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

doi:10.1016/S0140-6736(23)00350-1

The Lancet

Volume 401, Issue 10382, 1–7 April 2023, Pages 1079-1090

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https://doi.org/10.1016/S0140-6736(23)00350-1 Get rights and content

Summary

Background

Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein–kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema.

Methods

VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418.

Findings

Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of –87% (95% CI –96 to –58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00–0·31) for garadacimab and 1·35 (1·00–3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events.

Interpretation

Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults.

Funding

CSL Behring.

Introduction

Hereditary angioedema is a rare autosomal dominant disorder characterised by recurrent, painful angioedema episodes (attacks) that most commonly affect the skin, face, extremities, trunk, genitals, and mucous membranes of the gastrointestinal tract and upper airways. Attacks are unpredictable and potentially life-threatening, and negatively affect patient quality of life.1, 2, 3, 4, 5, 6 Hereditary angioedema attacks are caused by spontaneous, uncontrolled activation of the plasma kallikrein–kinin system and overproduction of the vasoactive peptide bradykinin, which increases endothelial permeability and causes subsequent extravasation of fluids into interstitial tissues.7, 8, 9 Activation of factor XII (FXII) initiates the kallikrein–kinin system, leading to bradykinin formation.7, 8, 9 In healthy individuals, the kallikrein–kinin system is tightly regulated by C1-esterase inhibitor (C1-INH);3, 7, 8, 9, 10 most cases of hereditary angioedema are associated with a deficiency (type I) or dysfunction (type II) in C1-INH caused by mutations in the C1-INH gene (SERPING1).1, 2

Approved prophylactic treatments for hereditary angioedema aim to compensate for C1-INH deficiency (C1-INH concentrates) or inhibit bradykinin release by targeting plasma kallikrein.1, 11 These treatments often require frequent dosing regimens (eg, twice-weekly administrations with C1-INH, administrations every 2 weeks with lanadelumab),12, 13 and in clinical trials have shown a delay in reaching maximum efficacy upon reaching steady-state concentrations (ie, 14 days or 70 days from the start of treatment, respectively), with most patients still having attacks in the first 2 months after treatment initiation.12, 13 Therefore, there is a need for new, well-tolerated, effective therapies, with enhanced convenience and early and sustained protection from hereditary angioedema attacks. The pivotal role of activated FXII (FXIIa) in initiating the kallikrein–kinin cascade provides a strong rationale for therapeutic targeting to prevent the downstream production of bradykinin that leads to hereditary angioedema attacks.

Garadacimab (CSL312), a first-in-class, fully-human monoclonal IgG4 antibody against FXIIa, was shown to prevent bradykinin formation in plasma samples from patients with hereditary angioedema with C1-INH deficiency.¹⁴ In a randomised, placebo-controlled, phase 2 trial, garadacimab significantly reduced the number of hereditary angioedema attacks per month compared with placebo over 12 weeks and provided the first clinical evidence of FXIIa inhibition as a novel strategy for hereditary angioedema prophylaxis.¹⁵ Here, the efficacy and safety of subcutaneous garadacimab were investigated in a 6-month, randomised, double-blind, placebo-controlled, pivotal phase 3 trial (VANGUARD) in patients with type I or type II hereditary angioedema.

Section snippets

Study design and participants

VANGUARD was a randomised, double-blind, placebo-controlled, pivotal phase 3 trial to investigate the efficacy and safety of an initial loading dose of subcutaneous garadacimab (two 200-mg injections) followed by once-monthly 200 mg garadacimab in adolescents and adults with a laboratory-confirmed diagnosis of type I or type II hereditary angioedema. Considering that maximum efficacy and a favourable safety profile were observed in the phase 2 trial, a once-monthly 200-mg maintenance dose of

Results

Discussion

In this double-blind, randomised, placebo-controlled, phase 3 trial, monthly subcutaneous administrations of the anti-FXIIa monoclonal antibody garadacimab resulted in statistically significant and clinically meaningful reductions in hereditary angioedema attacks compared with placebo. The incidence of adverse events with once-monthly 200 mg garadacimab was similar to that with placebo and there were no reports of thromboembolic events, bleeding, or anaphylaxis. The number of patients reporting

Data sharing

CSL Behring will consider requests to share individual patient data (IPD) from CSL Behring-sponsored studies with external bona-fide, qualified scientific and medical researchers on a case-by-case basis. When appropriate, IPD will generally be shared once review by major regulatory authorities (eg, US Food and Drug Administration or European Medicines Agency) is complete and the primary publication is available. Proposed research should seek to answer a previously unanswered important medical

Declaration of interests

TJC is a speaker for Pharming, CSL Behring, Takeda, Fresenius Kabi, and Grifols; has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, Spark, BioMarin, Fresenius Kabi, and Grifols; and is on the medical advisory board for the US Hereditary Angioedema Association, Director of ACARE Angioedema Center at Penn State University, Hershey, and on the Board of Directors for the American Academy of Allergy, Asthma, and Immunology. AR received research grants as a

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

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

Declaration of interests

Ann Allergy Asthma Immunol

Transfus Apheresis Sci

J Allergy Clin Immunol

Biochim Biophys Acta Mol Cell Res

J Allergy Clin Immunol

Lancet

Blood

The international WAO/EAACI guideline for the management of hereditary angioedema–the 2021 revision and update

Allergy

US HAEA Medical Advisory Board 2020 guidelines for the management of hereditary angioedema

J Allergy Clin Immunol Pract

Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients

Medicine (Baltimore)

Articles
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