PMID- 33638113 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210609 IS - 2193-8253 (Print) IS - 2193-6536 (Electronic) IS - 2193-6536 (Linking) VI - 10 IP - 1 DP - 2021 Jun TI - Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-L(Rx) (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy. PG - 375-389 LID - 10.1007/s40120-021-00235-6 [doi] AB - 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. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10). FAU - Coelho, Teresa AU - Coelho T AD - Department of Neuroscience, Centro Hospitalar Universitario do Porto, Porto, Portugal. FAU - Ando, Yukio AU - Ando Y AD - Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. FAU - Benson, Merrill D AU - Benson MD AD - Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. FAU - Berk, John L AU - Berk JL AD - Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA. FAU - Waddington-Cruz, Marcia AU - Waddington-Cruz M AD - National Amyloidosis Referral Center-CEPARM, University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Dyck, Peter J AU - Dyck PJ AD - Department of Neurology, Mayo Clinic, Rochester, MN, USA. FAU - Gillmore, Julian D AU - Gillmore JD AD - Division of Medicine, National Amyloidosis Centre, University College London, London, UK. FAU - Khella, Sami L AU - Khella SL AD - Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA. FAU - Litchy, William J AU - Litchy WJ AD - Department of Neurology, Mayo Clinic, Rochester, MN, USA. FAU - Obici, Laura AU - Obici L AD - Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. FAU - Monteiro, Cecilia AU - Monteiro C AD - Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. FAU - Tai, Li-Jung AU - Tai LJ AD - Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. FAU - Viney, Nicholas J AU - Viney NJ AD - Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. FAU - Buchele, Gustavo AU - Buchele G AD - Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. FAU - Brambatti, Michela AU - Brambatti M AD - Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. FAU - Jung, Shiangtung W AU - Jung SW AD - Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. FAU - St L O'Dea, Louis AU - St L O'Dea L AD - Akcea Therapeutics, Boston, MA, USA. FAU - Tsimikas, Sotirios AU - Tsimikas S AD - Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. AD - Vascular Medicine Program, Sulpizio Cardiovascular Center, Division of Cardiology, University of California San Diego, La Jolla, CA, USA. FAU - Schneider, Eugene AU - Schneider E AD - Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. FAU - Geary, Richard S AU - Geary RS AD - Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. FAU - Monia, Brett P AU - Monia BP AD - Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. FAU - Gertz, Morie AU - Gertz M AD - Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. gertz.morie@mayo.edu. LA - eng SI - ClinicalTrials.gov/NCT04136184 GR - I01 CX001631/CX/CSRD VA/United States GR - P50 CA186781/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20210226 PL - New Zealand TA - Neurol Ther JT - Neurology and therapy JID - 101637818 PMC - PMC8140170 OAB - 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-L(Rx) is an investigational treatment for hATTR-PN. AKCEA-TTR-L(Rx) 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-L(Rx) 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-L(Rx) every 4 weeks, or Inotersen once a week for 35 weeks, followed by a switch to AKCEA-TTR-L(Rx) every 4 weeks. People may continue to receive AKCEA-TTR-L(Rx) after the study treatment period ends. In this study, researchers will compare results from people who received AKCEA-TTR-L(Rx) 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. OABL- eng OTO - NOTNLM OT - AKCEA-TTR-Lrx OT - Antisense oligonucleotide OT - Clinical trial design OT - Hereditary transthyretin-mediated amyloid polyneuropathy OT - Phase 3 clinical trial EDAT- 2021/02/28 06:00 MHDA- 2021/02/28 06:01 PMCR- 2021/02/26 CRDT- 2021/02/27 05:42 PHST- 2020/12/02 00:00 [received] PHST- 2021/02/02 00:00 [accepted] PHST- 2021/02/28 06:00 [pubmed] PHST- 2021/02/28 06:01 [medline] PHST- 2021/02/27 05:42 [entrez] PHST- 2021/02/26 00:00 [pmc-release] AID - 10.1007/s40120-021-00235-6 [pii] AID - 235 [pii] AID - 10.1007/s40120-021-00235-6 [doi] PST - ppublish SO - Neurol Ther. 2021 Jun;10(1):375-389. doi: 10.1007/s40120-021-00235-6. Epub 2021 Feb 26.