Senior Director, Clinical Pharmacology Lead Intellia Therapeutics, New Jersey, United States
Disclosure(s):
Peijuan Zhu, PhD: No relevant disclosure to display
CRISPR-Cas9–based in vivo gene-editing therapy such as NTLA2001 is administered by intravenous infusion, and is intended to edit TTR in hepatocytes, leading to a decrease in the production of both wild-type and mutant TTR after a single administration. In clinical trials with ATTR-CM patients, single doses NTLA2001 resulted in durable reductions in serum TTR protein of ~90% by week 4 and therefore provide potentially greater TTR knockdown than currently available therapies (Fontana et al. 2024). The speaker will present case studies demonstrating how model-based drug development (MIDD) is being applied to CRISPR-CAS9 based in vivo gene-editing therapy. The case studies will primarily focus on using modeling and simulation to characterize PK and PK/PD relationships and using the PK/PD correlation to support dosing decisions for first-in-human and ultimately the confirmatory Phase 3 clinical trials. PD evaluation may include both on-target TTR reduction as well as off-target safety related biomarkers/endpoints. Discussions will be offered on selecting surrogate PK component for MIDD analysis when the treatment system is complex and includes many components as in the case of CRISPR-Cas9 delivered by lipid nano particle (LNP). Key covariates that impact PK/PD will be explored.
