inflammatory
disease


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 classes of immune system cells involved, and the pathways are networked and complex.


inflammatory
disease


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 classes of immune system cells involved, and the pathways are networked and complex.

Recent approaches involve combining drugs with a different mode of action. The combination of corticosteroids with Long Acting Beta-adrenoceptor Agonists (LABA) or Long Acting Muscarinic Antagonists (LAMA) for asthma treatment is a case in point. Also monoclonal antibodies such as dupilumab, that target two cytokines, are under investigation. Our approach is different and is based on the finding that negatively charged sugar molecules (GAG-mimetics) interact with a spectrum of key inflammatory molecules, modulating their activity. This does not involve complete blockage of activity, but instead we are interested in partial blockage of several key inflammatory factors, resulting in effective immune modulation without immune suppression.


Orthopaedic

BONE MARROW EDEMA (BME) and OSTEOARTHRITIS


PPS is well established in the treatment of inflammatory joint disease in dogs and horses.  More recently, reports of pilot clinical trials in human osteoarthritis patients highlight the significant potential for PPS for treating this common and debilitating disease.  Paradigm is now pursuing an advanced clinical development program for ZILOSUL® for the treatment of osteoarthritis.

Our development program will include a particular focus on patients with subchondral Bone Marrow Edema Lesions (BMLs) visible on MRI scan.   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.  It is estimated that subchondral BMLs are present in around 60-70% of osteoarthritis patients.

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 recently been involved to assist physicians with the treatment of patients in specially approved circumstances, with remarkable outcomes reported. One such case was recently published in a peer reviewed journal.

Our phase 2 clinical trial in patients with Knee OA and BMLs has commenced in October 2017.


ACUTE JOINT INJURY AND BME



Paradigm is investigating the use of PPS in Anterior Cruciate Ligament (ACL) injury, where BMEs are identified on MRI scan in association with the injury.  In some cases, the acute BME lesions 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 BMEs involves rest and immobilization of the joint. Clinical improvement is generally expected over a 6 -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 commenced an open label clinical trial in patients with ACL and BMEs in 2015.

Alphavirus

Ross River virus and Chikungunya

Ross River Virus (RRV) and Chikungunya (CHIKV) are arthritogenic alphaviruses transmitted by mosquito bites.  Alphavirus infection typically results in acute clinical symptoms of fever and inflammation 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.

Paradigm commenced a phase 2 study in RRV patients in August 2017.

 

RESPIRATORY


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

Allergic rhinitis is a significant and increasing global health problem affecting up to 30% of some populations. Symptoms include nasal congestion, rhinorrhea, 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 ie both short and long term anti-inflammatory effects are observed. Note that RHINOSUL® is not a steroid-based drug, so adverse long term side effects of corticosteroid use are not an issue. This makes PPS potentially the first drug in this therapeutic area that has dual action and is steroid-free.

A 2005 survey showed that more than 60% of AR patients are dissatisfied with their medication. Very recently a new class of combination drug has been announced for AR: WHO ATC R01AD58. Only a single drug is designated in this class, Dymista, which contains an antihistamine (azelastine hydrochloride) in combination with a corticosteroid (fluticasone propionate).

Due to its double action, RHINOSUL® is a candidate for this new class of AR drugs.

In addition to RHINOSUL® for AR, Paradigm Biopharma is also reviewing PPS to treat other respiratory diseases, including allergic asthma and chronic obstructive pulmonary disease (COPD).

ASTHMA

Asthma is a chronic disease characterized by recurrent attacks of breathlessness and wheezing, which is commonly caused by inhaling allergens. Up to 80% of asthmatics suffer from AR concurrently. Severe attacks can be life threatening. Worldwide 235-300 million people suffer from asthma.

For most asthma patients long term corticosteroid “preventer” inhalation with acute bronchodilator use stabilises the disease, although long term corticosteroid use can be a problem. The worldwide asthma prescription market was $US21.6 billion in 2011, with significant additional medical burden through hospitalisation. 10-20% of asthma patients have asthma that is not well controlled, so there is a need for new treatments.

With it multi-targeted modulation of critical cytokines and chemokines, PPS is a good candidate as a safe, new generation asthma treatment, with animal trials indicating both immediate and long term effects. Paradigm is exploring formulating and delivering PPS for asthma as a follow-on to its AR program.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

The most common diagnosis of COPD is as a result of cigarette smoking, although other pollutants are now recognised causative agents. In the past COPD was thought of as primarily associated with neutrophils and macrophages, in contrast to asthma, which is primarily associated with eosinophils.

This clear distinction is becoming less clearcut and indeed a recent article (Postma DS & Rabe KF (2015) N Engl J med 373: 1241-1249 The Asthma-COPD Overlap Syndrome) describes an overlap syndrome ACOS (Asthma-COPD Overlap Syndrome). Traditionally asthma is seen as corticosteroid responsive, while COPD (more neutrophil related) is not.

PPS has features of its multi-target action which suggest that it may be effective in treating COPD. Since COPD is a major health problem in China, Paradigm is beginning to explore repurposing of PPS for treating COPD.