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Author Spotlight: Evaluating Therapeutic Strategies to Enhance Liver Regeneration
Published on: May 24, 2024
First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure
Stefan Zwirner1, Anan A Abu Rmilah2, Sabrina Klotz3
1Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, Tübingen 72076, Germany; HepaRegeniX GmbH, Tübingen 72072, Germany.
Abstract:
Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.
Insights
New small molecule inhibitors targeting MKK4 (MKK4i) promote hepatocyte regeneration. This approach improved liver function in animal models and showed promise in early human trials for liver disease and post-surgery recovery.
Area of Science:
- Hepatology
- Drug Discovery
- Molecular Biology
Background:
- Impaired hepatocyte regeneration is a critical issue in liver diseases and after liver surgery.
- Current treatments for liver failure primarily rely on transplantation.
- There is a significant unmet need for therapies that enhance liver regeneration.
Purpose of the Study:
- To develop and characterize novel small molecule inhibitors of MKK4.
- To evaluate the efficacy of MKK4 inhibitors in promoting liver regeneration and treating liver disease.
- To assess the safety and pharmacokinetics of the clinical candidate HRX215 in humans.
Main Methods:
- Structure-based drug design and development of MKK4 inhibitors.
- Characterization using nuclear magnetic resonance (NMR) spectroscopy.
- Preclinical studies in murine and porcine models of liver injury and regeneration.
- First-in-human Phase I clinical trial (EudraCT 2021-000193-28).
Main Results:
- Developed first-in-class MKK4 inhibitors (MKK4i).
- MKK4i significantly enhanced liver regeneration in animal models, including survival in a lethal hepatectomy model.
- Demonstrated antisteatotic and antifibrotic effects in mouse models of liver disease.
- HRX215 exhibited excellent safety and pharmacokinetic profiles in a Phase I trial.
Conclusions:
- Small molecule MKK4 inhibitors represent a promising therapeutic strategy for promoting liver regeneration.
- HRX215 shows potential for preventing or treating liver failure in various clinical settings.
- Further clinical trials are warranted to investigate HRX215 for liver resection and transplantation patients.
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