PB1076 - Reduction of plasma kallikrein by in vivo CRISPR-based gene editing of KLKB1 does not alter coagulation in patients with hereditary angioedema

Tuesday, June 25, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Remy S. Petersen, MD

PhD Candidate
Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Amsterdam, Noord-Holland, Netherlands

Co-Author(s)

DC

Danny M. Cohn

M.D. PhD
Amsterdam University Medical Center, Amsterdam, the Netherlands
Amsterdam, Noord-Holland, Netherlands
PG

Padmalal Gurugama

Clinical Fellow in Clinical Immunology and Allergy
Cambridge University Hospitals, NHS Foundation Trust
Cambridge, England, United Kingdom
KL

Karen Lindsay

M.B., Ch.B.
Te Whatu Ora/Te Toka Tumai, Auckland, New Zealand
Auckland, Auckland, New Zealand
LF

Lauré M. Fijen

M.D. PhD
Amsterdam University Medical Center, Amsterdam, the Netherlands
Amsterdam, Noord-Holland, Netherlands
AG

Adele Golden

PhD
Intellia Therapeutics, Cambridge, MA, USA
Cambridge, Massachusetts, United States
CB

Carri Boiselle

Principal Scientist
Intellia Therapeutics
Cambridge, Massachusetts, United States
YX

Yuanxin Xu

M.D. PhD
Intellia Therapeutics, Cambridge, MA, USA
Cambridge, Massachusetts, United States
JB

James Butler

M.B.A.
Intellia Therapeutics, Cambridge, MA, USA
Cambridge, Massachusetts, United States
MS

Mrinal Y. Shah

PhD
Intellia Therapeutics, Cambridge, MA, USA
Cambridge, Massachusetts, United States
DM

David Maag

Senior Medical Director
Intellia Therapeutics
Cambridge, Massachusetts, United States
HL

Hilary Longhurst

Clinical Allergist and Immunologist
Te Whatu Ora/Te Toka Tumai
Auckland, Auckland, New Zealand

Background:

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by severe and unpredictable swelling attacks, resulting from a dysregulated contact activation pathway and increased bradykinin production. Kallikrein inhibition has been clinically validated as a therapeutic target for treatment of HAE. Individuals with congenital prekallikrein deficiency (Fletcher factor syndrome) are reported to be healthy aside from observed prolongation of activated partial thromboplastin time (aPTT), which does not appear to be associated with increased risk of hemorrhage. NTLA-2002 is an in vivo CRISPR-based gene editing therapy administered as a one-time treatment to reduce total plasma kallikrein protein levels by permanently editing the KLKB1 gene to prevent angioedema attacks.

Aims: To determine effects of KLKB1 reduction on aPTT in patients treated with NTLA-2002.

Methods: A phase 1/2 study of adults with HAE is ongoing. Phase 1 dose escalation is complete; the primary endpoint was safety/tolerability. Patients received a single dose of NTLA-2002: 25mg (N=3), 50mg (N=4), or 75mg (N=3). aPTT was measured utilizing standard silica-based mechanical detection methods.

Results: At the time of analysis, median duration of follow-up was 9.0 months. The most frequent adverse events (AEs) were infusion-related reactions and fatigue. No treatment-emergent serious AEs or ≥Grade 3 AEs were observed. No patients experienced thromboembolic or bleeding events. A dose-dependent reduction in total plasma kallikrein was observed, with mean reductions from baseline of 67%, 84%, and 95% at the 25mg, 50mg, and 75mg doses, respectively, without prolongation of aPTT (Table, Figure). A mean reduction from baseline of 95% was observed in monthly angioedema attack rate in all patients. An updated analysis will be presented.

Conclusion(s): A single dose of NTLA-2002 was well-tolerated. Treatment resulted in a significant, dose-dependent reduction in total plasma kallikrein and a decreased rate of angioedema attacks without apparent clinical consequence as related to the coagulation pathway.