icon-    folder.gif   Conference Reports for NATAP  
 
  EASL
43rd Annual Meeting of the European Association For The Study Of The Liver
Milan, Italy
April 23-27, 2008
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Safety of the HCV Protease Inhibitor TMC435350 in Healthy Volunteers and Safety and Activity in Chronic Hepatitis C Infected Individuals: A Phase I Study
 
 
  Reported by Jules Levin
43rd EASL Conference, April 23-27, 2008, Milan, Italy
 
H. Reesink,1 R. Verloes,2 K. Abou Farha,3 A. Van Vliet,3
C. Weegink,1 G. van Ôt Klooster,2 F. Aharchi,2 K. Marien,2
P. Van Remoortere,2 H. de Kock,2 F. Broeckaert,2 G. Fanning,2
P. Meyvisch,2 E. Van Beirendonck,2 K. Simmen2
1Academic Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands; 2Tibotec BVBA, Mechelen, Belgium and Tibotec Pharmaceuticals Ltd., Ireland; 3PRA International, Zuidlaren, The Netherlands
 
Author Conclusions and future directions
 
In healthy volunteers TMC435350 was well tolerated and PK supports QD dosing
 
In HCV treatment experienced patients, 5 days QD TMC43530 dosing was well tolerated
 
Once daily dosing resulted in robust antiviral activity in all patients with a maximal median decrease in HCV RNA of 3.9 Log10, at day 6
 
TMC435350is currently in a Phase IIA 4-week comination trial with Peg-IFN/ribavirin HCV genotype 1-infected patients.
 
TMC435350: a novel and potent HCV
protease inhibitor

 
In vitro profile
Reversible NS3/4A protease inhibitor (non-covalent)
 
Molecular weight = 750
 
EC50 = 8 nM in genotype 1 replicon
 
Ki <1 nM for genotype 1 enzymes
 
Synergy with IFN_ and polymerase inhibitors; additive with ribavirin
 
In vivo preclinical profile
 
High oral bioavailability: 45-80%
 
High liver to plasma ratio: >30
 
No cardiovascular alert
 
Objectives of TMC435350 Phase I study C101
 
Evaluate the safety and pharmacokinetic (PK) profile of single and multiple ascending doses of TMC435350 in healthy volunteers1,2
 
Evaluate safety, PK and antiviral activity of TMC435350 in HCV-infected patients

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HCV patients: minimal adverse events reported
 
No SAEs were observed
 
All adverse events were mild (Grade 1)
--Headache (n=3)
--Fatigue (n=2)
--Other AEs were observed in no more than 1 patient
 
No treatment-related discontinuations
 
No clinically relevant changes in vital signs, ECG and echocardiography parameters

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