Paradigm Biopharmaceuticals

One translational preclinical study, published in Frontiers in Immunology in February 2023. No clinical trial has followed it.

ARDS: proof of concept in mice

The Paradigm-sponsored Phase 2a trial in Lund closed in 2017 and did not meet its primary clinical endpoints.

AR: Phase 2a complete

No respiratory trial is open or planned. Paradigm is considering the potential of second-generation PPS molecules in allergic rhinitis.

Nothing currently guided

Close-up of a laboratory microscope's objective turret, three lenses angled over a slide on the illuminated stage, against a plain teal background. No people are in frame.

A posteroanterior chest radiograph showing both lungs and the surrounding rib cage.

A wide, brightly lit research laboratory with racks of glassware along the benches and a single researcher working at the bench, seen from behind.

Pollen-bearing tree catkins hanging from a bare branch in shallow focus.

Stylised three-dimensional render of a pair of human lungs and the bronchial airways, lit in violet and magenta.

Respiratory

Sign up to get the latest news, announcements and updates from Paradigm delivered straight to your inbox, and be the first to hear as our research advances.

Corporate Governance

Analyst Reports

Market Data

Webinars

Announcements

News & Videos

Our Board

Executive Team

Peer-Reviewed Publications

Cardiovascular

Lysosomal Storage Diseases

Inflammatory Arthritis

Osteoarthritis

About us

Contact

Home

Clinical Trials

Pipeline

Archivo

Respiratory diseases affect the lungs and airways, making it harder for people to breathe and maintain normal daily activity. These conditions can range from chronic inflammatory diseases to severe and progressive lung disorders, many of which place a major burden on patients, families and healthcare systems. Exploring new treatment options in respiratory disease is important because improved therapies may help reduce symptoms, prevent disease progression and support better long-term quality of life.

Paradigm’s respiratory work covers two separate indications at two very different stages, and this page keeps them apart. Acute respiratory distress syndrome (ARDS) is preclinical only

 It has been studied in the laboratory, in a mouse model of influenza A infection. There is no ARDS clinical trial and no human data. Allergic rhinitis (AR) reached human testing. A Phase 1 study of an intranasal PPS spray was followed by a Paradigm-sponsored Phase 2a trial in Sweden, which did not meet its primary clinical endpoints. On this page, “AR” always means allergic rhinitis.

Both indications remain exploratory. Paradigm’s immediate commercial focus is osteoarthritis.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition in which fluid collects in the alveoli (air sacs of the lungs), depriving organs of oxygen. 1

Patients with ARDS have severe, debilitating shortness of breath and often require ventilation. ARDS usually occurs in those who are critically ill or who have significant injuries. 1,2

The mainstay interventions are supportive lung protective ventilation and prone positioning. The mortality rate for ARDS is 30-40%, and few effective therapeutic modalities exist to ameliorate this life-threatening condition. 2,3

Following the onset of ARDS the ensuing acute inflammation and tissue injury result in structural changes in the lungs, this is called adverse tissue remodelling. As ARDS progresses, adverse tissue remodelling obstructs efficient lung function resulting in hypoxia which requires frequent oxygen ventilation to normalise blood oxygen levels. 2,4

ARDS survivors may experience post-traumatic stress disorder, post-intensive care syndrome, long-term physical disability, neuromuscular weakness and persistent pulmonary dysfunction. 2,5

In 2016, ARDS occurrence was estimated to be 10.4% in all ICU admissions and accounted for 23.4% of mechanically ventilated patients globally. 6

Paradigm’s rationale for the use of pentosan polysulfate sodium to target ARDS is based on its multiple mechanisms of action outlined in preclinical studies. The mechanisms of action of PPS that are relevant to modulating the pathophysiology of ARDS include:

Targeting the cytokine storm response via anti-inflammatory effects mediated by the inhibition of NF-κB 7

Inhibition of complement activation, which is involved in lung tissue degeneration 8

Inhibition of ADAMTS-4 activity, which is likely to be involved in adverse tissue remodelling 9-11

These mechanisms are drawn from preclinical laboratory work. None of them has been tested in people with ARDS.

A translational preclinical study evaluating pentosan polysulfate sodium (PPS) in an influenza A-induced mouse model of acute respiratory distress syndrome (ARDS) has been successfully completed in collaboration with the Menzies Health Institute at Griffith University. The peer-reviewed study demonstrated significant anti-inflammatory and anti-fibrotic effects, including reductions in inflammatory cytokines and pulmonary fibrosis biomarkers, together with improvements in oxygen saturation and clinical disease measures. These findings provide proof-of-concept supporting the potential evaluation of PPS for acute respiratory inflammatory diseases, including virus-induced ARDS and pulmonary fibrosis.

The model used immunocompetent C57BL/6J mice infected intranasally with a sublethal dose of influenza A virus (strain A/Puerto Rico/8/1934).

In those mice, the published results were reduced weight loss and improved oxygen saturation during acute infection; preservation of lung-resident alveolar macrophages despite viral persistence; systemic reductions in the inflammatory cytokines IL-6, IFN-γ, TNF-α, IL-12p70 and CCL2, reported without accompanying local lung tissue changes; and post-acute decreases in the fibrotic biomarkers sICAM-1 and C5b9.

This is the whole of the ARDS evidence base. There is no ARDS clinical trial, no registry entry and no human data.

Publication: Krishnan R, Stapledon CJM, Mostafavi H, Freitas JR, Liu X, Mahalingam S, Zaid A. Anti-inflammatory actions of Pentosan polysulfate sodium in a mouse model of influenza virus A/PR8/34-induced pulmonary inflammation. 

 2023;14:1030879. Published 9 February 2023. doi:10.3389/fimmu.2023.1030879

Allergic rhinitis (AR) (commonly referred to as Hay Fever) is a seasonal allergic respiratory condition largely driven by inflammation mediated by allergens. The most common allergens are pollens, dust mites, moulds, and insects, which when inhaled result in sneezing, itching, airflow obstruction (wheezing), and rhinorrhoea (a runny nose). 1,2

AR often co-exists with other conditions such as asthma, sinusitis, nasal polyposis, upper respiratory tract infections, middle ear infections, sleep disorders, and impaired learning and attention in children. 1

AR therapy is based on allergen avoidance, and the administration of anti-allergic and anti-inflammatory drugs (e.g., antihistamines, corticosteroids). Allergen-specific immunotherapy for induction of tolerance is a potential treatment option, however availability of this treatment may be limited. Patient dissatisfaction has been identified in AR surveys indicating the need for new treatment options. 3

Paradigm has investigated pentosan polysulfate sodium (PPS) as a potential treatment for allergic rhinitis, based on its anti-inflammatory properties and ability to inhibit TH2 (T helper 2) cytokines, which play an important role in the development of allergic responses.

Preclinical studies conducted at Lund University, Sweden demonstrated that intranasally administered PPS inhibited allergic rhinitis in a validated guinea pig model. These findings supported the development of an intranasal PPS formulation, followed by a Phase 1 study in which no serious adverse events were reported and a Phase 2a randomised, double-blind, placebo-controlled crossover allergen challenge study involving 80 participants.

In May 2017, Paradigm reported that the Phase 2a study did not meet its primary clinical endpoints.

While there is currently no allergic rhinitis clinical trial open or planned, the underlying anti-inflammatory activity of PPS remains of scientific interest. Paradigm may consider future opportunities to investigate second-generation PPS molecules, alternative formulations or different routes of administration to determine whether the therapeutic potential of PPS can be further explored in allergic rhinitis.

Paradigm’s immediate commercial focus is the development of injectable PPS (iPPS, brand name Zilosul®) for the treatment of osteoarthritis (OA). This is a global unmet need and Paradigm has advanced to phase 3 trials in the space. Addressing all aspects of the disease: inflammation, pain and cartilage regeneration, PPS has genuine disease modifying potential.

Other indications under investigation for PPS include the treatment of joint function, mobility, and pain in patients with mucopolysaccharidoses (MPS); treating alphavirus-induced arthralgia (such as Ross River virus and Chikungunya); chronic heart failure (HF); acute respiratory distress syndrome (ARDS); and allergic respiratory conditions, including allergic rhinitis (AR).

Paradigm continues to progress the development of Zilosul® with the IND (Investigational New Drug) cleared by the US FDA in October 2021.

Latest announcements