Phase IIa clinical trial of complement C3 inhibitor AMY-101 in adults with periodontal inflammation

Abstract

Background. Gingivitis and periodontitis are prevalent inflammatory diseases of the periodontal tissues. Current treatments are often ineffective or do not prevent disease recurrence.Uncontrolled complement activation and resulting chronic gingival inflammation is a hallmark of periodontal diseases. We determined efficacy and safety of a complement 3-targeted therapeutic, AMY-101, locally administered in adults with periodontal inflammation.Methods. Thirty-two patients with gingival inflammation were enrolled into a randomized, placebo-controlled, double-blind, split-mouth design phase 2a trial, after dose-escalation study to select safe and effective dose with additional 8 patients. Half of the mouth was randomly assigned to AMY-101 (0.1mg/site) or placebo injections at sites of inflammation, administered on days 0, 7 and 14 and evaluated for safety and efficacy outcomes at days 28, 60 and 90. The primary efficacy outcome was change in gingival inflammation, measured by modified gingival index (MGI), and secondary outcomes included changes in bleeding-on-probing (BOP), amount of plaque, pocket depth, clinical attachment level, and gingival crevicular fluid levels of matrix metalloproteinases (MMPs) over 90 days. Results.A once-per-week intragingival injection of AMY-101 for 3 weeks was safe and welltolerated in all participants resulting in significant (P<0.001) reductions in clinical indices measuring gingival inflammation (MGI and BOP). AMY-101 significantly (P<0.05) reduced MMP-8 and MMP-9 levels, indicators of inflammatory tissue destruction. These therapeutic effects persisted for at least 3 months post-treatment. Conclusion. AMY-101 causes significant and sustainable reduction in gingival inflammationwithout adverse events and merits further investigation for the treatment of periodontitis and other oral or peri-implant inflammatory conditions.Trial registration. ClinicalTrials.gov: NCT03694444.Funding. Amyndas Pharmaceuticals. Amyndas contributed to the design and conduct of the clinical trial and in the writing of the manuscript.

Salivary ACE2 and TMPRSS2 link to periodontal status and metabolic parameters

“…Notably, periodontitis has been found to be associated with the severity and adverse outcomes of COVID‐19, 13,14 as both diseases are related to extensive perturbation of immune systems (e.g., increased complement activation) 79,96,97 . Most recently, similar therapeutic strategies (e.g., using complement inhibitor AMY‐101) have been evaluated via clinical trials for controlling the two diseases 98,99 . ACE2 and TMPRSS2 are two pivotal players in the infection of SARS‐CoV‐2 16,17 .…”

Interconnection of periodontal disease and comorbidities: Evidence, mechanisms, and implications

“…In this regard, multi-center randomized controlled clinical trials are required to implicate periodontitis as a modifiable risk factor for linked comorbidities. Further improvement of local periodontal treatment via innovative adjunctive hostmodulation approaches, 39,40 such as by modulating complement with the C3-targeted drug AMY-101, which showed efficacy in a recent phase 2a trial in patients with periodontal inflammation, 37,38 may greatly contribute to prevent systemic inflammation and promote overall health.…”

“…These mechanistic insights, mostly derived from studies in preclinical models, imply that periodontitis is a modifiable risk factor for comorbidities, a notion that is supported by clinical interventional studies, which showed that treatment of periodontitis attenuates systemic inflammation and surrogate markers of comorbidities 34‐36 . Accordingly, emerging adjunctive host‐modulation therapies (eg, complement‐targeted intervention with efficacy in phase 2a trial in patients with periodontal inflammation 37,38 ), to improve periodontal treatment (beyond the level achieved by conventional approaches alone), acquire increased importance, as they could help reduce the risk of systemic comorbidities 39,40 …”

“…studies, which showed that treatment of periodontitis attenuates systemic inflammation and surrogate markers of comorbidities. [34][35][36] Accordingly, emerging adjunctive host-modulation therapies (eg, complement-targeted intervention with efficacy in phase 2a trial in patients with periodontal inflammation 37,38 ), to improve periodontal treatment (beyond the level achieved by conventional approaches alone), acquire increased importance, as they could help reduce the risk of systemic comorbidities. 39,40 In this volume, clinical and basic scientists, with expertise in the pathogenesis of periodontitis and associated disorders, review in detail the association of periodontitis with extra-oral comorbidities and its implications for the overall health.…”

The Complement System in the Central Nervous System: From Neurodevelopment to Neurodegeneration

“…APL-2 or percetacoplan is in different phases of clinical trials for PNH and age-related macular degeneration (AMD) [ 156 , 157 ]. A novel analog called AMY-101 has yet to reach clinical trials but is in early preparation [ 158 ].…”