Breakthrough Clinical Results
BridgeBio Pharma announced the first participant has been dosed in ACT-EARLY, the first-ever primary prevention study for transthyretin amyloid cardiomyopathy (ATTR-CM). ACT-EARLY will evaluate acoramidis, a TTR stabilizer already approved for treating ATTR-CM, in asymptomatic carriers of pathogenic TTR variants to determine if it can delay or prevent disease onset. The study will enroll approximately 600 participants, with the primary endpoint being the time to development of ATTR-CM and/or ATTR-PN. Positive results from the ATTRibute-CM Phase 3 trial, showing a significant reduction in risk of cardiovascular events with acoramidis in ATTRv-CM patients, support the hypothesis that early intervention can significantly benefit patients.
Key Highlights
- First participant dosed in ACT-EARLY, the first primary prevention study for ATTR amyloidosis.
- Acoramidis, a near-complete TTR stabilizer, is being investigated for its preventative potential.
- The study will enroll approximately 600 asymptomatic carriers of pathogenic TTR variants.
- Positive Phase 3 data from the ATTRibute-CM trial supports the study's hypothesis.
Incidence and Prevalence
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, underdiagnosed, and often fatal disease. It is characterized by the deposition of amyloid fibrils, derived from misfolded transthyretin protein, in the heart muscle. This deposition leads to impaired cardiac function and ultimately heart failure.
Epidemiology:
The prevalence and incidence of ATTR-CM are likely underestimated due to challenges in diagnosis. However, recent advances in non-invasive diagnostic techniques, such as cardiac scintigraphy and cardiac magnetic resonance imaging, have led to increased recognition of the disease.
A 2023 systematic literature review found that ATTR-CM prevalence ranged from 6.1 per million in the US to 232 per million in Portugal. This review highlighted the significant heterogeneity in reported prevalence across different regions, emphasizing the need for more comprehensive epidemiological studies.
Other studies have reported varying prevalence estimates depending on the population studied:
- 18% in patients with heart failure, preserved ejection fraction (HFpEF), and risk markers for ATTR-CM.
- 6.3% in a community-based screening of patients with HFpEF and left ventricular wall thickening.
- 1.3% in a community cohort of HFpEF patients without systematic screening.
- 19% in elderly patients with pacemakers and LVH.
- 1.1% in a heart failure population with myocardial hypertrophy.
- Almost one in five patients 50 years of age with hypertrophic cardiomyopathy.
Incidence data are even more limited, but one study estimated the incidence of ATTR-CM in France to be 3.6 per 100,000 person-years in 2019, a significant increase from 0.6 per 100,000 person-years in 2011.
Types of ATTR-CM:
ATTR-CM exists in two forms:
- Wild-type ATTR-CM (ATTRwt): This form is associated with aging and is more common in older adults, particularly men.
- Hereditary ATTR-CM (ATTRv or hATTR): This form is caused by mutations in the TTR gene and can affect individuals of any age. The V122I variant is the most common mutation, particularly prevalent in individuals of African descent.
Mortality:
ATTR-CM is associated with high mortality rates. A 2023 systematic literature review reported a 2-year mortality risk ranging from 10% to 30% for ATTRwt and 10% to 50% for ATTRv. Other studies have reported a median survival of 30 months from diagnosis.
Key Factors:
Several factors are associated with an increased risk of ATTR-CM, including:
- Age: Prevalence increases with age, particularly in men.
- Sex: Men are more commonly affected than women, although the disparity may be due to underdiagnosis in women.
- Ethnicity: The V122I variant is more common in individuals of African descent.
- Heart failure: ATTR-CM is a common cause of HFpEF.
- Left ventricular hypertrophy: Wall thickening is a characteristic feature of ATTR-CM.
- Other conditions: Carpal tunnel syndrome, spinal stenosis, and other musculoskeletal conditions are often seen in patients with ATTR-CM.
Diagnosis:
Early diagnosis is crucial for effective management of ATTR-CM. Diagnostic tools include:
- Echocardiography: Can detect characteristic structural and functional changes in the heart.
- Cardiac magnetic resonance imaging: Provides detailed images of the heart and can detect amyloid deposits.
- Nuclear scintigraphy: A non-invasive imaging technique that can detect amyloid deposits in the heart.
- Genetic testing: Can identify TTR gene mutations in patients with hereditary ATTR-CM.
- Biopsy: Tissue biopsy can confirm the presence of amyloid deposits, but is less commonly used with the availability of non-invasive techniques.
Treatment:
Several disease-modifying therapies are now available for ATTR-CM, including tafamidis, acoramidis, patisiran, inotersen, and vutrisiran. These therapies can stabilize or silence TTR production, slowing disease progression and improving survival. Supportive care, such as diuretics and other heart failure medications, is also important for managing symptoms.
Unmet Needs and Target Populations in ATTR-CM Research (Past 3 Years)
Research on transthyretin amyloid cardiomyopathy (ATTR-CM) has made significant strides in recent years, with several approved and emerging therapies. However, several unmet needs and target populations remain a focus of ongoing research:
1. Cost-Effectiveness and Affordability: The high cost of newly approved ATTR-CM medications poses a significant barrier to access. Research is needed to demonstrate the cost-effectiveness of these treatments and explore strategies to improve affordability and access for patients.
2. Early Diagnosis and Screening: ATTR-CM is often diagnosed late in its course, when significant cardiac damage has already occurred. Research efforts focus on developing and validating risk scores and diagnostic algorithms to identify patients earlier, particularly in high-risk populations like older adults with heart failure and preserved ejection fraction (HFpEF) and increased left ventricular wall thickness. Noninvasive diagnostic tools like technetium Tc 99m pyrophosphate scintigraphy (PYP) are crucial for early detection, and research aims to optimize their use and refine patient selection criteria. Studies also explore the prevalence of ATTR-CM in specific populations, such as those with pacemakers or aortic stenosis, to improve targeted screening.
3. Disease Progression Monitoring: Standardized guidelines for monitoring disease progression and treatment response are needed. Research is evaluating various clinical, biomarker (e.g., NT-proBNP, troponin), and imaging (e.g., echocardiography, cardiac magnetic resonance imaging) parameters to establish meaningful thresholds and frequencies for assessing disease activity and treatment efficacy.
4. Treatment Optimization: While tafamidis and acoramidis are approved for ATTR-CM, research continues to optimize treatment strategies. Studies are investigating the efficacy of tafamidis in different patient subgroups (e.g., based on genotype, disease stage, or ejection fraction) and exploring its long-term effects on cardiac function and survival. Research also focuses on the potential benefits of combining tafamidis with other therapies, such as sodium-glucose cotransporter 2 inhibitors (SGLT2i), to further improve outcomes. Emerging therapies, including gene silencing agents (siRNA, ASO), gene editing (CRISPR-Cas9), and monoclonal antibodies, are under investigation for their potential to halt or reverse disease progression, particularly in patients with advanced disease.
5. Specific Patient Populations:
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Women: ATTR-CM is more often diagnosed in men, and research is investigating potential sex-related differences in disease presentation, diagnosis, and outcomes. Studies are evaluating the effectiveness of diagnostic tools and therapies in women and exploring reasons for the lower diagnosis rates in this population.
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Older Adults: ATTR-CM disproportionately affects older adults, and research is focused on optimizing diagnostic and treatment strategies in this age group. Studies are evaluating the safety and efficacy of therapies in older patients and exploring age-related factors that may influence treatment response.
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Racial and Ethnic Minorities: ATTR-CM is more prevalent in certain racial and ethnic groups, particularly people of African descent. Research is examining disparities in diagnosis, treatment access, and outcomes among these populations and exploring strategies to improve health equity.
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Patients with Advanced Disease: Patients with advanced ATTR-CM have limited treatment options. Research is investigating novel therapies, such as amyloid-targeting antibodies and gene editing, to address this unmet need and improve outcomes in this patient population.
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Asymptomatic Patients: The natural history and optimal management of asymptomatic ATTR-CM are not well understood. Research is investigating the prognosis of asymptomatic patients, the potential benefits of early treatment with TTR stabilizers, and strategies for monitoring disease progression in this population.
6. Real-World Evidence: Real-world studies are essential to complement clinical trial data and provide insights into the effectiveness, safety, and cost of ATTR-CM therapies in everyday clinical practice. These studies can help to identify factors that influence treatment adherence and outcomes in diverse patient populations.
7. Patient-Reported Outcomes: Research is increasingly incorporating patient-reported outcome measures (e.g., quality of life questionnaires) to assess the impact of ATTR-CM and its treatments on patients' physical, emotional, and social well-being. These data can help to inform treatment decisions and improve patient-centered care.
Study Design Parameters
Several clinical trials and observational studies have evaluated treatments for ATTR-CM, focusing on efficacy, safety, and disease progression. Here's a summary of key trial design parameters and endpoints:
ATTR-ACT (Tafamidis):
- Design: Multicenter, international, double-blind, placebo-controlled, phase 3 randomized clinical trial.
- Participants: 441 adults with hereditary or wild-type ATTR-CM.
- Intervention: Tafamidis meglumine 80 mg, tafamidis 20 mg, or placebo for 30 months.
- Primary Endpoints: All-cause mortality and frequency of cardiovascular-related hospitalizations.
- Secondary Endpoints: Change from baseline in 6-minute walk test distance and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score.
- Key Findings: Tafamidis significantly reduced all-cause mortality and CV-related hospitalizations, slowed the decline in functional capacity and quality of life.
- Long-Term Extension (LTE): Patients completing ATTR-ACT could continue or start tafamidis, with data collected for up to 5 years, showing sustained benefits and the importance of early treatment.
ATTRibute-CM (Acoramidis):
- Design: Phase 3 randomized controlled trial with an open-label extension (OLE).
- Participants: 632 adults with ATTR-CM.
- Intervention: Acoramidis or placebo for 30 months, followed by open-label acoramidis in the OLE.
- Primary Endpoint: Hierarchical assessment of all-cause mortality, cardiovascular-related hospitalization, change in NT-proBNP, and change in 6-minute walk distance.
- Key Findings: Acoramidis showed significant efficacy on the primary endpoint, with sustained benefits in the OLE.
Other Trials and Studies:
- Tafamidis dose comparison: ATTR-ACT also compared 80 mg and 20 mg tafamidis doses, with longer-term data supporting 80 mg as optimal.
- Real-world studies: Observational studies like THAOS have confirmed the effectiveness of tafamidis in real-world settings.
- Studies of other agents: Trials have evaluated other agents like revusiran (discontinued due to safety concerns), patisiran, inotersen, vutrisiran, and eplontersen, with varying results. Many of these focus on ATTR amyloidosis with polyneuropathy, with some showing promise for ATTR-CM.
- SGLT2i studies: Observational studies have explored the use of SGLT2 inhibitors in ATTR-CM, suggesting potential benefits but requiring further investigation in randomized trials.
Endpoints:
Commonly used endpoints in ATTR-CM trials include:
- All-cause mortality: A key indicator of overall survival.
- Cardiovascular-related hospitalizations: Reflects the impact of the disease on cardiac morbidity.
- Functional capacity: Measured by the 6-minute walk test (6MWT).
- Quality of life: Assessed using questionnaires like the KCCQ.
- Biomarkers: NT-proBNP, troponin, and serum TTR levels are used to monitor disease progression and treatment response.
- Imaging: Echocardiography, cardiac magnetic resonance (CMR), and scintigraphy are used to assess cardiac structure and function, amyloid burden, and treatment effects.
Key Considerations:
- Disease heterogeneity: ATTR-CM can present with varying degrees of severity and different clinical manifestations, making it important to consider patient characteristics and disease stage when selecting endpoints.
- Diagnostic delay: Delayed diagnosis is common in ATTR-CM, highlighting the need for early detection and treatment.
- Cost-effectiveness: The high cost of some ATTR-CM therapies raises important economic considerations.
Further research is needed to optimize treatment strategies, identify the most effective therapies for different patient subgroups, and improve long-term outcomes in ATTR-CM.
Drug used in other indications
Acoramidis is primarily known for its use in treating Transthyretin amyloid cardiomyopathy (ATTR-CM). The provided text focuses heavily on the ATTRibute-CM trial, a Phase 3 study that led to its approval for this indication. While the text mentions other TTR amyloidosis treatments like tafamidis, patisiran, inotersen, vutrisiran, and diflunisal, it does not describe any trials investigating acoramidis for indications other than ATTR-CM.
Therefore, based on the provided information, acoramidis is not currently being trialed for other indications besides ATTR-CM. The provided text exclusively discusses its role and efficacy in treating this specific type of cardiomyopathy. It's important to note that this information is based on the provided text and may not reflect the most up-to-date clinical trial landscape. Consulting a clinical trial database like ClinicalTrials.gov would provide the most current information on ongoing acoramidis trials.