A fast increasing number of inflammatory and auto-immune diseases are being associated with aberrant activation of the NLRP3 inflammasome.

The initial clinical focus of Apaxen is on those diseases that could clearly benefit from treatment with NLRP3 inflammasome inhibitors, such as Gouty Arthritis and Pulmonary Arterial Hypertension (PAH).

Results from these initial indications paves the way to many other indications and patient subsets.

Gouty Arthritis

Gouty Arthritis, or Gout flares is an extremely painful inflammatory condition of joints,  driven by uptake of mono­ sodium urate crystals by macrophages and consequent activation of NLRP3 inflammasomes. IL­1β has a major role in inflammation induced by monosodium urate crystals. Gout flares are therefor a prototypical NLRP3 inflammasome driven disease in which to demonstrate effective inhibition of this pathway in the clinic.

Other important reasons for Apaxen to choose Gout Flares as a first inflammatory indication to show clinical Proof of Concept are that current treatment for Gout and Gout flares leaves much room for improvement. Traditional urate lowering drugs are often poorly tolerated, non-steroidal anti-inflammatory drugs are often contra-indicated and corticosteroid use is limited by adverse effects. Furthermore, Gout is the most common form of inflammatory arthritis seen in almost 4% of the Western population (>9M patients in the USA alone). 

Beyond Gout there are other crystal deposition driven diseases, known to be linked to NLRP3 inflammasome activation, that could be targeted, such as Chronic Kidney Disease, Atherosclerosis, NASH, Alzheimer’s and Parkinson’s disease.

Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a rare, chronic and life-threatening disease characterized by an abnormal and progressive increase in blood pressure in the small pulmonary arteries leading to hypertrophy of the right ventricle of the heart and ultimately to right heart failure. 

Available therapies are agents that focus on improving the vasoconstriction-vasodilation balance without addressing the underlying inflammatory cause of the disease. As a result, five-year median survival remains relatively low despite treatment.

Over the past 20 years, accumulating non-clinical and clinical evidence indicates that inflammation and immunity may play a determining role in the development of the anatomic changes that occur in the pulmonary vasculature and ultimately in disease progression and fatal outcome (Stacher et al. 2012; Le Hiress et al. 2015; Kuebler, Bonnet, and Tabuchi 2018).

More precisely and recently, the role of the NLRP3 inflammasome in pulmonary hypertension has emerged that supports the long recognized presence and role of specific cytokines, particularly IL-1beta and IL-18, but also enzymes such as caspase-1 in non-clinical models, as well as in patients suffering from PAH (Mariathasan et al. 2006; Martinon et al. 2006).

Apaxen’s novel anti-inflammatory approach promises to become a new, game changing tool for treatment of PAH and related pulmonary diseases. Tested in 2 different rat models of PAH (monocrotaline and sugen/hypoxia), both using preventative and curative treatment design, MFC-1040 induces robust reductions of all clinically relevant hemodynamic parameters including mean pulmonary arterial pressure and pulmonary vascular resistance and restores cardiac output with optimal effects. Consistently, MFC-1040 strongly attenuates right ventricle hypertrophy that correlates with an anti-fibrotic effect of the compound. In the lungs of rats with PAH-related phenotypes, MFC-1040 abolished the lesions seen in lung arterioles  as well as macrophage infiltration and type-2 pneumocytes hyperplasia, plus inflammatory markers related to vessel obstruction.