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Findings from Clinical Virology Studies on Sovaprevir, a Phase 2 HCV NS3 Protease Inhibitor, Indicate a High Pharmacological Barrier to Viral Resistance
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Reported by Jules Levin
EASL 2013 April 24-28 Amsterdam
Joanne Fabrycki, Yongsen Zhao, Dharaben Patel, Guangwei Yang, Steven Podos, Wengang Yang, Heather Robison, Lisa Robarge, Hetal Kocinsky,
Milind Deshpande and Mingjun Huang
Achillion Pharmaceuticals, Inc., New Haven, CT
EASL/2012: CONTINUED HIGH VIROLOGIC RESPONSE RATES WITH ACH-1625 DAILY DOSING PLUS PEGIFN-ALPHA 2A IN A 28-DAY AND 12-WEEK PHASE 2A TRIAL
http://www.natap.org/2012/EASL/EASL_76.htm
- In a phase 1b study in GT-1a HCV patients, resistant variants that carry mutations at NS3 amino acid residues 155, 156, or 168 were detected in on-treatment samples from all six patients, likely as a consequence of enrichment of pre-existing variants.
- In three patients (8019, 8023 and 8026), the variants were detected at frequencies of 6-34% as early as 12 hrs after the first dose. Yet, the viral RNA declined further during the dosing period
and even became undetectable in one of them (8026) (Figure 6). These data suggest that sovaprevir achieves high enough concentrations at the target site to inhibit these resistant variants.
- In a phase 2a study, an R155K variant at a frequency of ~ 100% by population sequencing was detected at baseline in one subject enrolled in the 800 mg sovaprevir/Peg-IFN/RBV group.
- The IL28B genotype of the subject was CT. The subject achieved cEVR (HCV RNA < LLOQ, TND) and SVR12.
- The efficacy of sovaprevir in this patient, along with the absence of viral breakthrough in all subjects while on sovaprevir/PEG-IFN/RBV treatment for 12 weeks, further supports the hypothesis
that sovaprevir can achieve levels at the target site sufficient for in vivo efficacy even against resistant variants.
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