NEURO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

A Phase 3 Global, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of ION-682884 in Patients With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

The main objective of this study was to evaluate the efficacy of eplontersen as compared with the historical control of the placebo cohort in the NEURO-TTR trial (NCT01737398/2012-001831-30), in subjects with hereditary transthyretin-mediated amyloidosis polyneuropathy (hATTR-PN). For more information, please visit http://www.neuro-ttransform.com/.

Study Overview

• Status: Completed
• Conditions: Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
• Intervention / Treatment: Drug: Eplontersen; Drug: Inotersen

Detailed Description

This study was a multicenter, open-label study in up to 168 participants, who were randomized to receive subcutaneous (SC) injections of either eplontersen once every 4 weeks or inotersen once a week. Participants also received daily supplemental doses of the recommended daily allowance of vitamin A. Participants included in the inotersen reference arm crossed over to eplontersen at Week 37 after completing the Week 35 assessments.

• Study Type: Interventional
• Enrollment (Actual): 168
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1023AAB
    • Stat Research
  • Buenos Aires, Argentina, C1428 AQK
    • Instituto Fleni
  • Buenos Aires
    • Ciudad Autónoma De Buenos Aires, Buenos Aires, Argentina, C1199ABB
      • Hospital Italiano de Buenos Aires
    • Florencio Varela, Buenos Aires, Argentina, 1888
      • Hospital El Cruce
• Australia
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Perron Institute for Neurological and Translational Science
• Brazil
  • Campinas, Brazil, 13083-970
    • Universidade Estadual de Campinas
  • Ribeirão Preto, Brazil, 14049-900
    • Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto
  • Rio De Janeiro, Brazil, 21941-617
    • Hospital Universitario Clementino Fraga Filho
  • São Paulo, Brazil, 04032-060
    • Associação de Assistência à Criança Deficiente - Unidade Lar Escola
  • Parana
    • Curitiba, Parana, Brazil, 81210-310
      • Instituto de Neurologia de Curitiba
  • Paraná
    • Curitiba, Paraná, Brazil, 81210-310
      • Instituto de Neurologia de Curitiba
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4C 3E7
      • Toronto General Hospital
• Cyprus
  • Egkomi, Cyprus, 2371
    • The Cyprus Institute of Neurology and Genetics
• France
  • Marseille, France, 13005
    • Hôpital de la Timone
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • Centre Hospitalier Universitaire de Toulouse
  • Ile-De-France
    • Le Kremlin-Bicêtre, Ile-De-France, France, 94270
      • Hôpital Bicêtre
• Germany
  • Heidelberg, Germany, 69120
    • Universitatsklinikum Heidelberg
  • Bayern
    • Würzburg, Bayern, Germany, 97080
      • Universitätsklinikum Würzburg
• Greece
  • Crete
    • Heraklion, Crete, Greece, 711 10
      • University General Hospital of Heraklion (PAGNI)
• Italy
  • Messina, Italy, 98124
    • Azienda Ospedaliera Universitaria Policlinico Gaetano Martino
  • Milano, Italy, 20133
    • Fondazione IRCCS Istituto Neurologico Carlo Besta
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San Matteo
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli
• New Zealand
  • Auckland
    • Grafton, Auckland, New Zealand, 1023
      • Auckland City Hospital
• Portugal
  • Lisbon, Portugal, 1649-028
    • Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria
  • Porto, Portugal, 4099-001
    • Centro Hospitalar Universitário do Porto - Hospital Geral de Santo Antonio
• Spain
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Illes Balears
    • Palma De Mallorca, Illes Balears, Spain, 07198
      • Hospital Son Llatzer
• Sweden
  • Umeå, Sweden, 907 37
    • Norrlands universitetssjukhus
• Taiwan
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
  • Guishan District
    • Taoyuan City, Guishan District, Taiwan, 333
      • Chang Gung Memorial Hospital - Linkou Branch
  • Taichung
    • Taichung City, Taichung, Taiwan, 40447
      • China Medical University Hospital
  • Taipei
    • Taipei City, Taipei, Taiwan, 11217
      • Taipei Veterans General Hospital
• Turkey
  • İstanbul, Turkey, 34093
    • İstanbul Üniversitesi - Istanbul Tıp Fakültesi
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic - Arizona
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine - Indianapolis
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University Neurology Research Office
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • New York
    • New York, New York, United States, 10032
      • The Neurological Institute of New York
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Hospitals - Neurology Clinic
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 82 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Aged 18 to 82 years at the time of informed consent
2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent
3. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the participant or the participantss non-pregnant female partner must be using a highly effective contraceptive method

4. Diagnosis of hereditary transthyretin-mediated polyneuropathy as defined by meeting all 3 of the following:

   • Stage 1 or Stage 2 Familial Amyloid Polyneuropathy (FAP) or Coutinho Stage
   • Documented genetic mutation in the TTR gene
   • Symptoms and signs consistent with neuropathy associated with transthyretin amyloidosis, including Neuropathy Impairment Score (NIS) ≥ 10 and ≤ 130

Key Exclusion Criteria:

1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a participants unsuitable for inclusion, including but not limited to abnormal safety labs
2. Karnofsky performance status ≤ 50
3. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes
4. Prior liver transplant or anticipated liver transplant within 1-yr of Screening
5. New York Heart Association (NYHA) functional classification of ≥ 3
6. Acute coronary syndrome within 6 months of screening or major surgery within 3 months of Screening
7. Other types of amyloidosis
8. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the Study
9. Current treatment with any approved drug for hereditary TTR amyloidosis such as Vyndaqel® / Vyndamax™ (tafamidis), Tegsedi™ (inotersen), Onpattro™ (patisiran), off-label use of diflunisal or doxycycline, and tauroursodeoxycholic acid (TUDCA). If previously treated with Vyndaqel® / Vyndamax™, diflunisal or doxycycline, and TUDCA, must have discontinued treatment for at least 2 weeks prior to Study Day 1
10. Previous treatment with Tegsedi™ (Inotersen) or Onpattro™ (patisiran), or other oligonucleotide or RNA therapeutic (including siRNA)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Inotersen; Participants received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, participants received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81.	Drug: Eplontersen; Eplontersen by subcutaneous injection; Other Names: ION-682884; AKCEA-TTR-LRx; IONIS-TTR-LRx; Drug: Inotersen; Inotersen by subcutaneous injection; Other Names: TEGSEDI; ISIS 420915
Experimental: Eplontersen; Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.	Drug: Eplontersen; Eplontersen by subcutaneous injection; Other Names: ION-682884; AKCEA-TTR-LRx; IONIS-TTR-LRx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66	mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: the NIS composite score (maximum of 244 points) & the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. Least square (LS) mean & standard error (SE) were analyzed using Mixed Effects Model with Repeated Measures (MMRM). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.	Baseline, Week 66
Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66	The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.	Baseline, Week 66
Percent Change From Baseline in Serum TTR Concentration at Week 65	As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.	Baseline, Week 65
Percent Change From Baseline in Serum TTR Concentration at Week 35	As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.	Baseline, Week 35
Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35	mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: NIS composite score (maximum of 244 points) & the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.	Baseline, Week 35

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Norfolk QOL-DN at Week 35	The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.	Baseline, Week 35
Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66	NSC score is a questionnaire composed of 38 questions divided into 5 domains: muscle weakness, sensory (hypo/loss of sensation), sensory (paresthesia, hyper sensation), autonomic (gastrointestinal & urinary incontinence), & autonomic (non-GI/non-urinary incontinence)]. Answers to questionnaire are yes/no and if yes, then degree of severity is graded as 1 (slight +), 2 (moderate ++) and 3 (severe +++). 0=no symptom. NSC total score is a sum of scores across all 5 domains. Total score= 0-114. Higher scores=more neuropathy symptoms. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.	Baseline, Week 35, Week 66
Change From Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65	SF-36 comprises 36 items that yield 8 subscales and 2 summary measures (PCS and Mental component summary [MCS]). Multi-item subscales (35 items) includes: physical function=10 items, role physical =4 items, bodily pain=2 items, general health=5 items, vitality=4 items, social functioning=2 items, role emotional =3 items and mental health=5 items. 8 subscales are scored from 0-100. Higher scores indicate better health. 8 subscales are aggregated into a PCS score ranging from 0-100. Higher scores indicate better health. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.	Baseline, Week 65
Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65	PND is a 5-stage scoring system. PND score is defined as I=sensory disturbances in limbs without motor impairment; II=difficulty walking without the need of a walking aid; IIIa=one stick or one crutch required for walking; IIIb=two sticks or two crutches needed; IV=wheelchair required or patient confined to bed. For analysis, no impairment is scored as 0, I is scored as 1, II as 2, IIIa as 3, IIIb as 4 and IV as 5. Lower scores indicate greater ambulatory function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.	Baseline, Week 65
Change From Baseline in Modified Body Mass Index (mBMI) at Week 65	mBMI is defined as body mass index in kilograms per square meter (kg/m^2) multiplied by serum albumin in grams per liter (g/L). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.	Baseline, Week 65

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Coelho T, Ando Y, Benson MD, Berk JL, Waddington-Cruz M, Dyck PJ, Gillmore JD, Khella SL, Litchy WJ, Obici L, Monteiro C, Tai LJ, Viney NJ, Buchele G, Brambatti M, Jung SW, St L O'Dea L, Tsimikas S, Schneider E, Geary RS, Monia BP, Gertz M. 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 Jun;10(1):375-389. doi: 10.1007/s40120-021-00235-6. Epub 2021 Feb 26.
• Coelho T, Marques W Jr, Dasgupta NR, Chao CC, Parman Y, Franca MC Jr, Guo YC, Wixner J, Ro LS, Calandra CR, Kowacs PA, Berk JL, Obici L, Barroso FA, Weiler M, Conceicao I, Jung SW, Buchele G, Brambatti M, Chen J, Hughes SG, Schneider E, Viney NJ, Masri A, Gertz MR, Ando Y, Gillmore JD, Khella S, Dyck PJB, Waddington Cruz M; NEURO-TTRansform Investigators. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy. JAMA. 2023 Oct 17;330(15):1448-1458. doi: 10.1001/jama.2023.18688.

Helpful Links

• The NEURO-TTRansform Study Website

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2019
• Primary Completion (Actual): April 11, 2023
• Study Completion (Actual): July 12, 2023

Study Registration Dates

• First Submitted: October 21, 2019
• First Submitted That Met QC Criteria: October 21, 2019
• First Posted (Actual): October 23, 2019

Study Record Updates

• Last Update Posted (Actual): December 13, 2024
• Last Update Submitted That Met QC Criteria: December 11, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: TTR; Amyloidosis; Polyneuropathy; ATTR
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Metabolic Diseases; Peripheral Nervous System Diseases; Proteostasis Deficiencies; Polyneuropathies; Amyloidosis; Amyloid Neuropathies
• Other Study ID Numbers: ION-682884-CS3; 2019-001698-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes