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Trek's HCV DAAs - MIV-802 / TD-6450
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PRECLINICAL CHARACTERISATION OF MIV-802, A NOVEL URIDINE NUCLEOTIDE HCV NS5B POLYMERASE INHIBITOR, FOR TREATMENT OF HEPATITIS C VIRUS INFECTION
http://www.natap.org/2015/EASL/EASL_152.htm
TD-6450, a Heterodimeric HCV NS5A Inhibitor with a High Barrier to Resistance and Pan-Genotypic Potency
http://www.natap.org/2013/hepDART/hepDART_06.htm
TD-6450, A NEXT GENERATION ONCE-DAILY NS5A
INHIBITOR, HAS POTENT ANTIVIRAL ACTIVITY FOLLOWING A
3-DAY MONOTHERAPY STUDY IN GENOTYPE 1 HCV INFECTION
E. Lawitz1, M. Rodriguez-Torres2, R. Kohler3, A. Amrite3, C. Barnes3, M.L.C. Pecoraro3, J. Budman3, M. McKinnell3, C.B. Washington3.
1Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States; 2Fundacion de Investigacion, San Juan,
Puerto Rico; 3Theravance Biopharma, South San Francisco, CA, United States
E-mail: cwashington@theravance.com
Background and Aims: TD-6450 is a next generation HCV NS5A inhibitor with superior in vitro potency against resistance-associated variants (RAVs) encountered with first-generation NS5A inhibitors. This study evaluated the safety, pharmacokinetics (PK) and antiviral activity of TD-6450 following multiple oral doses in HCV patients.
Methods: This was a double-blind, randomized, placebo-controlled study in treatment-naïve, non-cirrhotic HCV patients. In the dose ranging portion of the study, patients with GT-1a infection were randomized to receive multiple ascending oral doses of TD-6450 [60mg to 240mg daily (QD)] or placebo for 3 days. Additional
cohorts of GT-1b, GT-2 and GT-3 HCV patients were administered TD-6450 240mg QD and one GT-1a cohort was administered 240mg twice daily (BID) for 3 days. The antiviral activity of TD- 6450 was assessed using the COBAS®Ampliprep/COBAS®Taqman® HCV Test, 2.0 (limit of detection, LOD = 15 IU/mL) for up to 28 days after the first dose of TD-6450.
Results: Twenty-four patients with GT-1a infection were evaluated following daily oral doses (60mg to 240 mg) of TD-6450 (n = 21) or placebo (n = 3) for 3 days. The mean baseline viral loads ranged from 6.1 to 6.3 log10 IU/mL. All GT-1a patients in these cohorts had a maximum HCVRNA viral load decline of at least 3 log10 IU/mL.
The HCVRNA results are presented in Table 1. Seven patients (3 in the 120mg and 4 in the 240mg groups) had at least one HCVRNA viral load which fell below the LOD and two of these patients had persistent unmeasurable HCV-RNA at Day 28. All doses of TD-6450 were generally well tolerated after three doses and for the 28-day observation period. There were no serious adverse events and no patient discontinuations. There was no pattern of clinical adverse events or laboratory abnormalities related to treatment. The PK of TD-6450 was similar to that observed in healthy subjects and consistent with QD dosing. The evaluation of TD-6450 in GT-1a (BID), GT-1b, GT-2, and GT-3 HCV patients is currently ongoing but dosing has completed and results will be presented.
Conclusions: TD-6450 was generally well tolerated at all doses evaluated and demonstrated potent dose-dependent antiviral activity in treatment-naïve HCV GT-1 infected patients.
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