Sunday, May 11, 2025
5/11/2025
2-HOBA Phase 2 Clinical Trial in Rheumatoid Arthritis - Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease affecting 1% of the population. Aggressive treatment is a fundamental therapeutic strategy to improve disease-related outcomes and cardiovascular disease, which contributes to excess mortality in RA. Thus, therapeutics targeting novel pathways that treat RA and reduce cardiovascular risk are needed. A potential target is blocking the proinflammatory, immunogenic, and proatherogenic consequences of isolevuglandins (isoLGs). IsoLGs are highly reactive dicarbonyl products of oxidative stress that bind covalently to proteins causing conformational changes rendering them immunogenic and proinflammatory. Two decades of work at Vanderbilt led to the identification of 2-hydroxybenzylamine (2-HOBA) as a highly effective scavenger of reactive dicarbonyls such as isoLGs. Scavenging reactive dicarbonyls is preferable to using antioxidants because reactive oxygen species are necessary for normal cellular function. In animal models of autoimmunity, hypertension, and atherosclerosis 2-HOBA reduced inflammation, autoantibodies, blood pressure, and atherosclerosis, and in human phase 1 clinical studies in healthy volunteers 2-HOBA was well tolerated. We propose a phase 2 study to determine 2-HOBA’s tolerability, safety, and effect on isoLG- adducts, inflammation and blood pressure in RA patients. Twenty-eight subjects will be randomized to 750mg 2-HOBA or matching placebo three times a day for 12 weeks (14 per group). A visit at week 16 will assess for persisting effects after a 4-week washout. Aim 1 will compare tolerability and adverse events in active and placebo arms. Aim 2 will compare changes in cellular and plasma isoLG-adducts, markers of inflammation, DAS28 score, and 24-hour blood pressure in active and placebo arms. This pilot study will inform the feasibility and design of future studies to examine the efficacy of 2-HOBA in RA patients.
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