PK/PD modeling of FXI antisense oligonucleotides to bridge the dose‐FXI activity relation from healthy volunteers to end‐stage renal disease patients

Abstract

IONIS-FXI RX (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI and has been investigated in healthy volunteers and end-stage renal disease (ESRD) patients. FXI-LICA (BAY2976217) shares the same RNA sequence as IONIS-FXI RX but contains a GalNAc-conjugation that facilitates asialoglycoprotein receptor (ASGPR)-mediated uptake into hepatocytes. FXI-LICA has been studied in healthy volunteers and is currently investigated in ESRD patients on hemodialysis.We present a model-informed bridging approach that facilitates the extrapolation of the dose-exposure-FXI relationship from IONIS-FXI RX to FXI-LICA in ESRD patients and, thus, supports the selection of FX-LICA doses being investigated in ESRD patients. A two-compartment PK model, with mixed first-and zero-order subcutaneous absorption and first-order elimination, was combined with an indirect response model for the inhibitory effect on the FXI synthesis rate via an effect compartment. This PK/PD model adequately described the median trends, as well as the inter-individual variabilities for plasma drug concentration and FXI activity in healthy volunteers of IONIS-FXI RX and FXI-LICA, and in ESRD patients of IONIS-FXI RX . The Accepted ArticleThis article is protected by copyright. All rights reserved model was then used to predict dose dependent steady-state FXI activity following repeat once-monthly doses of FXI-LICA in a virtual ESRD patient population.Under the assumption of similar ASGPR expression in ESRD patients and healthy volunteers, doses of 40mg, 80mg, and 120mg FXI-LICA are expected to cover the target range of clinical interest for steadystate FXI activity in the Phase 2b study of FXI-LICA in ESRD patients undergoing hemodialysis.

Assessment of the Effect of Organ Impairment on the Pharmacokinetics of 2′‐MOE and Phosphorothioate Modified Antisense Oligonucleotides

“…26 ESRD was found to be a significant covariate on clearance; the estimated plasma clearance was reduced by a factor of 53% in patients with ESRD compared to HVs. 26 However, the model included data from lower-dose cohorts (50-200 mg) in HVs, which from a phase 1 study in HVs and a phase 2/3 study in patients with hereditary transthyretin amyloidosis to evaluate the exposure-response relationship and covariates affecting the PK exposure and transthyretin pharmacodynamic response, as previously described. 28 Four single-dose cohorts (SC administration of 50, 100, 200, and 400 mg) and 5 multiple-dose cohorts (SC administration of 50, 100, 200, 400, and 300 mg weekly) were evaluated in the phase 1 study.…”

Nanobodies against factor XI apple 3 domain inhibit binding of factor IX and reveal a novel binding site for high molecular weight kininogen

“…targeting FXI that have reached clinical trials. 2,[23][24][25]53 Nevertheless, the development of novel anticoagulants remains relevant as repeated administration of biopharmaceuticals has been related to the development of adverse immunogenicity against treatment with effects ranging from reduced bioavailability to the instigation of an autoimmune response. 28,29 Therefore, we have focused on the generation of FXI-targeting nanobodies.…”

Factor XI, a potential target for anticoagulation therapy for venous thromboembolism

“…However, the backbone of the drug is a phosphodiester skeleton, which is susceptible to the action of nucleases; as this affects the stability and activity of ASOs, it is necessary to modify the backbone to increase its stability during the drug design process ( 74 ). Current studies of ASOs include those on IONIS-FXI Rx ( 29 , 75 ) and FXI-LICA ( 76 ).…”

“…Therefore, the efficacy of 200 mg of IONIS-FXI Rx in the prevention of VTE was not inferior to that of enoxaparin, and the efficacy of 300 mg of IONIS-FXI Rx was better than that of enoxaparin. Other results of phase II clinical trials in patients with end-stage renal disease are in the process of being published ( 76 ). FXI-LICA (BAY2976217), also known as ION-957943, has the same RNA sequence as that of IONIS-FXI Rx .…”

“…FXI-LICA (BAY2976217), also known as ION-957943, has the same RNA sequence as that of IONIS-FXI Rx . Based on previous studies, the dose relationship was extrapolated from the IONIS-FXI Rx study to FXI-LICA for validation, and the data showed that 40, 80, and 120 mg of FXI-LICA could be used as doses for clinical trials in patients ( 76 ). Therefore, a phase II clinical trial (NCT04534114) is focused on the efficacy and safety of 40, 80, and 120 mg of FXI-LICA in inhibiting of thrombosis in patients with end-stage renal disease undergoing regular hemodialysis, with bleeding as a primary endpoint.…”