Extension Study Assessing Long Term Safety and Efficacy of IONIS-TTR Rx in Familial Amyloid Polyneuropathy (FAP)

An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (FAP)

This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.

Study Overview

• Status: Completed
• Conditions: Amyloidosis; Familial Amyloid Polyneuropathy; FAP; TTR; Transthyretin
• Intervention / Treatment: Drug: Inotersen

Detailed Description

Familial Amyloid Polyneuropathy (FAP) is a rare, hereditary disease caused by mutations in the transthyretin (TTR) protein. TTR is made by the liver and secreted into the blood. TTR mutations cause it to misfold and deposit in multiple organs causing FAP.

IONIS-TTR Rx is an antisense drug that is designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein will result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression.

This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.

• Study Type: Interventional
• Enrollment (Actual): 135
• Phase: Phase 3

Expanded Access

Approved for sale to the public. See expanded access record.

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • FLENI
• Brazil
  • Rio de Janeiro, Brazil, CEP 21941913
    • Federal University of Rio de Janeiro - University Hospital
  • Sao Paulo, Brazil
    • AACD
• France
  • Creteil, France, 94000
    • CHU Henri Mondor - Department of Neurology
  • Le Kremlin Bicetre, France, 94275
    • CHU Bicetre Aphp French Referral Center for FAP/Cornamyl Network
• Germany
  • Munster, Germany, 48149
    • UKM; Universitätsklinikum Münster, Klinik für Transplantationsmedizin
• Italy
  • Pavia, Italy, 27100
    • Centro per lo Studio e la Cura delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico San Matteo
  • Sicily
    • Messina, Sicily, Italy, 98124
      • Universita Degli Studi Di Messina - Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino"
• Portugal
  • Lisbon, Portugal, 1649-035
    • CHLN - Hospital de Santa Maria
  • Porto, Portugal, 4099-001
    • CHP-HGSA, Unidade Clinica de Paramiloidose
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clínic
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d' Hebron
• United Kingdom
  • London, United Kingdom, NW3 2PF
    • University College London - National Amyloidosis Centre
• United States
  • California
    • Orange, California, United States, 92868
      • University of California, Irvine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University Bayview Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine - Amyloid Treatment & Research Program
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center - The Neurological Institute
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Satisfactory completion of dosing & efficacy assessments in ISIS 420915-CS2

Exclusion Criteria:

• Any new condition or worsening of existing condition that could make the patient unsuitable for participation, or interfere with the patient participating in and/or completing the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Previous Placebo-Inotersen 300 mg; Participants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.	Drug: Inotersen; Inotersen SC; Other Names: TEGSEDI; ISIS 420915; IONIS-TTR Rx
Experimental: Previous Inotersen-Inotersen 300 mg; Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.	Drug: Inotersen; Inotersen SC; Other Names: TEGSEDI; ISIS 420915; IONIS-TTR Rx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug	An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence that at any dose that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported.	From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in Vital Signs	Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported.	From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in Weight	As prespecified in the protocol, percentage of participants with change from baseline in weight is reported in 2 categories, decrease of ≥7% from Baseline and increase of ≥7% from Baseline.	From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values	Clinical laboratory tests included the analysis of chemistry, haematology, and urinalysis. Any value outside the normal range will be flagged for the attention of the investigator who will assess whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. Normal range of creatinine clearance is 110 to 150 mL/min in males and 100 to 130 mL/min in females. Normal urine protein to creatinine (P/C) ratio= <0.2. Normal range for Alanine Aminotransferase (ALT) is 4 to 36 units per liter (U/L). Platelets normal range=140×10^9/L to 400×10^9/L.	From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG)	Normal QTcF at Baseline is defined as ≤450 milliseconds (ms) for males or ≤470 ms for females. Percentage of participants with QT interval outside of normal range are reported.	From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders	A concomitant therapy was any non-protocol-specified drug or substance (including over-the counter medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the final post-treatment visit for treating nervous and cardiovascular system disorders.	From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes		From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography		Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156	The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 Composite Score has a range of -22.32 to 346.32 and a higher mNIS+7 composite score indicates worsening disease. A positive change from Baseline indicates worsening of polyneuropathy impairments. Mixed Effects Model with Repeated Measures (MMRM) was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156	Heart rate to deep breathing is a quantitative autonomic test using the CASE IV instrument that measures a participant's change in heart rate after deep breathing. The score of this component ranges from 0 to 3.72 points. Higher scores indicate impairment. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156	The nerve conduction tests are quantitative tests that measure the conduction attributes of preselected nerves. The score range of this component is 0 to 18.6 points. Higher scores indicate impairment. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156	The Heat-Pain Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pain sensory thresholds in response to heat. The maximum score of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156	The Touch-Pressure Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pressure sensory thresholds in response to touch. The score range of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5	The NIS score is a measure of neurologic impairment. The NIS Score has a range of 0 to 244 and a higher NIS score indicates lower function. A positive change from Baseline indicates worsening. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5	Cranial Nerve assessment involves testing 3rd and 6th nerves and facial, palate, and tongue weakness. The score range for this component is 0 to 40 points. Higher scores indicate worsening. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5	Muscle weakness involves testing 19 movements of muscles. The score range of this component is 0 to 152 points. Higher scores indicate worsening. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5	The Reflexes Score involves testing 5 reflexes to stimuli. The score range of this component is 0 to 20 points. Higher scores indicate worsening. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5	The Sensory Score is based on testing an index finger and a big toe each to 4 stimuli. The score of this component ranges from 0 to 32 points. Higher scores indicate impairment. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156	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 136, and a higher Norfolk QoL-DN score indicates poorer QoL. A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score	The Norfolk QoL-DN physical functioning/large fiber neuropathy domain score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN physical function/large fiber neuropathy domain score has a range of -4 to 56, and a higher Norfolk QoL-DN domain score indicates poorer quality of life (QoL). A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the Week 52 of Year 4
Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156	BMI=weight (kg)/[height (m)^2]. The mBMI is the BMI multiplied by the serum albumin (g/L).	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156	BMI=weight (kg)/[height (m)^2].	Baseline, Weeks 78 and 156
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score	PND score is defined as I = sensory disturbances in limbs without motor impairment; II = difficulty walking without the need of a walking aid; III = one stick or one crutch required for walking; IV = two sticks or two crutches needed. V = wheelchair required or patient confined to bed. The change from Baseline values have been categorized as: improved, not changed, worsened, and unknown. Percentage of participants with changes from Baseline are presented category-wise in this outcome measure. Only categories with at least one participant with event are reported.	Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year)
Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set	GLS by ECHO is a measure of cardiac systolic function.	Baseline, Weeks 78 and 156
Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup	GLS by ECHO is a measure of cardiac systolic function.	Weeks 78 and 156
Change From Baseline in Transthyretin (TTR) Level	Transthyretin protein concentration in serum was measured.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in Retinol Binding Protein 4 (RBP4) Level	RBP4 protein concentration in serum was measured.	Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156, and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
Ctrough: Trough Plasma Concentration of ISIS 420915		Pre-dose on Days 1, 43, 85, 120, 176, 267, 358, 449, 540, 631, 722, 813, 904, 995, 1086, 1268; Days 1359 and 1450 of Year 4; Days 1632, 1723 and 1814 of Year 5

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Brannagan TH, Coelho T, Wang AK, Polydefkis MJ, Dyck PJ, Berk JL, Drachman B, Gorevic P, Whelan C, Conceicao I, Plante-Bordeneuve V, Merlini G, Obici L, Plana JMC, Gamez J, Kristen AV, Mazzeo A, Gentile L, Narayana A, Olugemo K, Aquino P, Benson MD, Gertz M; NEURO-T. T. R. Open-Label Extension Investigators. Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update. J Neurol. 2022 Dec;269(12):6416-6427. doi: 10.1007/s00415-022-11276-8. Epub 2022 Jul 31.
• Karam C, Brown D, Yang M, Done N, Zhu JJ, Greatsinger A, Bozas A, Vera-Llonch M, Signorovitch J. Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial. Muscle Nerve. 2022 Oct;66(4):438-446. doi: 10.1002/mus.27675. Epub 2022 Aug 4.
• Yarlas A, Lovley A, McCausland K, Brown D, Vera-Llonch M, Conceicao I, Karam C, Khella S, Obici L, Waddington-Cruz M. Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR. Neurol Ther. 2021 Dec;10(2):865-886. doi: 10.1007/s40120-021-00268-x. Epub 2021 Aug 5.
• Brannagan TH, Wang AK, Coelho T, Waddington Cruz M, Polydefkis MJ, Dyck PJ, Plante-Bordeneuve V, Berk JL, Barroso F, Merlini G, Conceicao I, Hughes SG, Kwoh J, Jung SW, Guthrie S, Pollock M, Benson MD, Gertz M; NEURO-TTR open-label extension investigators. Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial. Eur J Neurol. 2020 Aug;27(8):1374-1381. doi: 10.1111/ene.14285. Epub 2020 May 29.

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2014
• Primary Completion (Actual): September 11, 2020
• Study Completion (Actual): January 7, 2021

Study Registration Dates

• First Submitted: June 12, 2014
• First Submitted That Met QC Criteria: June 24, 2014
• First Posted (Estimated): June 26, 2014

Study Record Updates

• Last Update Posted (Estimated): November 20, 2023
• Last Update Submitted That Met QC Criteria: November 17, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: TTR; Amyloidosis; Transthyretin; FAP; Familial Amyloid Polyneuropathy
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Proteostasis Deficiencies; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Amyloidosis, Familial; Amyloidosis; Polyneuropathies; Amyloid Neuropathies; Amyloid Neuropathies, Familial
• Other Study ID Numbers: ISIS 420915-CS3; 2013-004561-13 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No