4 week therapy with the non-nucleosidic polymerase inhibitor BI 207127 in combination with peginterferon alfa2A and ribavirin in treatment naïve and t

4 week therapy with the non-nucleosidic polymerase inhibitor BI 207127 in combination with peginterferon alfa2A and ribavirin in treatment naïve and treatment experienced chronic HCV GT1 patients


Reported by Jules Levin
45th Annual Meeting of the European Association for the Study of the Liver (EASL), 14-18 April 2010, Vienna, Austria

Dominique Larrey,1 Ansgar Lohse,2 Victor de Ledinghen,3 Christian Trepo,4 Tilman Gerlach,5 Jean-Pierre Zarski,6 Albert Tran,7 Philippe Mathurin,8 Robert Thimme,9 Keikawus Arasteh,10 Christian Trautwein,11 Andreas Cerny,12 Nektarios Dikopoulos,13 Marcus Schuchmann,14 Markus H. Heim,15 Guido Gerken,16 Jerry O. Stern,17 Katherine Wu,17 Nasri Abdallah,18 Birgit Girlich,19 Joseph Scherer,17 Wulf Boecher,20 Frank Berger,21 Jurgen Steffgen20 for the BI 207127 study group 1INSERM632-CIC Hopital Saint Eloi Montpellier; 2Universitatsklinikum Hamburg-Eppendorf Hamburg; 3CHU de Bordeaux - Hopital Haut-Leveque Pessac; 4Hotel-Dieu Hospital Lyon; 5Kantonsspital St Gallen; 6CHU de Grenoble - Hopital A Michallon Grenoble; 7Hopital Archet 2 Nice; 8Hopital Claude Huriez Lille; 9Medizinische Universitatsklinik Freiburg; 10EPIMED - GmbH Berlin; 11Universitatsklinikum Aachen; 12Clinica Luganese Moncucco Lugano; 13Universitatsklinik Ulm; 14Universitatsmedizin Mainz; 15Universitatsspital Basel; 16Medizinische Universitatsklinik Essen; 17Boehringer Ingelheim Ridgefield CT; 18Reims; 19Basel; 20Biberach; 21Ingelheim

AUTHOR CONCLUSIONS

BI 207127 in combination with PegIFN/RBV induced rapid and strong antiviral responses

Subtype 1a and 1b virologic response was similar among TN patients, with 600 mg and 800 mg tid in combination with PegIFN/RBV

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 in combination 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

ABSTRACT

Background: BI 207127 is a specific non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase in vitro which showed potent antiviral effect during 5-day monotherapy in HCV patients.

Methods: In a double-blind, parallel group comparison, 57 HCV genotype-1 patients with compensated liver disease were treated for 28 days with 400, 600 or 800 mg BI 207127 or placebo tid as tablets in combination with peginterferon-alfa2A and ribavirin (PegIFN/RBV). Treatment naïve patients (TN; n=27) were randomized in a 2:2:2:3 ratio to one of the three BI 207127 doses or placebo and treatment experienced patients (TE, all PegIFN/RBV non-responders; n=30) in a 1:1:1 ratio to the three BI 207127 doses. Plasma HCV RNA was measured by Roche COBAS TaqMan assay.

Results: Mean age was 48.9 ± 10.9 years, BMI 25.5 ± 3.8 kg/m2, mean baseline HCV RNA 6.6 (log10 IU/mL). BI 207127 demonstrated a potent antiviral activity especially in TN patients as shown in the table.

TABLE: Median HCV RNA decrease, rapid virological response (RVR) at Day 28 and rebound (>1.0 log10 from nadir until Day 28); intent-to-treat population


One and four TE patients prematurely discontinued due to AE in the 600 and 800 mg dose groups. One drug-related SAE was reported in the 800 mg dose group (progressive rash, recovering after discontinuation of study treatment). Rash/photosensitivity reactions were reported more frequently at 600 and 800 mg BI 207127 (7/16 and 8/17 vs 2/16 and 2/8 at 400 mg and placebo). Most rashes (6/7 at 600, 4/8 at 800 mg) resolved during continued BI 207127 treatment. No relevant changes were observed in safety laboratory parameters.

Conclusions: BI 207127 in combination therapy with PegIFN/RBV induced a strong antiviral response. The best efficacy/tolerability profile was observed at 600 mg tid and support further study of BI 207127 in combination regimens for the treatment of chronic HCV infection.

Introduction

Hepatitis C virus (HCV) genotype-1 (GT-1) infection is associated with less than 50% sustained virological response rates to current standard treatment with pegylated interferon alfa and ribavirin (PegIFN/RBV), which highlights the need for more potent antiviral treatment options

BI 207127 is an orally bioavailable, reversible, thumb pocket one non-nucleoside inhibitor of the HCV RNA-dependent polymerase in vitro

BI 207127 exhibits potent and specific inhibition of the HCV RNA-dependent RNA polymerase with cell-based HCV subgenomic 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 treatment-experienced (TE) HCV 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 monotherapy1

The objective of this study was to assess antiviral potency, safety and pharmacokinetics of BI 207127 in combination with PegIFN/RBV in patients with chronic HCV infection of GT-1

METHODS

Study design and BI 207127 dosages

Design: double-blinded, group comparison; placebo-controlled for TN patients

BI 207127 doses: 400 mg, 600 mg or 800 mg were given three times a day (tid) from Day 1 to 28 orally (experimental tablet) in combination with PegIFN/RBV. The last dose of BI 207127 was administered on the morning of Day 28 (Figure 1)

After completion of triple therapy, all patients were offered to continue on standard of care (PegIFN/RBV) based on the investigators best clinical judgement TN patients were randomized in a 2:2:2:3 ratio to one of the three BI 207127 doses or placebo; TE patients were randomized in a 1:1:1 ratio to one of the three BI 207127 dose groups. Within both subpopulations, randomization was stratified by subgenotype 1a versus 1b

All patients were followed for an additional 10-14 days after completion of BI 207127 treatment

Patients

Inclusion criteria:
- Chronic HCV infection of GT-1
- 18-70 years of age
-- Male or female (with documented hysterectomy or postmenopausal)

FIGURE 1. Study design

- TN:
· No prior therapy with interferon or PegIFN and RBV - TE:
· Non-responders having received at least 12 weeks PegIFN/RBV therapy and documented medical history (dose, duration, virological response pattern) - Plasma viral load (VL) ≥100,000 IU/mL

· Exclusion criteria:
- Coinfection with HIV or HBV
- Concurrent liver disease other than HCV infection
- Past treatment with any experimental polymerase inhibitor
- Evidence of liver cirrhosis (must be ruled out by either histology or fibroscan within the last 24 months)
- Active drug or alcohol abuse
- Use of any comedication
- Ongoing or historical photosensitivity or recurrent rash
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 x upper limit of normal (ULN)
- Bilirubin >1.5 x ULN and not due to Gilbert's disease
- Alkaline phoshatase >2 x ULN
- 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
- Hemoglobin <12 g/dL
-- TSH and T4 outside normal range

Laboratory methods
HCV RNA was measured in plasma by Roche COBAS TaqMan assay with a lower limit of quantification (LLOQ) of 25 IU/mL and a lower limit of detection (LLOD) of approximately 10 IU/mL

Virological rebound was defined as a VL re-increase by ≥1.0 log10 IU/mL from nadir or to ≥1,000 IU/mL if previously below LLOD

HCV genotype was determined by Trugene Assay at screening (used for stratification). NS5B gene sequencing and phylogenetic analyses were used for definitive subtype assignment (all results and analyses)

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

Pharmacokinetic (PK) parameters were calculated using noncompartmental analysis

RESULTS

Patient baseline characteristics

A total of 57 (male and female) HCV GT-1 patients were randomized and treated (Table 1)

- 27 patients were naïve for previous anti-HCV therapy, 19 of them received BI 207127, eight received placebo
- 30 patients were treatment experienced, all received BI 207127
- The mean age of these 57 patients was 48.9 ± 10.9 years
- The mean body mass index (BMI) was 25.5 ± 3.8 kg/m2
-- At baseline the mean log10 HCV RNA was 6.6 ± 0.4 (log10 IU/mL)

Efficacy

All TN patients completed the 4-week combination therapy, whereas five TE patients (one at 600 mg and four at 800 mg) discontinued. All discontinuations were due to adverse events (AEs)

BI 207127 demonstrated potent antiviral activity especially in TN patients as shown in Table 2

There was no difference in virological response (LLOQ) at Day 28 between GT-1a and 1b in TN patients for the higher dose groups. In contrast, TE patients with GT-1b exhibited a stronger response than those with GT-1a (Table 3)

The median decrease in VL over time is shown for all subgenotypes combined and subgenotype 1a and 1b in Figure 2 for TN patients, and in Figure 3 for TE patients

TN patients:
- All TN patients treated with BI 207127 and PegIFN/RBV showed at least a drop of ≥3 log10 from baseline with no evidence of virological rebound (defined as >1 log10 increase in VL from nadir)
- None of the TN patients treated with placebo and PegIFN/RBV showed a drop of 3 log10 from baseline
- There was no evidence of a rebound in any of the TN patients treated with BI 207127
- After 4 weeks treatment with 400, 600 and 800 mg BI 207127 tid, 4/6, 6/7 and 6/6 patients exhibited an RVR with VL below LLOQ (<25 IU/mL), while 3/6, 4/7 and 3/6 had undetectable VL (below LLOD <10 IU/mL), respectively

TE patients:
- 4/10, 5/9 and 6/11 TE patients treated with BI 207127 400, 600, or 800 mg tid and PegIFN/RBV showed a drop of ≥3 log10 from baseline with no evidence of virological rebound
- 2/10, 2/9 and 1/11 TE patients treated with BI 207127 400, 600, or 800 mg tid and PegIFN/RBV had a rebound during the 4 weeks combination treatment. Sequencing of these viral RNAs is in progress
- After 4 weeks treatment with 400, 600 and 800 mg BI 207127 tid and PegIFN/RBV, 1/10, 3/9 and 2/11 patients were below LLOQ (<25 IU/mL) and 0/10, 2/9 and 2/11 had undetectable VL (LLOD <10 IU/mL), respectively

Safety and tolerability

Safety and tolerability were good or acceptable at all three dose levels

Of the 57 patients entered, four patients at 800 mg tid and one patient at 600 mg tid had preterm discontinuations of BI 207127 due to AE: one rash, one photosensitivity, two GI symptoms, one asymptomatic ALT flare. The ALT flare occurred in a patient with progressive F3 fibrosis, who had a similar complication during previous PegIFN/RBV treatment

One serious AE (SAE) was drug-related: a progressive moderate rash in the 800 mg dose group that recovered after discontinuation of BI 207127. Three further SAE were due to pre-existing conditions or occurred after BI 207127 treatment

AEs were all mild or moderate. Most AEs were typical of PegIFN/RBV treatment (Table 4)

GI effects appeared to be more frequent and dose-dependent in the BI 207127 groups, but were mild to moderate and could be managed in most cases

FIGURE 2. Median VL, normalized to baseline for each treatment group, TN patients. A) all subgenotypes; B) subgenotype 1a; C) subgenotype 1b

FIGURE 3. Median VL, normalized to baseline for each treatment group, TE patients. A) all subgenotypes; B) subgenotype 1a; C) subgenotype 1b

TABLE 4. Frequency of patients with AE occurring in at least two cases in any dose group during treatment, TN and TE patients combined

*Includes all reports of rash, (localized) erythema, photosensitivity or sunburn

Rash or photosensitivity reactions were reported more frequently at 600 and 800 mg BI 207127. Two rashes led to discontinuation of BI 207127 (including SAE), one patient in the 800 mg dose group had continuing mild rash onPegIFN/RBV, while all other rashes resolved either during continued BI 207127 or PegIFN/RBV treatment

Safety laboratory analyses showed that blood cell counts were reduced as is typical for PegIFN/RBV. No relevant changes were observed in other routine laboratory parameters including serum ALT and creatinine (Table 5)

TABLE 5. Safety laboratory changes with BI 207127 treatment: mean ± SD

Reference

1. Larrey D, et al. BI 207127 is a potent HCV RNA polymerase inhibitor during 5 days monotherapy in patients with chronic hepatitis C. The 60th meeting of the American Association for the Study of Liver Diseases (AASLD); Boston, MA, USA; 2009. Abstract 1599.