IN VIVO CRISPR/CAS9 EDITING OF KLKB1 IN PATIENTS WITH HEREDITARY ANGIOEDEMA: A FIRST-IN-HUMAN STUDY

Abstract

<h3>Introduction</h3> Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent, debilitating and potentially fatal swelling attacks. Prophylactic treatments targeting kallikrein, a protease encoded by the <i>KLKB1</i> gene, significantly reduce the frequency of attacks. NTLA-2002 is an investigational CRISPR/Cas9-based therapy targeting <i>KLKB1</i> in hepatocytes, with the goal of achieving life-long control of HAE attacks after a single administration. <h3>Methods</h3> NCT05120830 is a first-in-human phase 1/2 study of NTLA-2002 in patients with HAE. The phase 1 is a single-ascending dose design with the primary objective of evaluating safety and identifying up to two doses to advance to the randomized phase 2 for further evaluation of efficacy and safety. <h3>Results</h3> Cohort 1 (25 mg; n = 3) completed the 16-week primary observation period. No DLTs or clinically significant laboratory abnormalities were observed. TEAEs were non-serious and spontaneously resolving, with the most common being infusion-related reactions (n = 2; CTCAE G1). All subjects demonstrated clinically significant, durable reduction in plasma kallikrein levels (mean 62 ± 27% at week 16) and HAE attack frequency from baseline, with 2 subjects remaining attack-free since infusion. Three subjects have been treated in Cohort 2 (75 mg). Follow-up is ongoing for all subjects in both cohorts. <h3>Conclusion</h3> A single 25 mg dose of NTLA-2002 has been well-tolerated to date, meeting pre-specified criteria for advancement to phase 2 with reduction in plasma kallikrein levels and HAE attack rate maintained throughout the 16-week period following infusion. Safety, pharmacodynamic and HAE attack rate data for both cohorts will be presented.