LOW INCIDENCE OF GARADACIMAB IMMUNOGENICITY WITH NO IMPACT ON EFFICACY, SAFETY OR PHARMACOKINETICS: INTEGRATED ANALYSIS

Abstract

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.