent 2 PaBent 3 BLQ undetectable Days BLQ = below limit of quantification 19

20 Normalization of ALT on + Ritonavir ALT Levels Maintained After Treatment mg BID + Ritonavir 100 mg QD Post-treatment PaBent 1 PaBent 2 PaBent 3 ALT U/L Week Normal U/L 20

21 PK Boosted by Ritonavir Serum Concentration Increased 4-5 Fold 21

22 Viral Load Declines on + Peg IFN Week 4 Mean Change -1.8 Log Week 8 Mean Change -3.0 Log 0.0 LNF 100 mg BID + PEG IFN 180 mcg QW Post-treatment Change in Log HDV RNA copies/ml PaBent 1 PaBent 2 PaBent Week 22

23 ALT Improvement of + PEG IFN ALT Levels Continue to Decline After Treatment mg BID + PEG IFN α 2a 180 mcg QW Post Treatment 150 ALT U/L 100 PaBent 1 PaBent 2 PaBent 3 50 Normal U/L 0 Week Day 1 0 Week Day 284 Week Day 355 Day Week 56 8 Week Day

24 Earlier VL Decline with Combination Combinations Display Biphasic Kinetics and More Rapid Onset 0.0 On-Treatment Post-treatment Mean Viral Load Change ( Log Copies/mL) LNF 100 mg BID + RTN 100 mg QD (N=3) LNF 100 mg BID + PEG IFN-α 2a 180 mcg QW (N=3) Week 24

25 Earlier VL Decline with Combination Combinations Display Biphasic Kinetics and More Rapid Onset 0.0 On-Treatment Post-treatment Mean Viral Load Change ( Log Copies/mL) LNF 100 mg BID + RTN 100 mg QD (N=3) HIDIT-2: PEG IFN 180 mcg QW ± tenofovir QD (N=91) LNF 100 mg BID + PEG IFN-α 2a 180 mcg QW (N=3) Week 25

26 Earlier VL Decline with Combination Combinations Display Biphasic Kinetics and More Rapid Onset Mean VL Change (Log IU/mL) HIDIT-2: PEG IFN 180 mcg QW ± tenofovir QD (N=91) LNF 100 mg BID + PEG IFN 180 mcg QW (N=3) LNF 100 mg BID + RTN 100 mg QD (N=3) Week 26

27 Side effects Improved with LNF Combos Mainly GI side effects Graded according to Common Terminology Criteria for Adverse Events chronically dosed in Progeria for 2 years (PNAS, 2012, 16666) 27

28 Summary and Conclusions LOWR 1 Study: promising combos for further exploration - + Ritonavir 3 log drop at Month Pegasys 3 log drop at Month 2 LOWR 2 Study: Dose-Finding study on-going - Exploring lonafarnib + ritonavir combinations for longer dosing is first oral therapy for HDV - More rapid onset than PEG-IFN - Host-targeting Rx with high barrier to resistance 28

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