What side effects are associated with this type of intervention?

Common treatments for Transthyretin Amyloid Cardiomyopathy that reduce transthyretin production include antisense oligonucleotides (ASOs) like inotersen and small interfering RNA (siRNA) therapies like patisiran. Known side effects of these treatments can include injection site reactions, thrombocytopenia (low platelet count), renal toxicity, and peripheral neuropathy. Patients may also experience flu-like symptoms, including fever and fatigue. Regular monitoring is essential to manage these potential adverse effects effectively.

What prior FDA approvals exist?

The FDA has approved several treatments for Transthyretin Amyloid Cardiomyopathy that focus on reducing transthyretin production. Notably, patisiran and inotersen are RNA-targeted therapies that have been approved for this condition. Patisiran is a small interfering RNA (siRNA) that reduces transthyretin production by targeting its mRNA, while inotersen is an antisense oligonucleotide (ASO) that also inhibits transthyretin synthesis. These treatments are similar to ION-682884, which is currently being studied for its efficacy in reducing transthyretin production through antisense oligonucleotide technology.

What other types of research exist?

Promising alternatives to ION-682884 for ATTR-CM patients include: 1) RNA silencing therapies such as siRNA and other antisense oligonucleotides targeting TTR, which have shown potential in reducing amyloid deposition. 2) Gene editing approaches using CRISPR-Cas9 to knock out TTR production, which have demonstrated substantial reduction in serum TTR levels in early clinical studies. These alternatives are under investigation and may offer new treatment options in the near future.

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Antisense Oligonucleotide

ION-682884 for Transthyretin Amyloid Cardiomyopathy

Phase 2

Waitlist Available

Research Sponsored by Brigham and Women's Hospital

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Age 65-85 years

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.

Must not have

Cardiomyopathy not primarily caused by amyloidosis, for example, cardiomyopathy due to hypertension, valvular heart disease, or ischemic heart disease

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

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 48 months

Awards & highlights

No Placebo-Only Group

Summary

This trial involves injecting a special medicine under the skin to reduce a harmful protein in older patients with heart issues due to abnormal protein deposits. The medicine works by lowering the levels of a protein that can damage the heart.

Who is the study for?

This trial is for patients aged 65-85 with TTR amyloid cardiomyopathy who have completed a previous 24-month inotersen study. They must be stable (NYHA class I-III), able to self-administer injections, and willing to take Vitamin A supplements. Excludes those with severe heart issues, uncontrolled infections or arrhythmias, certain kidney conditions, blood disorders, high bilirubin levels, recent major cardiovascular events or surgeries.

What is being tested?

The trial tests the drug ION-682884's ability to slow down or stop heart damage caused by TTR amyloid deposits. It involves subcutaneous injections every four weeks and compares results against historical data using advanced cardiac imaging techniques over an open-ended period until FDA approval or discontinuation.

What are the potential side effects?

While specific side effects of ION-682884 are not listed here, similar drugs can cause injection site reactions, liver problems (like raised enzyme levels), potential kidney issues reflected in urine protein levels, and may require Vitamin A supplementation due to its reduction.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am between 65 and 85 years old.

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I completed 24 months in the inotersen study for TTR amyloid cardiomyopathy.

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I am willing to take Vitamin A supplements during and 3 months after the study.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My heart condition is not mainly due to amyloidosis.

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My blood thinner medication dose has been stable for 4 weeks, and I am monitored regularly.

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I haven't had major heart issues or surgeries in the last 4 weeks.

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I have been diagnosed with leptomeningeal amyloidosis.

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I have a condition that affects my blood's ability to clot.

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I have had or will have a liver or heart transplant, or need a LVAD within a year.

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I have a serious heart valve problem that hasn't been treated.

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I need considerable assistance and medical care.

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I have been diagnosed with AL amyloidosis.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 48 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~48 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 48 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change in cardiac MRI

Echocardiographic change

change in 6 minute walk

+3 more

Secondary study objectives

Response of transthyretin levels to therapy

Side effect profile: platelets

Side-effect profile: renal function

+1 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Drug subcutaneous injectionExperimental Treatment1 Intervention

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

0 / 12Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Transthyretin Amyloid Cardiomyopathy (ATTR-CM) include liver transplantation and antisense oligonucleotides like ION-682884. Liver transplantation aims to remove the source of the amyloidogenic protein in hereditary ATTR by replacing the liver, which produces the mutant transthyretin (TTR). However, this approach is not effective for wild-type ATTR. Antisense oligonucleotides, such as ION-682884, work by reducing the production of transthyretin in the liver, thereby decreasing the availability of misfolded TTR monomers that form amyloid deposits in the heart. This reduction in amyloid deposits can slow or halt the progression of cardiac damage, which is crucial for improving the quality of life and prognosis for patients with ATTR-CM.

Troponin-tropomyosin abnormalities in hamster cardiomyopathy.Combinatorial Treatment of Human Cardiac Engineered Tissues With Biomimetic Cues Induces Functional Maturation as Revealed by Optical Mapping of Action Potentials and Calcium Transients.Intracoronary Sarcoplasmic Reticulum Calcium-ATPase Gene Therapy in Advanced Heart Failure Patients with reduced Ejection Fraction: A Prospective Cohort Study.