PII-087 - POPULATION PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) MODELING OF DONIDALORSEN, AN ANTISENSE OLIGONUCLEOTIDE IN DEVELOPMENT FOR PROPHYLAXIS OF HEREDITARY ANGIOEDEMA.

J. Diep¹, M. Liu¹, P. Singh¹, S. Dorow¹, L. Bordone¹, K. Newman¹, X. Gao¹; ¹Ionis, Carlsbad, CA, USA.

Background: Hereditary angioedema (HAE) is a rare disorder linked to kallikrein-kinin system dysregulation which leads to uncontrolled activation of plasma prekallikrein. Donidalorsen is an investigational ligand-conjugated antisense oligonucleotide designed to selectively degrade prekallikrein mRNA and thereby reduce the production of prekallikrein protein. We characterized the PK/PD of donidalorsen to evaluate the impact of potential intrinsic/extrinsic covariates on exposure and prekallikrein response.

Methods: A population PK/PD model was developed using plasma donidalorsen and prekallikrein concentration data collected from Phase 1 to 3 studies in healthy volunteers (NCT03263507, 721744-CS9) and adult (≥ 18 years) and adolescent (≥ 12 to < 18 years) HAE patients (NCT04030598, NCT05139810). Evaluated dose regimens included 20, 40, 60, and 80 mg every-4-weeks, and 80 mg every-8-weeks, administered subcutaneously over a dosing period of 13 to 21 weeks. A total of 177 subjects (101 healthy volunteers and 76 HAE patients) were included in the modeling.

Results: Donidalorsen PK was well described by a linear 2-compartment model with first-order absorption. The population terminal elimination half-life was 31.4 days. Prekallikrein was well described by an indirect response model with inhibition of prekallikrein production rate by donidalorsen. Maximum fractional inhibition (Imax) was 0.992 (1.19 %RSE) and the 50% inhibitory concentration (IC50) was 0.158 ng/mL (11.0 %RSE). Covariate analysis identified body weight as the main factor affecting PK exposure. Simulations showed subjects with higher body weight had lower PK exposure; however, these PK differences were not considered clinically significant and did not significantly impact the prekallikrein percent reduction from baseline (difference < 7% between lowest and highest weight groups).

Conclusion: The developed population PK/PD model well characterized the donidalorsen exposure-prekallikrein response relationship. Modeling analyses support that no dose adjustment is needed with respect to intrinsic/extrinsic factors in adult and adolescent HAE patients.