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

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 improving neurologic function and quality of life in hATTR-PN patients. Methods/Design Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-L-Rx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-L-Rx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-L-Rx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-L-Rx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire. Conclusion NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-L-Rx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN. Plain Language Summary Hereditary transthyretin amyloidosis with peripheral neuropathy (hATTR-PN for short) is a rare inherited condition. In hATTR-PN, a protein called transthyretin (TTR for short) builds up and damages nerves throughout the body. This neuropathy causes symptoms such as weakness, loss of sensation, and pain. Currently available medicines can slow disease progression, but researchers are looking for more effective treatments with fewer side effects. AKCEA-TTR-LRx is an investigational treatment for hATTR-PN. AKCEA-TTR-LRx prevents the liver from making TTR, reducing the amount that causes disease progression. It is similar to an existing treatment called inotersen, but designed for better delivery to the liver and is more potent. This article describes the NEURO-TTRansform study that will evaluate how effective AKCEA-TTR-LRx is for treating hATTR-PN. Around 140 adults with hATTR-PN from the USA, Canada, and Europe will be able to take part in this study. The study treatment period will be 85 weeks long. People will receive injections underneath the skin of either: AKCEA-TTR-LRx every 4 weeks, or Inotersen once a week for 35 weeks, followed by a switch to AKCEA-TTR-LRx every 4 weeks. People may continue to receive AKCEA-TTR-LRx after the study treatment period ends. In this study, researchers will compare results from people who received AKCEA-TTR-LRx to results from people who received no active ingredients (called placebo) in a similar study (called NEURO-TTR). Researchers will measure the differences in peoples': Neuropathy symptoms. Quality of life. TTR protein levels in the blood.

Automated summary

AKCEA-TTR-L-Rx is a ligand-conjugated antisense drug being developed for the treatment of hereditary transthyretin amyloidosis. It utilizes a triantennary N-acetylgalactosamine moiety to increase drug potency for lower and less frequent dosing. The NEURO-TTRansform study aims to evaluate the efficacy of AKCEA-TTR-L-Rx in improving neurologic function and quality of life for hATTR-PN patients.