Eplontersen for Transthyretin Amyloid Cardiomyopathy

Enrolling by invitation at 134 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called eplontersen for individuals with transthyretin amyloid cardiomyopathy (ATTR-CM), a condition affecting the heart. The goal is to assess the safety and tolerability of eplontersen over an extended period. Participants will receive a monthly injection for up to three years. Those who have completed specific previous studies on this condition and are willing to take vitamin A supplements might be suitable candidates for this trial. As a Phase 3 trial, this study serves as the final step before potential FDA approval, offering participants the opportunity to contribute to the development of a promising treatment.

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.

Is there any evidence suggesting that eplontersen is likely to be safe for humans?

Research has shown that eplontersen has been tested on many people to assess its safety. In a large study with over 1,400 participants, eplontersen was administered as an injection under the skin. This study compared eplontersen to a placebo, which contains no active drug.

The results showed that patients generally tolerated eplontersen well. Most side effects were mild and similar to those experienced by people who received the placebo. Common side effects included reactions at the injection site, such as redness or swelling. Serious side effects were rare.

Overall, the data suggests that eplontersen is safe for use in humans, with most people experiencing only mild issues. This information comes from studies where eplontersen was used for other conditions, supporting its safety for ATTR-CM, a type of heart disease caused by amyloid protein build-up. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Eplontersen is unique because it targets transthyretin amyloid protein, which is involved in the progression of transthyretin amyloid cardiomyopathy. Unlike standard treatments that mainly focus on managing symptoms, Eplontersen aims to tackle the disease at its root by reducing the production of amyloid. This approach could potentially slow down or even halt disease progression. Additionally, Eplontersen is administered via a convenient monthly subcutaneous injection, which could improve patient adherence compared to more frequent dosing regimens. Researchers are excited about its potential to offer a more effective and patient-friendly solution.

What evidence suggests that eplontersen might be an effective treatment for ATTR-CM?

Research has shown that eplontersen holds promise for treating transthyretin amyloid cardiomyopathy (ATTR-CM). In earlier studies, eplontersen consistently helped patients with this condition by reducing the abnormal protein buildup in the heart, thereby improving heart function. The CARDIO-TTRansform trial demonstrated that eplontersen was more effective than a placebo, suggesting significant benefits for those with ATTR-CM. Overall, the evidence supports eplontersen's potential to enhance heart health in these patients. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04136171

NCT04136171 | CARDIO-TTRansform: A Study to Evaluate ... To evaluate the efficacy of eplontersen compared to placebo in participants with ATTR-CM receiving available standard of care (SoC). Detailed Description. This ...

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

P010. Evaluation of the Efficacy and Safety of AKCEA-TTR- ... The CARDIO-TTRansform trial is a large Phase 3 trial designed to evaluate the clinical efficacy and safety of AKCEA-TTR-LRx compared to placebo in patients ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10540057/

Eplontersen for Hereditary Transthyretin Amyloidosis With ... An independent data and safety monitoring board regularly reviewed efficacy, safety, and tolerability data, including the results of a ...

4. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2023/eplontersen-demonstrated-sustained-benefit-in-phase-iii-trial.html

Eplontersen demonstrated sustained benefit in Phase III ... The positive results from the 66-week analysis of the Phase III NEURO-TTRansform trial show that eplontersen provided consistent and sustained transthyretin ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05071300

NCT05071300 | A Study to Assess the Long-Term Safety ... The purpose of this study is to evaluate the safety and tolerability of extended dosing with eplontersen in participants with hereditary transthyretin-mediated ...

6. stanfordhealthcare.org stanfordhealthcare.org/trials/c/NCT04136171.html

CARDIO-TTRansform - clinical trials - Stanford Health Care Purpose. To evaluate the efficacy of eplontersen compared to placebo in participants with ATTR-CM receiving available standard of care (SoC).