Safety and Efficacy of the Complement Inhibitor AMY-101 in a Natural Model of Periodontitis in Non-human Primates

Abstract

Periodontitis is a chronic inflammatory disease associated with overactivation of the complement system. Recent preclinical studies suggest that host-modulation therapies may contribute to effective treatment of human periodontitis, which may lead to loss of teeth and function if untreated. We previously showed that locally administered AMY-101 (Cp40), a peptidic inhibitor of the central complement component C3, can inhibit naturally occurring periodontitis in non-human primates (NHPs) when given once a week. This study was undertaken to determine the local safety of increasing doses of the drug as well as its efficacy when given at a reduced frequency or after systemic administration. Our findings have determined a local dose of AMY-101 (0.1 mg/site) that is free of local irritation and effective when given once every 3 weeks. Moreover, a daily subcutaneous dose of AMY-101 (4 mg/kg bodyweight) was protective against NHP periodontitis, suggesting that patients treated for systemic disorders (e.g., paroxysmal nocturnal hemoglobinuria) can additionally benefit in terms of improved periodontal condition. In summary, AMY-101 appears to be a promising candidate drug for the adjunctive treatment of human periodontitis, a notion that merits investigation in human clinical trials.

Current understanding of periodontal disease pathogenesis and targets for host‐modulation therapy

“…Cp40 was effective also in a therapeutic setting in multiple subsequent studies. Importantly, in the absence of additional treatments such as scaling and root planing, the drug inhibited pre‐existing, naturally occurring periodontitis in aged nonhuman primates, even when given once every 3 weeks, and its protective effects lasted for at least 6 weeks after drug withdrawal . In the above‐discussed studies, C3 inhibition by Cp40 exerted a strong suppressive effect on interleukin‐17, a potent proinflammatory and pro‐osteoclastogenic cytokine (Figure ).…”

“…More recently, AMY‐101 was evaluated in a first‐in‐human clinical trial in healthy volunteers, in which it was shown to be safe and well tolerated . Overall, the safety and efficacy features of locally administered AMY‐101 suggest that this is a promising approach meriting investigation as a host‐modulation therapy in human periodontitis.…”

“…The promotion of tissue homeostasis can also be achieved by biologics as long as they are safe and effective. In this regard, although the C3 inhibitor AMY‐101 was administered locally in the gingiva of nonhuman primates as infrequently as once every 3 weeks and was withdrawn at 6 weeks, the treated animals maintained significantly reduced clinical periodontal/inflammatory indices for at least an additional 6‐week period . This long‐lasting protective effect was unexpected for a small‐molecule inhibitor that was not used throughout the experimental period.…”

New developments in neutrophil biology and periodontitis

“…Following the emergence of developmental endothelial locus‐1 as the first endogenous regulator of the leukocyte adhesion cascade, preclinical studies in mouse and nonhuman primate models have shown that excessive neutrophil infiltration and periodontitis (and other inflammatory conditions) can be controlled by local administration of developmental endothelial locus‐1 . Moreover, the involvement of complement in both the dysbiosis and the inflammation that drive periodontitis, in great part through neutrophil‐dependent effects, has led us and our collaborators to develop complement‐targeted interventions that have successfully treated both induced and naturally occurring periodontitis in nonhuman primates . A clinically developed complement C3 inhibitor (AMY‐101; Amyndas Pharmaceuticals, Glyfada, Greece) has been found to be safe in a phase I study and a phase II clinical trial in periodontitis is planned.…”

Clinical promise of next-generation complement therapeutics

“…Local injection of the C3-targeted inhibitory peptide Cp40 in the interdental papilla of primates afflicted with periodontitis has led to clinically meaningful reduction of key inflammatory indices, attenuating the osteoclastogenic bone loss that occurs in periodontal disease 89 . Following up on preclinical safety and tolerability studies 90 , the Cp40-based therapeutic AMY-101 recently received Investigational New Drug approval by the FDA for the conduct of the first clinical study to evaluate its efficacy in adults with gingivitis (ClinicalTrials.gov identifier: NCT03694444) (TABLE 1).…”