BackgroundPeriodontal disease is among the sixth most common inflammatory diseases worldwide with high risk to promote complications from other inflammatory diseases including diabetes, cardiovascular disease and Alzheimer’s Disease. Failure of active resolution of inflammation pathways is implicated in pathogenesis of periodontal diseases, including gingivitis. Lipoxin A4 (LXA4), a member of the specialized pro-resolving lipid mediators (SPMs) that drive resolution of inflammation via GPC-receptor mediated pathways, offered therapeutic advantages in preclinical models of periodontitis.MethodsWe conducted a randomized, placebo-controlled, parallel-group Phase 1 clinical trial to determine the safety and preliminary efficacy of an LXA4 analog in patients with gingival inflammation. One hundred twenty-seven (127) individuals were randomized to daily use of an oral rinse containing a LXA4 mimetic, methyl ester-benzo-lipoxin A4 (BLXA4), placebo rinse or a no-rinse control group for 28 days. Treatment emergent adverse events (TEAEs) were assessed for safety, the primary outcome. Secondary outcomes included the change in the level of gingival inflammation and periodontal pocket depth (PD). Serum SPMs were monitored using targeted lipid mediator lipidomics to assess potential systemic impact of BLXA4.ResultsThe frequency of TEAEs was similar in BLXA4 and placebo-treated groups with no study-related SAEs. Once-daily rinsing with BLXA4 for 28-days resulted in a greater decrease in gingival inflammation compared to placebo rinse and no-rinse control groups (mean change: 0.26 GI unit vs 0.21 and 0.17, respectively). PD reduction was also greater with BLXA4 oral rinse compared to placebo and no-rinse groups (mean reduction: 1.23 mm vs. 0.71 mm and 0.46 mm, respectively). Topical application of BLXA4 increased serum levels of SPMs.ConclusionTreatment with BLXA4 reduces local inflammation, and increases abundance of pro-resolution molecules systemically, which may dampen inflammation that can mediate progression and course of inflammatory diseases beyond periodontitis.Clinical Trial RegistrationClinicalTrials.gov, identifier (NCT02342691).

Biotherapeutics, owns stocks and filed multiple patents on ST266. Dr. Van Dyke has been a paid advisor and owns stocks in Noveome Biotheraputics. Authors' Contribution: HH substantially contributed to conception and design, acquisition, analysis, and interpretation of data; drafted and critically revised the article for important intellectual content. DS contributed to conception and design, analysis and interpretation of the data, critically revised the article. ET and TVD critically revised the manuscript with important intellectual contribution. MM and CF performed data and sample collection and data entry. MC supervised randomization, study execution and data acquisition. DN and DS performed analysis of biological specimens and critically revised the analytical sections. JS performed statistical analyses and contributed to interpretation of the results. All authors approved the final version of the article and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Word count: 5,146; Number of figures: 3; Number of tables: 3; Number of references: 47 Running title: Amnion-Derived Cytokine Solution for Gingivitis Treatment One sentence summary: In this Phase 1 trial oral topical application of amnion-derived cytokine solution, now termed ST266, significantly reduced the gingival inflammation in both tissue and GCF as shown by decreased level of proinflammatory cytokines.