Jacqueline Ernest 1, Xiaoying Zhao 2, Anis Khan 3, Rosie Yu 4, Jersey Chen 5, Diansong Zhou 6, David Boulton 3, David Boulton 3, Angelica Quartino 7
1 Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca (Barcelona, Spain), 2 Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca (Shanghai, China), 3 Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca (Gaithersburg, United States), 4 Preclinical Development, Ionis Pharmaceuticals, Inc. (Carlsbad, United States), 5 Clinical, Cardiovascular and Renal, AstraZeneca (Gaithersburg, United States), 6 Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca (Waltham, United States), 7 Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca (Gothenburg, Sweden)
Objectives
Eplontersen is an antisense oligonucleotide-GalNAc conjugate that reduces the amount of circulating transthyretin (TTR) protein by binding to TTR messenger ribonucleic acid (mRNA) in the liver, resulting in RNase H-mediated degradation. Hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN) is a progressive, debilitating, and fatal systemic disease. It is characterized by misfolded TTR protein variants that cause amyloid deposits which damage peripheral and autonomic nerves. The objective of this analysis was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) as measured by serum TTR concentration of eplontersen in Chinese healthy participants to support the use of the approved dosing regimen of monthly, 45-mg subcutaneous (SC) dosing in Chinese patients with ATTRv-PN.
Methods
PopPK and popPKPD models developed for the global population, which included three phase 1 and one phase 3 study, were used as a starting point for this analysis [1]. A phase 1 study of 12 healthy Chinese participants receiving a single SC dose of 45 mg was added for a final pooled dataset of 253 participants for the popPK model and 270 participants for the popPKPD model. The popPK and popPKPD parameters were re-estimated, and the impact of region (Chinese, Non-Chinese East Asian, Non-East Asian Asian, Non-Asian) was evaluated on popPK and popPKPD parameters based on a prespecified criterion of p < 0.001. For popPK, region was tested on apparent clearance and apparent central volume of distribution. The popPKPD was modeled sequentially where the empirical Bayes estimates of the PK parameters were used. For popPKPD, region was tested on baseline TTR, rate of TTR elimination, maximum inhibitory effect (Imax) and half maximal inhibitory concentration (IC50). Analysis was guided by visual inspections, likelihood ratio test, and biological plausibility. NONMEM 7.5, R v.4.1.3 and R package bbr v.1.11.0 were used for model development and simulations. Results Eplontersen PK in healthy Chinese participants was consistent with the global population and well described by the global model. The re-estimated PK parameters were consistent with the global model. The model consisted of a two-compartment disposition model (apparent central volume of 12.7 L [RSE = 5.76%] and peripheral volume of 11,100 L [fixed to value estimated using the rich sampling data only]) with parallel first-order/three-transit absorption, and parallel linear/nonlinear elimination. The apparent clearance was 7.2 L/h (7.11%) while the nonlinear elimination was characterized by a maximum metabolic rate of 0.371 mg/h (9.65%) and a Michaelis-Menten constant of 2.97 ng/mL (10.8%). Addition of region (Chinese, Non-Chinese East Asian, Non-East Asian Asian, Non-Asian) on PK parameters did not significantly improve the popPK model. The PKPD of eplontersen in healthy Chinese participants was consistent with the global population. The PKPD model with the addition of Chinese subjects showed consistent parameter estimates as that obtained from global subjects (IC50 of 0.046 ng/mL [8.91%] and maximum effect of 95.9% inhibition [0.594%] compared with global model estimates of 0.0455 ng/mL and 95.7% inhibition, respectively.) Addition of region on PKPD parameters did not significantly improve the population PKPD model. Conclusions Population PK and PKPD analyses of eplontersen in using the pooled data from global and healthy Chinese participants support that PK and PKPD is similar in Chinese as in global participants. Therefore, the monthly 45-mg SC regimen is appropriate in Chinese patients with ATTRv-PN.
Reference: PAGE 34 (2026) Abstr 11850 [www.page-meeting.org/?abstract=11850]
Poster: Drug/Disease Modelling - CNS