Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis

Banerji, Aleena; Busse, Paula J.; Shennak, Mustafa M.; Lumry, William R.; Davis-Lorton, Mark; Wedner, H. James; Jacobs, Joshua; Baker, James; Bernstein, Jonathan A.; Lockey, Richard F.; Li, H. Henry; Craig, Timothy J.; Cicardi, Marco; Riedl, Marc A.; Al-Ghazawi, Ahmad; Soo, Carolyn; Iarrobino, Ryan; Sexton, Daniel J.; TenHoor, Christopher; Kenniston, Jon A.; Faucette, Ryan; Still, James; Kushner, Harvey; Mensah, Robert; Stevens, Christopher J; Biedenkapp, Joseph C.; Chyung, Yung; Adelman, Burt

doi:10.1056/nejmoa1605767

Cited by 143 publications

(145 citation statements)

References 24 publications

(29 reference statements)

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“…A related anti-kallikrein IgG (DX-2930, Dyax) has been evaluated in phase 1b studies for angioedema. DX-2930 reduces plasma levels of cleaved HK and the frequency of angioedema episodes in patients with C1-INH deficiency [149,150]. It has not been tested for antithrombotic effects.…”

Section: Therapeutic Targeting Of Contact Factorsmentioning

confidence: 99%

Plasma contact factors as therapeutic targets

et al. 2018

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Direct oral anticoagulants (DOACs) are small molecule inhibitors of the coagulation proteases thrombin and factor Xa that demonstrate comparable efficacy to warfarin for several common indications, while causing less serious bleeding. However, because their targets are required for the normal host-response to bleeding (hemostasis), DOACs are associated with therapy-induced bleeding that limits their use in certain patient populations and clinical situations. The plasma contact factors (factor XII, factor XI, and prekallikrein) initiate blood coagulation in the activated partial thromboplastin time assay. While serving limited roles in hemostasis, pre-clinical and epidemiologic data indicate that these proteins contribute to pathologic coagulation. It is anticipated that drugs targeting the contact factors will reduce risk of thrombosis with minimal impact on hemostasis. Here, we discuss the biochemistry of contact activation, the contributions of contact factors in thrombosis, and novel antithrombotic agents targeting contact factors that are undergoing pre-clinical and early clinical testing.

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Section: Therapeutic Targeting Of Contact Factorsmentioning

confidence: 99%

Plasma contact factors as therapeutic targets

et al. 2018

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“…11 Subsequently, a phase 1b study has been completed with 37 subjects randomized to 4 doses of DX-2930 (30, 100, 300 or 400mg) or placebo. 12 The 300mg treatment arm demonstrated a 100% reduction in HAE attacks as compared to placebo (p<0.0001) and the 400mg arm showed a 88% reduction HAE attacks (p=0.05) in the primary efficacy assessment period from days 8 to 50. Cohort numbers were small but 4/4 patients in the 300mg arm were attack free during this assessment period, and 9/11 patients in the 400mg arm were attack free as compared to 3/11 patients in the placebo arm (p=0.026 and p=0.030, respectively).…”

Section: Emerging Therapies For Long Term Prophylaxismentioning

confidence: 90%

Emerging Therapies in Hereditary Angioedema

Meng

Riedl

2017

Immunology and Allergy Clinics of North America

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SYNOPSIS Remarkable progress has been made in the treatment of bradykinin mediated angioedema with the advent of multiple new angioedema specific therapies over the last decade, largely studied in patients with hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency. While affected individuals previously had little treatment available, patients in many parts of the world now have effective medications available for prophylaxis and treatment of acute angioedema attacks. Despite these advances, patients are still faced with challenges of a burdensome disease that can lead to debilitating and dangerous angioedema episodes associated with significant costs for individuals and society. The burden of treatment must also be addressed with regard to medication administration difficulties, treatment complications, and adverse side effects. Multiple new therapies with novel mechanisms of action are currently being investigated and may offer potential solutions to these challenges faced by patients and physicians. We herein review the emerging therapeutic options for the treatment of HAE.

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“…Dysregulated plasma kallikrein proteolysis of HMWK can result in accumulation of bradykinin, which induces vasopermeability resulting in the edematous attacks associated with C1-INH-HAE [12,[14][15][16][17]. Therapeutic intervention by inhibition of plasma kallikrein has led to acute and prophylactic treatments of C1-INH-HAE [18][19][20][21].…”

mentioning

confidence: 99%

“…As a result, there is considerable interest in developing sensitive and reliable assays to measure the level of cHMWK as a potential biomarker for C1-INH-HAE [10,[24][25]. Due to the lack of appropriate immunoassay reagents to specifically detect cleaved products, western blotting has currently been utilized to measure the cHMWK concentration for a variety of angioedema conditions and correlate it with drug efficacy in the early stage of clinical study [12,[18][19][20]24]. It represents a challenge to validate the western assays since they are generally semiquantitative, variable and of low sample throughput.…”

mentioning

confidence: 99%

2D-LC–MS/MS to Measure Cleaved High-Molecular-Weight Kininogen in Human Plasma as A Biomarker for C1-Inh-Hae

et al. 2017

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Aim: C1-INH-HAE is caused by activation of plasma kallikrein which subsequently cleaves high-molecular-weight kininogen (HMWK) to generate bradykinin and cHMWK. Materials & methods: A novel ion-pair 2D LC-MS/MS assay was developed to measure the 46 kDa cHMWK in plasma as a biomarker for C1-INH-HAE. The sample preparation included sodium dodecyl sulfate denaturation, methanol crash, chymotryptic digestion and peptide enrichment by solid phase extraction. Results: The LLOQ was 200 ng/ml. The overall cHMWK recovery combining crash and digestion was 57.5%. The precision of the method was ≤12.7% and accuracy ≤-13.8%. Conclusion: A reagent-free LC-MS assay has been developed for the quantitation of 46 kDa cHMWK, which was shown to be elevated in plasma of C1-INH-HAE patients due to C1-INH deficiency relative to that of healthy subjects.

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Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis

Abstract: In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).

Cited by 143 publications

References 24 publications

Plasma contact factors as therapeutic targets

Plasma contact factors as therapeutic targets

Emerging Therapies in Hereditary Angioedema

2D-LC–MS/MS to Measure Cleaved High-Molecular-Weight Kininogen in Human Plasma as A Biomarker for C1-Inh-Hae

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