C3-targeted therapy in periodontal disease: moving closer to the clinic

Hajishengallis, George; Hastürk, Hatice; Lambris, John D.; Apatzidou, Danae Anastasia; Belibasakis, Georgios N.; Bostancı, Nagihan; Corby, Patricia; Cutler, Christopher W.; D’Aiuto, F; Hajishengallis, Evlambia; Huber‐Lang, Markus; Ioannidou, Effie; Kajikawa, Tetsuhiro; Kantarcı, Alpdoğan; Korostoff, Jonathan; Kotsakis, Georgios A.; Maekawa, Tomoki; Mastellos, Dimitrios C.; Moutsopoulos, Niki M.; Myneni, Srinivas R.; Nagelberg, Richard H; Nilsson, Bo; Papapanou, Panos N.; Papathanasiou, Evgenia; Potempa, Jan; Risitano, Antonio M.; Sahingur, Sinem E.; Saitô, Atsushi; Sculean, Anton; Stavropoulos, Andreas; Teles, Flavia; Tonetti, Maurizio S.; Yancopoulou, Despina

doi:10.1016/j.it.2021.08.001

Cited by 35 publications

(27 citation statements)

References 56 publications

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“…Nevertheless, similarly to eculizumab, Empaveli was approved for paroxysmal nocturnal hemoglobinuria (PNH) with a risk evaluation and mitigation strategy in place that requires that patients are closely monitored during treatment to ensure effective mitigation of the risk of bacterial infection (46). However, in the context of periodontal disease, potential safety issues are further minimized not only because the treatment is local but also the injected amount of AMY-101 is considerably smaller than that used in systemic administration protocols, thus precluding any considerable drug exposure in circulation (47). Moreover, complement inhibition in preclinical models of periodontitis restrains rather than favors the expansion and persistence of periodontal pathogens (47).…”

Section: Amy-101 and Earlier Compstatin Analogues (Such As The Recently Fda-approved C3 Inhibitormentioning

confidence: 99%

“…However, in the context of periodontal disease, potential safety issues are further minimized not only because the treatment is local but also the injected amount of AMY-101 is considerably smaller than that used in systemic administration protocols, thus precluding any considerable drug exposure in circulation (47). Moreover, complement inhibition in preclinical models of periodontitis restrains rather than favors the expansion and persistence of periodontal pathogens (47).…”

Section: Amy-101 and Earlier Compstatin Analogues (Such As The Recently Fda-approved C3 Inhibitormentioning

confidence: 99%

“…Taken together, the results of this Phase 2a clinical trial in patients with gingival inflammation provide strong evidence that locally delivered C3 inhibition with the compstatin-based drug candidate AMY-101 can elicit potent and durable anti-inflammatory effects in humans. Thus, C3targeted complement intervention may serve as a novel host-modulatory therapeutic approach for the treatment of oral inflammatory diseases including periodontal and perhaps peri-implant diseases, where complement has also been implicated (47,53,54). Other indications considered for therapeutic interventions using AMY-101 (via systemic administration) include hematopoietic stem cell transplantation-associated thrombotic microangiopathy, complications of ABOincompatible kidney transplantation, hemodialysis-induced inflammation (24) as well as severe COVID-19, in which AMY-101 has already been tested in an exploratory study with promising results (55).…”

Section: Amy-101 and Earlier Compstatin Analogues (Such As The Recently Fda-approved C3 Inhibitormentioning

confidence: 99%

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

Hastürk¹,

Hajishengallis

Lambris

et al. 2021

Journal of Clinical Investigation

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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.

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Section: Amy-101 and Earlier Compstatin Analogues (Such As The Recently Fda-approved C3 Inhibitormentioning

confidence: 99%

Section: Amy-101 and Earlier Compstatin Analogues (Such As The Recently Fda-approved C3 Inhibitormentioning

confidence: 99%

Section: Amy-101 and Earlier Compstatin Analogues (Such As The Recently Fda-approved C3 Inhibitormentioning

confidence: 99%

See 1 more Smart Citation

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

Hastürk¹,

Hajishengallis

Lambris

et al. 2021

Journal of Clinical Investigation

Self Cite

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show abstract

“… 12 Extensive inflammatory cell infiltration appears in the connective tissue near the periodontal pocket epithelium. 13 It is generally believed that this low-grade inflammation will disturb the health of the whole body or worsen other systemic diseases. 14 Therefore, in the general population, chronic periodontitis may be an important source of invisible peripheral inflammation.…”

Section: Introductionmentioning

confidence: 99%

Oral microbiota in human systematic diseases

et al. 2022

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Oral bacteria directly affect the disease status of dental caries and periodontal diseases. The dynamic oral microbiota cooperates with the host to reflect the information and status of immunity and metabolism through two-way communication along the oral cavity and the systemic organs. The oral cavity is one of the most important interaction windows between the human body and the environment. The microenvironment at different sites in the oral cavity has different microbial compositions and is regulated by complex signaling, hosts, and external environmental factors. These processes may affect or reflect human health because certain health states seem to be related to the composition of oral bacteria, and the destruction of the microbial community is related to systemic diseases. In this review, we discussed emerging and exciting evidence of complex and important connections between the oral microbes and multiple human systemic diseases, and the possible contribution of the oral microorganisms to systemic diseases. This review aims to enhance the interest to oral microbes on the whole human body, and also improve clinician’s understanding of the role of oral microbes in systemic diseases. Microbial research in dentistry potentially enhances our knowledge of the pathogenic mechanisms of oral diseases, and at the same time, continuous advances in this frontier field may lead to a tangible impact on human health.

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“…Deciphering new non-canonical functions remains challenging although impressive recent progresses were made on this side. Lastly, a better understanding of these interrelated systems will open the door to new personalized therapeutic strategies including adjunctive treatment, for example to downregulate HMGB1 ( 139 ), while new drug developments are performed to control complement and HMGB1 pathological effects, as discussed in recent reviews or research papers ( 9 , 10 , 27 , 33 , 63 , 112 , 140 ).…”

Section: Discussionmentioning

confidence: 99%

Complement System and Alarmin HMGB1 Crosstalk: For Better or Worse

et al. 2022

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Our immune system responds to infectious (PAMPs) and tissue damage (DAMPs) signals. The complement system and alarmin High-Mobility Group Box 1 (HMGB1) are two powerful soluble actors of human host defense and immune surveillance. These systems involve molecular cascades and amplification loops for their signaling or activation. Initially activated as alarm raising systems, their function can be finally switched towards inflammation resolution, where they sustain immune maturation and orchestrate repair mechanisms, opening the way back to homeostasis. However, when getting out of control, these defense systems can become deleterious and trigger serious cellular and tissue damage. Therefore, they can be considered as double-edged swords. The close interaction between the complement and HMGB1 pathways is described here, as well as their traditional and non-canonical roles, their functioning at different locations and their independent and collective impact in different systems both in health and disease. Starting from these systems and interplay at the molecular level (when elucidated), we then provide disease examples to better illustrate the signs and consequences of their roles and interaction, highlighting their importance and possible vicious circles in alarm raising and inflammation, both individually or in combination. Although this integrated view may open new therapeutic strategies, future challenges have to be faced because of the remaining unknowns regarding the molecular mechanisms underlying the fragile molecular balance which can drift towards disease or return to homeostasis, as briefly discussed at the end.

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C3-targeted therapy in periodontal disease: moving closer to the clinic

Cited by 35 publications

References 56 publications

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

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

Oral microbiota in human systematic diseases

Complement System and Alarmin HMGB1 Crosstalk: For Better or Worse

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