ION-682884 in Patients With TTR Amyloid Cardiomyopathy

NCT04843020 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 2021P000784
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Transthyretin is a protein produced in the liver that transports thyroid hormone and vitamin A. A single substitution of an amino acid in the structure of TTR can result in a relatively unstable protein, the breakdown products of which (predominantly monomers) aggregate abnormally and produce proteinaceous deposits in nerves and the heart. These deposits are known as amyloid and produce progressive nerve and heart damage. Amyloidosis due to a mutant TTR is usually an autosomal dominant and hence is a familial condition. Wild-type TTR is also capable of producing amyloid deposits which predominantly involves the heart (rather than the nervous system) resulting in a progressive decrease in cardiac function with increasing signs of heart failure. This study aims to determine whether subcutaneous injection of an antisense oligonucleotide drug, known as ION-682884, that has been specifically designed to reduce production of the protein transthyretin by the liver, can slow or stop the progression of TTR amyloid cardiomyopathy as compared to historical controls, using advanced echocardiography and cardiac MRI. This study drug will only be administered to patients who have completed a 24-month study of a similar drug, inotersen (clinicaltrials.gov identifier NCT037028289).The study also aims to determine the tolerability and safety of this drug when administered over a 36+-month period to patients with TTR amyloid cardiomyopathy. The study duration is open-ended and will continue either until this agent is approved by the FDA, or production is discontinued based on results of ongoing double-blinded studies.

Conditions

Transthyretin Amyloid Cardiopathy

Keywords

amyloidosis; transthyretin; antisense oligonucleotide; ION682884; cardiomyopathy

Outcome Measures

Primary Outcomes (7)

• Echocardiographic change

  change in echocardiographically-derived left ventricular longitudinal strain (measured as percentage change from end diastole to end systole)

  48 months

• Change in cardiac MRI

  Change in extracellular volume (measure as a percentage of total of LV mass) between baseline MRI and 48 months

  48 months

• Change in cardiac MRI

  Change in left ventricular mass, measured by cardiac MRI (gm/m2) , between baseline and 48 months

  48 months

• change in 6 minute walk

  change in distance walked (measured in meters) between baseline 6 minute walk and walk after 48 months of therapy

  48 months

• change in cardiopulmonary testing

  change in maximal oxygen consumption (VO2 max measured in ml/kg.min) between baseline cardiopulmonary testing and cardiopulmonary testing at 48 months of therapy

  48 months

• change in the cardiac biomarker NTproBNP

  change between baseline and after 48 months of therapy of serum NTproBNP (measured in pg/ml)

  48 months

• change in the cardiac biomarker high-sensitivity troponin

  change between baseline and after 48 months of therapy of serum high-sensitivity troponin T measured in ng/L)

  48 months

Secondary Outcomes (4)

• Response of transthyretin levels to therapy

  3 months

• Time frame of response of TTR levels to therapy

  3 months

• Side-effect profile: renal function

  48 months

• Side effect profile: platelets

  48 months

Study Arms (1)

Drug subcutaneous injection

EXPERIMENTAL

Monthly injection of ION 682884, administered subcutaneously at a dose of 45 mg.

Drug: ION 682884

Interventions

ION 682884 DRUG

Subcutaneous injection every month

Drug subcutaneous injection

Eligibility Criteria

• Age: 65 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• \. Only patient who have completed 24 months of therapy in the open label clinical trial of inotersen, "A 24-month open-label study of the tolerability and efficacy of an antisense oligonucleotide (inotersen) in patients with transthyretin (TTR) amyloid cardiomyopathy" (Protocol #:2018-P001436) will be enrolled. All patients in that study had either wild-type transthyretin amyloidosis (ATTRwt) or mutant transthyretin amyloidosis (ATTRm) cardiac amyloidosis, defined by standard criteria. Additional criteria for the current study are as follows:
• Patients should, in the opinion of the Investigator, be in a stable state in terms of New York Heart Association (NYHA) class. Class I-III patients will be recruited.
• Age 65-85 years
• Male, or non-pregnant, non-lactating females. If a male partners with a premenopausal woman, he must be willing to use the following methods of contraception: condoms, oral/hormonal contraception, Intrauterine Device, diaphragm, or abstinence (all patients are either male of post-menopausal) (NB: There will be no premenopausal women in the proposed study)
• Written informed consent to be obtained prior to study treatment
• Willingness to return to the treating center for follow-up
• Willingness and ability to self-administer, or to have spouse administer subcutaneous injections of study drug every 4 weeks.
• Willingness to take oral Vitamin A supplementation throughout the study and for 3 months thereafter.

You may not qualify if:

• Alanine aminotransferase/aspartate aminotransferase (ALT/AST) \> 2.0 × upper limit of normal (ULN)
• Total bilirubin ≥ 1.5 × ULN (patients with total bilirubin ≥ 1.5 × ULN may be allowed on study if indirect bilirubin only is elevated, ALT/AST is not greater than the ULN and known to have Gilbert's disease)
• Platelets \< 125 × 109/L
• Urine protein creatinine ratio (UPCR) ≥ 750 mg/g. In the event of UPCR above this threshold ineligibility may be confirmed by a repeat random spot UPCR ≥ 750 mg/g
• Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 at Screening. If the eGFR is thought to be underestimated, the CKD-EPI creatinine-cystatin C equation can be used for confirmation.
• Abnormal thyroid function tests with clinical significance per Investigator judgement
• Hemoglobin A1c (HbA1c) \> 9.5% 8. Monoclonal gammopathy of undetermined significance (MGUS) and/or alterations in immunoglobulin free light chain (FLC) ratio, unless fat, bone marrow, or heart biopsy confirming the absence of light chain and the presence of TTR protein by mass spectrometry or immunoelectron microscopy. For patients with CKD and without presence of monoclonal protein in blood and urine, the acceptable FLC ratio is 0.26-2.25.
• \. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 10. Known history of or positive test for human immunodeficiency virus (HIV) (as evidenced by positive tests for HIV antibody and HIV RNA), hepatitis C (as evidenced by positive tests for HCV antibody and HCV RNA) or hepatitis B (as evidenced by a positive test for hepatitis B surface antigen) 11. History of bleeding, diathesis or coagulopathy (e.g., liver cirrhosis, hematologic malignancy, antiphospholipid antibody syndrome, congenital disorders such as hemophilia A, B, and Von Willebrand disease) 12. If receiving oral anticoagulants (except vitamin K antagonists), the dose must have been stable for 4 weeks prior to the first dose of Study Drug and regular monitoring must be performed, per clinical practice during the study. If the patient is receiving vitamin K antagonists (e.g., warfarin) INR should be in therapeutic range, as established by the Investigator, for 4 weeks prior to the first dose 13. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, prostate carcinoma grade group 1, breast ductal carcinoma in situ, or carcinoma in situ of the cervix successfully treated. Patients with a history of other malignancies who have been treated with curative intent and without recurrence within 5 years may also be eligible per Investigator judgment 14. Prior liver or heart transplant, and/or Left Ventricular Assist Device (LVAD) or anticipated liver transplant or LVAD within 1 year after randomization 15. Karnofsky performance status of ≤ 50% 16. Contraindication for immunosuppressive therapy, per Investigator's discretion 17. Known Light chain/Primary Amyloidosis (AL) 18. Known leptomeningeal amyloidos

Sponsors & Collaborators

• Brigham and Women's Hospital: lead

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Amyloidosis; Cardiomyopathies

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Heart Diseases; Cardiovascular Diseases

Study Officials

• Rodney H Falk

  Brigham and Women's Hospital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, BWH Amyloidosis Program

Model Details: open label study of investigational antisense oligonucleotide targeting TTR

Study Record Dates

• First Submitted: April 5, 2021
• First Posted: April 13, 2021
• Study Start: June 1, 2021
• Primary Completion: May 30, 2025
• Study Completion: December 31, 2025
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)