Sarcoidosis is an inflammatory disease characterized by the formation of granulomas, clumps of inflammatory cells, in one or more organs in the body. Sarcoidosis affects people of all ages, but typically presents before the age of 50 years, with the incidence peaking at 20 to 39 years. The disorder usually begins in the lungs, skin or lymph nodes, but can affect almost any organ. Sarcoidosis in the lungs is called pulmonary sarcoidosis and 90% or more of patients with sarcoidosis have lung involvement. Pulmonary sarcoidosis is a major form of interstitial lung disease (ILD) a group of immune-mediated disorders which cause progressive fibrosis of the lung interstitium. Estimates of prevalence vary, however, current data indicate that approximately 200,000 Americans live with pulmonary sarcoidosis. The prognosis for patients with pulmonary sarcoidosis ranges from benign and self-limiting to chronic, debilitating disease and death.
The pathogenesis of sarcoidosis is not yet well understood. A leading hypothesis is that granuloma formation involves the interplay between antigen, human leukocyte antigen (HLA) class II molecules, and T-cell receptors: a presumptive sarcoid antigen is engulfed by circulating antigen-presenting cells (APCs: macrophages, dendritic cells) and the subsequent interplay between APCs and CD4+ T-cells initiates granuloma formation. T lymphocyte activation subsequently plays a crucial role in sarcoidosis pathogenesis.
For patients with pulmonary sarcoidosis, the primary goal of treatment is typically to improve the patient’s quality of life. Treatment involves managing the inflammation associated with granuloma formation and preventing the development of more permanent fibrosis and impairment of lung function. Efzofitimod (ATYR1923) may provide a therapeutic benefit in pulmonary sarcoidosis by providing an immunomodulatory function to help resolve inflammation. Moreover, the mechanism of action of efzofitimod in T-cells and macrophages potentially overlaps with the cellular pathology observed in pulmonary sarcoidosis. In preclinical studies, efzofitimod has been observed to attenuate T-cell activation and inhibit cytokines and chemokines involved in regulation of inflammatory responses, while also modulating macrophage endosome maturation. We have discovered that NRP2 is up-regulated during activation of myeloid cells including macrophages, dendritic cells and neutrophils, and that efzofitimod can bind to NRP2 on these cell types. We have also shown that the active portion of efzofitimod has the ability to disrupt sarcoid granuloma formation in vitro. Furthermore, efzofitimod has been observed to significantly reduce inflammation-dependent pulmonary fibrosis and improve respiratory function in animal models of ILD. Accordingly, these data suggest that by inhibiting the inflammatory portion of the fibrotic cascade, efzofitimod could prove a safer, potentially more effective alternative to oral corticosteroids and other immunosuppressive therapies currently used to treat patients with pulmonary sarcoidosis.
We recently reported positive results from a Phase 1b/2a clinical trial evaluating efzofitimod in patients with pulmonary sarcoidosis. Click here to learn more. Based on these findings, we are evaluating efzofitimod in patients with pulmonary sarcoidosis in a global Phase 3 study known as EFZO-FIT™. To learn more about this study, please visit www.efzofit.com.