(M-103) Population Pharmacokinetic Analysis of QRL-201 in Plasma and CSF in Patients With Amyotrophic Lateral Sclerosis From A First-in-Human Phase 1 Multiple Ascending Dose Escalation Study

Mitali Gaurav – Clinical Pharmacology and Pharmacometrics – Simulations Plus; Amparo de la Peña – Clinical Pharmacology and Pharmacometrics – Simulations Plus; Keith MacCannell – ADME PKPD Consulting; Joy Yang – Clinical Pharmacology and Pharmacometrics – Simulations Plus; Daniel Elbaum – QurAlis Corporation; Xihui Xu – QurAlis Corporation; Megan Johnson – QurAlis Corporation; Sharon Lu – QurAlis Corporation; Emma Bowden – QurAlis Corporation

Objectives: To develop a population pharmacokinetic (popPK) model for QRL-201 in patients with Amyotrophic Lateral Sclerosis (ALS), using data from a First-in Human Phase 1 Study; and to evaluate the influence of key covariates on PK variability.

Methods: A popPK model was developed using plasma and cerebrospinal fluid (CSF) data from 12 patients with ALS who received at least 1 dose of QRL-201 at two dose levels, an antisense oligonucleotide (ASO). Plasma and CSF concentration-time data were analyzed using a nonlinear mixed effects modeling approach in Monolix 2024R1. Intrinsic and extrinsic factors were evaluated as covariates using COSSAC.

Results: The PK of QRL-201 was best described by a 3-compartment model (2 CSF compartments [VCSF/F and VCNS/F], and 1 central plasma compartment [Vc/F]) with linear apparent elimination from both CSF (CLCSF/F) and plasma (CLp/F). The elimination from the CSF served as the input to the plasma compartment. The apparent clearance of QRL-201 from CSF (CLCSF/F) and plasma (CLp/F) were estimated to be 0.15 and 17.25 L/h, respectively; and the inter-compartmental clearance between CSF and CNS tissue compartments was 0.13 L/h. Estimates for the apparent volumes of distribution for VCSF/F, VCNS/F, and VC/F were 3.99 L, 169.8 L, and 14.43 L respectively, values broadly consistent with similarly-administered ASO-type drugs. Exponential models were used to describe the inter-individual variability (IIV) on CLCSF/F, CLp/F, VCSF/F and Vc/F; assuming log-normal distribution of the parameters. Separate proportional error models for plasma and CSF were used to describe the residual variability. Dose was found to be a statistically significant covariate for CLCSF/F, with a dose-dependent increase in CLCSF/F. All fixed effect parameters were estimated with good precision (%RSE ≤29.5%), as were the random effect parameters (≤ 43.6% and ≤ 12.3% for IIV and residual variability respectively).

Conclusions: The PK of QRL-201 was well described by a 3-compartment model with linear apparent clearance. The final model goodness-of-fit was illustrated by good precision of PK parameters, reduction in variability, improvement in model diagnostics, and prediction-corrected visual predictive checks (pcVPCs). Dose was found to be a statistically significant covariate for CLCSF/F. No other intrinsic and extrinsic covariates were found to be significant predictors of variability in the PK model parameters.

Citations: Citations:
[1] MacCannell D, Berger Z, East L, Mercuri E, Kirschner J, Muntoni F, Farrar MA, Peng J, Zhou J, Nestorov I, Farwell W, Finkel RS. Population pharmacokinetics-based recommendations for a single delayed or missed dose of nusinersen. Neuromuscul Disord. 2021 Apr;31(4):310-318. doi: 10.1016/j.nmd.2021.02.014. Epub 2021 Feb 20. Erratum in: Neuromuscul Disord. 2022 Jan;32(1):e1. PMID: 33781694.
[2] Luu KT, Norris DA, Gunawan R, Henry S, Geary R, Wang Y. Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations. J Clin Pharmacol. 2017 Aug;57(8):1031-1041. doi: 10.1002/jcph.884. Epub 2017 Mar 29. PMID: 28369979.
[3] Yamamoto Y, Sanwald Ducray P, Björnsson M, et al. Development of a population pharmacokinetic model to characterize the pharmacokinetics of intrathecally administered tominersen in cerebrospinal fluid and plasma. CPT Pharmacometrics Syst Pharmacol. 2023; 12: 1213-1226. doi:10.1002/psp4.13001.

Keywords: ALS, ASO, Intrathecal-administration