Eplontersen for Transthyretin Amyloid Cardiomyopathy

Recruiting at 96 trial locations

Overseen By Sarah Dalley

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Ionis Pharmaceuticals, Inc.

Must be taking: Eplontersen

Disqualifiers: New condition, Worsening condition, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: up to 36 months

1400 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not clearly state if you need to stop your current medications, but it mentions that you cannot take medications that were not allowed in the previous study. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug Eplontersen for treating transthyretin amyloid cardiomyopathy?

Eplontersen is designed to reduce the production of transthyretin (TTR) protein, which is involved in the progression of amyloidosis, a condition where abnormal protein deposits can damage organs. Similar drugs, like tafamidis, have shown effectiveness in slowing down the progression of heart-related symptoms in amyloidosis, suggesting that Eplontersen may also be beneficial. ^{1 2 3 4 5}

Is Eplontersen safe for humans?

Eplontersen, also known as AKCEA-TTR-LRx or ION-682884, is being studied for its safety in treating transthyretin amyloidosis, a serious disease. It is designed to reduce the production of a protein that causes the disease, and studies are ongoing to ensure it is safe and effective for patients. ^{1 2 3 5 6}

How is the drug Eplontersen different from other treatments for transthyretin amyloid cardiomyopathy?

Eplontersen is unique because it is an antisense oligonucleotide that targets the mRNA responsible for producing transthyretin (TTR) protein, reducing both variant and wild-type TTR production. This approach is different from other treatments that focus on stabilizing TTR or breaking down existing amyloid deposits. ^{1 2 3 5 7}

What is the purpose of this trial?

This trial tests the safety of eplontersen, a medication given periodically, in patients with a specific heart condition (ATTR-CM). The drug aims to reduce harmful proteins to improve heart health.

Eligibility Criteria

This trial is for adults with a heart condition called ATTR-CM who have completed a previous eplontersen study or were part of the ISIS 420915-CS101 study and judged suitable by the investigator. Participants must be willing to take vitamin A as required and not have any new or worsening conditions that could affect their participation.

Inclusion Criteria

I am willing to follow the vitamin A supplement plan.

You have completed the treatment and follow-up visits for a previous study related to the same condition, or you have been diagnosed with a specific heart condition and have participated in a related study.

My doctor agrees to treat me with eplontersen.

Exclusion Criteria

Have any new condition or worsening of an existing condition that in the opinion of the Investigator or Sponsor would make the participant unsuitable for enrolment, or which could interfere with the participant participating in or completing the study, including the need for treatment with medications disallowed in the Index Study

Permanently discontinued study drug administration while participating in the Index Study (ION 682884-CS2) or IST (ISIS 420915-CS101 Study)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

≤ 10 weeks

Treatment

Participants receive eplontersen once every 4 weeks for up to 36 months, along with daily supplemental doses of vitamin A

up to 36 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 6 months

Treatment Details

Interventions

• Eplontersen

Trial Overview The trial is testing the long-term safety of continued doses of a drug named Eplontersen in patients with Transthyretin-Mediated Amyloid Cardiomyopathy, which affects the heart. It aims to understand how well people tolerate this medication over an extended period.

Participant Groups

Group I: Eplontersen Experimental Treatment 1 Intervention

Eplontersen will be administered once every month by sub-cutaneous (SC) injection for up to 36 months or 6 months after eplontersen is approved and available in the site's country, whichever occurs first.

Eplontersen is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as Wainua for:

• Polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults

Approved in European Union as Wainua for:

• Hereditary transthyretin-mediated amyloidosis (ATTRv) and stage 1 or 2 polyneuropathy in adults

Approved in United Kingdom as Wainua for:

• Hereditary transthyretin-mediated amyloidosis (ATTRv) and stage 1 or 2 polyneuropathy in adults

Who Is Running the Clinical Trial?

Ionis Pharmaceuticals, Inc.

Lead Sponsor

Trials

151

Recruited

27,800+

Dr. Brett P. Monia

Ionis Pharmaceuticals, Inc.

Chief Executive Officer since 2020

PhD in Pharmacology from the University of Pennsylvania, BSc in Molecular Biology and Analytical Chemistry from Stockton State College

Dr. Eric Bastings

Ionis Pharmaceuticals, Inc.

Chief Medical Officer

MD

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

Eplontersen, an antisense oligonucleotide targeting TTR mRNA, effectively inhibits the production of transthyretin protein, which is crucial for treating transthyretin-mediated amyloidosis, as shown in phase 1 studies with healthy volunteers.

The pharmacokinetic model revealed that factors like lean body mass and injection site (abdomen vs. arm) influence drug absorption and clearance, but these variations do not significantly affect the drug's therapeutic response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic/pharmacodynamic modelling of eplontersen, an antisense oligonucleotide in development for transthyretin amyloidosis. Diep, JK., Yu, RZ., Viney, NJ., et al.[2022]

AKCEA-TTR-LRx, an antisense drug designed for targeted delivery to liver cells, showed a significant increase in potency—about 50-fold in cell cultures and 30-fold in animal models—compared to the unconjugated drug inotersen, indicating its potential for more effective treatment of ATTR amyloidosis.

In a phase 1 clinical trial with healthy volunteers, AKCEA-TTR-LRx demonstrated a strong safety profile with no serious adverse events and achieved substantial reductions in transthyretin (TTR) levels, with a maximum reduction of 93.8% after multiple doses, supporting its further development for treating ATTR-related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. Viney, NJ., Guo, S., Tai, LJ., et al.[2022]

The NEURO-TTRansform study is evaluating eplontersen, an antisense oligonucleotide aimed at reducing transthyretin (TTR) mRNA, in 168 patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), highlighting its potential as a targeted treatment for this severe disease.

The study population is diverse, with patients aged 18-82 years, predominantly male (69%), and primarily in early stages of the disease, indicating that eplontersen is being tested in a representative cohort reflective of real-world clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen. Coelho, T., Waddington Cruz, M., Chao, CC., et al.[2023]

Tafamidis meglumine, a transthyretin stabilizer, appears to be effective in delaying the progression of TTR amyloid cardiomyopathy in a 73-year-old patient with the Val30Met mutation, as shown by stable cardiac imaging results after 12 months of treatment.

This case suggests that using serial native T1 and extracellular volume measurements could be useful non-invasive methods for monitoring treatment response in patients with cardiac amyloidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring treatment response to tafamidis by serial native T1 and extracellular volume in transthyretin amyloid cardiomyopathy. Shintani, Y., Okada, A., Morita, Y., et al.[2021]

Transthyretin (TTR)-related cardiac amyloidosis treatment includes both supportive therapies for managing complications and disease-modifying therapies aimed at slowing down amyloid fibril production, involving various innovative drug strategies.

Current therapies target different stages of amyloidogenesis, including gene silencing (e.g., patisiran, inotersen), stabilization of TTR to prevent fibril formation (e.g., tafamidis), and ongoing research into antibodies for breaking down existing amyloid deposits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The treatment of amyloidosis is being refined. Cantone, A., Sanguettoli, F., Dal Passo, B., et al.[2022]

AKCEA-TTR-LRx is a new drug designed to treat hereditary transthyretin amyloidosis (hATTR) by targeting liver cells more effectively, allowing for lower and less frequent dosing compared to the previously approved drug inotersen.

The ongoing NEURO-TTRansform study will assess the safety and efficacy of AKCEA-TTR-LRx in about 140 adults with hATTR polyneuropathy, aiming to improve neurological function and quality of life, with results expected to compare favorably against historical placebo data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Coelho, T., Ando, Y., Benson, MD., et al.[2021]

In a study of 144 adults with hereditary transthyretin amyloidosis (ATTRv), eplontersen treatment for 65 weeks led to a significant improvement in cardiac function, specifically a 4.3% increase in left ventricular ejection fraction and a 10.64 mL increase in stroke volume compared to a historical placebo group.

Eplontersen demonstrated stable or improved cardiac structure and function in patients with ATTRv polyneuropathy and cardiomyopathy, suggesting its potential as an effective treatment, with further investigations ongoing in the CARDIO-TTRansform trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Eplontersen on Cardiac Structure and Function in Patients With Hereditary Transthyretin Amyloidosis. Masri, A., Maurer, MS., Claggett, BL., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic/pharmacodynamic modelling of eplontersen, an antisense oligonucleotide in development for transthyretin amyloidosis. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Monitoring treatment response to tafamidis by serial native T1 and extracellular volume in transthyretin amyloid cardiomyopathy. [2021]

5. England pubmed.ncbi.nlm.nih.gov

The treatment of amyloidosis is being refined. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

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. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Effect of Eplontersen on Cardiac Structure and Function in Patients With Hereditary Transthyretin Amyloidosis. [2023]