Phase 1 Investigation of a Ligand-Conjugated Antisense Oligonucleotide with Increased Potency for the Treatment of Transthyretin Amyloidosis

Abstract

Introduction Hereditary transthyretin amyloidosis (hATTR) is a rare, progressive fatal disease caused by pathogenic variants in the transthyretin (TTR) gene that destabilize the normal tetrameric structure of the TTR oligomers leading to formation of insoluble, extracellular amyloid deposits in multiple organ systems. hATTR patients predominantly develop neuropathy and/or cardiomyopathy. Wild-type TTR can also form amyloid deposits, leading to congestive heart failure. Inotersen is an antisense oligonucleotide (ASO) that inhibits production of both variant and wild-type TTR protein by degradation of the TTR messenger RNA. Inotersen is approved for the treatment of hATTR patients with polyneuropathy. AKCEA-TTR-LRx (ION-682884), an ASO of similar design and sequence, is conjugated to a ligand for selective, receptor-mediated delivery to hepatocytes, the principal source of systemically circulating TTR. This delivery approach has yielded a 20 to 30-fold increase in potency and improved the safety and tolerability profiles of ASOs in human clinical trials. In preclinical studies, AKCEA-TTR-LRx produced significant dose-dependent reductions of TTR messenger RNA and protein levels, with a marked increase in potency compared to inotersen. AKCEA-TTR-LRx is currently in early phase development for the treatment of both hereditary and wild-type ATTR. Hypothesis Based on prior clinical experience with ligand-conjugated ASOs and supporting preclinical results, AKCEA-TTR-LRx is expected to have an increased potency and improved tolerability and safety profile compared to inotersen. Methods A phase 1/2 study was designed to evaluate AKCEA-TTR-LRx in healthy volunteers and patients with transthyretin-mediated amyloidosis (NCT03728634). In phase 1, eligible subjects were assigned to one of two multiple-dose cohorts (45 and 90 mg, n=12 per cohort) and randomized 10:2 (active:placebo) to receive 4, once monthly, SC doses of study drug. A higher, single-dose cohort of healthy volunteers was also evaluated. Results This study is ongoing. Assessment of the safety, tolerability, pharmacokinetics and pharmacodynamics of AKCEA-TTR-LRx in the phase 1 healthy volunteer cohorts will be presented. Conclusions These phase 1 results will guide selection of the dose and treatment schedule for near-term studies to be initiated in patients with ATTR, including phase 3 studies.