Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jun;25(2):161-178.
doi: 10.1007/s40268-025-00511-y. Epub 2025 May 28.

Network Meta-Analysis of Pharmacological Therapies for Long-Term Prophylactic Treatment of Patients with Hereditary Angioedema

Sarah Walsh  1 , Meaghan Bartlett  1 , Elizabeth M Salvo-Halloran  1 , John Sears  2 , Yinglei Li  2 , Maebh Kelly  3 , Simona Gavata-Steiger  4 , Chiara Nenci  4 , Iris Jacobs  2 , Ingo Pragst  5 , Neelanjana Ray  2 , Imtiaz A Samjoo  6
Affiliations

Network Meta-Analysis of Pharmacological Therapies for Long-Term Prophylactic Treatment of Patients with Hereditary Angioedema

Sarah Walsh et al. Drugs R D. 2025 Jun.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Declarations. Funding: This work was supported by CSL Behring. The authors have received no other financial and/or material support for this research or the creation of this work apart from that disclosed. Conflict of interest: John Sears, Yinglei Li, Iris Jacobs, and Neelanjana Ray are employees of CSL Behring, USA. Maebh Kelly is an employee of CSL Behring Ltd. Simona Gavata-Steiger and Chiara Nenci are employees of CSL Behring AG. Ingo Pragst is an employee of CSL Innovation GmbH, Germany. Sarah Walsh, Meaghan Bartlett, Elizabeth M. Salvo-Halloran, and Imtiaz A. Samjoo are employees of EVERSANA, Canada, which was a paid consultant to CSL Behring in connection with the development of this article. Ethics approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable. Availability of data and material: Openly available data that support the findings of this study are available within the paper and its supplementary information. Data that are not openly available are available upon reasonable request in accordance with the internal CSL Behring data sharing policy. Code availability: Not applicable. Author contributions: All authors participated in the conception and design of the study. SW, MB, EH, and IAS contributed to the collection and analysis of the data. All authors contributed to the interpretation of the data and critically reviewed for the importance of intellectual content for the work. All authors were responsible for drafting or reviewing the manuscript and for providing final approval. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and have given their approval for this version to be published.

Figures

Fig. 1
Fig. 1
Evidence network for the time-normalized number of hereditary angioedema attacks. C1INH C1 esterase inhibitor, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 2
Fig. 2
Evidence network for the proportion of attack-free patients. C1INH C1 esterase inhibitor, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 3
Fig. 3
Evidence network for the time-normalized number of hereditary angioedema attacks treated with on-demand therapy. C1INH C1 esterase inhibitor, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 4
Fig. 4
Evidence network for the time-normalized number of moderate and/or severe hereditary angioedema attacks. C1INH C1 esterase inhibitor, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 5
Fig. 5
Evidence network for treatment-emergent adverse events. C1INH C1 esterase inhibitor, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 6
Fig. 6
Evidence network for the change from baseline in the angioedema quality-of-life total score. GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 7
Fig. 7
Forest plot (active treatments vs placebo) for the fixed-effect network meta-analysis of the time-normalized number of hereditary angioedema attacks. C1INH C1 esterase inhibitor, CrI credible interval, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 8
Fig. 8
League table for the fixed-effect network meta-analysis of the time-normalized number of hereditary angioedema attacks. Values are rate ratios (95% credible interval) for relative effectiveness for all possible pairs of treatments in the network. A rate ratio < 1 implies that the column is better than the row. Pink squares are statistically significant. C1INH C1 esterase inhibitor, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 9
Fig. 9
Forest plot (active treatments vs placebo) for a fixed-effect network meta-analysis of the proportion of attack-free patients. C1INH C1 esterase inhibitor, CrI credible interval, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 10
Fig. 10
League table for the fixed-effect network meta-analysis of the proportion of attack-free patients. Values are hazard ratio (95% credible interval) for relative effectiveness for all possible pairs of treatments in the network. A hazard ratio > 1 implies that the column is better than the row. Pink squares are statistically significant. C1INH C1 esterase inhibitor, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 11
Fig. 11
Forest plot (active treatments vs placebo) for the fixed-effect network meta-analysis of the time-normalized number of hereditary angioedema attacks treated with on-demand therapy. C1INH C1 esterase inhibitor, CrI credible interval, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 12
Fig. 12
League table for the fixed-effect network meta-analysis of the time-normalized number of hereditary angioedema attacks treated with on-demand therapy. Values are rate ratio (95% credible interval) for relative effectiveness for all possible pairs of treatments in the network. A rate ratio < 1 implies that the column is better than the row. Pink squares are statistically significant. C1INH C1 esterase inhibitor, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 13
Fig. 13
Forest plot (active treatments vs placebo) for a fixed-effect network meta-analysis of the time-normalized number of moderate and/or severe hereditary angioedema attacks. C1INH C1 esterase inhibitor, CrI credible interval, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 14
Fig. 14
League table for the fixed-effect network meta-analysis of time-normalized number of moderate and/or severe hereditary angioedema attacks. Values are rate ratios (95% credible interval) for relative effectiveness for all possible pairs of treatments in the network. A rate ratio < 1 implies that the column is better than the row. Pink squares are statistically significant. C1INH C1 esterase inhibitor, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 15
Fig. 15
Forest plot (active treatments vs placebo) for the fixed-effect network meta-analysis of treatment-emergent adverse events. C1INH C1 esterase inhibitor, CrI credible interval, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 16
Fig. 16
League table for the fixed-effect network meta-analysis of treatment-emergent adverse events. Values are hazard ratio (95% credible interval) for relative effectiveness for all possible pairs of treatments in the network. A hazard ratio > 1 implies that the column is better than the row. Pink squares are statistically significant. C1INH C1 esterase inhibitor, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 17
Fig. 17
Forest plot (active treatment vs placebo) for a fixed-effect network meta-analysis of a change from baseline in the angioedema quality-of-life total score. CrI credible interval, GARA 200 QM garadacimab 200 mg once monthly, HAEG 60 BIW subcutaneous C1INH 60 IU/kg twice weekly, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
Fig. 18
Fig. 18
League table for the fixed-effect network meta-analysis of a change from baseline in the angioedema quality-of-life total score. Values are mean difference (95% credible interval) for relative effectiveness for all possible pairs of treatments in the network. A mean difference < 0 implies that the column is better than the row. Pink squares are statistically significant. GARA 200 QM garadacimab 200 mg once monthly, ORL 150 QD berotralstat 150 mg once daily, PBO placebo, TAK 300 Q2W lanadelumab 300 mg once every 2 weeks, TAK 300 Q4W lanadelumab 300 mg once every 4 weeks
See this image and copyright information in PMC

References

    1. Lumry WR. Hereditary angioedema: the economics of treatment of an orphan disease. Front Med (Lausanne). 2018;5:22. - PMC - PubMed
    1. Bernstein J. Severity of hereditary angioedema, prevalence, and diagnostic considerations. AM J Manag Care. 2018;24(14 Suppl.):S292–8. - PubMed
    1. Raja A, Shuja MH, Raja S, Qammar A, Kumar S, Khurram L, et al. Efficacy and safety of donidalorsen in hereditary angioedema with C1 inhibitor deficiency: a systematic review and a meta analysis. Arch Dermatol Res. 2025;317(1):110. - PubMed
    1. Caballero T. Treatment of hereditary angioedema. J Investig Allergol Clin Immunol. 2021;31(1):1–16. - PubMed
    1. Busse PJ, Christiansen SC, Riedl MA, Banerji A, Bernstein JA, Castaldo AJ, et al. US HAEA medical advisory board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin Immunol Pract. 2021;9(1):132-50.e3. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources