Successful treatment and management of disease or injury involving inflammation remains a great challenge in modern medicine. There is consensus that this area will not be resolved with single target drugs as there are numerous types of immune and structural cells involved, and the pathways are networked and complex.
Inflammatory disease - lead indications
The effectiveness of the drug, Pentosan Polysulfate Sodium (PPS) in a broad range of therapeutic areas can be explained by its ability to inhibit multiple biological processes that lead to the development of chronic diseases. The biological targets of PPS have been described in several peer-reviewed scientific publications.
Inflammation, tissue damage and/or adverse tissue remodeling are the biological processes that lead to the development of chronic diseases such as osteoarthritis, heart failure and respiratory diseases such as asthma and hay fever. Currently we are focused on target indications in the areas of: Orthopaedics (Bone Marrow Edema Lesions (BML) and Osteoarthritis (OA)); Mucopolysaccharidosis (MPS); Alphaviral arthritis; and Respiratory Disease.
Bone Marrow Edema Lesions (BML) and Osteoarthritis (OA)
Bone Marrow Edema Lesions (BML) are changes that occur in the subchondral bone of patients with OA and a range of other musculoskeletal conditions. BMLs are detected by Magnetic Resonance Imaging (MRI), assessed using fat-suppressed proton density or T2-weighted MRI sequences. These lesions reflect accumulations of blood, fluid, inflammatory cells and proteins, and structural changes in bone and cartilage which contribute significantly to pain and disease progression in OA. It is estimated that subchondral BMLs are present in around 60-70% of osteoarthritis patients.
At present, there are no registered products for the treatment of subchondral BML. Patients who do not respond to current anti-inflammatory therapies are left with limited treatment options and may resort to operative management with Total Knee Arthroplasty (TKA). Paradigm’s, Zilosul (IM or SC administered) provides an effective treatment for an unmet medical need to treat a large population of patients with osteoarthritis.
PPS is a strong therapeutic candidate for osteoarthritis patients given that it:
- has been shown to block the effect of cartilage degrading enzymes,
- has anti-inflammatory effects, targeting multiple cytokines involved in OA, and
- may improve micro-circulation in the subchondral bone.
Paradigm has been involved in assisting doctors who seek to prescribe PPS treatment for patients with OA via the Therapeutic Goods Administration Special Access Scheme (TGA SAS). Paradigm has currently received data from a total of 125 patients treated by their doctors under the TGA SAS. The feedback data to-date demonstrate that patients treated with PPS are responding with an average of 51.5% reduction in pain compared to their pre-treatment pain. The results from these 125 patients provides important Real-World Evidence (RWE) data, which would serve in combination with Randomised Controlled Clinical Trials to support product registration for repurposed pharmaceuticals under the 505(b)(2) regulatory pathway.
In December 2018, Paradigm announced results from its 126-patient Phase 2b, randomised, double-blind, placebo-controlled clinical trial. Having successfully met its primary endpoint, Paradigm is now preparing for pivotal phase 3 studies.
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Acute joint injury and BME
Paradigm is investigating the use of PPS in Anterior Cruciate Ligament (ACL) injury, where acute BMLs are identified on MRI scan in association with the injury. In some cases, the acute BML may self-resolve with time, while others can persist and contribute to pain and a significantly increased risk of progressive joint degeneration, called Post Traumatic Osteoarthritis.
Current treatment for patients with acute knee injury and BMLs involves rest and immobilization of the joint. Clinical improvement is generally expected over a 6 to 18-month period, during which time patients may suffer significantly diminished quality of life. Analgesic and anti-inflammatory drugs, including NSAIDS and corticosteroids, may be used, although they can interfere with the healing process. These current treatment options do not alter the underlying pathology and risks of progression, including a 9-fold likelihood of progression to knee replacement.
Our approach is to use ZILOSUL® to address joint injury at an early stage, where there is a chance of reversal and avoidance of progression to osteoarthritis, which is a known outcome of acute joint injury.
Paradigm announced the successful completion of an open label clinical trial in patients with ACL and BMLs in November 2017. The trial met its primary endpoint of safety and tolerability and its secondary endpoint, demonstrating a statistically significant reduction in bone marrow lesion (BML) volume as measured by MRI. These data suggest that PPS could be a new treatment for acute joint injuries and may limit the progression of early onset osteoarthritis.
Mucopolysaccharidosis (An Orphan Indication)
The mucopolysaccharidoses (MPS) are a family of Orphan Diseases caused by inherited defects in the catabolism of sulfated components of connective tissue known as glycosaminoglycans (GAGs).
Due to enzyme deficiency GAG accumulation in all MPS types has a direct effect on connective tissue formation and function, resulting in skeletal, skin and other connective tissue abnormalities, as well as lesions in other organs such as the central nervous system.
The basic cumulative rate for all types of MPS is around 3.5 in 100 000 live births and generally the
patients present in one of three ways:
- As a dysmorphic syndrome (MPS IH, MPS II, MPS VI) often with early onset middle ear disease, deafness, or upper airways obstruction
- With learning difficulties, behavioural disturbance and dementia and mild somatic abnormalities (MPS III)
- As a severe bone dysplasia (MPS IV)
The current standards of care are not adequate in treating pain associated with joint inflammation and musculoskeletal issues and these drugs currently equate to a market size of around US$1.4b per annum.
In November 2018, Paradigm in-licensed the MPS indication from the Icahn School of Medicine at Mount Sinai, New York. The License includes successful Phase 2a safety and efficacy data. The preliminary open label study demonstrated that PPS treatment was well tolerated (safe) and resulted in a significant reduction of urinary GAG excretion and in an improvement of joint function, mobility and pain.
In addition, there is strong evidence that iPPS could be a very good adjunct (similar to combination) therapy for existing Enzyme Replacement Therapy (ERT) treatments, enhancing the attractiveness of this program to large pharma companies currently serving the MPS market with ERT treatments.
Paradigm has established a scientific advisory committee and is currently preparing for a Phase 2/3 pivotal randomised placebo-controlled double blinded clinical trial in subjects with MPS I, MPS II and MPS VI in clinical trial sites in US, Europe and Australia.
Ross River virus and Chikungunya
Ross River Virus (RRV) and Chikungunya (CHIKV) are closely related arthritogenic alphaviruses transmitted by mosquito bites. Alphavirus infection typically results in acute symptoms of fever, malaise and pain in the joints and muscles. While RRV outbreaks are mostly restricted to Australia, CHIKV causes large scale epidemics of severe musculoskeletal disease in many countries.
Currently, analgesic and non-steroidal anti-inflammatory drugs are often ineffective in the management of arthralgia, and many patients are left incapacitated with symptoms which may persist for many months or years.
Clinical development of PPS as a therapy for joint symptoms of RRV and CHIKV follows compelling preclinical evidence in alphavirus models. PPS treatment was shown to significantly alleviate severity of disease, with significant reduction in the inflammatory response (quantified by cytokine profiles) and loss of articular cartilage.
The potential for therapeutic translation into the human form of disease is supported by observed clinical benefits in RRV patients with debilitating arthralgia who were treated with PPS on a compassionate basis via the Therapeutic Goods and Administration (TGA) – Special Access Scheme.
In August 2018 Paradigm finalised recruitment of its Phase 2a randomised, double-blinded placebo-controlled pilot clinical trial in participants with persistent Ross River virus (RRV) induced arthralgia (painful joints) treated with injectable pentosan polysulfate sodium (iPPS).
The RRV pilot study is aimed at providing the clinical evidence for the design of a larger clinical trial in Chikungunya Virus (CHIKV) induced arthralgia which affects a larger population globally.
Clinical development of PPS as a therapy for joint symptoms of RRV and CHIKV follows compelling preclinical evidence in alphavirus models
Paradigm acquired intellectual property from Glycan Biosciences LLC which protects use of PPS, delivered by inhalation, to treat AR, asthma and COPD. PPS’s activity in a guinea pig model indicated that this drug has activity in stabilising mast cells (early affects) while also modulating the cytokine and chemokine disfunction that occurs in long term inflammation in these respiratory diseases.
Allergic rhinitis is a significant and increasing global health problem affecting up to 30% of some populations. Symptoms include nasal congestion, rhinorrhoea, sneezing and itching. Exposure to an allergen leads to a short-term response (within 30 minutes), followed by a late phase (6-8 hr) response which can persist. The short-term response involves histamine release by activated mast cells which trigger acute inflammatory effects. The late phase response results from invasion of inflammatory cells.
Two common therapies for treating AR include (fast acting) antihistamines and (long acting) intranasal corticosteroids. Paradigm’s pre-clinical results to date indicate PPS has dual action in treating AR i.e. both short- and long-term anti-inflammatory effects are observed.
Scientific basis supporting PPS as a treatment for Allergic Rhinitis
- PPS is a potent Th2 cytokine-binding molecule targeting the cytokines IL-4, IL-5 and IL-13 with biological neutralization capacity and broad anti-inflammatory effects (Sanden et al, Immunity, Inflammation and Disease; 2017 DOI: 10.1002/iid3.164)
- After OVA challenge in Guinea pig model of Allergic Rhinitis, total leukocyte, eosinophil and neutrophil numbers in the nasal lavage fluid were equally inhibited by PPS and budesonide (Astra Zeneca Rhinocort)
- PPS significantly reduces allergen-induced plasma extravasation and influx of leukocytes into the nasal cavity
PPS has a powerful dose dependent inhibitory effect on mast cell release of histamine which is more potent than di-sodium cromoglycate (cromolyn) (Chiang et al, J Urol. 2000 Dec;164(6):2119-25)
- PPS is potentially a first-in-class, non-steroidal intranasal spray to treat the acute and chronic phases of allergic rhinitis
Paradigm announced in June 2017 that its Phase 2a allergic rhinitis (hay fever) clinical trial did not meet its primary endpoints (total nasal symptom score and peak nasal respiratory flow) using the current nasal formulation. Paradigm is currently investigating new formulations that will allow improved penetration of PPS into the nasal mucosa retention of the agent without wash-out effects.