VK2809 (Viking Therapeutics) is a thyroid hormone receptor (THR) β-selective agonist which is selective to liver tissue. It is delivered as a prodrug. VK2809 selectively activates the cytochrome P450 isozyme 3A4 (CYP3A4), which is predominantly found in the liver. This allows increased hepatic exposure, which simultaneously reduces systemic exposure to other tissues such as skeletal muscle and the heart.
The positive, albeit preliminary, results from a Phase II trial in patients with hyperlipidemia and non-alcoholic fatty liver disease (NAFLD) have led Viking Therapeutics to pursue a Phase IIb study assessing histological endpoints in biopsy-confirmed non-alcoholic steatohepatitis (NASH) patients. VK2809 demonstrated a strong ability to reduce liver fat content, measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF), with 70% of patients treated with either 5mg or 10mg achieving ≥50% reduction at 12 weeks, a highly significant change for a short period of time. In addition, VK2809 reduced MRI-PDFF hepatic fat by 57% at 12 weeks. In comparison, resmetirom (Madrigal Pharmaceuticals), another THR β-selective agonist, demonstrated mean liver fat reductions of 42% in the highest dose group at 12 weeks. Although VK2809 demonstrated numerically stronger results, the trial was conducted in patients with NAFLD rather than biopsy-proven NASH. It will be interesting to see if the robust reduction in liver fat is maintained and translates into fibrosis regression over a longer period of time in NASH patients.
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