HRX-215 / HepaRegeniX - LARVOL DELTA

HRX-215 attenuates cartilage fibrosis in osteoarthritis progression and microfracture repair by targeting MKK4. (PubMed, Biochem Pharmacol) - "HRX-215 also has an inhibitory effect on the expression of MKK4 in human chondrocytes. Taken together, the results of this study indicate that HRX-215 inhibits cartilage fibrosis by targeting MKK4, providing a promising therapeutic candidate for osteoarthritis and microfracture repair."

Journal • Fibrosis • Immunology • Musculoskeletal Diseases • Osteoarthritis • Pain • Rheumatology • MAP2K4 • MAPK8

HRX215, A First Generation MKK4 Inhibitor Drug, for the Treatment of Patients With Colorectal Liver Metastasis After Undergoing a Portal Vein Embolization (clinicaltrials.gov) - P2 | N=80 | Not yet recruiting | Sponsor: Mayo Clinic

New P2 trial • Colorectal Cancer • Oncology • Solid Tumor

Safety, pharmacokinetics, and clinical activity of HRX215 after hepatectomy due to colon carcinoma metastases: interim results from pilot cohort of a 1b/2a clinical trial (EASL 2026) - "HRX215 was well tolerated in participants undergoing minor liver resection for CRCLM, with safety profile consistent with expected AEs in this patient population and comparable pharmacokinetics to healthy participants. Rapid restoration of liver volume and liver function was observed in all 5 participants. The potential for HRX215 to accelerate liver volume recovery in participants undergoing more extensive liver resections will be investigated in the next phases of the study."

Clinical • Late-breaking abstract • PK/PD data • Colon Cancer • Colorectal Cancer • Hepatology • Liver Failure • Oncology • Solid Tumor • MAP2K4

Darizmetinib (HRX215): A Promising 1st-in-Class Liver Regenerating Drug in Phase 1b/2a Clinical Development, Targeting the Stress Signaling Protein Kinase MKK4. (PubMed, J Med Chem) - "Darizmetinib was derived from a known BRaf inhibitor, and through extensive structure-activity relationship (SAR) studies, we successfully engineered potency and selectivity for MKK4 while eliminating the original BRaf on-target activity. Preclinical proof-of-concept studies, along with in vivo evaluations of different lead candidates, identified darizmetinib, demonstrating dose-dependent efficacy across various disease-relevant pharmacological models."

Journal • P1/2 data • MAP2K4 • MAPK8

HRX215-CR03-LR01: Study to assess how safe and effective is HRX215 in participants who underwent minor and major liver surgery due to colon carcinoma metastases (clinicaltrialsregister.eu) - P1/2 | N=29 | Not yet recruiting | Sponsor: HepaRegeniX GmbH

New P1/2 trial • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

Safety of HRX215 in Patients After Minor and Major Liver Resection (clinicaltrials.gov) - P1/2 | N=40 | Recruiting | Sponsor: HepaRegeniX GmbH | N=29 ➔ 40

Enrollment change • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

Safety of HRX215 in Patients After Minor and Major Liver Resection (clinicaltrials.gov) - P1/2 | N=80 | Recruiting | Sponsor: HepaRegeniX GmbH | N=25 ➔ 80

Enrollment change • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

Safety of HRX215 in Patients After Minor and Major Liver Resection (clinicaltrials.gov) - P1/2 | N=25 | Recruiting | Sponsor: HepaRegeniX GmbH | Trial completion date: Jul 2026 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ Jul 2027

Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

Targeting the JNK Gatekeepers: Structural Evolution and Medicinal Chemistry of MKK4 and MKK7 Inhibitors. (PubMed, Molecules) - "We contrast the distinct therapeutic landscapes of the two kinases: while MKK4 inhibition has emerged as a breakthrough strategy for unlocking liver regeneration (exemplified by the first-in-class clinical candidate HRX215), MKK7 inhibition is primarily pursued for its anti-fibrotic and anti-inflammatory potential. Special attention is given to structure-based design strategies, including the exploitation of the unique hinge-region cysteine (Cys218) for MKK7-specific covalent targeting and the optimization of scaffold selectivity against off-targets like BRAF. Finally, we discuss emerging modalities, such as PROTACs and dual inhibitors, outlining a roadmap for the next generation of precision therapeutics targeting the MKK-JNK axis."

Journal • Review • CNS Disorders • Fibrosis • Immunology • Inflammation • BRAF • MAP2K4 • MAPK8

Safety of HRX215 in Patients After Minor and Major Liver Resection (clinicaltrials.gov) - P1/2 | N=25 | Recruiting | Sponsor: HepaRegeniX GmbH | Not yet recruiting ➔ Recruiting | Trial completion date: Oct 2025 ➔ Jul 2026 | Initiation date: Nov 2024 ➔ May 2025 | Trial primary completion date: Jul 2025 ➔ Dec 2025

Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

Karl Wilhelm von Kupffer basic science State-of-the-Art: From bench to bedside a success story in liver regeneration (EASL 2025) - "Learning Objectives:· Current treatment options for acute and chronic liver diseases (brief overview).· Potential of functional genetic screening techniques (shRNAmir, Crispr/CAS9), in particular direct in vivo screens, to pinpoint therapeutic targets in complex biological systems.· Functional genetic validation of MKK4 as a target to increase liver regeneration in preclinical mouse models.· Function of stress-activated protein kinase (SAPK)/mitogen-activated protein kinase (MAPK) signaling networks.· Structure-based development and characterization (NMR-spectroscopy) of first-in- class small molecule inhibitors of the dual specific kinase MKK4 (MKK4i).· Preclinical characterization of MKK4i increased liver regeneration upon hepatectomy in murine and porcine models.· Phase I trial results with the clinical candidate HRX215 (safety and pharmacokinetics) in humans.· Discussion of clinical trial designs to probe HRX215 for..."

Hepatology • Liver Failure • MAP2K4

HepaRegeniX completes €21.5 million financing to support clinical advancement of HRX-215 for liver regeneration (GlobeNewswire) - "HepaRegeniX GmbH...announced the second closing and completion of a €21.5 million financing round with the addition of Wellington Partners to its investor syndicate. HepaRegeniX plans to use the proceeds to complete its ongoing Phase Ib trial and to advance the Phase IIa clinical trial for HRX-215, the company’s lead clinical candidate in liver regeneration."

Financing • Hepatology

Safety of HRX215 in Patients After Minor and Major Liver Resection (clinicaltrials.gov) - P1/2 | N=25 | Not yet recruiting | Sponsor: HepaRegeniX GmbH

New P1/2 trial • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

HepaRegeniX raises €15 million Series C round to advance clinical development of HRX-215 for liver regeneration (GlobeNewswire) - "HepaRegeniX GmbH...today announced the closing of a Series C round led by Vesalius Biocapital IV with participation of existing investors Novo Holdings, Boehringer Ingelheim Venture Fund (BIVF), and High-Tech Gründerfonds (HTGF). The new funds of €15 million will be used to advance the clinical development of the Company’s clinical candidate HRX-215...'With the new funds, HepaRegeniX will advance with its clinical plans for a Phase Ib study in the US and an international Phase IIa study to enhance liver recovery and prevent liver failure.'"

Financing • Hepatology • Liver Failure