Safety and Preliminary Efficacy of a Novel Host-Modulatory Therapy for Reducing Gingival Inflammation

Abstract

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).

Role of Specialized Pro-Resolving Mediators in Modifying Host Defense and Decreasing Bacterial Virulence

“…There was a clinical trial examining the use of a stable LxA4 analog in periodontitis. In this trial, 1 µM of LxA4 analog mouthwash reduced the amount of gingivitis plaque and bleeding over the 28-day time course of the study [66], providing clinical evidence that an SPM can be beneficial in resolving infectious inflammation. In this particular setting, it appears that inhibiting chronic host defense activation was beneficial.…”

Novel Insight into the Mechanisms of the Bidirectional Relationship between Diabetes and Periodontitis

“…In the last decades, a better understanding of the pathogenesis of periodontitis and of the mechanistic links between periodontitis and comorbidities, including DM, has led to the identification of novel potential therapeutic targets. Strategies that modulate the host response, using drugs targeting complement, pro-resolution pathways, trained immunity, and Th17/Treg imbalance, appear promising [ 251 , 252 ] though most of studies were performed in experimental animals and results need to be confirmed in humans. Studies using cutting-edge technologies and integrated multi-omics approaches may further improve our current understanding of the systemic and tissue-specific changes that occur in periodontitis and/or DM and provide additional prevention/intervention strategies in the next future.…”

Regulation of T-Cell Immune Responses by Pro-Resolving Lipid Mediators

“…In this line, a RvE1 mimetic, RX-10045, has been tested as an ophthalmic solution for dry eye symptoms (NCT00799552), allergic conjunctivitis (NCT01639846), and in patients undergoing cataract surgery (NCT02329743). Promising results were recently reported in a phase 1 trial evaluating the safety and efficacy of BLXA4, a LXA4 analog, to treat periodontitis (NCT02342691): daily rinsing with mouthwash containing BLXA4 reduced gingival inflammation, and this was associated with a shift in serum lipid mediators toward a pro-resolving profile ( 94 ).…”