The relationship between sustained virological response and plasma concentrations of (BI 201335) or deleobuvir (BI 207127) in HCV GT1-infected patients in SOUND-C2

Stephen Olson,1 Kyle Baron,2 Matthew Riggs,2 Wulf O Bocher,3 Federico J Mensa1

1Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 2Metrum Research Group LLC, Tariffville, CT, USA; 3Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany

8h International Workshop on Clinical Pharmacology of Hepatitis Therapy Cambridge, MA, 26-27 June, 2013. Disclosures

• Presenter: Stephen Olson, PhD is an employee of Pharmaceuticals, Inc. and this presentation includes information on faldaprevir (BI 201335) and deleobuvir (BI 207127) which are investigational compounds and not yet approved • Kyle Baron, PhD is an employee of Metrum Research Group, LLC • Matthew Riggs, PhD is an employee of Metrum Research Group, LLC • Wulf O Böcher, MD is an employee of Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany • Federico Mensa, MD is an employee of Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT

2 Acknowledgments

This work was supported by Böehringer Ingelheim. The authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and were fully responsible for all content and editorial decisions, and were involved at all stages of presentation development. The authors received no compensation related to the development of the poster, but are consultants for BIPI and did receive research grant support for this study. Writing, editorial support, and formatting assistance for this presentation was provided by Adelphi Communications, Ltd., which was contracted and compensated by BIPI for these services.

3 Background

faldaprevir deleobuvir BI 201335 BI 207127

• Second-wave linear tripeptide • Non-nucleoside thumb pocket 1 NS3/4A protease inhibitor NS5B inhibitor • Nanomolar potency • Nanomolar potency • EC50 6.5 nmol/L vs GT-1a in vitro • EC50 23 nmol/L vs GT-1a in vitro • EC50 3.1 nmol/L vs GT-1b in vitro • EC50 11 nmol/L vs GT-1b in vitro • PK profile supports QD dosing • PK profile supports BID dosing Introduction

• Phase 2b Trial: SOUND-C2 – Evaluated efficacy/safety of -free combination of faldaprevir plus deleobuvir (BI 207127) ± (RBV) in treatment-naïve HCV genotype 1 (GT-1) patients • SVR12 varied by HCV subtype (GT-1a or GT-1b) and patient IL28B genotype (CC or non-CC, rs12979860) • Post hoc pharmacokinetic (PK) analysis examined relationship between SVR12 and plasma concentrations of faldaprevir and deleobuvir during Weeks 1–4 – PK analysis of Phase 1b SOUND-C1 study found combined administration of faldaprevir and deleobuvir transiently increased the exposure of both drugs

Sabo JP, et al. Hepatology 2012; 56(Suppl S1):568A [Abstract No. 777] SOUND-C2 Study design

faldaprevir 120 mg QD + TID16W Follow-up (n=81) deleobuvir 600 mg TID + RBV

TID28W faldaprevir 120 mg QD + deleobuvir 600 mg TID + RBV Follow-up (n=80)

TID40W faldaprevir 120 mg QD + deleobuvir 600 mg TID + RBV Follow-up (n=77)

BID28W faldaprevir 120 mg QD + deleobuvir 600 mg BID + RBV Follow-up (n=78)

TID28W-NR faldaprevir 120 mg QD + deleobuvir 600 mg TID, no RBV Follow-up (n=46)

Day 1 Week 16 Week 28 Week 40

• Phase IIb, multicenter, open-label, randomized (1:1:1:1:1)a • Treatment-naïve patients with chronic HCV GT-1 • Stratified by GT-1 subtype (1a vs 1b) and IL28B (CC vs non-CC) • Compensated cirrhosis included, 18–75 years of age, HCV RNA >100 000 IU/mL • Stopping rule: HCV RNA detectable between Weeks 6 and 8 • Primary endpoint: SVR 12 weeks after treatment completion

aRandomization to the non-RBV arm stopped early (per FDA request) after 46 patients were randomized. SVR12 results from the SOUND-C2 study by GT-1 subtype (ITT population) GT-1a-CC GT-1b 100 85 80 75 75 69 63 60 60 56 56 57 (%) SVR12 40 33

20

0 ITT 5/9 35/47 5/8 33/48 6/10 24/43 6/8 41/48 2/6 16/28 n/N deleobuvir dosing TID TID TID BID TID Duration (weeks) 16 28 40 28 28 RBV + + + + -

ITT, intention-to-treat Zeuzem S et al. J Hepatol 2012a;56(Suppl 2):S45 Zeuzem S, et al. Gastroenterology 2011;141:2047–2055 Time dependent PK for both compounds

Trough mean concentrations of deleobuvir for 600mg BID and faldaprevir 120mg QD

Week 0.5 1 2 4 6 8 12 16 N 54 56 57 58 44 44 37 34 faldaprevir 4570 6000 5310 4120 3520 3490 2920 3390 deleobuvir 12000 9530 7090 5430 5320 4830 4320 4660

Is time dependent exposure an SVR risk factor? Methods: Post hoc PK Analysis

• Geometric mean trough concentrations of faldaprevir and deleobuvir investigated as predictors of SVR12

in regression models • Data analyzed for HCV GT-1a IL28B CC and HCV GT-1b patients (irrespective of IL28b genotype) receiving 16-, 28-, and 40-week RBV-containing regimens • Separate logistic regression models generated for faldaprevir and deleobuvir for plasma concentrations obtained during different time windows over the first 4 weeks of treatment Methods: Post hoc PK Analysis

• Standard form of the regression model:

logit (πSVR12,i) = β0 + β1 · DUR16i + β2 · 1aCCi + β3 · (Cmini – Cminref) + β4 · (Cmini – Cminref) · DUR16i + β5 · (Cmini – Cminref) · 1aCCi • Trough concentrations defined using deleobuvir PK observations 6–18 (12±6) hours after administration, and faldaprevir PK observations 18–30 (24±6 hours after administration • Logistic regression models were fitted using the MCMCpack Bayesian estimation package (Version 1.2–4) in R

Relationship between faldaprevir trough concentration and probability of achieving SVR12

• Probability of SVR12 was high across examined

faldaprevir and deleobuvir concentration ranges • HCV GT-1b patients, irrespective of IL28B concentration

genotype – Flat or shallow analyte relationships between trough concentrations of faldaprevir and deleobuvir and probability of achieving SVR12 Probability of SVR12 of SVR12 Probability by

faldaprevir concentration (nmol/mL) Relationship between deleobuvir trough concentration and probability of achieving SVR12

• GT-1a IL28B CC patients – Greater effect of trough

concentration on probability of achieving SVR12 for both faldaprevir and deleobuvir concentration – Had predicted SVR12 >70% only at higher

analyte concentrations • Probabilities of achieving SVR12 and concentration– response relationship were comparable for 16-, 28-, and 40-week treatment durations Probability of SVR12 of SVR12 Probability by

deleobuvir concentration (nmol/mL) Conclusions

• HCV GT-1b patients, irrespective of IL28B genotype, achieve high SVR rates (>70%) across broad plasma concentration ranges of faldaprevir and deleobuvir + RBV • Results suggest that even with observed lower exposure of faldaprevir and deleobuvir in BID regimen, plasma drug levels are predicted to be high enough for HCV GT-1b patients to achieve an SVR • The exposure–response relationship in HCV GT-1a IL28B CC patients was not flat – Lower SVR12 rates were predicted at lower plasma levels of faldaprevir and deleobuvir vs HCV GT-1b patients • Phase III HCVerso 1 (NCT01732796) and HCVerso 2 (NCT01728324) are ongoing in HCV GT-1b patients – Faldaprevir 120 mg QD and deleobuvir 600 mg BID plus RBV for 16 or 24 weeks