Coelho, TeresaAndo, YukioBenson, Merrill D.Berk, John L.Waddington-Cruz, MárciaDyck, Peter J.Gillmore, Julian D.Khella, Sami L.Litchy, William J.Obici, LauraMonteiro, CeciliaTai, Li-JungViney, Nicholas J.Buchele, GustavoBrambatti, MichelaJung, Shiangtung W.O’Dea, Louis St. L.Tsimikas, SotiriosSchneider, EugeneGeary, Richard S.Monia, Brett P.Gertz, Morie2022-12-162022-12-162021-06Coelho T, Ando Y, Benson MD, et al. 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. Neurol Ther. 2021;10(1):375-389. doi:10.1007/s40120-021-00235-6https://hdl.handle.net/1805/30757Introduction: AKCEA-TTR-LRx 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-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx 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-LRx 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-LRx 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-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx 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-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN.en-USAttribution-NonCommercial 4.0 InternationalAKCEA-TTR-LrxAntisense oligonucleotideClinical trial designHereditary transthyretin-mediated amyloid polyneuropathyPhase 3 clinical trialArticle