Garadacimab for hereditary angioedema attack prevention: long-term efficacy, quality of life, and safety data from a phase 2, randomised, open-label extension study.

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 39·0 years (IQR 27·0-53·0), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 87·9 weeks (IQR 50·0-106·6) in the garadacimab 200 mg group and 44·1 weeks (24·1-56·1) in the garadacimab 600 mg group. Median monthly attack rates were 0·0 (IQR 0·0-0·1) in the garadacimab 200 mg group and 0·1 (0·0-0·4) 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.
Funding: CSL Behring.
Competing Interests: Declaration of interests TJC is a speaker for CSL Behring, Takeda, BioMarin, Astria, Regeneron, and Grifols, and has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, BioMarin, Intellia, KalVista, Pharvaris, Ionis, Astria, and GlaxoSmithKline; he is on the Medical Advisory Board for the US Hereditary Angioedema Association and is Director of the Angioedema Centers of Reference and Excellence International Angioedema Center at Penn State University, Hershey, PA, USA. DSL received research grants from, and is a speaker and consultant for, CSL Behring, Takeda, BioCryst, Grifols, Pharming, and KalVista. AR received research grants as a principal investigator, speaker, and adviser for CSL Behring, Takeda/Shire, BioCryst, Pharming, Pharvaris, Ionis, and Shulov Innovative Science. WRL is a speaker for CSL Behring, Pharming, AstraZeneca, Sanofi and Regeneron, GlaxoSmithKline, and Takeda/Shire, and has served as a consultant for BioCryst, BioMarin, CSL Behring, Fresenius Kabi, Intellia, KalVista, Pharming, Pharvaris, and Takeda/Shire; WRL is also a board member of the US Hereditary Angioedema Association Medical Advisory Board, and has received grants or research support from ALK, BioCryst, CSL Behring, Ionis, Gossamer, KalVista, Kedrion, Therapure, and Takeda/Shire. IM-S has received honoraria, research funding, and travel grants from BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire, and has served as a consultant or participated in advisory boards for these companies. JSJ is a speaker for Takeda/Shire, CSL Behring, Teva, AstraZeneca, GlaxoSmithKline, Sanofi Genzyme, and Regeneron, and has received research funding or consultancy fees from CSL Behring, Takeda/Shire, BioCryst, Novartis, Genentech, AstraZeneca, Allakos, Fresenius Kabi, GlaxoSmithKline, and Regeneron. WHY has been a speaker and advisory board member for, and has received honoraria from, CSL Behring, Takeda/Shire, Novartis, Sanofi Genzyme, and Merck; he has received research grants from CSL Behring, Takeda/Shire, BioCryst, Pharming, Aimmune, DBV Technologies, Eli Lilly, Pharvaris, AstraZeneca, Novartis, GlaxoSmithKline, Genentech/Roche, Amgen, Sanofi Genzyme, Regeneron, Galderma, AnaptysBio, Glenmark, ALK, Dermira, Ionis, and Celgene; and he also serves as a medical adviser (volunteer) for Hereditary Angioedema Canada, a patient organisation, and is a member of ACARE. BR has been a speaker and advisory board member for CSL Behring and Takeda but has not received personal reimbursement for these activities; he has participated in multiple clinical trials involving investigational drugs for CSL Behring, Takeda, BioCryst, Dyax, and Pharming; and he serves as a volunteer medical scientific adviser to Hereditary Angioedema Canada, a patient organisation. EA-P has received honoraria as a speaker, adviser, or as grant support or clinical trial investigator support from Astria Therapeutics, BioCryst, BioMarin Europe, Centogene, CSL Behring, Intellia, KalVista, Pharming Technologies, Pharvaris, and Takeda/Shire. PKK has been a speaker, advisory board member, or consultant for, and has received honoraria from, ALK, AstraZeneca, Bausch, BioCryst, Canadian Agency for Drugs and Technologies in Health, Canadian Pharmacists Association, CSL Behring, GlaxoSmithKline, Medexus, Merck, Novartis, Sanofi Genzyme, Takeda/Shire, and Valeo; has received research grants from CSL Behring and Takeda/Shire; serves as a medical adviser (volunteer) for Hereditary Angioedema Canada, a patient organisation; serves as a board member (volunteer) for the Canadian Hereditary Angioedema Network, a physician organisation; and is an employee of McMaster University. PB has been a speaker, advisory board member, or consultant for, and has received honoraria from, BioMarin, BioCryst, CSL Behring, CVS Specialty, Ionis, KalVista, Medscape, Novartis, Pharvaris, Prime, Regeneron, and Takeda; and has received research funding from CSL Behring, KalVista, and Takeda. MM has received financial support from CSL Behring for acting as a study-centre investigator during the conduct of the study, and consulting fees from CSL Behring, Takeda/Shire, Pharming Technologies, BioCryst, Novartis, Octapharma, and KalVista outside of the submitted work. At the time of the study, HF, MAB, IJ, and IP were employees of CSL Behring Innovation GmbH (HF, MAB, IP) or CSL Behring LLC (IJ) and shareholders of CSL Ltd.
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