Tafamidis for Transthyretin Amyloid Cardiomyopathy

Recruiting in Palo Alto (17 mi)

+2 other locations

Overseen by Jan Griffin, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: University of Texas Southwestern Medical Center

Must be taking: Tafamidis

Must not be taking: Inotersen, Patisiran, Diflunisal

Disqualifiers: Low eGFR, Active malignancy, others

No Placebo Group

Prior Safety Data

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

Transthyretin cardiac amyloidosis (ATTR-CA) is a relentlessly progressive disease that can progress to end stage heart failure, at which point recently approved transthyretin production silencing or structure stabilizing therapies provide no clinical benefit. For well-selected individuals, heart transplantation is an excellent therapeutic option to improve survival. Historically, concomitant liver transplantation has been used to halt the progression of non-cardiac transthyretin amyloidosis (ATTR) manifestations, especially for individuals with TTR genotypes associated with significant neuropathy. However, despite this, patients continue to experience progressive non-cardiac manifestations, particularly gastrointestinal and neuropathic, which can have a substantial influence on post-heart transplantation morbidity. Concomitant liver transplantation is also associated with substantial morbidity and its future therapeutic role is questionable with recently established therapies for ATTR. Therefore, there is a clear unmet need to determine the utility and safety of ATTR targeted therapies for patients with recent heart transplantation for end-stage ATTR-CA. The central hypothesis of this proposal is that in patients who have received a heart transplantation for end-stage ATTR-CA, tafamidis therapy will be efficacious and well-tolerated. We aim to determine the safety and efficacy of tafamidis in stable patients who have undergone heart or combined heart/liver transplantation for ATTR (wild-type or variant) cardiac amyloidosis. The proposed study will be a single-arm intervention clinical trial with tafamidis. Because of the efficacy of tafamidis for both variant ATTR-CA and wild-type ATTR-CA, there is no clinical equipoise for an inactive-comparator placebo arm. The primary endpoint of this study will be serial change in plasma transthyretin (TTR) levels from baseline to 12 months at 3-month intervals. The secondary endpoints of this study will include serial changes in neuropathy assessments, modified body mass indices, incident transplant-specific adverse events, and pharmacokinetics of tafamidis. Observations from this study will establish the role of tafamidis use for the management of ATTR in patients after transplantation for end-stage ATTR-CA.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken certain medications like tafamidis, inotersen, patisiran, or diflunisal recently. It's best to discuss your current medications with the trial team.

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

Research shows that Tafamidis significantly reduces the risk of death and hospitalizations related to heart problems in patients with transthyretin amyloid cardiomyopathy. It also helps maintain physical ability and quality of life better than a placebo over a 30-month period. ^{1 2 3 4 5}

Is tafamidis safe for human use?

Tafamidis is generally considered safe for human use, with clinical trials showing it has a safety profile similar to a placebo, meaning it doesn't cause more side effects than a sugar pill. It has been well tolerated in patients with transthyretin amyloid cardiomyopathy and familial amyloid polyneuropathy, with fewer adverse events reported compared to other treatments. ^{1 2 4 6 7}

How is the drug Tafamidis unique in treating transthyretin amyloid cardiomyopathy?

Tafamidis is unique because it is the first drug approved specifically for transthyretin amyloid cardiomyopathy, working by stabilizing the transthyretin protein to prevent its breakdown into harmful forms, which reduces mortality and hospitalizations compared to previous treatments that only managed symptoms. ^{1 2 3 4 8}

Research Team

Justin Grodin, MD

Principal Investigator

UT Southwestern Medical Center

Jan Griffin, MD

Principal Investigator

Medical University of South Carolina

Eligibility Criteria

This trial is for patients who've had a heart transplant at least 12 months ago due to end-stage Transthyretin Amyloid Cardiomyopathy (ATTR-CA). They should be relatively healthy otherwise, with stable organ function and not taking high doses of immune-suppressing drugs. People with active cancers (except certain skin cancers), infections like hepatitis or HIV, severe heart issues post-transplant, recent rejection treatments, very poor kidney function, or other types of amyloidosis can't join.

Inclusion Criteria

I am on a stable medication regimen for my immune system, taking 10 mg or less of prednisone.

I am mostly able to care for myself and carry out daily activities.

I had a heart transplant over a year ago due to advanced ATTR.

Exclusion Criteria

You are currently taking part in a clinical trial for treatments that target ATTR.

I have been treated for organ rejection in the last 3 months.

My heart's pumping ability is reduced (LVEF <50%).

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tafamidis therapy post heart or heart/liver transplantation for 12 months

12 months

Visits at baseline, 3, 6, 9, and 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Treatment Details

Interventions

• Tafamidis (Transthyretin Stabilizer)

Trial Overview The study tests Tafamidis 61 MG's safety and effectiveness in patients after a heart transplant due to ATTR-CA. It's a single-arm trial where all participants receive the drug—no placebo group—focusing on how it affects protein levels related to ATTR-CA over one year and its impact on nerve health, body mass index changes, specific side effects related to the transplant, and how the body processes the drug.

Participant Groups

Group I: Treatment Arm Experimental Treatment 1 Intervention

Tafamidis 61 mg

Tafamidis is already approved in Japan for the following indications:

Approved in Japan as Vyndaqel for:

• Transthyretin amyloid polyneuropathy (ATTR-PN)
• Transthyretin amyloid cardiomyopathy (ATTR-CM)

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Daniel K. Podolsky

University of Texas Southwestern Medical Center

Chief Executive Officer since 2008

MD from Harvard Medical School

Robert L. Bass

University of Texas Southwestern Medical Center

Chief Medical Officer since 2019

MD from University of Texas Southwestern Medical School

Findings from Research

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]

Tafamidis is the first approved medication for transthyretin amyloid cardiomyopathy (ATTR-CM), significantly reducing mortality and cardiovascular-related hospitalizations compared to placebo, based on clinical studies.

The drug works by stabilizing transthyretin, preventing its dissociation into harmful monomers, and has a favorable safety profile with fewer adverse events than placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafamidis: A First-in-Class Transthyretin Stabilizer for Transthyretin Amyloid Cardiomyopathy. Park, J., Egolum, U., Parker, S., et al.[2020]

Tafamidis has been shown to significantly reduce all-cause mortality and cardiovascular hospitalizations in patients with transthyretin cardiac amyloidosis, highlighting its efficacy as a treatment option.

The Japanese Ministry of Health has approved tafamidis for treating cardiomyopathy caused by both wild-type and mutated transthyretin-derived amyloidoses, indicating its recognized importance in managing this underdiagnosed and serious condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Statement on the Appropriate Administration of Tafamidis in Patients With Transthyretin Cardiac Amyloidosis. Endo, J., Sano, M., Izumiya, Y., et al.[2020]

Tafamidis meglumine is a first-in-class drug that effectively stabilizes the transthyretin (TTR) protein, preventing the formation of harmful amyloid aggregates associated with transthyretin familial amyloid polyneuropathy (TTR-FAP).

Clinical trials have shown that tafamidis slows disease progression and improves nerve function in patients with TTR-FAP, leading to better overall health outcomes, and it has received marketing authorization in Europe, with ongoing review in the U.S. for the same condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafamidis for transthyretin amyloidosis. de Lartigue, J.[2017]

Tafamidis significantly reduces all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), with a median follow-up of 51 months from the ATTR-ACT trial and its long-term extension study.

The 80 mg dose of tafamidis showed a greater survival benefit compared to the 20 mg dose, while both doses had a safety profile comparable to placebo, suggesting that 80 mg is the optimal dose for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study. Damy, T., Garcia-Pavia, P., Hanna, M., et al.[2021]

References

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

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

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

Tafamidis: A First-in-Class Transthyretin Stabilizer for Transthyretin Amyloid Cardiomyopathy. [2020]

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

Efficacy of Tafamidis in Patients With Hereditary and Wild-Type Transthyretin Amyloid Cardiomyopathy: Further Analyses From ATTR-ACT. [2021]

4. Japan pubmed.ncbi.nlm.nih.gov

A Statement on the Appropriate Administration of Tafamidis in Patients With Transthyretin Cardiac Amyloidosis. [2020]

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

Extrapolation of Survival Benefits in Patients with Transthyretin Amyloid Cardiomyopathy Receiving Tafamidis: Analysis of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial. [2020]

6. Spain pubmed.ncbi.nlm.nih.gov

Tafamidis for transthyretin amyloidosis. [2017]

7. England pubmed.ncbi.nlm.nih.gov

The effect of tafamidis on the QTc interval in healthy subjects. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study. [2021]