Probiotics In Gingivitis Management: A Randomized Clinical Trial. Jordi Espadaler, PhD. Director of Innovation

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1 Probiotics In Gingivitis Management: A Randomized Clinical Trial Jordi Espadaler, PhD. Director of Innovation espadaler@ab-biotics.com

2 Improving oral care Mechanical plaque removal, brushing and rinsing reduces but does not eliminate harmful bacteria Add healthy bacteria to improve oral microbiome balance PROBIOTIC STRAINS

3 Gingival microbiota and gingival disease Many bacteria can live associated to the gingival epithelium Progression towards more harmful organisms ( red complex ) occurs in gingivitis and periodontitis Among red complex, Tannerella forsythia displays the strongest association to bleeding and to worsening of gingivitis towards periodontitis (Socransky et al. 2005, Pereira et al. 2013)

4 Strains Selection Procedure 1. Define target mechanisms of action 2. Screen strains bank, comparing performance to commercial controls 3. Select top performing 1-3 strains for optimal formula Final formula

5 In vitro properties of strains in AB-Dentalac Gum 1 Good survival in the Oral Cavity Low Acidogenic Activity Absence of production of Volatile Sulfur Compounds (VSC) Co-Aggregation Activity Antagonistic Activity against periodontal pathogens Adhesion to different Oral Cavity Surfaces (epithelium and teeth) The combination of strains L. brevis CECT7480, L. plantarum CECT7481 and P. acidilactici CECT8633 fulfills all these properties 1) Bosch et al. Archiv Oral Biol 2012

6 Clinical Study 1 : Entry criteria Interventions: Probiotic tablets + tooth brushing with fluoride paste 2 (b.i.d, 6 weeks) Placebo tablets + tooth brushing with fluoride paste 2 Adult male and female years old, non-smokers for the last 6 months Mean gingival index (GI) at baseline > 1.3 No inter-proximal attachment loss >2mm at the majority of the sites Exclusion: Carious lesions or inadequate restorations Undergoing orthodontic therapy or wearing occlusal bite-guards Potentially interfering medications 3 or other probiotics Use of mouthwashes forbidden during the study 1) Montero et al. J. Periodontol 2017 (Accepted); 2) 1450 ppm of fluoride; 3) anti-inflammatory agents, diphenylhydantoin, calcium channel blockers, cyclosporine A, immunomodulators, antibiotics within 2 months

7 Clinical Study: Outline Visit 1 Day 0 6 weeks Visit 2 Day 42 PMPR Randomization Clinical examination Bacterial sampling Adverse events Clinical examination Bacterial sampling STUDY INTERVENTION (b.i.d): Standard of care: tooth brushing + placebo tablets Probiotic: tooth brushing + verum tablets

8 Clinical Study: Flow of Patients Assessed for eligibility (n=84) Excluded (n=25) Not meeting inclusion criteria (n=25) Declined to participate (n=0) Other reasons (n=0) Randomized (n=59) Allocated to Probiotic Received allocated treatment (n=30) Allocated to Standard of Care ( Control ) Received allocated treatment (n=29) No differences regarding age (32 ± 13), gender, mean GI (1.6 ± 0.3) and concentration of target bacteria at baseline Follow-up on week 6 (n=29) Loss to follow-up (n=1) Follow-up on week 6 (n=23) Withdrawal of informed consent (n=1) Not related AE (n=1) Loss to follow-up (n=4)

9 Gingival Index SoC Probiotic Clinical Study: Change in Mean Gingival Index SoC Probiotic Baseline Endpoint Endpoint (LOCF) Mean GI > to BASELINE STUDY ENDPOINT Averages of mean GI Scores Distribution of mean GI scores Significant clinical improvement in mean GI (T-test p < 0.001) in both groups, all patients in remission at the end of the study (mean GI < 1.3). More subjects with higher GI values in SoC group at study endpoint (Fisher p = 0.08) Becomes significant in Last Observation Carried Forward analysis (Fisher p = 0.02) 1 1) Appling LOCF to all lost to follow-up patients, but not the individual in the control group that withdrew consent nor, to the individual in the control group that discontinued due to unrelated AE

10 Change in log-counts/ml Clinical Study: Change in Periodontal Pathogens P. gingivalis Aggregatibacter Fusobacterium T. forsythia C. rectus * * * SoC SoC + Probiotic T. forsythia and F. nucleatum 1 log more concentrated than other species at baseline Statistics corrected for multiple testing Significant reduction of Aggregatibacter in both groups (Wilcoxon p < 0.05) Importantly, reduction in Tannerella forsythia significant in test group only (Wilcoxon p < 0.01)

11 Clinical Study: Microbiology correlation to Gingival Index In multivariate analysis, Tannerella forsythia was only species associated to number of sites with spontaneous bleeding in study sample Optimal regression model for sites with spontaneous bleeding (GI=3) Correlation coefficient r = 0.50 p < Coefficients S.E t statistic P-value Intercept Study Visit T. forsythia

12 Take Home Messages Standard gingivitis treatment successfully improves gingival index, but has a reduced impact on key periodontal pathogens AB-Dentalac GUM formula contains unique strains L. brevis CECT7480, L. plantarum CECT7481 and P. acidilactici CECT8633 of oral origin Strongly binds to oral surfaces and can form biofilms Has low acidogenic activity and does not produce volatile sulfur compounds Has low susceptibility to common antiseptic substances in mouthwashes Helps improve microbial balance, reduces key pathogenic species (Tannerella forsythia) Helps reduce number of subjects with residual gingivitis Improvement over standard of care

13 THANK YOU! Jordi Espadaler, PhD. Director of Innovation