Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Craig, Timothy J.; Reshef, Avner; Li, H Henry; Jacobs, Joshua; Bernstein, Jonathan A.; Farkas, Henriette; Yang, William H.; Stroes, Erik S.G.; Ohsawa, Isao; Tachdjian, Raffi; Manning, M. A.; Lumry, William R.; Saguer, I. Martinez; Aygören‐Pürsün, Emel; Ritchie, Bruce; Sussman, Gordon; Anderson, J.; Kawahata, Kimito; Suzuki, Yusuke; Staubach, Petra; Treudler, Regina; Feuersenger, Henrike; Glassman, Fiona Y.; Jacobs, Iris; Magerl, Markus

doi:10.1016/s0140-6736(23)00350-1

Cited by 48 publications

(16 citation statements)

References 18 publications

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“…22 The first clinical studies targeting FXIIa indicate that indeed hemostasis is not impaired and there is no indication of an increased bleeding risk caused by FXIIa inhibition. [23][24][25][26] An im previously portant difference in this study compared with previous work using nonconjugated 3F7 as a therapeutic agent in carotid thrombosis is the administration of 3F7-NIR after the injury had been induced, rather than allowing the antibody to circulate beforehand. 22 This reflects the most common clinical use of targeted imaging agents: when a patient presents with a suspected thrombotic event.…”

Section: Discussionmentioning

confidence: 97%

“…22 The first clinical studies targeting FXIIa indicate that indeed hemostasis is not impaired and there is no indication of an increased bleeding risk caused by FXIIa inhibition. 23–26…”

Section: Discussionmentioning

confidence: 99%

“…16,22 An affinity-matured version of 3F7, garadacimab, is currently under clinical investigation in a phase 3 study for the prevention of hereditary angioedema. 23 Phase 2 results showed significant reduction in angioedema attacks between the treatment and placebo groups without any adverse side effects including bleeding effects. 24 Furthermore, a phase 2 study for the treatment of patients with severe COVID-19 did not show significant clinical benefits but confirmed the safety profile of garadacimab, with no bleeding even in combination with heparin.…”

mentioning

confidence: 95%

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Activated Coagulation FXII: A Unique Target for In Vivo Molecular Imaging

Walsh

McFadyen

et al. 2023

ATVB

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BACKGROUND: Current clinical imaging of thromboembolic diseases often relies on indirect detection of thrombi, which may delay diagnosis and ultimately the institution of beneficial, potentially lifesaving treatment. Therefore, the development of targeting tools that facilitate the rapid, specific, and direct imaging of thrombi using molecular imaging is highly sought after. One potential molecular target is FXIIa (factor XIIa), which initiates the intrinsic coagulation pathway but also activates the kallikrein-kinin system, thereby initiating coagulation and inflammatory/immune responses. As FXII (factor XII) is dispensable for normal hemostasis, its activated form (FXIIa) represents an ideal molecular target for diagnostic and therapeutic approaches, the latter combining diagnosis/identification of thrombi and effective antithrombotic therapy. METHODS: We conjugated an FXIIa-specific antibody, 3F7, to a near-infrared (NIR) fluorophore and demonstrated binding to FeCl 3 -induced carotid thrombosis with 3-dimensional fluorescence emission computed tomography/computed tomography and 2-dimensional fluorescence imaging. We further demonstrated ex vivo imaging of thromboplastin-induced pulmonary embolism and detection of FXIIa in human thrombi produced in vitro. RESULTS: We demonstrated imaging of carotid thrombosis by fluorescence emission computed tomography/computed tomography and measured a significant fold increase in signal between healthy and control vessels from mice injected with 3F7-NIR compared with mice injected with nontargeted probe ( P =0.002) ex vivo. In a model of pulmonary embolism, we measured increased NIR signal in lungs from mice injected with 3F7-NIR compared with mice injected with nontargeted probe ( P =0.0008) and healthy lungs from mice injected with 3F7-NIR ( P =0.021). CONCLUSIONS: Overall, we demonstrate that FXIIa targeting is highly suitable for the specific detection of venous and arterial thrombi. This approach will allow direct, specific, and early imaging of thrombosis in preclinical imaging modalities and may facilitate monitoring of antithrombotic treatment in vivo.

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Section: Discussionmentioning

confidence: 97%

“…22 The first clinical studies targeting FXIIa indicate that indeed hemostasis is not impaired and there is no indication of an increased bleeding risk caused by FXIIa inhibition. 23–26…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

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Activated Coagulation FXII: A Unique Target for In Vivo Molecular Imaging

Walsh

McFadyen

et al. 2023

ATVB

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“…Emerging therapies for long‐term prophylaxis of angioedema attacks include antisense inhibitors of prekallikrein and drugs targeting excess FXII activation 62,63 . Gene therapy is also being investigated, as this could prevent acute episodes, while reducing the burden of repeated medication use; however, its safety and tolerability in HAE is currently unknown 62 .…”

Section: Looking Forwardmentioning

confidence: 99%

Could it be hereditary angioedema?—Perspectives from different medical specialties

Magerl,

Sala‐Cunill,

Weber‐Chrysochoou

et al. 2023

Clinical & Translational All

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Hereditary angioedema (HAE) is a rare autosomal dominant disease, with patients often suffering with associated symptoms for many years before receiving a correct diagnosis. The symptoms greatly impact a patient's quality of life (QoL) and include excruciating abdominal pain and angioedema of the skin and submucosa. Angioedema of the larynx represents a significant mortality risk in undiagnosed patients, and a large proportion of patients with HAE receive incorrect diagnoses and undergo unnecessary surgery. HAE‐specific treatments can control and prevent acute life‐threatening episodes, in addition to improving QoL, emphasizing the value of early diagnosis for patients. Diagnostic delay may be due to a lack of HAE awareness by healthcare professionals and the similarity of HAE symptoms with those of more common conditions, complicating differential diagnosis. The multifaceted nature of the condition may result in visits to one of many different medical settings, for example: the Emergency Room, pediatrics, general practice, otolaryngology, gastroenterology, and dermatology. Therefore, it is crucial that physicians in multiple healthcare specialties are aware of the disease to ensure that patients with HAE receive a timely diagnosis. Using patient cases from various medical specialties, this review highlights the necessity for cross‐specialty awareness of HAE and outlines the essential information for the various healthcare professionals that may encounter a patient with HAE symptoms, in order to effectively treat and/or diagnose HAE.

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“…Garadacimab is a novel fully human recombinant monoclonal antibody inhibitor of human activated Factor XII (FXIIa) that has recently completed its Phase 3 trial for the prophylactic treatment of HAE patients with C1-INH deficiency. Results from the most recent clinical trial show that garadacimab was able to significantly reduce HAE attacks in patients aged 12 years and older and had a favourable safety profile (Craig et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for inhibition of βFXIIa by garadacimab

Drulyte,

Ghai,

et al. 2023

Preprint

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FXIIa is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of Hereditary Angioedema (HAE). Here, we describe a high-resolution cryo-EM structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This atypical structural mechanism is likely the primary contributor in the inhibition of activated FXII proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXII. Structural analysis with other bonafide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a conserved mechanism of βFXIIa inhibition, a novel finding of this study. In summary, garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes. This work reaffirms the benefits of cryo-EM as a primary tool to study antigen-antibody complexes in near native state, particularly where other methods have fallen short.

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Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Cited by 48 publications

References 18 publications

Activated Coagulation FXII: A Unique Target for In Vivo Molecular Imaging

Activated Coagulation FXII: A Unique Target for In Vivo Molecular Imaging

Could it be hereditary angioedema?—Perspectives from different medical specialties

Structural basis for inhibition of βFXIIa by garadacimab

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