Population pharmacokinetic/pharmacodynamic modelling of eplontersen, an antisense oligonucleotide in development for transthyretin amyloidosis.

July 2022

Abstract

Aims

Transthyretin-mediated amyloidosis is a progressive and fatal disease caused by the build-up of misfolded transthyretin (TTR) protein. Eplontersen is a triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotide targeting TTR messenger ribonucleic acid (mRNA) to inhibit production of both variant and wild-type TTR. We aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for eplontersen and to evaluate the impact of covariates on exposure and response.

Methods

Plasma eplontersen and serum TTR concentration data were obtained from two phase 1 studies in healthy volunteers (ClinicalTrials.gov: NCT03728634, NCT04302064). Model development was conducted using a nonlinear mixed-effects approach.

Results

Eplontersen PK was well described by a two-compartment model. Evaluation of demographics identified significant covariates of lean body mass on clearance and body weight on intercompartmental clearance and volumes of distribution. Population PK modelling showed the absorption rate was 29.6% greater with injection into the abdomen versus the arm. The typical population terminal elimination half-life was 25.5 days. Serum TTR was well described by an indirect response model with inhibition of TTR production by eplontersen. Maximum fractional inhibition (I_max) was 0.970 (0.549%RSE) and the half maximal inhibitory concentration (IC₅₀) was 0.0283 ng/ml (13.3%RSE). Simulations showed subjects with lower weight had higher exposure (AUC, C_max), while higher C_max was observed when comparing site of administration (ratio abdomen/arm = 1.18), but differences in exposure did not significantly impact response at evaluated doses.

Conclusion

The exposure-response relationship of eplontersen was well characterised by the PKPD model. Weight and injection site were found to affect systemic exposure, but this effect does not seem to result in clinically relevant variation in response.

What is hATTR?

Hereditary transthyretin amyloid (hATTR) is a type of heritable, autosomal dominant amyloidosis due to deposition of transthyretin- derived fibrils (transthyretin is a transport protein for, among other thing, thyroxine). Neuropathy is often the presenting symptom (bilateral carpal tunnel syndrome is common), but spinal stenosis, biceps tendon rupture, and involvement of other organs also occur. In patients with neuropathy in addition to unexplained cardiac, renal, or pulmonary disease, hATTR is an important diagnosis to consider, both because it is autosomal dominant and thus carries important genetic repercussions and because there is effective treatment.

From: The Only Neurology Book You Will Ever Need
Written by: Malcolm S. Thaler, Alison I. Thaler
February 3, 2022