BI 201335, a NS3/4A Serine Protease Inhibitor, and BI 207127, a NNI - PowerPoint PPT Presentation

BI 201335, a NS3/4A Serine Protease Inhibitor, and BI 207127, a NNI NS5b Polymerase Inhibitor for treatment of chronic HCV infection Wulf Otto Böcher Boehringer Ingelheim Pharma, Biberach, Germany

NS3/4A Protease Inhibitor BI 201335 Chemical structure of BI 201335 BI 201335 bound to GT1 NS3 (active site highlighted) EC 50 (nM) CC50 (nM) Inhibitor GT1a GT 1b Huh7 (MTT) BI 201335 6.5 ± 0.9 3.1 ± 1.2 30,000 Telaprevir 700 ± 50 540 ± 30 37,000 Boceprevir 550 ± 210 520 ± 220 >70,000 72-hour assay; HCV RNA determined by quantitative RT-PCR White et al., EASL 2010, A777

BI 201335 Antiviral Activity in Monotherapy – treatment-naive GT-1 Patients BI 201335 20 mg once daily Start of PegIFN/RBV 48 mg once daily 120 mg once daily 1 240 mg once daily x x Placebo x x Change in VL from baseline x x 0 x -1 x log 10 IU/mL -2 -3 -4 -5 0 1 2 3 4 6 10 14 21 28 Treatment day Manns et al. AASLD 2008

BI 201335: in vitro drug susceptibility of viral NS3 protease Sensitivity of chimeric NS3 replicons to BI 201335 and PegIFN: Fold change in EC 50 between D1 and D14 in treatment-naïve pts. treated with monotherapy 1A 1B 20 mg 48 mg 120 mg 240 20 mg 48 mg 120 mg 240 mg mg Fold change between Days 1 and 14 7,000 D168V 6,000 D168V D168V D168V D168V D168V D168V D168V 5,000 D168V D168V D168V D168V 4,000 3,000 2,000 1,000 900 BI 201335 800 R155K R155K R155K R155K R155K 700 R155K IFN- α R155K D168E/V 600 500 R155K R155K D168E Below limit of * 400 300 detection (BLD) 200 100 10 * * 1 20N4 20N6 20N7 20N8 48N1 48N5 48N8 120N1 120N2 120N3 120N4 120N7 240N3 240N6 240N8 20N1 20N2 20N3 20N5 48N2 48N3 48N4 48N6 48N7 48N9 120N5 120N6 120N8 120N9 240N1 240N2 240N4 240N5 240N7 Kukolj et al., EASL 2009, A954

1220.2: Longitudinal clonal sequence analysis Clonal sequence analysis of #20N2 (GT 1b) at BL, D14 and D56 (after EoT BI 201335) 20N2 (GT Clones (%) 1b) Baselin Day 14 Day 56 e WT 99 1 10 8 10 7 D168V 70 86 10 6 D168H 15 VL IU/mL 10 5 D168Y 5 10 4 10 3 D168A 3 10 2 BLQ D168G 1 3 10 1 BLD R155K 1 14 10 0 0 7 14 21 2830 130230330430 530 R155T 1 Days Kukolj et al., EASL 2009, A954

BI 201335 Antiviral Activity in Combination Therapy – Treatment-experienced GT-1 Patients Start of PegIFN/RBV Mean change in VL from baseline to day 28 1 Change in VL from baseline, BI 201335 0 48 mg once daily -1 120 mg once daily 240 mg once daily IU/mL log 10 -2 -3 -4 -5 -6 -7 0 1 2 3 4 6 14 10 21 28 Treatment day Manns, M et al. AASLD 2008

Phase IIb in treatment-naive GT-1 patients: 12 weeks interim analysis Week 4 BLQ (<25 IU/mL) Week 12 BLD (<10 IU/mL) 100 92 91 90 84 84 82 Virologic response (%) 75 50 42 25 16 71 143 146 69 71 143 146 69 0 PegIFN/ 240 mg 120 mg PegIFN/ 240 mg 240 mg 120 mg 240 mg RBV QD QD LI RBV QD QD LI QD LI QD LI BLQ = below limit of quantification; BLD = below limit of detection; LI = 3-day lead-in Sulkowski et al., AASLD 2009

Phase IIb in non-response GT-1 patients: 12 weeks interim analysis Week 4 BLQ (<25 IU/mL) Week 12 BLD (<10 IU/mL) 100 Virologic response (%) 75 69 64 62 59 59 54 50 25 76 142 70 76 142 70 0 240 mg 240 mg 240 mg 240 mg 240 mg 240 mg QD BID LI QD QD LI BID LI QD LI +LI RVR on Day 25 of BI 201335; –LI RVR on Day 28 of BI 201335 BLQ = below limit of quantification; BLD = below limit of detection; LI = 3-day lead-in Sulkowski et al., EASL 2010

Phase IIb in treatment-naive GT-1 patients: Most frequent Adverse Events: PegIFN/RBV 240 mg QD 240 mg QD LI 120 mg QD LI AEs n (%) n (%) n (%) n (%) Influenza-like illness 29 (40.8) 50 (34.2) 45 (31.5) 23 (33.3) Fatigue 22 (31.0) 37 (25.3) 34 (23.8) 15 (21.7) Insomnia 17 (23.9) 22 (15.1) 18 (12.6) 11 (15.9) Anemia 11 (15.5) 12 (8.2) 11 (7.7) 8 (11.6) Neutropenia 6 (8.5) 6 (4.1) 9 (6.3) 6 (8.7) Headache 23 (32.4) 49 (33.6) 43 (30.1) 21 (30.4) Nausea 13 (18.3) 60 (41.1) 57 (39.9) 15 (21.7) Diarrhea 10 (14.1) 38 (26.0) 40 (28.0) 8 (11.6) Pruritus 7 (9.9) 44 (30.1) 40 (28.0) 18 (26.1) Jaundice – all grades 1 (1.4) 30 (21.0) 24 (16.4) 4 (5.8) Rash – all grades 9 (12.7) 38 (26.6) 48 (32.9) 14 (20.3) AEs = adverse events; LI = 3-day lead-in Sulkowski et al., AASLD 2009

BI 201335 Summary • Virologic response – BI 201335 in combination with PegIFN/RBV produced a robust RVR and EVR in treatment-naïve HCV genotype-1 and in pts with non-response to PegIFN/RBV – The different BI 201335 dose regimens achieved similar antiviral activity • Adverse events – GI disorders, jaundice (unconjugated hyperbilirubinemia), and rash / photosensitivity were dose dependent and more frequently with BI 201335 – These events were mostly mild or moderate and managed without treatment modification – Discontinuation for AE was very low (<4%) for the 120 mg QD and 240 mg QD dose groups

BI 207127 Introduction – reversible, thumb pocket 1 non-nucleoside HCV polymerase inhibitor in vitro – exhibits potent and specific inhibition of the HCV RNA- dependent RNA polymerase with cell-based HCV sub-genomic replicon EC 50 values of 23 nM and 11 nM for GT-1a and GT-1b, respectively – A phase I trial in treatment-naïve (TN) and -experienced (TE) HCV genotype 1 (GT-1) patients demonstrated potent antiviral effects and good safety and tolerability of 200 to 1,200 mg BI 207127 given every 8 hours for 5 days as monotherapy

Phase I: 5 days monotherapy with BI 207127 VL reductions in GT1 patients Genotype 1a Genotype 1b BI 207127 q 8h BI 207127 q 8h Pb Pb 0 0 Mean change in BL adjusted viral load 100 mg 100 mg 200 mg 200 mg -1 -1 (Log 10 ) 400 mg 400 mg 800 mg 800 mg -2 -2 1200 mg 1200 mg -3 -3 -4 -4 0 24 48 72 96 120 144 0 24 48 72 96 120 144 Hours Hours  strong antiviral activity in GT1b > GT1a  AE: mild to moderate rash / photosensitivity and GI symptoms  Viral mutants in only 5/59, all in GT1b D. Larrey et al., AASLD 2

Phase I: 4 wks triple combo BI 207127 + PegIFN/RBV VL reductions Treatment-naive patients GT-1a (treated set) Naïve GT1A All GT-1 0 Naïve -1 0 median HCV RNA reduction (log 10 IU/mL) -2 10 -1 -3 -4 -2 -5 -3 -6 0 7 14 21 28 treatment day -4 GT-1b Naïve GT1B -5 0 -1 -6 -2 0 7 14 21 28 treatment day -3 -4 placebo 400 mg t.i.d -5 600 mg t.i.d -6 800 mg t.i.d 0 7 14 21 28 treatment day Larrey et al., LB poster #2007, EASL 2010

Phase I: 4 wks triple combo BI 207127 + PegIFN/RBV Rapid Virological Response (day 28) TN (n=27) TE * (n=30) BI 207127 Rebound Rebound < 25 IU/ml < 10 IU/ml < 25 IU/ml < 10 IU/ml dose (tid) >1.0 log >1.0 log 400 mg 4/6 3/6 0/6 1/10 0/10 2/10 3/9 1 2/9 1 600 mg 6/7 4/7 0/7 2/9 800 mg 6/6 3/6 0/6 2/11 2 2/11 2 1/11 Placebo 0/8 0/8 0/8 n.a. n.a. n.a. * TE: null- or partial responders, no relapsers 1 1 drop-out due to AE before d29 2 4 drop-outs due to AE before d29 Larrey et al., LB poster #2007, EASL 2010

NNI BI 207127: Conclusions •BI 207127 alone or in combination with PegIFN/RBV induced rapid and strong antiviral responses •Subtype 1a and 1b virologic response at 600 mg and 800 mg tid with PegIFN/RBV was similar among TN patients •Virologic response in PegIFN/RBV non-responder patients was less pronounced with BI 207127 in combination with PegIFN/RBV compared to TN patients •No rebound was observed in TN patients •BI 207127 with PegIFN/RBV was safe and tolerable with the best efficacy/tolerability profile at 600 mg tid •The results support further assessment of BI 207127 in combination regimens for the treatment of chronic HCV GT-1 infection