PharmAkea has deep expertise in anti-fibrotic research and is dedicated to the generation of novel therapies for fibrotic diseases that offer the potential for improved efficacy and tolerability in patients either alone or in combination with existing treatments.
Fibrosis is characterized by excessive or abnormal extracellular matrix (ECM) accumulation following injury and leads to organ dysfunction and disease. Pathological tissue fibrosis results from both increased matrix deposition as well as decreased turnover and enhanced stabilization through increased cross-linking. The covalent cross-linking of collagen and elastin results in a more stable, insoluble ECM which is resistant to degradation. This then promotes excess matrix accumulation and limits reversibility of established fibrosis. In addition, cross-linking of collagen and elastin increases the tensile strength or stiffness of the ECM which leads to signaling changes within resident cells in the ECM network and contributes to a pro-fibrotic feed-forward loop. The accumulation of extracellular matrix within a disease tissue, which occurs in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF), systemic sclerosis and liver fibrosis, leads to scarring and destruction of the normal tissue architecture and ultimately to organ failure. Fibrotic diseases affect a large number of patients with devastating effects on their health, and this imposes a severe burden on their families as well as the healthcare system. Treatments are limited and they offer only modest benefits, therefore new drugs are urgently required.
IPF is a chronic, progressive and irreversible lung disease characterized by scarring or fibrosis in the lung interstitium. There are currently only two approved therapies to treat IPF: pirfenidone (Esbriet®) and nintedanib (Ofev®) and both slow down progression of functional impairment. However, there is a significant degree of heterogeneity among IPF patients in response to treatment and the disease continues to advance in an unpredictable and variable nature in all patients, including those on the current therapies. These data suggest that many different biological factors and pathways contribute to the pathogenesis of IPF and highlight the need for additional therapies. In particular, combination therapies that target distinct and multiple molecular/cellular pathways are likely to provide improved benefit over monotherapy.
PharmAkea has developed inhibitors to two pro-fibrotic molecular targets, the secreted enzymes autotaxin (ATX) and lysyl oxidase-like 2 (LOXL2). ATX inhibition is expected to affect multiple cellular pathways that drive fibrogenesis, including epithelial cell death, vascular leakage, fibroblast migration and myofibroblast activation and survival. The LOXL2 enzyme functions in a completely different manner by promoting matrix cross-linking which directly affects extracellular matrix remodeling and indirectly activates resident fibroblasts to become myofibroblasts. Both enzymes promote the deposition and accumulation of collagen that leads to scarring and destruction of the normal tissue architecture.