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Interplay between on-demand treatment trials for hereditary angioedema and treatment guidelines
Danny M Cohn1, Daniel F Soteres2, Timothy J Craig3
1Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Abstract:
Over the past 2 decades, guidelines for the on-demand treatment of hereditary angioedema attacks have undergone significant evolution. Early treatment guidelines, such as the Canadian 2003 International Consensus Algorithm, often gated on-demand treatment by attack location and/or severity. Pivotal trials for on-demand injectable treatments (plasma-derived C1 esterase inhibitor, icatibant, ecallantide [United States only], and recombinant human C1 esterase inhibitor), which were approved in the United States and the European Union between 2008 and 2014, were designed accordingly. Subsequent post hoc analyses of clinical trial data alongside real-world evidence led to a paradigm shift. In 2013, the US Hereditary Angioedema Association guidelines recommended that all attacks, irrespective of location or severity, be considered for treatment as early as possible after onset to minimize morbidity and mortality. This approach remains the cornerstone of current treatment guidelines and has shaped the design of recent clinical trials, such as those for the investigational agents, oral plasma kallikrein inhibitor sebetralstat and oral bradykinin B2 receptor antagonist deucrictibant. This narrative review discusses the evolution of on-demand treatment guidelines, the clinical trial and real-world data that prompted significant revisions, and the subsequent changes to trial designs introduced to facilitate guideline compliance.
Insights
Hereditary angioedema (HAE) on-demand treatment guidelines evolved from restricting therapy by attack severity to recommending early treatment for all attacks. This shift, supported by clinical and real-world data, now influences new HAE drug development.
Area of Science:
- Immunology
- Pharmacology
- Clinical Medicine
Background:
- On-demand treatment guidelines for hereditary angioedema (HAE) attacks have evolved significantly over 20 years.
- Early guidelines restricted treatment based on attack location and severity.
- Pivotal trials for injectable HAE treatments (approved 2008-2014) were designed around these restrictive guidelines.
Purpose of the Study:
- To review the evolution of on-demand HAE treatment guidelines.
- To examine the clinical trial and real-world evidence that drove guideline revisions.
- To discuss how revised guidelines impact the design of trials for new HAE therapies.
Main Methods:
- Narrative review of historical and current treatment guidelines for HAE.
- Analysis of pivotal clinical trial data and real-world evidence for on-demand HAE therapies.
- Examination of clinical trial designs for investigational HAE agents in light of guideline changes.
Main Results:
- A paradigm shift occurred in HAE treatment recommendations, moving away from location/severity gating.
- US HAE Association guidelines (2013) now advocate for treating all attacks as early as possible.
- This updated approach influences the design of trials for novel oral HAE therapies like sebetralstat and deucrictibant.
Conclusions:
- On-demand treatment guidelines for HAE have shifted towards universal and early intervention.
- Clinical and real-world evidence were crucial in driving this guideline evolution.
- Current and future HAE clinical trial designs are adapting to align with these patient-centered guidelines.
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