PI-087 - POPULATION PHARMACOKINETICS AND EXPOSURE-RESPONSE ANALYSIS FOR NTLA-2002 IN PATIENTS WITH HEREDITARY ANGIOEDEMA

A. Abdelhady¹, R. Wada², P. Ko³, D. Maag¹, M. Shah¹, J. Butler¹, A. Golden¹, P. Zhu¹; ¹Intellia Therapeutics, Cambridge, MA, USA, ²QuanTx Consulting, Mountain View, CA, USA, ³QuanTx, San Diego, CA, USA.

Background: NTLA-2002 is an investigational, in vivo CRISPR-based therapy designed to reduce total plasma kallikrein protein levels by permanently editing the KLKB1 gene to prevent angioedema attacks after a single intravenous dose. NTLA-2002 employs a proprietary lipid nanoparticle (LNP) delivery system to direct CRISPR/Cas9 components to the liver, where KLKB1 is expressed. The pharmacometrics analyses presented here characterize the population pharmacokinetics (PK), and exposure-response (ER) relationships to support the Phase 3 dose selection based on data from the first-in-human Ph1/2 study (NCT05120830).

Methods: The analyses were performed using pooled data from Ph1 (open label; dose escalation) and Ph2 (placebo-controlled; double-blind) parts of the trial. A total of 37 patients (10 in Ph1, 27 in Ph2) who received a single dose of 25, 50, or 75mg of NTLA-2002 or placebo were included. PopPK and ER analyses applied non-linear mixed-effects modeling with NONMEM and R. The PopPK model describes the liver uptake and endocytosis by hepatocytes followed by endosomal breakdown, after which the components of NTLA-2002 are recirculated into plasma. Liver transaminases were characterized by linear mixed-effects models. Kallikrein reduction was characterized by sigmoid-Emax model. HAE attack related endpoints were characterized by logistic regression Emax models and Poisson regression Emax models.

Results: PK of NTLA-2002 components showed dose proportional plasma exposure. The PK of LP000001, a representative analyte, was adequately characterized by a 3-compartment model. Exposure-response analyses demonstrated that NTLA-2002 is projected to be well-tolerated with a low risk of transaminase elevations exceeding 3xULN over an 8-week period following a single dose up to 75mg. Furthermore, plasma exposures equivalent to 50mg or higher are projected to achieve clinically meaningful (>90%) reduction in HAE monthly attack rate.

Conclusion: The totality of the observed safety, efficacy, and pharmacodynamic data accompanied by the quantitative PopPK and ER analyses support the selection of a 50mg dose for further investigation in Phase 3.