In Vivo Loss-of-function Studies Unravel Protein Tyrosine Phosphatase Delta As a Regulator of Liver Regeneration During Metabolic Liver Disease

accelerated liver regeneration and improved survival were recently obtained in 85% hepatectomy pig model upon treatment with the MKK4 inhibitor HRX-0215 (5 mg/kg i.v.) (Klotz et al., Hepatology, 2021).Here, we now report data from a FIH clinical trial for HRX-0215 related to safety, tolerability and pharmacokinetics.Method: A FIH Clinical trial for HRX-0215 was conducted in 48 healthy volunteers to assess safety, tolerability and pharmacokinetics in a single-center, double-blind, randomized, placebo-controlled manner.In the Single Ascending Dose part volunteers were dosed from 5 to 500 mg, the Multiple Ascending dose part used daily doses between 100 and 500 mg.HRX-0215 was well tolerated at all doses, no relevant changes of any clinical or laboratory parameters were observed.Within a given dosing strength, PK analysis revealed a dose-proportional increase of exposure with very low interindividual variability.Concentration vs. time profiles of HRX-0215 supports a once-daily dose regimen during further clinical development.Results: In the 4 wk GLP toxicity study in rats and dogs, a NOAEL of 300 mg/kg p.o. and 250 mg/kg p.o. was obtained, respectively.No organ toxicity was observed, which is in line with results from 12 mths ubiquitously, genetically suppressed MKK4 expression in mice.Most importantly, risk mitigation for liver tumor burden was achieved in a diet-induced obese mouse model with biopsyconfirmed NASH (non-alcoholic steatohepatitis) and advanced fibrosis, where HRX-0215 administered at a dose level of 30/kg once daily for 12 weeks attenuated progression in tumor numbers and growth.Conclusion: Our FIH clinical trial demonstrates a favorable safety profile of HRX-0215 and confirms that pharmacological MKK 4 inhibition is well tolerated.PK characteristics indicate that therapeutic efficacy is achieved with a once-daily dose regimen This profile enables further clinical development and Phase 2 trials of HRX-0215 in patients with acute and chronic liver diseases.