PHARMACOMETRIC ANALYSIS SUPPORTS EARLY ONSET OF PROTECTION WITH GARADACIMAB AGAINST HEREDITARY ANGIOEDEMA ATTACKS

Abstract

Introduction

Garadacimab (anti-activated factor XII antibody) demonstrated durable protection against hereditary angioedema (HAE) attacks with favorable long-term safety/tolerability profiles in clinical studies. Pharmacometric analyses assessed the relationship between garadacimab pharmacokinetics (PK) and attack rate (AR).

Methods

A repeated-time-to-event exposure–response (ER) model relating longitudinal garadacimab concentration with AR was built with data from 177 unique patients with HAE who received garadacimab/placebo across Phase 2 and Phase 3 (pivotal and open-label extension) studies. Simulations (n=1000) were used to infer efficacy (i.e., predicted AR and relative risk of attacks) of garadacimab 200 mg subcutaneous (SC) once-monthly dosing regimen with 2x200 mg SC loading dose (LD) as first administration.

Results

Per pivotal Phase 3 PK data, garadacimab achieved steady-state exposures as early as Week 1 after LD (first administration) and remained at steady state between subsequent once-monthly dosing intervals. ER predictions demonstrated increasing efficacy with increasing exposure, with higher probability of exceeding and remaining above the target therapeutic threshold of ≥90% relative-risk reduction in attacks after LD (first administration). Population predictions demonstrated exposures above target therapeutic threshold for most patients, with 75% predicted to achieve ≥90% AR reduction vs run-in at steady state. ER-predicted ARs rapidly declined after LD (first administration) and remained consistently low throughout treatment.

Conclusion

PK data and ER predictions demonstrated garadacimab achieving steady-state exposures after LD (first administration) and maintaining steady–state exposures over subsequent once-monthly dosing intervals. LD maximizes the likelihood of reaching target therapeutic threshold resulting in early onset of protection against attacks as early as Week 1 after first administration.