Teresa Coelho1, Yukio Ando2, Merrill D Benson3, John L Berk4, Márcia Waddington-Cruz5, Peter J Dyck6, Julian D Gillmore7, Sami L Khella8, William J Litchy6, Laura Obici9, Cecilia Monteiro10, Li-Jung Tai10, Nicholas J Viney10, Gustavo Buchele10, Michela Brambatti10, Shiangtung W Jung10, Louis St L O'Dea11, Sotirios Tsimikas10,12, Eugene Schneider10, Richard S Geary10, Brett P Monia10, Morie Gertz13. 1. Department of Neuroscience, Centro Hospitalar Universitário do Porto, Porto, Portugal. 2. Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. 3. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. 4. Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA. 5. National Amyloidosis Referral Center-CEPARM, University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 6. Department of Neurology, Mayo Clinic, Rochester, MN, USA. 7. Division of Medicine, National Amyloidosis Centre, University College London, London, UK. 8. Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA. 9. Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 10. Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. 11. Akcea Therapeutics, Boston, MA, USA. 12. Vascular Medicine Program, Sulpizio Cardiovascular Center, Division of Cardiology, University of California San Diego, La Jolla, CA, USA. 13. Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. gertz.morie@mayo.edu.
Abstract
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 ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).
RCT Entities:
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 hATTRpolyneuropathy (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-PNpatients. 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 ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).