While there have been significant advances in lupus treatments, there is still an unmet need for safer and more effective therapies. Dr. Niewold and his collaborator Vineet Gupta at UTMB have developed a first-of-its-kind drug called ONT01, a twice-daily pill that targets a protein called integrin subunit alpha M (ITGAM or CD11b), which plays an important role in the immune system. Genetic mutations in ITGAM are linked to an increased risk of developing lupus, making it a key target for treatment. In multiple mouse models, ONT01 significantly reduced the symptoms of lupus and lupus nephritis by blocking important inflammatory signals, including interferon and IL-6, through a molecular pathway called Toll-like receptor signaling. By modulating how the immune system responds, ONT01 could help prevent or reduce lupus flare-ups and kidney damage.

Dr. Niewold will conduct a 12-week phase 1b clinical trial of ONT01 in up to 36 lupus patients who do not have kidney involvement. The trial will primarily assess the drug’s safety and determine the correct dosage. Dr. Niewold will also investigate how ONT01 impacts disease activity and key biomarkers of lupus, including inflammatory molecules called cytokines and autoantibodies. The data gathered from this study will be critical for moving the drug forward into a phase II study.

What this means for people with lupus

ONT01 could offer a targeted way to reduce inflammation in lupus without using broad immunosuppressive therapies. If successful, findings from Dr. Niewold’s study could build the foundation for a phase II trial and offer a safer and more effective option for managing the disease.

We have developed a first-in-class novel small molecule agonist of integrin subunit alpha M (ITGAM or CD11b). This agonist, named Ontegimod, significantly ameliorates lupus and lupus nephritis in murine models, and interrupts key cytokine pathways such as interferon and IL-6 signaling in human and murine cells via modulation of Toll-like receptor signaling (Faridi MH, et al, J Clin Invest. 2017, and Li et al., submitted). We have studied other suppressive receptors and pathways, including immunoglobulin-like transcript 7 (ILT7) and blood dendritic cell antigen 2 (BDCA2). Both of these other targets have been advanced by others to the early stage pipeline for lupus, but our studies indicated a significant disease suppressive effect of ITGAM ligation, both in vitro and in vivo, that allows us to target a completely novel therapeutic pathway in lupus. Herein we propose a phase Ib trial of Ontegimod in non-renal SLE patients. We will assay biomarkers of pathway inhibition and molecular response to the drug, generate safety and dosing data, and perform initial phase I trial assessments of potential clinical impact.