Safety, pharmacokinetics and antiviral effect of BI 207127

EASL 44th Annual Meeting
April 22-26, 2009
Copenhagen, Denmark Back

Safety, pharmacokinetics and antiviral effect of BI 207127, a novel HCV RNA polymerase inhibitor, after 5 days' oral treatment in patients with chronic hepatitis C
Reported by Jules Levin
EASL Copenhagen, April 23-26 2009

Boerhinger Ingelheim reported on their HCV protease inhibitor at AASLD Nov 2008 where they reported the drug showed about 4 log reductions viral load in early studies. Phase II is ongoing and results from that study should be reported soon. They say in this poster in conclusions below they are planning a combination study of these 2 oral HCV drugs. The future of HCV therapy is multiple oral drugs in combination with peg/rbv until a company can establish that a regimen of oral drugs alone will produce an SVR without peg/RBV, which all the companies are planning to study. I expect 2 oral drugs plus peg/RBV should produce 75% or higher SVR rates in treatment-naives an a little owe in African-Americans and prior null and nonresponders.

Dominique Larrey1, Yves Benhamou2, Ansgar W Lohse3, Christian Trepo4, Christian Molleken5, Jean-Pierre Bronowicki6, Keikawus Arasteh7, Marc Bourliere8, Markus Heim9, Jaime Enriquez10, Andreas Erhardt11,Jean-Pierre Zarski12, Reiner Wiest13, Tilman Gerlach14, Heiner Wedemeyer15, Thomas Berg16, Jerry Stern17, Katherine Wu17, Nasri Abdallah18, Gerhard Nehmiz19, Wulf Boecher19, Jurgen Steffgen19 for the BI 207127 study group

1INSERM 632-CIC Hopital Saint Eloi, Montpellier, 2Hopital La Pitie Salpetriere Paris, 3Universitatsklinikum Hamburg-Eppendorf Hamburg, 4Hopital Hotel Dieu Lyon, 5Universitatsklinik Bochum, 6Hopital de Brabois Nancy, 7Epimed GmbH Berlin, 8Hopital Saint Joseph Marseille, 9Universitatsspital Basel, 10Hospital de la Santa Creu I Sant Pau Barcelona,11Universitatsklinikum Dusseldorf, 12Hopital Michalon Grenoble, 13Klinikum der Universitat Regensburg, 14Kantonsspital St. Gallen, 15Medizinische Hochschule Hannover, 16Charite Berlin Campus Virchow-Klinikum Berlin; Boehringer Ingelheim 17Ridgefield CT, 18Reims and 19Biberach

AUTHOR CONCLUSIONS

BI 207127 is a potent inhibitor of viral replication in monotherapy, causing a steep decline of VL at 800 mg q8h in the first 24 hours (5/9 patients with >4 log10 VL reduction at Day 5, no VL breakthroughs)

BI 207127 was safe and overall well tolerated; the only drug-related SAE, a moderate erythema, was managed effectively. One mild transient rash did not require BI207127 dose reduction or discontinuation

The results from the present study demonstrate, that further clinical development of this promising direct antiviral in combination therapy with PegIFN/RBVis warranted

A 4-week combination study will initiate in late Q2/2009

ABSTRACT

Background: BI207127 is a potent and specific non-nucleoside inhibitor of the HCVRNA-dependent RNApolymerase in vitro.

Methods: In a double blinded, sequential group comparison, 48 male and female HCVgenotype-1 patients with minimal to mild liver fibrosis were randomized (9 active, 3 placebo per group) and treated with 100, 200, 400 or 800 mg BI207127 q8h over 5 days, given p.o. as experimental tablet. Afurther dose level with 1,200 mg is ongoing. All patients were followed for 10-14 days. Plasma HCVRNAvirus load (VL) was measured by Roche COBAS TaqMan assay.

Results: Mean age was 49.5 ± 10.2 years, BMI25.3 ± 3.0 kg/m2. 13/48 patients were naive for anti-HCVtherapy. Mean log10 VL (IU/mL) at baseline was 6.40. VL decreased by >1 log10 in 2/9, 6/9, 8/9 and 8/9 patients treated with 100, 200, 400 and 800 mg, respectively. No response was seen with placebo.

No breakthrough was observed during treatment.

In the 800 mg group, 5/9 patients showed a >4 log10 drop in VL, and the effect persisted at least 24 hours after the last drug intake.

Mean VL drops on day 5 were 0.6, 1.2, 1.9 and 3.1 log10 steps, respectively.

One SAE was reported for 800 mg, a moderate generalized erythema with facial involvement, which resolved within 2 days after discontinuation of BI207127 and after antihistaminic treatment. A further, mild localized rash was also reported on 800 mg. These 2 patients showed by far the highest PK exposures. All other AEs were rated "mild" or "moderate" and were not dose-related. Investigators judged tolerability as "good" in 42/48 patients. Laboratory parameters did not show any relevant changes from baseline.

Plasma drug levels exhibited supra-proportional pharmacokinetics from 400 mg on. The first phase of VL decline was correlated with the early BI207127 plasma exposure.

Conclusions: BI207127, given as monotherapy p.o., demonstrated reliable antiviral activity against HCVgenotype 1.

INTRODUCTION

Hepatitis C virus (HCV) genotype 1 (GT-1) is mostly prevalent in the USA and Europe, but is also significant in Asia and Australia. Chronic GT-1 infection is associated with a sustained virological response to standard treatment with pegylated interferon and ribavirin in less than 50% of patients. This limited response stresses the need for new and more potent antiviral treatments

BI 207127 is a reversible, orally bioavailable, non-nucleoside inhibitor of the HCV RNA-dependent RNApolymerase in vitro

BI 207127 exhibits potent and specific inhibition of the HCV RNA-dependent RNA polymerase in enzymatic and cell-based assays with EC50 values of 23 nM and 11 nM for GT-1a and GT-1b, respectively

The aims of this study were to assess safety, pharmacokinetics and the antiviral effect of BI 207127 in patients with chronic HCV infection of GT-1

METHODS

BI 207127 dosages

This phase 1b trial was a double blinded, sequential, dose-escalating group comparison, studying doses of 100 mg, 200 mg, 400 mg, 800 mg and 1,200 mg every 8 hours (q8h), given for 5 days orally (experimental tablet). At each dose level, patients were randomized either to BI207127 (n=9) or a matching placebo (n=3)

All patients were followed for 10-14 days

Results from the first four dose levels (100 to 800 mg q8h) are presented here- As of April 2009, the 1,200 mg q8h cohort is ongoing

Overview of key protocols

· HCV RNA was measured by Roche COBAS TaqMan assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 10 IU/mL

· HCV genotype was determined by Inno-LIPA, confirmation of subtypes by NS5B sequencing is ongoing

· Plasma levels of BI 207127 were determined by HPLC-MS/MS

· Pharmacokinetic (PK) parameters were calculated using non-compartmental analysis

Patient criteria
· Patients with chronic HCV infection of GT-1 were enrolled, with the following characteristics
- 18-70 years of age
- either treatment-naÏ ve or non-responders to a previous standard course of pegylated interferon and ribavirin
- minimal to mild liver fibrosis
- plasma HCVRNAvirus load (VL) ≥100,000 IU/mL
· Exclusion criteria were
- co-infection with HIV or HBV
- concurrent liver disease other than HCV
- past treatment with any experimental HCVpolymerase inhibitor
- evidence of liver cirrhosis, active drug or alcohol abuse
- use of any comedication
- alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper limit of normal (ULN)
- bilirubin >1.5 x ULN and not due to Gilbert's disease
- partial thromboplastin time (PTT) (International Normalized Ratio, INR) >1.5 x
ULN
- creatinine >1 x ULN
- white blood cell (WBC) count <2,000/mm3
- platelet count <100,000/mm3
-- haemoglobin <12 g/dL

RESULTS

Patient characteristics

· A total of 48 (male and female) HCV GT-1 patients were enrolled In the first four dose groups (100-800 mg q8h) (Table 1)
- Overall, 36 patients received BI207127, 12 patients received placebo
- 19/48 patients were naive for previous anti-HCV therapy

· The mean age of these 48 patients was 49.5 ± 10.2 years (n=48)

· The mean body mass index (BMI) was 25.3 ± 3.0 kg/m2 (n=48)

· At baseline the mean log10 VL was 6.40 IU/mL (n=48)

Pharmacokinetics

· Plasma drug levels exhibited supra-proportional pharmacokinetics at steady state with 400 mg and 800 mg doses (Figure 1)

· These data plus the PK profile from a single dose escalation study in healthy volunteers suggest that BI207127 may be suitable for three times a day dosing (instead of strict q8h) in the treatment of chronic HCV infection

Viral load

· The antiviral effect of BI 207127 was dose related

· VL decreases by ≥2 log10 were achieved in the majority of patients receiving doses of 400 mg or 800 mg q8h (Table 2)

· Mean (median) VL drops in the morning of Day 5 (log10 steps; Figure 2) were

- 0.6 (0.4) receiving 100 mg
- 1.1 (0.8) receiving 200 mg
- 1.9 (1.3) receiving 400 mg
- 3.1 (3.8) receiving 800 mg
· No response was seen with placebo

· No breakthrough was observed during treatment

· In the group receiving 800 mg, 5/9 patients showed a ≥4 log10 maximal drop in VL, 2/9 patients achieved VL <25 IU/mL

-- The antiviral effect persisted at least 24 hours after the last drug intake (Figure 3)

Safety profile

Overall AEs were rated mild or moderate and were not considered dose-related (Table 3)

Investigators judged tolerability of BI 207127 as good in 88% (n=32/36) of active-treated patients

Two cases of rash were reported, these two patients exhibited the highest PK exposures

- The only serious adverse event (SAE) related to the intake of BI207127 was a moderate generalized erythema with facial involvement. This patient was receiving 800 mg q8h and the SAE resolved within 2 days after discontinuation of BI207127 and after antihistaminic treatment
- Another patient reported rash (800 mg q8h) which was mild, localized and transient under continued treatment

Laboratory parameters did not show any relevant changes from baseline. There were no signs of liver, kidney or haematotoxicity (Table 4)