Paradigm Biopharmaceuticals Ltd (ASX:PAR) has received positive proof-of-concept data from a pre-clinical animal model trial assessing the efficacy of pentosan polysulfate sodium (PSS) for the treatment of heart failure with preserved ejection fraction (HFpEF).
There are currently no commercial treatments available for HFpEF. Paradigm has been working on repurposing PPS for a multitude of applications, specifically aiming at creating treatments for osteoarthritis, bone marrow lesions, chronic heart failure and alpha viral arthritis (commonly known as Ross River Virus and Chikungunya).
During this preclinical trial, PPS demonstrated improvement in diastolic function as measured by echocardiography compared to control, while also potentially inhibiting accumulation of versican (part of the extracellular matrix) cleavage products in the myocardium (a muscle layer of the heart) of ZSF1 obese rats, suggesting a beneficial effect of PPS on the myocardium.
“Suggests improvement in cardiac function”
Principal investigator and cardiology researcher at the Institute for Experimental Medical Research at University of Oslo, Dr Maria Vistnes, said: “The findings in this pilot study in the ZSF1 model of HFpEF are promising data that support the mechanism of action of PPS as an inhibitor of ADAMTS enzymes that cleave the extracellular matrix component versican, which, in turn, drive heart failure development.
“I'm excited that this pilot study also suggests an improvement in cardiac function by PPS in this state-of-the-art model of HFpEF.”
There is an urgent need for commercially available HFpEF treatments, with clinicians reporting overall prevalence of 1.1-5.5% in the general population and a mortality rate of 20-29% annually, climbing to 53-74% mortality over five years.
Heart failure is a clinical syndrome characterised by typical symptoms and signs caused by a structural and/or functional cardiac abnormality that results in reduced cardiac output and/or elevated intracardiac pressures.
Heart failure is classified based on the pumping function of the heart as determined by the ejection fraction (EF) by echocardiography. The two subpopulations are heart failure with reduced EF (HFrEF) and heart failure with preserved EF (HFpEF).
Both HFrEF and HFpEF have different disease mechanisms, co-morbidities and response to treatment.
While HFrEF is induced by direct and single myocardial insults like infarction or cardiomyopathy, HFpEF develops in response to a combination of risk factors like diabetes, hypertension and obesity.
Due to the increase in prevalence and limited options for therapy, there is a pressing need for novel and improved treatment strategies for HFpEF patients.
Despite several therapies having been found to improve patient morbidity and mortality with HFrEF, there are no therapeutics commercially available for the treatment of HFpEF.
“Cutting edge data”
“Heart failure with preserved ejection fraction is an unmet medical need requiring urgent therapeutic attention,” Paradigm chief science officer Dr Ravi Krishnan said.
“We are very pleased that the pilot study conducted in the laboratory of Dr Maria Vistnes has provided cutting edge data to further clarify the mechanism of action of PPS in HFpEF.
“The next steps for Paradigm are: firstly, to confirm these findings in a larger preclinical study, and, secondly, map out potential target patient populations for a pilot clinical trial.”
Diastolic heart function was improved in PPS-treated ZSF1 rats compared to those that received the control vehicle. This was assessed by echocardiography by measuring the diastolic tissue velocity (e’) alone and in a ratio with blood flow into the left ventricle (E/e’).
These parameters reflect changes in the extracellular matrix of the myocardium and are the most commonly used functional parameters to assess cardiac function in HFpEF patients.
The myocardial tissue content of versican, which is degraded to cleavage fragments produced by ADAMTS enzymes, were reduced in PPS-treated rats, suggesting a beneficial effect of PPS on the myocardium.
This observation is in line with previous studies which demonstrated a reduction in versican fragments upon PPS treatment in a model representing HFrEF.
These promising results with PPS require further confirmation in a larger study in the ZSF1 animal model which evaluates additional biomarkers of inflammation associated with HFpEF.
PAR shares have been as much as 4.8% higher to $1.98 while the market cap is approximately A$442.67 million.
About Paradigm Biopharmaceuticals
Paradigm Biopharmaceuticals is a drug repurposing company driven by core competencies and experience at board and executive level in clinical and commercial pharmaceutical development.
The company’s approach is to take an existing approved drug, which has demonstrated safety in its approved indications, and repurposing the drug in a new patented therapeutic application.