Sebastian Ueckert 1, John Diep 2, Joanna Parkinson 3, Oskar Clewe 4, Peter Wessman 3, Nicholas J Viney 2, Jersey Chen 3, Xiang Gao 2, Rosie Yu 2, Angelica Quartino 3
1 Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca at time of project involvement, now: Ribocure Pharmaceuticals (Gothenburg, Sweden), 2 Ionis Pharmaceuticals, Inc., (Carlsbad, USA), 3 Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca (Gothenburg, Sweden), 4 Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca at time of project involvement, now: Pharmetheus (Gothenburg, Sweden)
Objectives
To characterize the population PK (popPK), PKPD (popPKPD), and exposure–response (ER) relationships for efficacy and safety of eplontersen, supporting a dosing regimen of 45 mg subcutaneously (SC) monthly in patients with hereditary transthyretin-mediated polyneuropathy (ATTRv-PN) is appropriate and no dose adjustment is required.
Methods
Integrated popPK and popPKPD analyses were conducted using pooled data from healthy volunteers (Phase I: ION-682884-CS1 [1], -CS20, -CS21) and patients with ATTRv-PN (Phase III: ION-682884-CS3 [2]) to characterize eplontersen PK and PD after SC dosing and to assess covariate effects.
A previous popPK and popPKPD analysis for healthy volunteers was used as a starting point for the structural models [3]. PK samples at and beyond the onset of anti-drug antibodies (ADA) were excluded, since trough concentrations for ADA-positive samples were higher than for ADA-negative samples. For the popPKPD analysis placebo participants were excluded, justified by the lack of trends in PD (serum transthyretin, TTR) over time among placebo-treated healthy volunteers and in a previous study in patients with ATTRv-PN [4].
ER analyses at 45 mg Q4W were based on data from the Phase III study. Efficacy ER for percent change in serum TTR, change in modified Neuropathy Impairment Score +7 (mNIS+7), and Norfolk Quality of Life – Diabetic Neuropathy (QoL-DN) total score employed mixed models for repeated measures including time, exposure metrics, and pre-defined covariates. Safety ER was explored graphically for treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), and adverse events leading to dose modification/discontinuation.
The popPK and popPKPD analysis was performed using NONMEM, version 7.4 and the ER analyses were performed in R, version 4.1.1.
Results
The popPK analysis included 230 participants. The final popPK model comprised of a two-compartment disposition, parallel first-order and 3-transit compartment absorption, and parallel linear/nonlinear elimination to capture slightly greater-than-dose-proportional exposure. Eplontersen showed rapid absorption (Tmax 2 hours), followed by biphasic decline with an initial faster disposition, reflecting the rapid tissue distribution phase, and a slower terminal elimination phase (t1/2 of 3 weeks), reflecting the elimination from the tissue. With Q4W dosing, no accumulation in Cmax or AUC was observed, consistent with time-invariant plasma kinetics and low Ctrough relative to Cmax. Ctrough accumulated over time with steady state achieved at approximately 17 weeks.
PopPK covariate analysis identified body weight (BWT), race, baseline renal function (eGFR), injection site, and drug product presentation (vial+syringe vs autoinjector) as statistically significant covariates on PK parameters. However, the differences in exposures across the covariate groups were small compared with the within-group variability and were not considered clinically meaningful. Sex, age, geographic region, disease stage, Val30Met mutation, mild hepatic impairment, and baseline ALT, AST, bilirubin, albumin, and UPCR did not have statistically significant effects.
The popPKPD model adequately described serum TTR in 258 participants. The popPKPD model described TTR via an indirect response model (zero-order production, first-order elimination), with eplontersen inhibiting TTR production through an Imax function driven by individual plasma PK predictions. The estimated Imax (RSE %) was 95.7% (0.8%) and EC50 was 0.0455 (9.5%) ng/mL. At steady state following 45 mg Q4W, serum TTR reduction at Ctrough,ss was estimated at 83.1%, reached by 17 weeks. BWT, sex, race, disease status, and Val30Met mutation were statistically significant covariates; age and disease stage (1 vs 2) were not significant.
ER analyses demonstrated flat relationship between eplontersen exposure and PD (TTR reduction) or efficacy endpoints (changes in mNIS+7 and Norfolk QoL-DN) at 45 mg Q4W, indicating exposures were sufficient to achieve clinically meaningful responses across observed the exposure range. Safety ER showed similar exposure distributions among patients with versus without moderate/severe TEAEs, with versus without AESIs, and with versus without AEs leading to dose modification/discontinuation, indicating AE incidence was not associated with exposure.
Conclusions
Across integrated popPK, popPKPD, and ER analyses at 45 mg Q4W, eplontersen exhibits predictable PK, robust PD, exposure-independent efficacy within the achieved range, and no exposure–dependent safety signals. Albeit some covariates were identified as statistically significant for popPK and popPKPD models, they were not considered clinically meaningful when taking into account the overall variability in PK, impact on TTR reduction, and the therapeutic window for eplontersen. These findings support that 45 mg Q4W is appropriate for patients with ATTRv-PN without dose modification.
References:
[1] Viney et al. ESC Heart Fail . (2021) 8(1):652-661
[2 ] Coelho T et al. JAMA (2023) 330(15):1448–1458
[3] Diep JK et al. Br J Clin Pharmacol. (2022) 88(12):5389–5398.
[4] Benson MD et al. N Engl J Med. (2018) 379(1):22-31
Reference: PAGE 34 (2026) Abstr 12055 [www.page-meeting.org/?abstract=12055]
Poster: Drug/Disease Modelling - CNS