What Is Acoramidis?
Acoramidis is an investigational drug classified as a transthyretin (TTR) stabilizer. TTR is a protein produced by the liver that helps transport thyroid hormone and vitamin A. In certain conditions, this protein can break down and form harmful clumps called amyloid. These amyloid deposits can accumulate in various organs, including the heart, where they can interfere with normal function.
By stabilizing the TTR protein, acoramidis aims to prevent or reduce the formation of these amyloid clumps. This mechanism is being investigated for its potential to treat conditions like transthyretin amyloidosis, particularly when it affects the heart, leading to cardiomyopathy and heart failure. Studies are also exploring its use as a preventative measure in individuals who carry a pathogenic TTR gene variant but do not yet show clinical signs of the disease.
Uses and Conditions Under Study
Acoramidis is currently being studied in clinical trials for several conditions related to transthyretin (TTR) amyloidosis, a disease where misfolded TTR proteins accumulate in tissues and organs. The drug's role as a TTR stabilizer aims to prevent or slow down this accumulation.
- Transthyretin Amyloidosis (ATTR): This broad category includes conditions where TTR protein misfolds and forms amyloid deposits. Acoramidis is being investigated to stabilize the TTR protein, potentially preventing or reducing these harmful deposits. This includes studies specifically for Amyloidosis (4 trials), Transthyretin Amyloidosis (2 trials), and Amyloidosis in Transthyretin (TTR) (1 trial).
- Cardiac Manifestations of ATTR: When TTR amyloid deposits in the heart, it can lead to serious heart conditions. Acoramidis is being studied to address these cardiac issues by stabilizing TTR. Conditions in this group include Cardiomyopathies (3 trials), Amyloid Cardiomyopathy (3 trials), Amyloid Cardiomyopathy, Transthyretin-Related (2 trials), Heart Diseases (2 trials), and Heart Disease (1 trial). The goal is to improve heart function and manage heart failure symptoms caused by TTR amyloid accumulation.
- Polyneuropathies: TTR amyloid can also affect the nervous system, leading to polyneuropathies, which are nerve disorders. Acoramidis is being evaluated for its potential to prevent or reduce TTR amyloid deposits in nerves, thereby addressing the symptoms of polyneuropathy. This condition is being studied in 2 trials.
- Healthy Participants: One trial involving healthy individuals is being conducted to assess how acoramidis is processed by the body and to evaluate its safety profile.
Dosing
Acoramidis is administered orally in tablet form. The drug has been studied in various strengths, including 356 mg and 400 mg film-coated tablets. The recommended dose of acoramidis is 712 mg, which typically involves taking two 356 mg tablets orally, twice daily. This corresponds to a total daily dose of 1424 mg.
Other investigational doses have included 800 mg, which could be administered as two 400 mg tablets. Acoramidis is generally taken twice daily (BID). These dosing regimens are being evaluated in clinical trials for conditions such as transthyretin amyloidosis and related cardiomyopathies.
Side Effects
In a clinical trial involving 421 patients with transthyretin amyloid cardiomyopathy, the most commonly reported adverse events for Acoramidis compared to placebo included:
- Cardiac failure occurred in 16.4% of patients taking Acoramidis, compared to 28.9% on placebo.
- Atrial fibrillation occurred in 13.1% of patients taking Acoramidis, compared to 17.1% on placebo.
- Dyspnoea (shortness of breath) occurred in 12.1% of patients taking Acoramidis, compared to 17.5% on placebo.
- Constipation occurred in 12.1% of patients taking Acoramidis, compared to 14.7% on placebo.
- Diarrhea occurred in 11.4% of patients taking Acoramidis, compared to 7.6% on placebo.
- Arthralgia (joint pain) occurred in 11.2% of patients taking Acoramidis, compared to 10.4% on placebo.
- Gout occurred in 10.9% of patients taking Acoramidis, compared to 8.1% on placebo.
- Dizziness occurred in 10.7% of patients taking Acoramidis, compared to 10.4% on placebo.
Clinical Trial Results
Transthyretin Amyloid Cardiomyopathy
The efficacy of Acoramidis was evaluated in a clinical trial (NCT03860935) involving patients with transthyretin amyloid cardiomyopathy. The study assessed a hierarchical combination of outcomes including all-cause mortality, cardiovascular-related hospitalizations, and changes in biomarkers and functional capacity over 30 months.
- In the primary analysis, patients treated with Acoramidis achieved a higher percentage of "wins" in the hierarchical outcome, with 63.7% of wins, compared to 35.9% for those on placebo. This indicates that patients on Acoramidis had better overall outcomes across the combined measures.
- Regarding all-cause mortality by Month 30, 79 participants in the Acoramidis group experienced death, heart transplant, or cardiac mechanical assist device implantation, compared to 52 participants in the placebo group. The Acoramidis group had 18.8% of its patients experience these events.
- Treatment with Acoramidis led to an increase in serum transthyretin (TTR) levels, a key protein involved in the condition. After 30 months, patients on Acoramidis showed an average increase of 5.78 mg/dL in TTR levels from baseline, while those on placebo experienced an average decrease of 1.32 mg/dL. An increase in TTR levels is considered beneficial as it helps stabilize the protein.
- Patients taking Acoramidis also showed a smaller decline in their walking ability as measured by the 6-Minute Walk Test (6MWT). After 30 months, the average distance walked decreased by 64.65 meters in the Acoramidis group, which was less than the average decrease of 104.29 meters observed in the placebo group. This suggests Acoramidis helped preserve physical function.
- The Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS), which measures quality of life, also showed a smaller decline in the Acoramidis group. The average score decreased by 11.48 points for patients on Acoramidis, compared to a 21.42-point decrease for those on placebo. A smaller decline indicates better preservation of quality of life.
Currently Recruiting Trials
Several clinical trials are currently recruiting participants to further understand acoramidis and its potential benefits for individuals with transthyretin amyloidosis. These studies aim to gather more information on how the drug works in different settings and patient populations.
One active study, NCT07298044, sponsored by Bayer, is a Phase 4 trial designed to learn about changes in blood levels of transthyretin when participants with transthyretin amyloidosis with cardiomyopathy switch from tafamidis to acoramidis. This study seeks to enroll 50 participants. Transthyretin (TTR) is a protein that can break down and form harmful clumps called amyloid, which deposit in the heart wall and impair its pumping function.
Another trial, NCT07235462, also sponsored by Bayer, is investigating the use of acoramidis in a real-world setting for patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM). This condition involves misfolded TTR protein building up as amyloid fibrils in the heart muscle, causing stiffness and leading to restrictive cardiomyopathy. This study aims to enroll 2000 participants.
Alexion Pharmaceuticals, Inc. is sponsoring NCT07306949, a Phase 4 study focused on the real-life clinical efficacy of acoramidis in participants with ATTR-CM and its association with cardiac biomarkers. This trial seeks to confirm that acoramidis treatment prevents the deterioration of the ATTR-CM disease progression index, and that these indexes can serve as surrogate markers for disease progression. It plans to enroll 200 participants.
Finally, the ACT-EARLY study, NCT06563895, sponsored by Eidos Therapeutics, a BridgeBio company, is a Phase 3 trial for asymptomatic carriers of a pathogenic TTR variant. This study aims to prevent transthyretin amyloidosis, a disease where TTR protein forms amyloid plaques that accumulate in organs and cause damage. This trial is recruiting 587 participants and includes conditions such as amyloidosis, amyloid cardiomyopathy, and polyneuropathies.
Where to Participate
Clinical trials for acoramidis are being conducted across a broad geographic area, with study sites located in 39 locations across 33 cities and 23 states. This wide reach helps ensure diverse participation in the research efforts.
Some of the cities with multiple participating sites include:
- New York, New York
- Boston, Massachusetts
- Baltimore, Maryland
- Chicago, Illinois
To be eligible for these studies, participants must generally be between 18 and 100 years of age. All genders are welcome to participate, but healthy volunteers and children are not being recruited for these specific trials.
Development Timeline
The journey of acoramidis in clinical development began on March 4, 2019, with the first trial initiated by Eidos Therapeutics, a BridgeBio company. Since then, the development program has steadily expanded, with the latest trial projected to conclude by the end of 2025.
Initially, the research for acoramidis explored conditions such as IBS-C and hyperphosphatemia. However, the focus quickly shifted and broadened to address various forms of amyloidosis, particularly those affecting the heart and nervous system. Key conditions now include Amyloid Cardiomyopathy, Transthyretin Amyloidosis, and Transthyretin-Related Familial Amyloid Polyneuropathy, reflecting a strategic expansion into areas of high unmet medical need.
Overall, 10 clinical trials have been conducted or are ongoing for acoramidis, enrolling a total of 4,140 participants. The development has progressed through various phases, with two Phase 1 studies, five Phase 3 studies, and two Phase 4 studies, alongside one trial where the phase was not specified. Eidos Therapeutics, a BridgeBio company, has been a primary driver, sponsoring six trials, while Alexion Pharmaceuticals, Inc. and Bayer have each sponsored two trials, contributing to the comprehensive understanding of this investigational therapy.