BACKGROUND:Hereditary angioedema (HAE) with normal C1 inhibitor (HAE-nC1INH), including HAE arising from F12 (HAE-FXII) or PLG (HAE-PLG) mutations, has a high unmet therapeutic need. OBJECTIVE:Our aim was to explore long-term prophylaxis with monthly subcutaneous garadacimab (anti-activated factor XII mAb) in patients with HAE-FXII or HAE-PLG. METHODS:Efficacy and safety were evaluated for HAE-FXII or HAE-PLG in open-label phase 2 (a 13-week treatment period [TP1] and subsequent ≥44-week extension period [TP2]; 600 mg of garadacimab during each period) and ongoing phase 3 open-label extension (OLE; garadacimab dose 200 mg) studies. RESULTS:Patients 1 and 2 (HAE-FXII) completed phase 2 and then continued into OLE (total exposure time 42.9 and 40.2 months, respectively); patient 3 (HAE-FXII) discontinued TP1 (because of lack of efficacy). Patients 4 to 6 (HAE-PLG) completed TP1 only. Patients 1 and 2 (HAE-FXII) had a reduction in monthly attack rate (AR) of 88% or more versus run-in during phase 2 (TP1 AR = 0.4 and 0.0 and TP2 AR= 0.1 and 0.2, respectively; run-in = 3.2 for both) and were attack-free during the OLE. The AR was increased for patients 4 and 5 (HAE-PLG) and reduced for patient 6 (HAE-PLG). During TP1, 4 of 6 patients (HAE-FXII [n = 2]; HAE-PLG [n = 2]) experienced treatment-emergent adverse events (TEAEs): patient 1 (HAE-FXII) experienced a garadacimab-related TEAE (mild injection-site reaction), and patient 3 (HAE-FXII) experienced an unrelated serious TEAE (severe HAE attack). Patients 1 and 2 (HAE-FXII) collectively experienced 13 mild or moderate TEAEs during TP2 and 2 mild TEAEs during the OLE. CONCLUSIONS:Garadacimab showed a favorable safety profile in all 6 patients with HAE-nC1INH. Garadacimab also demonstrated efficacy in 2 of the 3 patients with HAE-FXII; a reduction in AR was observed in 1 of the 3 patients with HAE-PLG.

Aim: This study aimed to estimate the relative efficacy between garadacimab 200 mg once monthly (200 QM) and two dosing regimens of lanadelumab (300 mg once every 2 weeks [300 Q2W] and 300 mg once every 4 weeks [300 Q4W]) in adolescent/adult patients with hereditary angioedema (HAE) using matching-adjusted indirect comparisons (MAICs), in the absence of head-to-head randomized controlled trials. Materials & methods: Individual patient data were available from the phase II (NCT03712228) and the phase III VANGUARD (NCT04656418) trials investigating garadacimab, and published summarylevel data from the phase III HELP trial investigating lanadelumab (NCT02586805). The primary outcome was time-normalized number of HAE attacks. Secondary efficacy outcomes included time-normalized number of HAE attacks requiring on-demand treatment, time-normalized number of moderate and/or severe HAE attacks, and proportion of attack-free patients. Quality of life (QoL) was also assessed via change from baseline in AE-QoL total score. Results: Compared with lanadelumab 300 Q2W, garadacimab 200 QM statistically significantly reduced number of moderate and/or severe HAE attacks (rate ratio [RR]; 95% confidence interval: 0.25; 0.07, 0.84) and improved AE-QoL score (mean difference: -17.38; - 33.67, -1.08). Compared with lanadelumab 300 Q4W, garadacimab 200 QM showed statistically significant improvements in all outcomes: HAE attacks (RR: 0.29; 0.13, 0.63), attacks requiring on-demand treatment (RR: 0.29; 0.13, 0.66), moderate and/or severe HAE attacks (RR: 0.15; 0.05, 0.49), proportion of attackfree patients (hazard ratio: 3.25; 1.45, 7.29), and AE-QoL score (mean difference: -21.29; -37.39, - 5.18). Conclusion: These MAICs showed improved efficacy and QoL with garadacimab compared with lanadelumab across multiple endpoints. These findings demonstrate that garadacimab may provide improved therapeutic benefit compared with lanadelumab in the long-term prophylactic treatment of patients with HAE.

BACKGROUND AND OBJECTIVES:Several treatments for long-term prophylaxis (LTP) of hereditary angioedema (HAE) are in clinical use, such as garadacimab, lanadelumab, subcutaneous C1 esterase inhibitor (C1INH), and berotralstat. In the absence of head-to-head comparative evidence, indirect comparison methods are needed to compare LTP treatments in patients with HAE. The objective of this analysis was to estimate the comparative efficacy, safety, and impact on quality of life of LTP treatments for patients with HAE through NMAs. METHODS:A systematic literature review was conducted to identify randomized controlled trials (RCTs) investigating LTP treatments in patients (at least 12 years old) with HAE (PROSPERO protocol #CRD42022359207). A network meta-analysis (NMA) feasibility assessment evaluated trial suitability and Bayesian NMAs were conducted for evaluable efficacy, safety, and quality of life (QoL) outcomes. RESULTS:The results of these NMAs show improved efficacy, QoL, and reduced rate of adverse events with garadacimab (200 mg once monthly), lanadelumab (300 mg every two or four weeks), subcutaneous C1INH (60 IU/kg twice weekly), and berotralstat (150 mg once daily) compared to placebo in the treatment of patients with HAE. For the primary outcome of time-normalized number of HAE attacks, garadacimab statistically significantly reduced the rate of attacks compared to lanadelumab Q4W and berotralstat. A similar statistically significant reduction was shown for HAE attacks treated with on-demand treatment. Garadacimab showed statistically significant reduction in the rate of moderate and/or severe HAE attacks compared to lanadelumab Q2W. Garadacimab also showed statistical improvements in change from baseline in AE-QoL total score as compared to berotralstat. CONCLUSIONS:Overall, garadacimab ranked as the most probable effective treatment among all comparators assessed, with lanadelumab Q2W or subcutaneous C1INH ranking second, across most outcomes.

Garadacimab (anti-activated factor XII monoclonal antibody) is being evaluated for long-term prophylaxis of hereditary angioedema (HAE). Inhibition of FXIIa-mediated kallikrein activity can be used as a measure of garadacimab effect. We assessed the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between garadacimab concentration and FXIIa-mediated kallikrein activity, and the impact of intrinsic/extrinsic factors in population subgroups.

Background Garadacimab is a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII. This study evaluated long -term efficacy, health-related quality of life (HRQoL), and safety data for garadacimab in adults with hereditary angioedema. Methods This global phase 2 study comprised a treatment period 1 (TP1: 12 weeks, double -blind, placebo-controlled) and a treatment period 2 (TP2: >= 44-week open -label extension). Patients aged 18-65 years with clinically confirmed hereditary angioedema were eligible. In TP1, 32 patients were randomly assigned (1:1:1:1) to receive subcutaneous garadacimab (75 mg, 200 mg, or 600 mg) or placebo every 4 weeks (once monthly). Randomisation was done using interactive response technology via block randomisation (block sizes 1-4). Subsequently, six additional patients in TP1 were assigned to open -label garadacimab 400 mg every 2 weeks. At the start of TP2, patients were re-randomised (if receiving placebo, garadacimab 75 mg, or garadacimab 400 mg) or continued to receive garadacimab 200 mg or garadacimab 600 mg once monthly. After a protocol amendment on March 20, 2020, patients originally assigned to the 600 mg dose were down-titrated to 200 mg at their next visit. The primary endpoint (published previously) was monthly attack rate for patients receiving 200 mg or 600 mg garadacimab in TP1 in the intention-to-treat population. Here, we assessed the impact of garadacimab on patient-reported and investigator-reported outcomes and HRQoL as well as long -term efficacy and safety. This trial is registered with ClinicalTrials.gov, NCT03712228, and is completed. Findings Of 54 patients screened between Oct 29, 2018, and Aug 28, 2019, 32 randomised and six open -label patients completed TP1 and entered TP2 (20 in the garadacimab 200 mg group; 18 in the garadacimab 600 mg group; total 38 patients). Median age was 390 years (IQR 270-530), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 879 weeks (IQR 500-1066) in the garadacimab 200 mg group and 441 weeks (241-561) in the garadacimab 600 mg group. Median monthly attack rates were 00 (IQR 00-01) in the garadacimab 200 mg group and 0 center dot 1 (00-04) in the garadacimb 600 mg group. Median reduction in monthly attack rate versus run -in was 100% (IQR 98-100) with garadacimab 200 mg. HRQoL improvements observed during TP1 with garadacimab were sustained throughout TP2. TP2 safety signals were consistent with TP1. Two patients experienced serious adverse events of diverticular perforation and asthma (not garadacimab-related). Treatment-emergent adverse events were mostly mild or moderate in severity. The most common adverse events were headache (nine of 38, 24%) and abdominal pain (seven of 38, 18%). There were no treatment-related deaths. Interpretation Once-monthly garadacimab for more than 2 years in patients with hereditary angioedema was well tolerated and efficacious in reducing monthly attack rate and improving HRQoL. These results reveal the potential of long -term prophylactic treatment with 200 mg once-monthly garadacimab towards complete disease control of patients with hereditary angioedema.

Introduction Monoclonal antibody (mAb) treatment may induce anti-drug antibodies (ADAs). We report integrated immunogenicity data across Phase 1, Phase 2, pivotal Phase 3 (VANGUARD), and Phase 3 open-label extension (OLE) studies evaluating garadacimab (anti-activated factor XII mAb) for hereditary angioedema (HAE) long-term prophylaxis. Methods ADAs against garadacimab were monitored by bridging immunogenicity assay across three Phase 1, single-ascending dose studies in healthy volunteers (follow-up 85 days). ADAs were also monitored in patients with HAE treated with garadacimab subcutaneously in a Phase 2 study (12-week placebo-controlled period, subsequent ≥44-week open-label period; 75/200/600 mg once-monthly or 400 mg every 2 weeks), pivotal Phase 3 study (6-month placebo-controlled period) and ongoing OLE study (both 200 mg once-monthly; data ≤1.8 years, cut-off February 2023). Results No ADAs were reported following a single dose in healthy volunteers (N=201). Low incidence of ADAs was reported in patients with HAE from Phase 2 and 3 studies (2.9%, 5/172), all with low reciprocal titers (≤320). Monthly HAE attack rate in patients with ADAs during 5.3–14.3 months of garadacimab treatment ranged 0.0–0.2 (Table), which was consistent with the attack rate in the overall population (0.2–0.3). Of patients with treatment-emergent ADAs, 2/5 experienced no treatment-emergent adverse event (TEAE); 3/5 experienced non-serious mild/moderate TEAEs (non-treatment-related, n=1; treatment-related, n=2; Table). ADAs did not impact pharmacokinetics: garadacimab concentrations were within range observed in patients without ADA. Conclusion Throughout the clinical development program, incidence and titers of garadacimab immunogenicity were low, with no observed impact on efficacy, safety, pharmacodynamics or pharmacokinetics.

Introduction Hereditary angioedema (HAE) attacks are recurrent, unpredictable, debilitating, and potentially life-threatening. Current guidelines state HAE treatment goals are complete disease control and normalization of life. Garadacimab, a fully human, once-monthly, anti-activated factor XII monoclonal antibody, was evaluated as HAE long-term prophylaxis in the pivotal Phase 3 (VANGUARD) study, and 62% of garadacimab-treated patients were attack-free (all patients receiving placebo experienced attacks). This post hoc analysis evaluated potential association between baseline patient characteristics and attack-free status. Methods In the 6-month, randomized, pivotal Phase 3 (VANGUARD) study, patients received garadacimab 200 mg subcutaneously (n=39) or placebo (n=25) once monthly. Patients treated with garadacimab who were attack-free (n=24) vs those with ≥1 attack (n=15) were compared across patient characteristics: age, body mass index, age at diagnosis, attacks per month during the run-in period, rate of mild/moderate/severe attacks during the run-in period, and combined rate of moderate/severe attacks during the run-in period. Youden-index was calculated for each characteristic, whereby 0 indicates no predictive ability for attack-free status and 1 indicates perfect predictive ability. Results All evaluated characteristics had low predictive ability for attack-free status (Youden-index range 0.18–0.39; sensitivity 25.0–79.2%; specificity 53.3–93.3%; Table). Attacks per month during the run-in period had the highest predictive power, but still had a low ability to predict attack-free status (Youden-index 0.39). Conclusion In the pivotal Phase 3 (VANGUARD) study, patients with HAE achieved attack-free status with garadacimab independently of evaluated baseline patient characteristics. Regardless of baseline characteristics, patients with HAE have the potential to achieve attack-free status with garadacimab.

This open-label, parallel-group, Phase 1, single-center, bridging study characterized the pharmacokinetic parameters of a single subcutaneous garadacimab injection administered via autoinjector/pre-filled pen (AI/PFP) or needle safety device (NSD) in healthy adults.

Hereditary angioedema (HAE) attacks are unpredictable and debilitating. We report integrated safety and efficacy across Phase 2, pivotal Phase 3, and open-label extension (OLE) studies evaluating garadacimab (anti-activated factor XII monoclonal antibody) for HAE prophylaxis. Subcutaneous garadacimab was evaluated in an integrated analysis comprising Phase 2 (12-week placebo-controlled period with subsequent open-label period; 75/200/600 mg once-monthly or 400 mg once every 2 weeks), pivotal Phase 3 (6-month placebo-controlled period), and >12-month OLE studies (both 200 mg once-monthly). Endpoints included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs, per protocol: thromboembolic/abnormal bleeding events, severe hypersensitivity/anaphylaxis) and efficacy. Overall, 172 patients received garadacimab (any dose; median [range] exposure 1.3 [0.2–4.2] years; 83.1% and 19.2% had ≥1 and ≥2 years' exposure, respectively). Of these, 148/172 (86%) experienced ≥1 TEAE (97.6% mild/moderate), an exposure-adjusted rate of 3.1 TEAE/patient-year. Seven patients experienced SAEs, none garadacimab-related. One AESI per protocol was experienced by 1 patient (Phase 2, 600 mg, epistaxis, not garadacimab-related). The most common garadacimab-related TEAEs were mild/moderate injection-site reactions. Per integrated efficacy set, the mean (standard deviation) monthly attack rate in garadacimab 200 mg-treated patients (n=164) was 0.17 (0.40) versus 3.55 (2.40) during run-in, corresponding to a 94.2% reduction. Over a median 1.2 years' observation, the majority of garadacimab-treated patients (94/164, 57.3%) remained attack-free. No placebo-receiving patients (n=25) were attack-free. These data further corroborate the robust garadacimab efficacy over >1 year for long-term HAE prophylaxis along with the favorable and consistent safety profile so far observed.

Background: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunc-tional C1-esterase inhibitor (C1-INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1-INH in Japanese patients with HAE.Methods: The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1-INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1-INH functional activity at Week 16.Results: Nine patients entered the treatment period and completed the study. Treatment with C1-INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1-INH (SC) at Week 16, the mean trough concentration of C1-INH was 59.8%, and the mean area under the plasma concentration-time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h.%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation. Conclusions: C1-INH (SC) (60 IU/kg twice weekly) was efficacious and well tolerated as a prophylaxis against HAE attacks in Japanese patients with HAE types I or II, which was supported by the increased and maintained C1-INH functional activity. EudraCT Number 2019-003921-99; JapicCTI-205273 & COPY; 2023 Japanese Society of Allergology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The efficacy and safety of garadacimab, a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII for the prevention of hereditary angioedema (HAE) attacks, were evaluated in a randomized, placebo-controlled, 6-month, Phase 3 trial (NCT04656418). Patients aged ≥12 years with type I/II HAE were randomized (3:2) to receive monthly subcutaneous (SC) garadacimab 200 mg or placebo after an initial SC loading dose of garadacimab 400 mg or volume-matched placebo. Efficacy, safety, and quality-of-life (QOL) measures were assessed. Once-monthly SC garadacimab significantly reduced the attack rate (AR) compared with placebo (p<0.001), resulting in an AR reduction of 86.5% (95% CI: 57.8–95.7). Adjusted for baseline AR, garadacimab-treated patients (n=39) experienced mean monthly ARs of 0.22 vs 2.07 for placebo-administered patients (n=24), resulting in an AR reduction vs placebo of 89.2% (95% CI: 75.6–95.2). Twenty-four (61.5%) garadacimab-treated patients were attack-free during the 6-month study, and 74.4% achieved ≥90% attack reduction vs the run-in period. The time to first attack was ≥72 days for 75% of garadacimab-treated patients vs 5 days for placebo-administered patients. Forty (62.5%) patients experienced ≥1 treatment-emergent adverse event (TEAE), totaling 129 events, including one severe, serious non-related TEAE (overnight hospital observation for laryngeal attack). The most common TEAEs were 5 mild injection-site reactions from 4 (6%) patients. No adverse events led to discontinuation. Angioedema-QOL total mean score improved by 23.7 points following first garadacimab administration. Once-monthly SC garadacimab was well tolerated throughout the treatment period and significantly reduced the AR vs placebo in patients with HAE.

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 center dot 27, 95% CI 0 center dot 05 to 0 center dot 49) than in the placebo group (2 center dot 01, 1 center dot 44 to 2 center dot 57; p<0 center dot 0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0 center dot 0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0 center dot 00-0 center dot 31) for garadacimab and 1 center dot 35 (1 center dot 00-3 center dot 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.Copyright (c) 2023 Elsevier Ltd. All rights reserved.

What is this summary about? This summarizes an article about the clinical study 'VANGUARD' that was published in The Lancet journal in February 2023. Hereditary angioedema (HAE) is a rare genetic disease that causes swellings throughout the body (called HAE attacks). HAE attacks in the upper airways (including the tongue and vocal cords) can be life threatening by making breathing difficult. HAE attacks may occur frequently and without warning, and people with HAE have a lower quality of life than other people. In the VANGUARD study, researchers tested the safety of a new medicine called garadacimab and whether it could prevent HAE attacks. Garadacimab was injected subcutaneously (just under the skin) with a needle once a month. What were the results? In the VANGUARD study, patients took garadacimab or placebo (an identical-looking dummy substance with no medical effect, used for comparison). The aim was to see if garadacimab could prevent HAE attacks better than placebo. Patients taking garadacimab had very few or no HAE attacks, but those taking placebo carried on having attacks. Garadacimab gave protection from HAE attacks shortly after it was first used, and this carried on for the 6 months of treatment. Most patients taking garadacimab (62%) had no HAE attacks throughout the 6 months of treatment (were attack free), but 100% of patients taking placebo had HAE attacks throughout the study. More patients taking garadacimab (82%) than placebo (33%) had a 'good' or 'excellent' experience living with HAE. Patients taking garadacimab and placebo had similar rates of side effects. Only 5% (2 out of 39) of patients taking garadacimab had discomfort or skin changes at the place of injection compared with 12% (3 out of 25) taking placebo. What do the results mean? Taking garadacimab once a month helps prevent HAE attacks from happening, with most patients being attack free throughout the 6 months of treatment. Garadacimab had very few and mostly mild or moderate side effects. Overall, garadacimab is a beneficial treatment for preventing HAE attacks.