Biotech Values

[genisi]

Safety signal for MRK's non-nuc MK-3281 - severe myoclonus. AASLD abstract:

Safety and Antiviral Activity of NS5B Polymerase Inhibitor MK-3281, in Treatment-Naïve Genotype 1A, 1B AND 3 HCV-Infected Patients

D. M. Brainard1; M. S. Anderson1; A. Petry1; K. Van Dyck1; I. De Lepeleire1; K. Sneddon1; C. E. Cummings1; R. B. Nachbar1; R. J. Barnard1; P. Sun1; P. Panorchan1; J. B. Sanderson2; E. Udezue3; F. Wagner4; M. Iwamoto1; J. Chodakewitz1; J. A. Wagner1
1. Merck & Co., Inc., Whitehouse Station, NJ, USA.
2. Chiltern (Early Phase) Limited, Dundee, United Kingdom.
3. Chiltern Place, Slough, United Kingdom.
4. Charité Research Organisation, Berlin, Germany.


Background: MK-3281 is a novel non-nucleoside hepatitis C virus (HCV) NS5B polymerase inhibitor with potent and selective in vitro activity against HCV genotypes (GT) 1a/b and 3 HCV. Safety, tolerability, pharmacokinetics (PK), resistance, and antiviral activity were assessed during multiple dose administration in HCV-infected patients.

Methods: This was a double-blind, placebo-controlled, serial panel study in 22 treatment-naïve HCV-infected patients who received 800 mg MK-3281 (17 patients: 4 x GT1b, 6 x GT3, 6 x GT1a, 1 x non-typeable [1-NT]) or placebo (5 patients) q12 hr for 7 days. All patients were followed for two weeks post therapy. Safety and resistance evaluations were performed throughout the study. Plasma samples were collected for MK-3281 PK and HCV viral RNA determination (using the Roche COBAS Taqman assay).

Results: There were no serious adverse experiences (AEs) reported. One patient discontinued due to an AE of myoclonus on study Day 2 of approximately 1.5 h in duration, preliminarily judged possibly-related to MK-3281 and rated of severe intensity. Other AEs were limited in number, transient, and rated mild to moderate in intensity with headache the most frequently reported AE. No clinically relevant laboratory safety signals were observed. However, several patients on therapy showed transient reductions in liver function tests. The PK of MK-3281 in HCV-infected patients were similar to previously reported values observed in healthy subjects. Mean maximum reductions from baseline of HCV viral RNA (SEs) were 1.3 (0.15), 3.8 (0.19), and 1.2 (0.16) log10 IU/mL for GT1a/1-NT, 1b, and 3, respectively. No on-treatment viral rebound was observed in any GT 1b patient, while 1 of 6 GT1a and 1 of 6 GT3 patients showed evidence of on-treatment viral rebound. Upon 2 week follow-up, plasma levels of HCV-RNA had returned to baseline levels in all individuals. Resistance analysis was performed on GT1a and GT1b patients.

Conclusions: MK-3281 as monotherapy for 7 days was well tolerated and demonstrated strong antiviral activity against GT1b HCV with no evidence of viral breakthrough. In vivo activity against GT1a and GT3 was limited. These findings support further clinical investigation of MK-3281 for the treatment of chronic HCV infection.