Poxel Reports Positive Preclinical Results for PXL065 in HCM
POXEL SA, a clinical-stage biopharmaceutical company dedicated to developing innovative treatments for chronic and serious diseases with metabolic pathophysiology, including metabolic dysfunction-associated steatohepatitis (MASH) and rare metabolic disorders, has announced positive top-line results from a preclinical study evaluating PXL065 in a mouse model of hypertrophic cardiomyopathy (HCM). PXL065 is a proprietary deuterium-stabilized R-stereoisomer of pioglitazone, a compound known to exert beneficial effects by reducing inflammation and fibrosis, improving mitochondrial function, and restoring metabolic balance.
Hypertrophic cardiomyopathy (HCM) is a prevalent genetic cardiac disorder characterized by myocardial hypertrophy, cardiac fibrosis, ventricular dysfunction, arrhythmias, and an increased risk of sudden cardiac death. It is primarily caused by mutations in sarcomere protein genes, leading to metabolic dysregulation, oxidative stress, and mitochondrial dysfunction. The prevalence of HCM is estimated to be 0.2%, affecting approximately 1 in 500 adults, with an incidence of about 5 per 100,000 person-years. Current therapeutic options are limited in efficacy, safety, and accessibility, making the development of novel treatments a pressing medical need.
Thomas Kuhn, CEO of Poxel, emphasized the significance of the findings: “We are very pleased with these top-line results, which illustrate the potential of PXL065 for treating hypertrophic cardiomyopathy, the most common genetic cardiac disorder. Current therapeutic options for this disease are limited, with either low efficacy, a difficult safety profile, or addressing a limited patient population. There is therefore a high medical need for novel, effective, and well-tolerated treatments that would prevent disease progression and help to avoid invasive procedures such as heart surgery. We look forward to initiating the clinical development of PXL065 in this indication based on these promising results.”
The preclinical study was conducted at the TUM University Hospital German Heart Center, with funding from the German Center for Cardiovascular Research (DZHK). The research was led by Prof. Dr. Cordula Wolf, Director of the Center for Rare Congenital Heart Diseases. Commenting on the study’s significance, Prof. Dr. Wolf stated: “The findings of the preclinical study conducted in collaboration with Poxel represent a major step in the development of a novel therapeutic approach to treat hypertrophic cardiomyopathy, a severe and progressive disease that can lead to life-threatening cardiac events.
Results obtained during this preclinical study showed that PXL065 may have the potential to improve the clinical outcomes for patients suffering from this genetic condition by reducing left ventricular hypertrophy, decreasing cardiac fibrosis, and improving the underlying pathophysiological mechanisms. The profile of PXL065 also compares well versus standard of care, including mavacamten, with a highly differentiated mechanism of action. Building on the data package available for this novel compound, in our view, the study results support the development of PXL065 as a disease modifier and long-term treatment for HCM patients.”
The mechanism of action of PXL065 involves the inhibition of the mitochondrial pyruvate carrier (MPC) and Acyl CoA Synthetase 4 (ACSL4), which play key roles in oxidative stress, inflammation, and fibrosis. In the preclinical study, mice with HCM were treated with PXL065 for 10 weeks, resulting in a significant reduction in myocardial hypertrophy and cardiac fibrosis. These findings highlight the compound’s potential for addressing the pathophysiology of HCM and modifying disease progression.
The collaboration between Poxel and the TUM University Hospital German Heart Center leveraged Poxel’s extensive data and patent portfolio on PXL065. Prof. Dr. Wolf and her research group have also contributed significantly to understanding the disease mechanisms of HCM and exploring the therapeutic potential of thiazolidinediones (TZDs). The preclinical study’s top-line results indicate that PXL065 effectively prevents pathological myocardial remodeling in an HCM mouse model, including both hypertrophy and fibrosis. Further analysis of the transcriptome and proteomics will provide additional insights into the mechanistic pathways influenced by PXL065, reinforcing its potential as a long-term treatment option for HCM.
Given the promising results observed in the preclinical study, Poxel is preparing to initiate clinical development of PXL065 for HCM, pending additional financing and further data analysis. The company plans to define the optimal patient population for treatment based on available data and the compound’s mechanism of action. Additionally, Poxel will work closely with regulatory agencies and leading HCM experts, including Prof. Dr. Wolf, to establish a comprehensive clinical development and regulatory strategy.
The full results of this preclinical study have been submitted for presentation at an upcoming scientific meeting. The data will provide further insights into PXL065’s therapeutic potential and help shape future research and clinical development efforts.
PXL065’s potential differentiation from existing therapies, including mavacamten, is of particular interest. Mavacamten, a cardiac myosin inhibitor, is currently approved for treating obstructive HCM but has a mechanism of action distinct from PXL065. By targeting mitochondrial function, oxidative stress, inflammation, and fibrosis, PXL065 offers a novel approach that may complement or provide an alternative to existing treatments. Furthermore, PXL065’s deuterium-stabilized formulation is expected to enhance metabolic stability, potentially leading to improved efficacy and safety profiles compared to traditional pioglitazone.
