Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data

Abstract

Aims Amyloidogenic transthyretin (ATTR) amyloidosis is a fatal disease characterized by progressive cardiomyopathy and/or polyneuropathy. AKCEA-TTR-L Rx (ION-682884) is a ligand-conjugated antisense drug designed for receptor-mediated uptake by hepatocytes, the primary source of circulating transthyretin (TTR). Enhanced delivery of the antisense pharmacophore is expected to increase drug potency and support lower, less frequent dosing in treatment. Methods and results AKCEA-TTR-L Rx demonstrated an approximate 50-fold and 30-fold increase in potency compared with the unconjugated antisense drug, inotersen, in human hepatocyte cell culture and mice expressing a mutated human genomic TTR sequence, respectively. This increase in potency was supported by a preferential distribution of AKCEA-TTR-L Rx to liver hepatocytes in the transgenic hTTR mouse model. A randomized, placebo-controlled, phase 1 study was conducted to evaluate AKCEA-TTR-L Rx in healthy volunteers (ClinicalTrials.gov: NCT03728634). Eligible participants were assigned to one of three multiple-dose cohorts (45, 60, and 90 mg) or a single-dose cohort (120 mg), and then randomized 10:2 (active : placebo) to receive a total of 4 SC doses (Day 1, 29, 57, and 85) in the multiple-dose cohorts or 1 SC dose in the single-dose cohort. The primary endpoint was safety and tolerability; pharmacokinetics and pharmacodynamics were secondary endpoints. All randomized participants completed treatment. No serious adverse events were reported. In the multiple-dose cohorts, AKCEA-TTR-L Rx reduced TTR levels from baseline to 2 weeks after the last dose of 45, 60, or 90 mg by a mean (SD) of À85.7% (8.0), À90.5% (7.4), and À93.8% (3.4), compared with À5.9% (14.0) for pooled placebo (P < 0.001). A maximum mean (SD) reduction in TTR levels of À86.3% (6.5) from baseline was achieved after a single dose of 120 mg AKCEA-TTR-L Rx. Conclusions These findings suggest an improved safety and tolerability profile with the increase in potency achieved by productive receptor-mediated uptake of AKCEA-TTR-L Rx by hepatocytes and supports further development of AKCEA-TTR-L Rx for the treatment of ATTR polyneuropathy and cardiomyopathy.

Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

“…The AKCEA-TTR-L Rx dosage regimen under investigation in phase 3 was selected on the basis of the pharmacodynamics and safety analyses of the phase 1 randomized placebo-controlled study in 47 healthy volunteers. AKCEA-TTR-L Rx dosed at 45 mg every 4 weeks produced a mean reduction from baseline in serum TTR of 86% after four doses and an absence of potential tolerability or safety issues, such as the increases in liver transaminase levels observed in the upper dose range of this study [ 29 ]. The GalNAc-mediated delivery of AKCEA-TTR-L Rx to hepatocytes supports low-dose therapy and a more convenient dosage regimen (i.e., monthly administration) relative to the unconjugated ASO therapy used for the treatment of hATTR-PN [ 22 – 25 ].…”

“…AKCEA-TTR-L Rx is a GalNAc-conjugated ASO with a nucleotide sequence identical to inotersen, but with fewer phosphorothioate-modified internucleotide linkages, which is expected to improve its safety profile. Results from a first-in-human phase 1 study of AKCEA-TTR-L Rx in healthy volunteers demonstrated that AKCEA-TTR-L Rx 45 mg SC once every 4 weeks produced sustained decreases in serum TTR levels within 30 days of treatment initiation, achieving a mean reduction from baseline of 86% after four doses of treatment [ 29 ]. No treatment-related safety or tolerability issues were identified under this dosing regimen.…”

“…No treatment-related safety or tolerability issues were identified under this dosing regimen. Consequently, AKCEA-TTR-L Rx requires a lower dose and less frequent administration (45 mg SC every 4 weeks, a 27-fold reduction in monthly exposure) than the unconjugated ASO, inotersen, to achieve a similar (if not better) pharmacological effect [ 26 , 29 , 30 ].…”

Improvements in the Tolerability Profile of 2′-O-Methoxyethyl Chimeric Antisense Oligonucleotides in Parallel with Advances in Design, Screening, and Other Methods

“…In conclusion, the improvements made to the tolerability profile of this set of 2¢MOE ASOs indicate the effectiveness of improvements made in Ionis' drug discovery and preclinical screening platform, which continues to evolve, as well as insights gained through clinical development of this class of ASOs. The potency and safety of many of the 2¢MOE-modified ASOs included in this analysis have been further improved by conjugation of the triantennary N-acetylgalactosamine (GalNAc 3 ) moiety for preferential and productive uptake by hepatocytes [27][28][29][30][31][32][33]. This enhancement in drug delivery increases ASO potency for RNA targets expressed by hepatocytes to support lower and less-frequent dosing, which upon integrated assessments may indicate a marked improvement in the tolerability profile for this emerging class of ASO drugs.…”

Multidisciplinary Approaches for Transthyretin Amyloidosis

“…Because glomerulonephritis and thrombocytopenia were reported as severe adverse events, close monitoring of platelet count and renal function is required in patients receiving inotersen. To improve the safety profile, a ligand-conjugated ASO of a nucleotide sequence identical to that of inotersen designed to facilitate receptor-mediated uptake by hepatocytes was also designed [122]. Currently, it is under investigation in phase III trials in ATTRv amyloidosis patients with polyneuropathy and ATTR patients with cardiomyopathy [122,123].…”