Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial

Craig, Timothy J.; Magerl, Markus; Levy, Donald S.; Reshef, Avner; Lumry, William R.; Martinez‐Saguer, Inmaculada; Jacobs, Joshua; Yang, William H.; Ritchie, Bruce; Aygören‐Pürsün, Emel; Keith, Paul K.; Busse, Paula J.; Feuersenger, Henrike; Pawaskar, Dipti; Jacobs, Iris; Pragst, Ingo; Doyle, Mittie K.

doi:10.1016/s0140-6736(21)02225-x

Cited by 43 publications

(27 citation statements)

References 23 publications

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“…Notably, the efficacy of C1-INH products for long-term prophylaxis was generally demonstrated in populations with a more severe HAE phenotype (on-placebo or pretreatment attack rate ∼4‒7 attacks/month) ( 40 , 50 , 54 ) than in similar trials of single-pathway treatment options (∼2–4 attacks/month) ( Tables 3 , 4 ) ( 63 , 68 ). However, the phase 2 trial of garadacimab, an agent that targets both contact and fibrinolytic pathways, included patients with a more severe phenotype (mean 3.5–7.5 attacks/month) ( 73 ).…”

Section: Discussionmentioning

confidence: 99%

“…This reflects the central role of the contact pathway in angioedema generation and the multiple feedback loops between the contact pathway and other pathways implicated in angioedema generation. Further, new targeted agents in development for HAE have shown promise, albeit in small populations ( 73 , 75 ).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown to potently inhibit bradykinin formation in plasma samples from patients with HAE and to reduce edema in animal models ( 72 ). Data have been published from a phase 2, randomized, double-blind trial ( 73 ). Patients were randomly assigned to receive an IV loading dose (placebo or garadacimab 40, 100, or 300 mg) followed by SC administration (placebo [ n = 8], garadacimab 75 mg [ n = 9], garadacimab 200 mg [ n = 8], or garadacimab 600 mg [ n = 7]) on day 6 and then every 4 weeks for 12 weeks.…”

Section: Investigational Treatmentsmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Investigational Treatmentsmentioning

confidence: 99%

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

Valerieva

Longhurst

2022

Front. Allergy

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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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“…Its additional central role in inflammatory disorders is evident by the association of excess FXII activity with the sometimes life-threatening inflammatory disorder, hereditary angioedema (HAE) ( 102 , 105 ). Indeed, anti-FXIIa treatments are holding promise as prophylaxis against angioedema due to C1-INH deficiency ( 106 ).…”

Section: Complement and Coagulation And The Seamless Webmentioning

confidence: 99%

Coagulation and complement: Key innate defense participants in a seamless web

2022

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In 1969, Dr. Oscar Ratnoff, a pioneer in delineating the mechanisms by which coagulation is activated and complement is regulated, wrote, “In the study of biological processes, the accumulation of information is often accelerated by a narrow point of view. The fastest way to investigate the body’s defenses against injury is to look individually at such isolated questions as how the blood clots or how complement works. We must constantly remind ourselves that such distinctions are man-made. In life, as in the legal cliché, the devices through which the body protects itself form a seamless web, unwrinkled by our artificialities.” Our aim in this review, is to highlight the critical molecular and cellular interactions between coagulation and complement, and how these two major component proteolytic pathways contribute to the seamless web of innate mechanisms that the body uses to protect itself from injury, invading pathogens and foreign surfaces.

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Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial

Cited by 43 publications

References 23 publications

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

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

Recent advances in factor XII structure and function

Coagulation and complement: Key innate defense participants in a seamless web

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