Inhibition of Prekallikrein for Hereditary Angioedema

Fijen, Lauré M.; Riedl, Marc A.; Bordone, Laura; Bernstein, Jonathan A.; Raasch, Jason; Tachdjian, Raffi; Craig, Timothy J.; Lumry, William R.; Manning, M. A.; Alexander, Veronica J.; Newman, Ken; Revenko, Alexey S.; Baker, Brenda F.; Nanavati, Charvi; MacLeod, A. Robert; Schneider, Eugene; Cohn, Danny M.

doi:10.1056/nejmoa2109329

Cited by 46 publications

(34 citation statements)

References 18 publications

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“…Second, a potential limitation of this study were the ~75% reductions in prekallikrein levels. This has previously been shown to be sufficient for decreasing angioedema attack rates 1 and we contributed with our study to the growing number of evidence that this amount of PK reduction does not increase thrombotic risk in HAE patients. However, we acknowledge that in congenital prekallikrein deficiency the PK levels are lower than in our study, meaning that our results cannot be extrapolated one-to-one to the thrombotic risk in patients with congenital prekallikrein deficiency.…”

Section: Accepted Manuscriptmentioning

confidence: 89%

The Influence of Plasma Prekallikrein Oligonucleotide Antisense Therapy on Coagulation and Fibrinolysis Assays: A Post-hoc Analysis

et al. 2022

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Background Congenital prekallikrein deficiency has been associated with increased risk of thrombosis in a few uncontrolled studies. Prekallikrein levels were reduced by 36-94% (median 75%) in a phase 2 study with the prekallikrein specific antisense oligonucleotide, donidalorsen, in patients with hereditary angioedema (HAE). Objectives To estimate the effects of plasma prekallikrein reduction on coagulation and fibrinolysis. Methods Plasma samples were obtained from 16 HAE patients treated with donidalorsen and six placebo-treated patients. Calibrated automated thrombogram (CAT), clot lysis time, high-molecular-weight kininogen activity, factor XI activity, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes, D-dimer, plasminogen activity, plasmin-α2-antiplasmin complexes, and α2-antiplasmin activity were measured before and after four months of treatment. Results No significant changes following donidalorsen treatment were observed between baseline and after four months of treatment: CAT lag time 3.0 min and 3.0 min, CAT peak thrombin concentration 109% and 129%, CAT endogenous thrombin potential 98% and 108%, factor XI activity 110% and 115%, F1+2 levels 251 pMol/L and 161 pMol/L, thrombin-antithrombin complexes 2.6 µg/L and 1.9 µg/L, high-molecular-weight kininogen activity 87% and 93%, clot lysis time 92% and 99%, D-dimer levels 0.65 µg/L and 0.36 µg/L, plasminogen activity 116% and 125%, plasmin-α2-antiplasmin complexes 533 ng/mL and 328 ng/mL, and α2-antiplasmin activity 122% and 127%, respectively. There were also no differences between donidalorsen and placebo treatment. Conclusions Reduction of plasma prekallikrein by donidalorsen in HAE patients neither affected thrombin formation nor fibrinolytic activity. Our data suggest that partial plasma prekallikrein reduction does not influence thrombotic risk.

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Section: Accepted Manuscriptmentioning

confidence: 89%

The Influence of Plasma Prekallikrein Oligonucleotide Antisense Therapy on Coagulation and Fibrinolysis Assays: A Post-hoc Analysis

et al. 2022

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“…Excessive bradykinin production or heightened vascular sensitivity to bradykinin appears to underlie HAE [19 ▪ ,21 ▪ ]. Angioedema in the most common forms of HAE responds to FXIIa-neutralizing antibodies [22], PKa inhibitors [23] and reduction of plasma prekallikrein [24], attesting to the importance of the KKS in the disease process.…”

Section: Disease Processes Involving Factor XIImentioning

confidence: 99%

Recent advances in factor XII structure and function

Shamanaev

Litvak

Gailani

2022

Current Opinion in Hematology

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Purpose of review Factor XII (FXII), the precursor of the protease FXIIa, contributes to pathologic processes including angioedema and thrombosis. Here, we review recent work on structure-function relationships for FXII based on studies using recombinant FXII variants. Recent findings FXII is a homolog of pro-hepatocyte growth factor activator (Pro-HGFA). We prepared FXII in which domains are replaced by corresponding parts of Pro-HGA, and tested them in FXII activation and activity assays. In solution, FXII and prekallikrein undergo reciprocal activation to FXIIa and kallikrein. The rate of this process is restricted by the FXII fibronectin type-2 and kringle domains. Pro-HGA replacements for these domains accelerate FXII and prekallikrein activation. When FXII and prekallikrein bind to negatively charged surfaces, reciprocal activation is enhanced. The FXII EGF1 domain is required for surface binding. Summary We propose a model in which FXII is normally maintained in a closed conformation resistant to activation by intramolecular interactions involving the fibronectin type-2 and kringle domains. These interactions are disrupted when FXII binds to a surface through EGF1, enhancing FXII activation and prekallikrein activation by FXIIa. These observations have important implications for understanding the contributions of FXII to disease, and for developing therapies to treat thrombo-inflammatory disorders.

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“…A phase 2, randomized, double-blind, placebo-controlled trial was conducted to further examine the efficacy and safety of once monthly SC donidalorsen 80 mg in adults with HAE ( 76 ). During the ≤8-week study run-in period, the 20 patients (donidalorsen [ n = 14]; placebo [ n = 6]) included in the trial experienced a mean 2.7 HAE attacks/month (range, 1.0 to 5.6) ( 76 ). Donidalorsen significantly reduced the mean number of monthly attacks compared with placebo (0.2 vs. 2.2, respectively; 90% difference; P < 0.001) ( 76 ).…”

Section: Investigational Treatmentsmentioning

confidence: 99%

“…During the ≤8-week study run-in period, the 20 patients (donidalorsen [ n = 14]; placebo [ n = 6]) included in the trial experienced a mean 2.7 HAE attacks/month (range, 1.0 to 5.6) ( 76 ). Donidalorsen significantly reduced the mean number of monthly attacks compared with placebo (0.2 vs. 2.2, respectively; 90% difference; P < 0.001) ( 76 ). Donidalorsen decreased plasma prekallikrein activity from baseline by 61% ( 76 ).…”

Section: Investigational Treatmentsmentioning

confidence: 99%

Treatment of hereditary angioedema—single or multiple pathways to the rescue

Valerieva

Longhurst

2022

Front. Allergy

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Hereditary angioedema (HAE) is a rare disease caused by mutations in the SERPING1 gene. This results in deficient or dysfunctional C1 esterase inhibitor (C1-INH) and affects multiple proteases involved in the complement, contact-system, coagulation, and fibrinolytic pathways. Current options for the treatment and prevention of HAE attacks include treating all affected pathways via direct C1-INH replacement therapy; or specifically targeting components of the contact activation system, in particular by blocking the bradykinin B2 receptor (B2R) or inhibiting plasma kallikrein, to prevent bradykinin generation. Intravenously administered plasma-derived C1-INH (pdC1-INH) and recombinant human C1-INH have demonstrated efficacy and safety for treatment of HAE attacks, although time to onset of symptom relief varied among trials, specific agents, and dosing regimens. Data from retrospective and observational analyses support that short-term prophylaxis with intravenous C1-INH products can help prevent HAE attacks in patients undergoing medical or dental procedures. Long-term prophylaxis with intravenous or subcutaneous pdC1-INH significantly decreased the HAE attack rate vs. placebo, although breakthrough attacks were observed. Pathway-specific therapies for the management of HAE include the B2R antagonist icatibant and plasma kallikrein inhibitors ecallantide, lanadelumab, and berotralstat. Icatibant, administered for treatment of angioedema attacks, reduced B2R-mediated vascular permeability and, compared with placebo, reduced the time to initial symptom improvement. Plasma kallikrein inhibitors, such as ecallantide, block the binding site of kallikrein to prevent cleavage of high molecular weight kininogen and subsequent bradykinin generation. Ecallantide was shown to be efficacious for HAE attacks and is licensed for this indication in the United States, but the labeling recommends that only health care providers administer treatment because of the risk of anaphylaxis. In addition to C1-INH replacement therapy, the plasma kallikrein inhibitors lanadelumab and berotralstat are recommended as first-line options for long-term prophylaxis and have demonstrated marked reductions in HAE attack rates. Investigational therapies, including the activated factor XII inhibitor garadacimab and an antisense oligonucleotide targeting plasma prekallikrein messenger RNA (donidalorsen), have shown promise as long-term prophylaxis. Given the requirement of lifelong management for HAE, further research is needed to determine how best to individualize optimal treatments for each patient.

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Inhibition of Prekallikrein for Hereditary Angioedema

Cited by 46 publications

References 18 publications

The Influence of Plasma Prekallikrein Oligonucleotide Antisense Therapy on Coagulation and Fibrinolysis Assays: A Post-hoc Analysis

The Influence of Plasma Prekallikrein Oligonucleotide Antisense Therapy on Coagulation and Fibrinolysis Assays: A Post-hoc Analysis

Recent advances in factor XII structure and function

Treatment of hereditary angioedema—single or multiple pathways to the rescue

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