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Combination Therapy of TMC647055 With Simeprevir (TMC435) in Genotype 1 HCV Patients
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Reported by Jules Levin
EASL 2013 April 24-28 Amsterdam
S. Bourgeois1*, H.W. Reesink2, J. Leempoels3, L. Vijgen4, M.-C. Rouan4, K. Marien4, P. Van Remoortere5, G. Fanning4, G. Picchio5, K. Simmen4, R. Verloes4
1Hepatologie, Stuivenberg Ziekenhuis, Antwerpen, Belgium, 2Dept Gastroenterologie en Hepatologie, Amsterdam Medical Center, Amsterdam, The Netherlands, 3SGS Life Sciences, Antwerpen, 4Janssen Infectious Diseases, Beerse, Belgium, 5Janssen Infectious Diseases, Titusville, NJ, USA.
From Jules: in speaking with Janssen it appears low-dose RTV fixes the autoinduction issue of TMC647055 (healthy volunteer data) and renders it a low dose qd compound (see results below on PK). The data for this was submitted to EASL but not accepted so will be submitted at another conference.
TMC055 Monotherapy data:
Human safety, pharmacokinetics and antiviral activity of TMC647055, a novel HCV non-nucleoside polymerase
inhibitor.......http://www.natap.org/2011/AASLD/AASLD_04.htm
Here is the link to the study on clinical trials.gov where you can see low dose 30mg RTV is used:
A Study to Evaluate the Safety, Tolerability, and Effectiveness of a 12-Week Combination Therapy of TMC647055 and TMC435 With a Pharmacokinetic Enhancer With and Without Ribavirin in Chronic Genotype-1 Hepatitis C Infected Patients.......http://clinicaltrials.gov/ct2/show/NCT01724086?term=tmc647055&rank=3
METHODS
HCV Infected Patients
Eight patients were enrolled, all treatment-naive (N=6) or prior-relapser (N=2) to a previous (pegylated)IFN/RBV regimen. Patients had minimal or no fibrosis (biopsy, elastography) and a compensated liver function. A majority of HCV genotype 1a infected patients was enrolled (7 GT1a, 1 GT1b).
Dosing
Patients were dosed orally for 10 days with TMC647055 at 1000 mg bid and simeprevir at 150 mg qd. The trial medication was taken together with approximately 200 mL of water within 10 minutes after completion of a meal.
Study Evaluations
At screening, HCV genotype and subtype were determined by using the Siemens Versant HCV Genotype LiPA2 assay and confirmed by NS5B population sequencing. Plasma HCV RNA was measured by quantitative real-time PCR (Roche Cobas Taqman HPS HCV Test v2.0). Viral population sequencing of the NS5B polymerase and the NS3/4A protease was performed for all patients in baseline, on-treatment and follow-up samples, if HCV RNA was above 100 IU/mL (sequencing limit). Safety was evaluated by assessment of adverse events, vital signs, ECG, physical examination, and clinical laboratory tests. Plasma concentrations of TMC647055 and simeprevir were determined by HPLC-MS/MS and pharmacokinetic parameters were determined using non-compartmental analysis.
Statistical Methods
Data from all patients receiving at least one dose of study drug were summarized.
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