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Paradigm Biopharmaceuticals Limited (ASX:PAR) is an ASX-listed late-stage drug development company focused on delivering new therapies to address unmet medical needs. Paradigm is currently developing pentosan polysulfate sodium (PPS), an FDA-approved drug that has a long track record of safely treating inflammation over 60 years. Paradigm’s primary focus is to develop PPS (under the name Zilosul®) to treat osteoarthritis (OA), with an addressable population of over 72m in key markets (US, EU5, AU, CAN).
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Last updated 28/10/22 3:45pm
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Biological
Process
Chronic
Disease
Key Pathological Mechanism
Therapeutic
Action
Reference
Last Update
Chronic Disease
Osteoarthritis
Key Pathological Mechanism
Increased expression of NGF mRNA and protein in osteocytes in the subchondral bone of osteoarthritic joints.
Therapeutic Action
Reduction of NGF mRNA and protein expression by osteocytes derived from the subchondral bone of osteoarthritic joints.
Reference
Human osteocyte expression of Nerve Growth Factor: The effect of Pentosan Polysulfate Sodium (PPS) and implications for pain associated with knee osteoarthritis. Stapledon CJM, Tsangari H, Solomon LB, Campbell DG, Hurtado P, Krishnan R, Atkins GJ. PLoS One. 2019 Sep 26;14(9):e0222602. doi: 10.1371/journal.pone.0222602. eCollection 2019
Last Update
26 Apr, 2022
Chronic Disease
Mucopolysaccharidosis
Key Pathological Mechanism
Pain is a common feature amongst all MPS subtypes related to congenital dismorphosis (bone malalignment).
Therapeutic Action
PPS reduced pain intensity scores in patients with MPS I.
Reference
Treatment with pentosan polysulphate in patients with MPS I: results from an open label, randomized, monocentric phase II study
Julia B. Hennermann, Seyfullah Gökce, Alexander Solyom, Eugen Mengel, Edward H. Schuchman, Calogera M. Simonaro
J Inherit Metab Dis, 39: 831-837. https://doi.org/10.1007/s10545-016-9974-5
Last Update
26 Apr, 2022
Chronic Disease
Osteoarthritis
Heart Failure
Key Pathological Mechanism
Over-expression of the inflammatory cytokines IL-1 beta and TNF-alpha instigate tissue damaging cellular immune responses within heart tissue and cartilage.
These cytokines are common to inflammation in OA and Heart Failure.
Therapeutic Action
PPS Blocks translocation of transcription factor NF-kB from the cytoplasm to the nucleus mediated by IL-1 or TNF-alpha.
Reduced NF-kB transcription results in down-regulation of IL-1 and TNF synthesis, leading to reduction in inflammation in cartilage and heart tissues.
Reference
Inhibitory effects of pentosan polysulfate sodium on MAP-kinase pathway and NF-κB nuclear translocation in canine chondrocytes in vitro. Sunaga T, Oh N, Hosoya K, Takagi S, Okumura M.
J Vet Med Sci. 2012 Jun;74(6):707-11. Epub 2011 Dec 28.
Last Update
26 Apr, 2022
Chronic Disease
Allergic Rhinitis
Asthma
Key Pathological Mechanism
High expression of inflammatory TH2 cytokines IL-4, IL-5, IL-13 causes infiltration of immune cells into the nasal mucosa and lungs.
In AR, damage to the nasal barrier causes chronic sensitivity to the allergen.
Therapeutic Action
Antagonist effect of PPS mediated by binding of PPS to pro-inflammatory ligands of TH2 cytokines, resulting in inhibition of TH2 cytokine mediated inflammation in allergic disease.
Reference
Broad Th2 neutralization and anti-inflammatory action of pentosan polysulfate sodium in experimental allergic rhinitis.
Sanden C, Mori M, Jogdand P, Jönsson J, Krishnan R, Wang X, Erjefält JS.
Immun Inflamm Dis. 2017 Sep;5(3):300-309. doi: 10.1002/iid3.164. Epub 2017 May 12.
Last Update
26 Apr, 2022
Chronic Disease
Mucopolysaccharidosis
Key Pathological Mechanism
Glycosaminoglycan (GAG) accumulation in MPS initiates chronic inflammation that results in proliferation (e.g., of synoviocytes) and apoptosis (e.g., of chondrocytes) of connective tissue cells, and further exacerbates the disease pathology.
GAGs signal through the toll-like receptor (TLR) leading to the activation of NF-kB and pro-inflammatory molecules.
Therapeutic Action
PPS clears cellular and tissue accumulation of GAGs.
PPS treatment reduces the activation of NF-kB mediated via TLR signalling thus reducing expression of pro-inflammatory cytokines such as IL-8 and TNF-α.
Reference
Pentosan Polysulfate: Oral Versus Subcutaneous Injection in Mucopolysaccharidosis Type I Dogs
Julia B. Hennermann, Seyfullah Gökce, Alexander Solyom, Eugen Mengel, Edward H. Schuchman, Calogera M. Simonaro
PLoS One. 2016;11(4):e0153136. Published 2016 Apr 11. doi:10.1371/journal.pone.0153136
Last Update
26 Apr, 2022
Remodelling
Chronic Disease
Osteoarthritis
Key Pathological Mechanism
Increased levels of aggrecan degrading enzymes such as ADAMTS-4, ADAMTS-5, matrix metalloproteinase 3 (MMP-3).
Degradation of cartilage causes impairment of joint function and potentially bone marrow oedema and bone pain.
Hyaluronic acid (HA) is reduced.
Therapeutic Action
PPS forms a stable complex with the enzyme inhibitor (TIMP-3) for ADAMTS-5, this reduces cartilage degradation.
PPS also inhibits the synthesis of the metalloproteinase, MMP-3 (Troeberg) involved in degrading cartilage.
PPS increases endogenous HA levels, facilitating joint movement (Verbruggen).
Reference
Pentosan polysulfate increases affinity between ADAMTS-5 and TIMP-3 through formation of an electrostatically driven trimolecular complex.
Troeberg L, Mulloy B, Ghosh P, Lee MH, Murphy G, Nagase H.
Biochem J. 2012 Apr 1;443(1):307-15. doi: 10.1042/BJ20112159.
Intra-articular injection of pentosan polysulphate results in increased hyaluronan molecular weight in joint fluid.
Verbruggen G, Veys EM. Clin Exp Rheumatol [Internet]. 1992;10:249–254. https://www.ncbi.nlm.nih.gov/pubmed/1374695.
Last Update
26 Apr, 2022
Remodelling
Chronic Disease
Heart Failure
Key Pathological Mechanism
Increased ADAMTS-4 levels leads to Versican degradation products resulting in adverse tissue remodelling of the heart (increased heart size and poor cardiac function).
Therapeutic Action
Reduction in the synthesis of ADAMTS-4 mRNA.
Reduction in ADAMTS-4 protein.
Inhibition of ADAMTS-4 enzyme activity.
Improved cardiac function.
Reference
Pentosan polysulfate decreases myocardial expression of the extracellular matrix enzyme ADAMTS-4 and improves cardiac function in vivo in rats subjected to pressure overload by aortic banding.
Vistnes M, Aronsen JM, Lunde IG, Sjaastad I, Carlson CR, Christensen G.
PLoS One. 2014 Mar 3;9(3):e89621. doi: 10.1371/journal.pone.0089621. eCollection 2014.
Last Update
26 Apr, 2022
Remodelling
Chronic Disease
Mucopolysaccharidosis
Key Pathological Mechanism
GAGs that are incompletely degraded in MPS, accumulate in many sites, damaging tissues and cells, leading to a variety of clinical manifestations.
Therapeutic Action
PPS reduces urinary and tissue GAG accumulation in animal models of MPS I and MPS VI.
Reference
Pentosan Polysulfate: Oral Versus Subcutaneous Injection in Mucopolysaccharidosis Type I Dogs Julia B. Hennermann, Seyfullah Gökce, Alexander Solyom, Eugen Mengel, Edward H. Schuchman, Calogera M. Simonaro
Treatment with pentosan polysulphate in patients with MPS I: results from an open label, randomized, monocentric phase II study
Julia B. Hennermann, Seyfullah Gökce, Alexander Solyom, Eugen Mengel, Edward H. Schuchman, Calogera M. Simonaro J Inherit Metab Dis, 39: 831-837. https://doi.org/10.1007/s10545-016-9974-5
Last Update
26 Apr, 2022
*Paradigm continues to assess new molecules for repurposing. We welcome approach from organisations and researchers with repurposing candidates for partnering or acquisition.
To view our approach to product development, click here
Development Pipeline
P.O.CÂ – Proof of Concept | REG. – Registration
POC – Proof of Concept | P1 – Phase One |
P2 – Phase Two
P3 – Phase Three | REG – Registration
Clinical Trials
Paradigm Biopharmaceuticals Ltd is currently recruiting for clinical trials.
Please note that Paradigm Biopharmaceuticals Ltd is unable to discuss individuals’ eligibility for clinical trials or any matters relating to your condition.
Contact information for centres conducting clinical trials can be found in the links below.