- Email: [email protected]
1159 ABSENCE OF PHOTOSENSITIVITY POTENTIAL OF TMC435 IN HEALTHY VOLUNTEERS
POSTERS with advanced disease. This translates to a 5-year NNT of 90 for dual therapy vs. 23 for triple therapy. Conclusions: These findings highlight the benefits of DAAs and indicate substantial additional benefits in treating patients with advanced disease despite lower SVR rates in this group. This analysis provides clinically important information for both the caring physician and the patient when considering retreatment in patients with HCV. 1158 PEG-IFNA/RIBAVIRIN/PROTEASE INHIBITOR COMBINATION IS HIGHLY EFFECTIVE IN HCV-MIXED CRYOGLOBULINEMIA VASCULITIS D. Saadoun1 , S. Pol2 , P. Lebray3 , F. Blanc4 , G. Pialoux5 , A. Karras6 , D. Bazin-Kara7 , E. Plaisier8 , P. Cacoub1 . 1 Internal Medicine, Hˆ opital Piti´e Salpˆetri`ere, 2 Medicinal Hepatology, Hˆ opital Cochin, 3 Hepato-Gastro-Enterology, Hˆ opital Piti´e Salpˆetri`ere, Paris, 4 Internal and Addictology Medicine, Hˆ opital Saint Eloi, Montpellier, 5 Infectious Diseases, Hˆ opital Tenon, Paris, 6 Nephrology, Hˆ opital Strasbourg, 7 Nephrology, Nouvel Hˆ opital Civil, Strasbourg, 8 Nephrology, Hˆ opital Tenon, Paris, France E-mail: [email protected] Background: The standard of care treatment of patients presenting a HCV-mixed cryoglobulinemia (MC) vasculitis includes Peg-IFNa plus Ribavirin, w/wo Rituximab. Thirty to 40% of patients are nonresponders or relapsers to such combination. Objective: To analyze the safety and efficacy of a PegIFNa/Ribavirin/Protease inhibitor combination on HCV-MC vasculitis. Patients and Methods: Open label prospective single-center cohort study, 27 patients with HCV-MC vasculitis entered the study, of whom 13 with sufficient follow-up were analysed. PegIFNa/Ribavirin was associated to Telaprevir (375 mg three times daily, 8 patients) or Boceprevir (800 mg three times daily, 5 patients). Results: Mean age 61 years, 54% women, all 13 HCV genotype 1 patients received previous antiviral therapy with PegIFNa/Ribavirin, including 5 (38%) relapsers and 8 (62%) nonresponders; 10 (77%) had been also treated by Rituximab. Mean HCV RNA level was 5.85Log copies/mL; Metavir fibrosis score was of stage 4 in 6 cases, stage 3 in 4 cases and stage 2 in 3 cases. Twelve patients (92%) had a type II IgMk MC and 1 had a type III. Main HCV-MC manifestations included purpura (n = 10), polyneuropathy (n = 10), arthralgia (n = 6), and kidney involvement (n = 3). The mean serum MC, C4 and rheumatoid factor levels were of 1.3 g/l, 0.09 g/l and 157 IU/ml, respectively. After 1 month of Peg-IFNa/Ribavirin/protease inhibitor, 11 (85%) patients showed an early virological response (HCV RNA level <1.1 Log copies/mL). Nine (69%) patients showed a complete clinical response of MC vasculitis and 4 (31%) were partial responders. After 3 months of Peg-IFNa/Ribavirin/protease inhibitor, MC serum level dropped from 1.3 to 0.3 g/l while C4 level increased from 0.09 to 0.13 g/l. All 13 patients experienced at least one treatment side effect including asthenia in 92%, anaemia in 84%, neutropenia and bacterial infection in 53%, nausea and low grade (<3) skin eruption under Telaprevir in 30% and thrombocytopenia in 15%. Conclusion: Peg-IFNa/Ribavirin/protease inhibitor combination seems highly effective in HCV-MC vasculitis. Such therapeutic regimen should be administered cautiously considering the high rates of side effects.
1159 ABSENCE OF PHOTOSENSITIVITY POTENTIAL OF TMC435 IN HEALTHY VOLUNTEERS A. Simion1 , L. Janssens2 , M. Peeters3 , S. Ouwerkerk-Mahadevan1 , K. Spittaels1 , G. De Smedt1 , S.H. Akuma1 , M. Beumont-Mauviel1 . 1 Department of Clinical Development, Tibotec BVBA, 2 Department of Biostatistics and Programming, Janssen Research and Development, Janssen Pharmaceutica NV, 3 Department of Statistics, Tibotec BVBA, Beerse, Belgium E-mail: [email protected] Background and Aims: Drug-induced phototoxicity is a nonimmunologic skin response observed following exposure to radiation. TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor in Phase III development for the treatment of chronic hepatitis C virus infection. This Phase I study assessed the photosensitising potential of TMC435. Methods: A Phase I, randomised, double-blind, double-dummy, placebo- and positive-controlled, parallel group trial was performed in 36 healthy volunteers. Volunteers were randomised to receive TMC435 150 mg QD (n = 12), ciprofloxacin 500 mg BID (n = 12), or placebo (n = 12) for 9 days. Ciprofloxacin, a known mild photosensitiser, was used as a positive control. Volunteers were tested at baseline (three consecutive days prior to dosing) and post-dose (Days 8, 9 and 10) with a series of irradiation doses of 7 preselected wavebands (UVB [295±5nm, 300±5nm, and 305±5nm], UVA [335±30nm and 365±30nm], visible light [400±30nm and 430±30nm]), and a solar simulator. Skin responses were assessed 24 hours post-irradiation to determine the precise minimum erythema dose (MED) for delayed erythema. The primary photosensitivity variable for delayed erythema was photosensitivity index (PI, baseline MED divided by post-dose MED). Results: No statistically significant differences in PI were observed between TMC435 150 mg QD and placebo group at any waveband tested or with solar simulator. Assay sensitivity was proven through statistically significant differences between ciprofloxacin 500 mg twice daily (BID) and placebo at UVA 335±30nm and 365±30nm wavebands, in line with historical ciprofloxacin phototoxicity data. Two serious adverse events (AE) occurred, grade 3 head injury in one ciprofloxacin group volunteer and grade 2 amnesia with hangover in one TMC435 group volunteer, which were considered not related and doubtfully related to study medication, respectively. There were no discontinuations due to AEs. The most frequently observed AEs were excoriation (1 (8%) in TMC435, 1 (8%) in placebo and 3 (25%) in ciprofloxacin group), vessel puncture site haematoma (2 (17%) in TMC435 and 2 (17%) in ciprofloxacin group), and contact dermatitis (1 (8%) in TMC435 and 2 (17%) in ciprofloxacin group). Conclusions: TMC435 150 mg QD was not associated with a photosensitising effect in healthy volunteers. Administration of TMC435 150 mg QD was generally safe and well tolerated. 1160 METFORMIN INCREASES THE RESPONSE TO INTERFERON ALPHA BY INHIBITING PROTEIN TYROSINE PHOSPHATASES IN INSULIN RESISTANT MICE ´ ´ GomezI. Garc´ıa-Ruiz1 , P. Sol´ıs-Munoz ˜ 2 , A.M. Valverde3 , E. ´ 4 1 Izquierdo , T. Munoz-Yag ˜ ue ¨ , J. Sol´ıs-Herruzo1,5 . 1 Research Institute, University Hospital ‘12 de Octubre’, Madrid, Spain; 2 Institute of Liver Studies, King’s College Hospital, London, UK; 3 Instituto de Investigaciones Biom´edicas Alberto Sols, Consejo Superior de Investigaciones Cient´ıficas, 4 Research Center, University Hospital ‘12 de Octubre’, 5 Department of Medicine, Complutense University, Madrid, Spain E-mail: [email protected] Background and Aims: In previous studies, we have demonstrated that induction of insulin resistance increases protein tyrosine phosphatase (PTP) gene expression and activity, particularly of PTP-
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1159 ABSENCE OF PHOTOSENSITIVITY POTENTIAL OF TMC435 IN HEALTHY VOLUNTEERS A. Simion1 , L. Janssens2 , M. Peeters3 , S. Ouwerkerk-Mahadevan1 , K. Spittaels1 , G. De Smedt1 , S.H. Akuma1 , M. Beumont-Mauviel1 . 1 Department of Clinical Development, Tibotec BVBA, 2 Department of Biostatistics and Programming, Janssen Research and Development, Janssen Pharmaceutica NV, 3 Department of Statistics, Tibotec BVBA, Beerse, Belgium E-mail: [email protected] Background and Aims: Drug-induced phototoxicity is a nonimmunologic skin response observed following exposure to radiation. TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor in Phase III development for the treatment of chronic hepatitis C virus infection. This Phase I study assessed the photosensitising potential of TMC435. Methods: A Phase I, randomised, double-blind, double-dummy, placebo- and positive-controlled, parallel group trial was performed in 36 healthy volunteers. Volunteers were randomised to receive TMC435 150 mg QD (n = 12), ciprofloxacin 500 mg BID (n = 12), or placebo (n = 12) for 9 days. Ciprofloxacin, a known mild photosensitiser, was used as a positive control. Volunteers were tested at baseline (three consecutive days prior to dosing) and post-dose (Days 8, 9 and 10) with a series of irradiation doses of 7 preselected wavebands (UVB [295±5nm, 300±5nm, and 305±5nm], UVA [335±30nm and 365±30nm], visible light [400±30nm and 430±30nm]), and a solar simulator. Skin responses were assessed 24 hours post-irradiation to determine the precise minimum erythema dose (MED) for delayed erythema. The primary photosensitivity variable for delayed erythema was photosensitivity index (PI, baseline MED divided by post-dose MED). Results: No statistically significant differences in PI were observed between TMC435 150 mg QD and placebo group at any waveband tested or with solar simulator. Assay sensitivity was proven through statistically significant differences between ciprofloxacin 500 mg twice daily (BID) and placebo at UVA 335±30nm and 365±30nm wavebands, in line with historical ciprofloxacin phototoxicity data. Two serious adverse events (AE) occurred, grade 3 head injury in one ciprofloxacin group volunteer and grade 2 amnesia with hangover in one TMC435 group volunteer, which were considered not related and doubtfully related to study medication, respectively. There were no discontinuations due to AEs. The most frequently observed AEs were excoriation (1 (8%) in TMC435, 1 (8%) in placebo and 3 (25%) in ciprofloxacin group), vessel puncture site haematoma (2 (17%) in TMC435 and 2 (17%) in ciprofloxacin group), and contact dermatitis (1 (8%) in TMC435 and 2 (17%) in ciprofloxacin group). Conclusions: TMC435 150 mg QD was not associated with a photosensitising effect in healthy volunteers. Administration of TMC435 150 mg QD was generally safe and well tolerated. 1160 METFORMIN INCREASES THE RESPONSE TO INTERFERON ALPHA BY INHIBITING PROTEIN TYROSINE PHOSPHATASES IN INSULIN RESISTANT MICE ´ ´ GomezI. Garc´ıa-Ruiz1 , P. Sol´ıs-Munoz ˜ 2 , A.M. Valverde3 , E. ´ 4 1 Izquierdo , T. Munoz-Yag ˜ ue ¨ , J. Sol´ıs-Herruzo1,5 . 1 Research Institute, University Hospital ‘12 de Octubre’, Madrid, Spain; 2 Institute of Liver Studies, King’s College Hospital, London, UK; 3 Instituto de Investigaciones Biom´edicas Alberto Sols, Consejo Superior de Investigaciones Cient´ıficas, 4 Research Center, University Hospital ‘12 de Octubre’, 5 Department of Medicine, Complutense University, Madrid, Spain E-mail: [email protected] Background and Aims: In previous studies, we have demonstrated that induction of insulin resistance increases protein tyrosine phosphatase (PTP) gene expression and activity, particularly of PTP-
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Journal of Hepatology 2012 vol. 56 | S389–S548