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HepaRegeniX: Harnessing the liver’s regenerative power

HepaRegeniX is pioneering a novel therapeutic approach that enables faster regeneration of healthy and diseased livers.

MKK4: A novel molecular key to liver regeneration

HepaRegeniX was founded on the discovery of a novel molecular target, Mitogen-Activated Protein (MAP) Kinase Kinase 4 (MKK4).1 (click to see publication) MKK4 belongs to the family of MAP Kinases, signaling enzymes that regulate cellular processes like growth and survival. Activated in response to stress, MKK4 inhibition redirects stress signaling in hepatocytes, the liver cells responsible for most liver functions, enhancing regeneration without triggering uncontrolled proliferation.1(click to see publication) HepaRegeniX is developing oral small molecule inhibitors of MKK4 to treat liver disease through regeneration.

Fig. 1: MKK4 plays a central role in liver degeneration and regeneration.2 (click to see publication)

Unlocking the regenerative capacity of the liver

A healthy liver holds almost limitless regenerative potential thanks to the regenerative ability of mature hepatocytes. However, liver damage limits this capability, hindering the liver’s natural ability to heal and regenerate. MKK4 suppression improves hepatocyte proliferation in both healthy and diseased livers. HepaRegeniX is targeting MKK4 with an oral small molecule inhibitor to reverse the progression of acute and chronic liver diseases and to enable lifesaving liver surgeries, treatment of severe alcoholic hepatitis and living donor liver transplantion.

Opening new doors to liver disease treatments

Liver disease accounts for more than 2 million deaths per year4 (click to see publication) and transplantation is the only therapeutic option for chronic, end-stage liver disease.  However, many patients who meet the eligibility for liver transplantation lose their lives while waiting for a new organ because a suitable liver is not available in time. HRX-215 treatment could open possibilities for living donor liver transplants that are not currently feasible by allowing surgeries from living donors with livers of almost any size. The liver’s regenerative properties, enhanced by HRX-215, may increase the safety of liver transplantation for the living donor by allowing resection of a smaller donor graft and expand the pool of people eligible to donate. 

Clinical development of our frontrunner MKK4 inhibitor, HRX-215, addresses the unmet need for patients whose livers are currently considered unresectable due to primary liver tumors and liver metastases. Surgical resection of the tumor-bearing parts of the liver offers the highest overall chance for long-term survival. After resection, the remaining tumor-free, healthy liver tissue can maintain liver function and, remarkably, grow back to the original volume. However, when tumors are too widely distributed across the liver, the remaining liver tissue may be too small to support life after resection, leading to post-operative liver failure. These patients currently represent a high medical need group with limited treatment options allowing long-term survival or even a potential cure.

In an experimental model of extended, life-threatening liver resection in pigs, treatment with HRX-215 greatly improved post-hepatectomy prognosis and survival by ameliorating the condition of hepatocytes and promoting the regeneration of functional liver tissue.3 (click to see publication) This highly translational preclinical study demonstrated the potential of our clinical development candidate, HRX-215, to allow these patients to be considered eligible for surgical resection of their tumors and survive longer than with nonsurgical treatments.

MKK 4 – A First-in-class therapeutic target

  • Validated in pre-clinical models
  • Stabilizes / protects hepatocytes
  • Unlocks / increases regeneration in diseased livers
  • Suppresses / reverts fibrosis
  • Suppresses / reverts steatosis
  • Shows no risk of tumorigenesis in knockdown mice

Our Scientific History

The HepaRegeniX approach is based on findings from the research team of Prof. Lars Zender at the University Hospital of Tübingen. His group discovered the molecular target, MKK4, and showed that inhibiting MKK4 with a small RNA molecule led to increased liver regeneration.1 (click to see publication) Our lead candidate, HRX-215 was designed by HepaRegeniX in collaboration with Prof. Zender’s team. The team’s work, along with the work done in collaboration with HepaRegeniX, has been published in two papers in Cell.1,3 (click to see publication)

Publications

[1] Wüstefeld T et al., Cell 2013; 153(2):389-401; DOI: doi.org/10.1016/j.cell.2013.03.026 

[2] Willenbring H and Grompe M, Cell 2013; 153(2): 283-284; DOI: 10.1016/j.cell.2013.03.033

[3] Zwirner S et al., Cell 2024; 187(7): 1666-1684; DOI: 10.1016/j.cell.2024.02.023

[4] Asrani SK et al., J Hepatol. 2019 Jan;70(1):151-171. DOI: 10.1016/j.jhep.2018.09.014

[5] Jansen RA et al. PNAS 2024; 121 (9): e2319492121. DOI: 10.1073/pnas.2319492121