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

Abstract

Introduction: AKCEA-TTR-L Rx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-L Rx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-L Rx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-L Rx is safe and efficacious, with the aim of improv-Supplementary Information The online version contains supplementary material available at

Liver‐directed drugs for transthyretin‐mediated amyloidosis

“…Phase 3 clinical trials are currently underway to determine the effect of eplontersen on disease course in patients with ATTRv-PN and all ATTR-CM. 40,[47][48][49]…”

“…40,52 In the NEURO-TTRansform and the CARDIO-TTRansform studies, 45 mg of the GalNAc conjugated ASO, eplontersen, is subcutaneously administered every 4 weeks either in the clinic or at home with an option for self-administration, while the unconjugated ASO with the same sequence (inotersen), requires 284 mg dosing once weekly to produce a similar level TTR protein reduction. [47][48][49] siRNAs conjugated to GalNAc may be administered less frequently, subcutaneously, and with no pre-medication required (eg, corticosteroids), in contrast to LNP-encapsulated siRNA that commonly require intravenous administration. 34,36,67,71 The GalNAc conjugated siRNA vutrisiran is administered by a health care professional every 3 months in the HELIOS-A and HELIOS-B trials, 62,63 while the unconjugated, LNP formulated siRNA patisiran is administered every 3 weeks by IV infusion.…”

Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment

“…The safety profile of patisiran was acceptable [ 62 ], whereas glomerulonephritis and thrombocytopenia were reported as severe adverse events of inotersen [ 63 ], necessitating close monitoring of renal function and platelet count. To improve the safety profile of inotersen, a ligand-conjugated antisense oligonucleotide designed to facilitate receptor-mediated uptake by hepatocytes was designed [ 65 , 66 ].…”

Multidisciplinary Approaches for Transthyretin Amyloidosis

“…A bull's eye plot is shown in the lower right panel endomyocardial biopsy in the diagnosis of cardiomyopathy resulting from ATTR amyloidosis. 123 I-Metaiodobenzylguanidine (MIBG) scintigraphy is an imaging technique to show cardiac sympathetic innervation [84]. MIBG has been used to evaluate heart failure in the cardiology field [85], whereas neurologists have also considered reduced myocardial MIBG uptake as one of the early signs of autonomic dysfunctions in neurological diseases, including ATTRv amyloidosis, even in the absence of heart failure [25,50,86].…”

“…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].…”