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Complement C3 inhibition in severe COVID-19 using compstatin AMY-101.

ABSTRACT: Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 (n = 16) or placebo (n = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101-treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug's inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.

SUBMITTER: Skendros P

PROVIDER: S-EPMC9385148 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Complement C3 inhibition in severe COVID-19 using compstatin AMY-101.

Skendros Panagiotis P Germanidis Georgios G Mastellos Dimitrios C DC Antoniadou Christina C Gavriilidis Efstratios E Kalopitas Georgios G Samakidou Anna A Liontos Angelos A Chrysanthopoulou Akrivi A Ntinopoulou Maria M Kogias Dionysios D Karanika Ioanna I Smyrlis Andreas A Cepaityte Dainora D Fotiadou Iliana I Zioga Nikoleta N Mitroulis Ioannis I Gatselis Nikolaos K NK Papagoras Charalampos C Metallidis Simeon S Milionis Haralampos H Dalekos George N GN Willems Loek L Persson Barbro B Manivel Vivek Anand VA Nilsson Bo B Connolly E Sander ES Iacobelli Simona S Papadopoulos Vasileios V Calado Rodrigo T RT Huber-Lang Markus M Risitano Antonio M AM Yancopoulou Despina D Ritis Konstantinos K Lambris John D JD

Science advances 20220817 33

Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 (<i>n</i> = 16) or placebo (<i>n</i> = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101 ...[more]

PMID: 35977025

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Project description:BackgroundGingivitis 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 the resulting chronic gingival inflammation are hallmarks of periodontal diseases. We determined the efficacy and safety of a complement 3-targeted therapeutic, AMY-101, which was locally administered to adult patients with periodontal inflammation.MethodsThirty-two patients with gingival inflammation were enrolled in a randomized, placebo-controlled, double-blind, split-mouth phase IIa trial that followed a dose escalation study to select a safe and effective dose in an additional 8 patients. Half of the patient's mouth was randomly assigned to AMY-101 (0.1 mg/site) or placebo injections at sites of inflammation, administered on days 0, 7, and 14, and then evaluated for safety and efficacy outcomes on days 28, 60, and 90. The primary efficacy outcome was a change in gingival inflammation, measured by a modified gingival index (MGI), and secondary outcomes included changes in bleeding on probing (BOP), the amount of plaque, pocket depth, clinical attachment level, and gingival crevicular fluid levels of matrix metalloproteinases (MMPs) over 90 days.ResultsA once-weekly intragingival injection of AMY-101 for 3 weeks was safe and well tolerated in all participants and resulted 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 after treatment.ConclusionAMY-101 treatment resulted in a significant and sustainable reduction in gingival inflammation without adverse events and, we believe, merits further investigation for the treatment of periodontitis and other oral or peri-implant inflammatory conditions.Trial registrationClinicalTrials.gov identifier NCT03694444.FundingAmyndas Pharmaceuticals.

Dataset Information

Complement C3 inhibition in severe COVID-19 using compstatin AMY-101.

Publications

Complement C3 inhibition in severe COVID-19 using compstatin AMY-101.

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