Paradigm Biopharmaceuticals

Paradigm’s cardiovascular research has focused on pathways associated with inflammation, extracellular matrix degradation and adverse cardiac remodelling. Preclinical research has identified enzymes including ADAMTS-4 as potential contributors to pathological remodelling in heart failure.

Scientific rationale

IIn a rat model of pressure overload induced by aortic banding, pentosan polysulfate sodium reduced myocardial ADAMTS-4 expression and was associated with improvements in cardiac function. These findings were published in PLOS ONE in March 2014.

Preclinical evidence

Additional preclinical work, including studies in the ZSF-1 obese rat model, has examined diastolic cardiac function and myocardial tissue architecture. The cardiovascular program remains preclinical, and the relevance of these findings to patients with heart failure has not yet been established. Paradigm is not currently guiding further cardiovascular development.

Current stage of development

An electrocardiogram trace running across a dark patient-monitor display. No people are in frame.

Stylised three-dimensional render of a human heart in violet and magenta, with an electrocardiogram trace across it.

Three-dimensional render of red blood cells flowing through the lumen of a blood vessel, the vessel wall in deep red around them. No people are in frame.

A bright research laboratory bench lined with glass reagent bottles, graduated pipettes and a red rack of small vials, with a single researcher in a white coat working at the bench, back to the camera.

Close-up of a microscope objective turret positioned above a prepared glass slide on the stage, against a teal background. No people are in frame.

Cardiovascular

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Cardiovascular diseases affect the heart and blood vessels and remain one of the leading causes of illness and death worldwide. These conditions can reduce the body’s ability to circulate blood effectively, increasing the risk of serious complications such as heart attack, stroke and heart failure. Continued innovation in cardiovascular disease is essential to address the ongoing need for therapies that can improve outcomes, reduce risk and support healthier lives.

Heart failure (HF) is a major emerging public health problem associated with increasing prevalence in the ageing population, the high morbidity and mortality rates, and the challenges involved with patient management and healthcare costs (1).

The number of patients with heart failure worldwide increased from 33.5 million in 1990 to 64.3 million in 2017 and this number is projected to increase in the next decade (2). Common risk factors that predispose individuals to heart failure include age (>65 years), coronary artery disease, a history of myocardial infarction, hypertension, obesity, smoking and diabetes.

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 (3). There are two distinct subpopulations of HF classified based on the pumping function measured by echocardiography called HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), respectively. HFrEF and HFpEF are distinguished further by different disease mechanisms, co-morbidities and responses to treatment (3,4). The prevalence estimates for HFpEF lies in the range from 1 to 3 %, and is anticipated to increase (5,6). HFpEF is associated with high mortality rates of 20-29 % annually, and 53-74 % in a 5-year period (5,7). Due to the increase in prevalence and limited options for therapy, there is an urgent need for novel and improved treatment strategies for HFpEF patients.

Inflammation, tissue damage and/or adverse tissue remodeling are the biological processes that lead to the development of chronic heart failure (8). In HF, extracellular matrix degrading enzymes present in myocardial tissues such as ADAMTS-4 cause adverse tissue remodelling; as well as inflammation and vascular endothelial cell activation which affect cardiac function. (9,10)

Pentosan Polysulfate Sodium (PPS) has been investigated as a therapeutic agent targeting tissue remodelling in HFrEF in preclinical animal models (aortic banding and myocardial infarction animal models). In these models, PPS was shown to target ADAMTS-4, a key enzyme that degrades the extracellular matrix (ECM) component called versican, in myocardial tissue (9). Additionally, PPS therapy may complement standard of care (SOC) treatments in both HFpEF and HFrEF patients due to its anti-inflammatory actions resulting in improved vascular perfusion. There is currently an unmet medical need for the treatment of adverse cardiac remodelling for HF.

In summary, the mechanisms of action of PPS that are potentially relevant to the treatment of heart failure include:

Reduction in the synthesis of ADAMTS-4 mRNA and protein. (9)

Inhibition of adverse cardiac tissue remodeling evidenced by reduction in versican degradation. (9)

Reduction in pro-inflammatory cytokines and inhibition of transcription factor activity: e.g. NF-κB (15)

Paradigm has successfully completed a translational preclinical study in the industry-standard ZSF-1 obese rat model of heart failure with preserved ejection fraction (HFpEF). Conducted in collaboration with the Center for Heart Failure Research and the Institute for Experimental Medical Research at the University of Oslo, the study demonstrated improved diastolic cardiac function and preservation of myocardial tissue architecture through modulation of extracellular matrix remodelling. These findings provide compelling proof-of-concept supporting the continued evaluation of PPS as a potential treatment for HFpEF.

The mechanistic rationale for PPS in heart failure rests on one peer-reviewed publication, in rats:

Vistnes M, Aronsen JM, Lunde IG, Sjaastad I, Carlson CR, Christensen G. 

Pentosan polysulfate decreases myocardial expression of the extracellular matrix enzyme ADAMTS4 and improves cardiac function in vivo in rats subjected to pressure overload by aortic banding.

 PLOS ONE 2014;9(3):e89621. Published 3 March 2014. 

The translational study in the ZSF-1 obese rat model of HFpEF, run with the Center for Heart Failure Research and the Institute for Experimental Medical Research at the University of Oslo, has not been published. Paradigm’s full list of peer-reviewed publications across every indication is on this hub.

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