ION-682884 for Transthyretin Amyloid Cardiomyopathy

Overseen By Sarah Cuddy, MB

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brigham and Women's Hospital

Must be taking: Inotersen

Must not be taking: Antivirals, Antimicrobials, Anticoagulants

Disqualifiers: Uncontrolled hypertension, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 48 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a new treatment, ION-682884, can slow or stop heart problems caused by transthyretin, a protein that can lead to amyloidosis (a condition where protein deposits build up and harm the heart). The treatment involves monthly injections and will be compared to past results to assess its effectiveness and safety over an extended period. Individuals who participated in a 24-month study with a similar drug and have a stable heart condition related to amyloidosis might be suitable candidates for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on oral anticoagulants, the dose must be stable for 4 weeks before starting the study drug, and regular monitoring is required during the study.

Is there any evidence suggesting that ION-682884 is likely to be safe for humans?

Research has shown that ION-682884, a type of genetic treatment, appears safe for people with transthyretin amyloid cardiomyopathy, a heart condition. This treatment aims to lower the production of transthyretin, a protein that can accumulate and damage the heart.

Earlier trials suggested that this drug is generally well-tolerated. Participants who took ION-682884 did not experience severe side effects different from those seen with similar treatments. Safety checks revealed that common reactions were mild, such as redness or swelling at the injection site.

Further research is underway to confirm these results, but current data is encouraging regarding the safety of ION-682884. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for transthyretin amyloid cardiomyopathy aim to stabilize the transthyretin protein or remove amyloid deposits, like tafamidis or patisiran. But ION-682884 works differently, targeting the production of the transthyretin protein itself to reduce amyloid formation at its source. This treatment is administered via a monthly subcutaneous injection, which offers a convenient dosing schedule. Researchers are excited because this novel approach could lead to more effective management of the disease by directly addressing its root cause.

What evidence suggests that ION-682884 might be an effective treatment for transthyretin amyloid cardiomyopathy?

Research shows that ION-682884 is designed to treat transthyretin amyloid cardiomyopathy by reducing the production of transthyretin, a protein that can become unstable and cause harmful deposits in the heart. Previous studies have shown that ION-682884, a type of genetic therapy, can slow or even stop these deposits from accumulating. Specifically, the CARDIO-TTRansform study found that this treatment improved heart function in patients with this condition. Overall, these findings suggest that ION-682884 could help manage the progression of heart damage caused by transthyretin amyloidosis. ^{1 2 3 6 7}

Who Is on the Research Team?

Rodney H Falk

Principal Investigator

Brigham and Women's Hospital

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

I am between 65 and 85 years old.

I am a man or a woman who is not pregnant or breastfeeding. If I am a man with a premenopausal partner, we use contraception.

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

Exclusion Criteria

Uncontrolled clinically significant cardiac arrhythmia, per Investigator's assessment (e.g., no pacemaker, although indicated)

Your ALT or AST levels are more than double the normal limit.

My doctor advised against immunosuppressive therapy for me.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive subcutaneous injections of ION-682884, with follow-up visits at six weeks, 12 weeks, three months, and six months thereafter.

48 months

Monthly visits (in-person), weekly lab draws (home)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with ongoing assessments including echocardiogram, lab work, and cardiopulmonary exercise testing.

Open-ended

Open-label extension

Participants may continue receiving the study drug until FDA approval or study termination.

Open-ended

What Are the Treatments Tested in This Trial?

Interventions

• ION-682884

Trial Overview 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.

How Is the Trial Designed?

Group I: Drug subcutaneous injection Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Published Research Related to This Trial

Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), significantly reducing all-cause mortality and cardiovascular-related hospitalizations compared to placebo in the phase III ATTR-ACT trial, which involved patients over a 30-month period.

The treatment was well tolerated with a safety profile similar to placebo, making it a suitable long-term option for patients, and it provides a disease-modifying therapy rather than just symptom management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafamidis: A Review in Transthyretin Amyloid Cardiomyopathy. Lamb, YN.[2021]

Citations

1. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/5764/425860/Rationale-and-Design-of-a-Phase-3-Study-to

Rationale and Design of a Phase 3 Study to Evaluate the ... This study aims to determine if treatment with AKCEA-TTR-LRx (ION-682884), an antisense oligonucleotide (ASO), is safe and superior to placebo ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04136171

NCT04136171 | CARDIO-TTRansform: A Study to Evaluate ... CARDIO-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 ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0147956321001229

P010. Evaluation of the Efficacy and Safety of AKCEA-TTR- ... Evaluation of the Efficacy and Safety of AKCEA-TTR-LRx (ION-682884) in Patients with Transthyretin-mediated Amyloid Cardiomyopathy: The CARDIO-TTRansform Study.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11754378/

Transthyretin Cardiac Amyloidosis: Current and Emerging ... This review is of current drugs approved or being studied for ATTR cardiomyopathy (ATTR-CM), including stabilizers, silencers, and depleters.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04843020

ION-682884 in Patients With TTR Amyloid Cardiomyopathy The study is limited to those patients who have completed 24 months in our single-center open-label trial of inotersen for amyloid cardiomyopathy (NCT037028289) ...

6. orpha.net orpha.net/en/research-trials/clinical-trial/657172

CARDIO-TTRansform: A Phase 3 Global, Double-Blind, ... ... Safety of ION-682884 in Patients with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM) - GB. Geographic coverage: International (beyond Europe).

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33283485/

Ligand conjugated antisense oligonucleotide for the ... These findings suggest an improved safety and tolerability profile with the increase in potency achieved by productive receptor-mediated ...