OBJECTIVES: Hereditary angioedema (HAE) substantially impairs quality of life (QoL). World Allergy Organization/European Academy of Allergy and Clinical Immunology guideline treatment goals are complete disease control and to normalize patients’ lives. Garadacimab (anti-activated factor XII monoclonal antibody) demonstrated durable protection from HAE attacks with a favorable safety profile in the pivotal Phase 3 VANGUARD study, associated with QoL improvements. Here, we evaluate the meaningfulness of QoL improvements with garadacimab vs placebo in the Phase 3 study, as per the 2023 Food and Drug Administration (FDA) patient-focused drug development guidance and Institute for Quality and Efficiency in Health Care (IQWiG) methods.

METHODS: Patients with HAE in the 6-month, randomized, Phase 3 study received garadacimab 200 mg subcutaneously (400 mg loading dose; n=39) or placebo (n=25) once-monthly. Angioedema (AE)- QoL questionnaire (exploratory endpoint) assessed QoL across four domains (functioning, nutrition, fatigue/mood, fear/shame); higher scores indicate greater impairment. The likelihood and magnitude of AE-QoL improvement with garadacimab vs placebo was evaluated with meaningful score differences (MSDs) equivalent to recommended AE-QoL clinically meaningful thresholds (−6 per literature and a more stringent threshold of −15 per IQWiG).

RESULTS: At Month 6, separation between cumulative distribution frequency plots for all changes from baseline were observed across all AE-QoL domains and total score between garadacimab and placebo. More patients with garadacimab (MSD −6: 88%, MSD −15: 80%) improved beyond AE-QoL total score MSD vs placebo (MSD −6: 60%, MSD −15: 30%) with greater separation at the higher MSD -15. The average difference in AE-QoL total score was 22.0, exceeding both pre-established MSD thresholds. The difference in all individual AE-QoL domains was >15 except nutrition (11.7).

CONCLUSIONS: Using FDA recommended methods for AE-QoL interpretation, patients with HAE are more likely to experience a clinically meaningful improvement in QoL when receiving garadacimab compared with placebo, exceeding both clinically meaningful thresholds.