Apaxen’s lead compound, MFC-1040, is a novel, first-in-class, orally bioavailable and highly potent small molecule inhibitor NLRP3 Inflammasome activation by neutralizing MIF (macrophage migration inhibitory factor), a protein that interacts with vimentin and NLRP3 and which is required for the oligomerization of NLRP3 into active NLRP3 Inflammasomes.

MFC-1040 is being developed for the treatment of pulmonary arterial hypertension (PAH) and shown robust in vivo efficacy in multiple rodent models of the disease (J. Med. Chem. 2018, 61, 2725-2736), namely monocrotaline (MCT), Sugen/chronic hypoxia (SuHx) and Bleomycine (BLM), both as monotherapy and/or as a combination with other PAH commercialized drugs. These in vivo preclinical models of pulmonary hypertension cover a large spectrum of the human PAH in terms of etiology and etiopathogeny. MFC-1040 has also shown efficacy in an animal model of idiopathic pulmonary fibrosis (Int. J. Mol. Sci. 2018, 19, 4105).

The mechanism of action of MFC-1040 combines potent anti-inflammatory, anti-fibrotic and anti-proliferative effects. It has the potential to revolutionize the standard of care of PAH, by halting or reverting the progression of the disease while available therapies only address the symptoms of this disease.

Pre-clinical development for MFC-1040 is currently in progress. Apaxen expects to start first-in-human (FIH) clinical trials for MFC-1040 at end of 2022. 

MFC-1040 in vivo efficacy in pulmonary hypertension

MFC-1040 has shown to reverse pulmonary hypertension by improving hemodynamic, structural, histological and inflammatory endpoints (J. Med. Chem. 2018, 61, 2725-2736). MFC-1040 treatment in rodent performed in a curative approach leads to:

  • Decrease in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), and increase in cardiac output (CO)
  • Decrease in right ventricular hypertrophy (RVH)
  • Reduction in pulmonary arterial wall thickness and right ventricular fibrosis (RVF) 
  • Decrease in circulating levels of key inflammatory biomarkers and cytokines which are known to contribute to PAH
  • Protection of small arteries of the lung

MFC-1040 in vivo efficacy in pulmonary fibrosis

MFC-1040 has shown efficacy against pulmonary fibrosis in the well-established prophylactic bleomycin (BLM) mouse model of IPF (Int. J. Mol. Sci. 2018, 19, 4105). 

MFC-1040 was shown to: 

  • Decrease collagen content in lungs of mice 
  • Normalize level of macrophage infiltration in the lungs of mice as well as serum level of inflammatory markers
  • Improve pulmonary hypertension secondary to pulmonary fibrosis