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

Teresa Coelho, Yukio Ando, Merrill D. Benson, John L. Berk, Márcia Waddington-Cruz, Peter J. Dyck, Julian D. Gillmore, Sami L. Khella, William J. Litchy, Laura Obici, Cecilia Monteiro, Li Jung Tai, Nicholas J. Viney, Gustavo Buchele, Michela Brambatti, Shiangtung W. Jung, Louis St. L. O’Dea, Sotirios Tsimikas, Eugene Schneider, Richard S. GearyBrett P. Monia, Morie Gertz

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Introduction: 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. Trial Registration: The study is registered at (NCT04136184) and EudraCT (2019-001698-10).

Original languageEnglish (US)
Pages (from-to)375-389
Number of pages15
JournalNeurology and Therapy
Issue number1
StatePublished - Jun 2021


  • Antisense oligonucleotide
  • Clinical trial design
  • Hereditary transthyretin-mediated amyloid polyneuropathy
  • Phase 3 clinical trial

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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