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Treatment of COVID-19 With Conestat Alfa, a Regulator of the Complement, Contact Activation and Kallikrein-Kinin System.

ABSTRACT: A dysregulated immune response with hyperinflammation is observed in patients with severe coronavirus disease 2019 (COVID-19). The aim of the present study was to assess the safety and potential benefits of human recombinant C1 esterase inhibitor (conestat alfa), a complement, contact activation and kallikrein-kinin system regulator, in severe COVID-19. Patients with evidence of progressive disease after 24 h including an oxygen saturation <93% at rest in ambient air were included at the University Hospital Basel, Switzerland in April 2020. Conestat alfa was administered by intravenous injections of 8400 IU followed by 3 additional doses of 4200 IU in 12-h intervals. Five patients (age range, 53-85 years; one woman) with severe COVID-19 pneumonia (11-39% lung involvement on computed tomography scan of the chest) were treated a median of 1 day (range 1-7 days) after admission. Treatment was well-tolerated. Immediate defervescence occurred, and inflammatory markers and oxygen supplementation decreased or stabilized in 4 patients (e.g., median C-reactive protein 203 (range 31-235) mg/L before vs. 32 (12-72) mg/L on day 5). Only one patient required mechanical ventilation. All patients recovered. C1INH concentrations were elevated before conestat alfa treatment. Levels of complement activation products declined after treatment. Viral loads in nasopharyngeal swabs declined in 4 patients. In this uncontrolled case series, targeting multiple inflammatory cascades by conestat alfa was safe and associated with clinical improvements in the majority of severe COVID-19 patients. Controlled clinical trials are needed to assess its safety and efficacy in preventing disease progression.

SUBMITTER: Urwyler P

PROVIDER: S-EPMC7456998 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Treatment of COVID-19 With Conestat Alfa, a Regulator of the Complement, Contact Activation and Kallikrein-Kinin System.

Urwyler Pascal P Moser Stephan S Charitos Panteleimon P Heijnen Ingmar A F M IAFM Rudin Melanie M Sommer Gregor G Giannetti Bruno M BM Bassetti Stefano S Sendi Parham P Trendelenburg Marten M Osthoff Michael M

Frontiers in immunology 20200814

A dysregulated immune response with hyperinflammation is observed in patients with severe coronavirus disease 2019 (COVID-19). The aim of the present study was to assess the safety and potential benefits of human recombinant C1 esterase inhibitor (conestat alfa), a complement, contact activation and kallikrein-kinin system regulator, in severe COVID-19. Patients with evidence of progressive disease after 24 h including an oxygen saturation <93% at rest in ambient air were included at the Univers ...[more]

PMID: 32922409

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Project description:Background: The kallikrein kinin system (KKS) is an established pharmacological target for the treatment and prevention of attacks in hereditary angioedema (HAE). Proteolytic activities of FXIIa and single-chain Factor XII (FXII) zymogen contribute to KKS activation and thereby may play roles in both initiating and propagating HAE attacks. In this report, we investigated the effects of potent small molecule FXIIa inhibitors on FXIIa and single chain FXII enzymatic activities, KKS activation, and angioedema in mice. Methods: We examined the effects of 29 structurally distinct FXIIa inhibitors on enzymatic activities of FXIIa and a mutant single chain FXII with R334A, R343A and R353A substitutions (rFXII-T), that does not undergo zymogen conversion to FXIIa, using kinetic fluorogenic substrate assays. We examined the effects of a representative FXIIa inhibitor, KV998086, on KKS activation and both carrageenan- and captopril-induced angioedema in mice. Results: FXIIa inhibitors designed to target its catalytic domain also potently inhibited the enzymatic activity of rFXII-T and the pIC50s of these compounds linearly correlated for rFXIIa and rFXII-T (R 2 = 0.93). KV998086, a potent oral FXIIa inhibitor (IC50 = 7.2 nM) inhibited dextran sulfate (DXS)-stimulated generation of plasma kallikrein and FXIIa, and the cleavage of high molecular weight kininogen (HK) in human plasma. KV998086 also inhibited rFXII-T mediated HK cleavage (p < 0.005) in plasma from FXII knockout mice supplemented with rFXII-T and stimulated with polyphosphate or DXS. Orally administered KV998086 protected mice from 1) captopril-induced Evans blue leakage in colon and laryngotracheal tissues and 2) blocked carrageenan-induced plasma HK consumption and paw edema. Conclusion: These findings show that small molecule FXIIa inhibitors, designed to target its active site, also inhibit the enzymatic activity of FXII zymogen. Combined inhibition of FXII zymogen and FXIIa may thereby suppress both the initiation and amplification of KKS activation that contribute to hereditary angioedema attacks and other FXII-mediated diseases.

Dataset Information

Treatment of COVID-19 With Conestat Alfa, a Regulator of the Complement, Contact Activation and Kallikrein-Kinin System.

Publications

Treatment of COVID-19 With Conestat Alfa, a Regulator of the Complement, Contact Activation and Kallikrein-Kinin System.

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