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

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Oct 27, 2023 468 likes •636 views

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

SLIDE 1

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

SLIDE 2

NS3/4A Protease Inhibitor BI 201335

72-hour assay; HCV RNA determined by quantitative RT-PCR White et al., EASL 2010, A777

Chemical structure of BI 201335 BI 201335 bound to GT1 NS3 (active site highlighted)

EC50 (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

SLIDE 3

Manns et al. AASLD 2008

0 1 2 3 4 6 10 14 21

1 Change in VL from baseline log10 IU/mL

x x x x x x x

Start of PegIFN/RBV Treatment day

BI 201335 Antiviral Activity in Monotherapy – treatment-naive GT-1 Patients

Placebo 240 mg once daily 120 mg once daily 48 mg once daily 20 mg once daily

BI 201335

SLIDE 4

Sensitivity of chimeric NS3 replicons to BI 201335 and PegIFN: Fold change in EC50 between D1 and D14 in treatment-naïve pts. treated with monotherapy

BI 201335: in vitro drug susceptibility of viral NS3 protease

Fold change between Days 1 and 14 20N4 20N6 20N7 20N8 48N1 48N5 48N8 120N1 120N2 120N3 120N4 120N7 240N3 240N6 240N8

7,000 6,000 5,000 4,000 3,000 2,000 1,000 900 800 700 600 500 400 300 200 100 10 1

1A 1B

20 mg 48 mg 120 mg 240 mg 20 mg 48 mg 120 mg 240 mg

* *

20N1 20N2 20N3 20N5 48N2 48N3 48N4 48N6 48N7 48N9 120N5 120N6 120N8 120N9 240N1 240N2 240N4 240N5 240N7

R155K R155K R155K R155K R155K R155K R155K R155K R155K D168V D168V D168V D168V D168V D168V D168V D168V D168V D168V D168V D168E D168E/V

BI 201335 IFN-α Below limit of detection (BLD)

D168V

Kukolj et al., EASL 2009, A954

SLIDE 5

Clonal sequence analysis of #20N2 (GT 1b) at BL, D14 and D56 (after EoT BI 201335)

1220.2: Longitudinal clonal sequence analysis

108 107 106 105 104 103 102 101 100 VL IU/mL

7 14 21 2830 130230330430 530

Days BLQ BLD 20N2 (GT 1b)

Clones (%) Baselin e Day 14 Day 56 WT 99 1 D168V 70 86 D168H 15 D168Y 5 D168A 3 D168G 1 3 R155K 1 14 R155T 1 Kukolj et al., EASL 2009, A954

SLIDE 6

Manns, M et al. AASLD 2008

Mean change in VL from baseline to day 28

48 mg once daily 120 mg once daily 240 mg once daily

BI 201335

6 4 3 2 1 10 14 21 28 Treatment day Change in VL from baseline, IU/mL log10

1 Start of PegIFN/RBV

BI 201335 Antiviral Activity in Combination Therapy – Treatment-experienced GT-1 Patients

SLIDE 7

16 92 84 90 42 91 82 84 100 75 50 25 Virologic response (%) PegIFN/ RBV 240 mg QD 240 mg QD LI 120 mg QD LI PegIFN/ RBV 240 mg QD 240 mg QD LI 120 mg QD LI Week 4 BLQ (<25 IU/mL) Week 12 BLD (<10 IU/mL)

BLQ = below limit of quantification; BLD = below limit of detection; LI = 3-day lead-in

71 143 146 69 71 143 146 69

Phase IIb in treatment-naive GT-1 patients: 12 weeks interim analysis

Sulkowski et al., AASLD 2009

SLIDE 8

62 64 69 59 59 54 100 75 50 25 Virologic response (%) 240 mg QD 240 mg QD LI 240 mg BID LI 240 mg QD 240 mg QD LI 240 mg BID 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

Week 4 BLQ (<25 IU/mL) Week 12 BLD (<10 IU/mL) 76 142 70 76 142 70

Phase IIb in non-response GT-1 patients: 12 weeks interim analysis

Sulkowski et al., EASL 2010

SLIDE 9

Most frequent Adverse Events:

AEs PegIFN/RBV n (%) 240 mg QD n (%) 240 mg QD LI n (%) 120 mg QD LI 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

Phase IIb in treatment-naive GT-1 patients:

SLIDE 10

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

SLIDE 11

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 EC50 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

SLIDE 12

 strong antiviral activity in GT1b > GT1a  AE: mild to moderate rash / photosensitivity and GI symptoms  Viral mutants in only 5/59, all in GT1b

24 48 72 96 120 144

Pb 100 mg 200 mg 400 mg 800 mg 1200 mg BI 207127 q 8h Hours Mean change in BL adjusted viral load (Log10)

24 48 72 96 120 144

Pb 100 mg 200 mg 400 mg 800 mg 1200 mg BI 207127 q 8h Hours

Genotype 1a Genotype 1b

D. Larrey et al., AASLD 2

Phase I: 5 days monotherapy with BI 207127 VL reductions in GT1 patients

SLIDE 13

Phase I: 4 wks triple combo BI 207127 + PegIFN/RBV VL reductions Treatment-naive patients (treated set)

placebo 400 mg t.i.d 600 mg t.i.d 800 mg t.i.d

7 14 21 28

treatment day

GT1B Naïve 7 14 21 28

treatment day

10 GT1A Naïve

7 14 21 28 treatment day

median HCV RNA reduction (log10 IU/mL)

Naïve

All GT-1 GT-1a GT-1b

Larrey et al., LB poster #2007, EASL 2010

SLIDE 14

BI 207127 dose (tid) TN (n=27) TE * (n=30) < 25 IU/ml < 10 IU/ml Rebound >1.0 log < 25 IU/ml < 10 IU/ml Rebound >1.0 log 400 mg 4/6 3/6 0/6 1/10 0/10 2/10 600 mg 6/7 4/7 0/7 3/91 2/91 2/9 800 mg 6/6 3/6 0/6 2/112 2/112 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