Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy

Study Overview
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Brief Summary
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Phase 3 efficacy and safety study to evaluate acoramidis (AG10) HCl 800 mg administered orally twice a day compared to placebo in subjects with symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM).

Detailed Description
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Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed condition believed to affect more than 400,000 people worldwide. In ATTR-CM, the accumulation of transthyretin (TTR) amyloid results in thickening and stiffening of the heart, which often leads to heart failure or even death. There are two forms of ATTR-CM: Wild Type* This form of the condition primarily develops in older individuals who do not carry gene mutations. Hereditary* This form of the condition comes from gene mutations passed down in families. In this study we are researching the investigational drug acoramidis HCl 800 mg administered orally twice a day. Through the study, we want to evaluate the efficacy and safety of acoramidis in patients with ATTR-CM versus placebo. This is a 30 month, randomized, double-blind, placebo-controlled study. This means that, during the 30 month study, investigators conducting the research and study participants will not know whether the study participant is receiving acoramidis or placebo. The primary outcomes of the study are: The impact of acoramidis versus placebo on the change in distance walked on the 6 minute walk test (6MWT) after 12 months of treatment compared to baseline. The impact of acoramidis versus placebo on the hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP, and change in from baseline in 6MWT over a 30-month fixed treatment duration. At the end of 30 months, participants may be eligible to receive investigational acoramidis, and there is no placebo. This is called an open label extension. This separate study may help us better understand the safety related to taking acoramidis over a longer period of time.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of AG10 in Subjects With Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM Trial)

Conditions
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Amyloidosis, Amyloid Cardiomyopathy, Transthyretin Amyloidosis, Cardiomyopathies, Heart Diseases

Intervention / Treatment
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* Drug: acoramidis
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have an established diagnosis of ATTR-CM with either wild-type TTR or variant TTR genotype Have a history of heart failure evidenced by at least one prior hospitalization for heart failure or clinical evidence of heart failure without prior heart failure hospitalization manifested by signs or symptoms of volume overload or elevated intracardiac pressures or heart failure symptoms that required or require ongoing treatment with a diuretic. New York Heart Association (NYHA) Class I-III symptoms due to ATTR cardiomyopathy. On stable doses of cardiovascular medical therapy Completed ≥150 m on the 6MWT on 2 tests that are within 15% of total distance walked prior to randomization Biomarkers of myocardial wall stress, NT-proBNP level ≥300 pg/mL at screening Have left ventricular wall (interventricular septum or left ventricular posterior wall) thickness ≥12 mm Exclusion Criteria: Had acute myocardial infarction, acute coronary syndrome or coronary revascularization, or experienced stroke or transient ischemic attack within 90 days prior to screening Has hemodynamic instability Likely to undergo heart transplantation within a year of screening Confirmed diagnosis of primary (light chain) amyloidosis Biomarkers of myocardial wall stress, NT-proBNP level ≥8500 pg/mL at screening Measure of kidney function, eGFR by MDRD formula <15 mL/min/1.73 m2 Current treatment with marketed drug products and other investigational agents for the treatment of ATTR-CM Current treatment with calcium channel blockers with conduction system effects (e.g. verapamil, diltiazem). The use of dihydropyridine calcium channel blockers is allowed. The use of digitalis will only be allowed if required for management of atrial fibrillation with rapid ventricular response

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: acoramidis HCl 800 mg<br>Subjects will receive acoramidis HCl 800 mg twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP levels, and change from baseline in distance walked on the 6MWT will be assessed after 30 months of treatment. | Drug: acoramidis<br>* TTR stabilizer administered orally twice daily (BID)<br>* Other names: ALXN2060;|
| Placebo Comparator: Placebo<br>Subjects will receive placebo to match twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP levels, and change from baseline in distance walked on the 6MWT will be assessed after 30 months of treatment. | Drug: Placebo Oral Tablet<br>* Non-active control administered orally twice daily (BID)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-Minute Walk Test (6MWT) through Month 12 | Change from baseline to Month 12 of treatment in the total distance walked in 6 minutes | 12 months | 
| A hierarchical combination of all-cause mortality, cumulative frequency of cardiovascular-related hospitalization, change from baseline in NT-proBNP, and change from baseline in 6MWT over a 30-month fixed treatment duration | Each subject will be compared to every other subject within a stratum over outcomes of all-cause mortality (death due to any cause), cumulative frequency of cardiovascular-related hospitalizations (number of times a subject is hospitalized for cardiovascular-related causes), change from baseline in NT-proBNP, and change from baseline in the total distance walked in 6 minutes (distance in meters). The hierarchical approach with the Finkelstein-Schoenfeld test will be applied and the test recognizes the greater importance of the mortality endpoint. Scores are transformed to -1, 0, +1. The alternative hypothesis is a subject in the acoramidis treatment group will have a greater score than a subject in the placebo group. | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate effects of acoramidis on quality of life (QoL) through Month 12 | Change from Baseline to Month 12 as measured in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life in subjects with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life (QoL). An Overall Summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, scores are transformed to a range of 0-100 using the formula, 100*[(mean of questions actually answered) - 1]/4, in which higher scores reflect better health status. The Overall Summary score is the mean of the domains scores, range from 0 to 100, in which higher scores reflect better health status. | 12 months | 
| Evaluate 6-Minute Walk Test (6MWT) through Month 30 | Change from baseline to Month 30 of treatment in the total distance walked in 6 minutes | 30 months | 
| Evaluate effects of acoramidis on quality of life (QoL) through Month 30 | Change from Baseline to Month 30 as measured in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life in subjects with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life (QoL). An Overall Summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, scores are transformed to a range of 0-100 using the formula, 100*[(mean of questions actually answered) - 1]/4, in which higher scores reflect better health status. The Overall Summary score is the mean of the domains scores, range from 0 to 100, in which higher scores reflect better health status. | 30 months | 
| Assess PD effects of circulating prealbumin by in vivo biomarker stabilization through Month 30 | Change from baseline to Month 30 in serum TTR (prealbumin) level (an in vivo measure of TTR stabilization) | 30 months | 
| Assess all-cause mortality | All-Cause Mortality by Month 30 including death due to any cause, heart transplant, or CMAD | 30 months | 
| Assess safety and tolerability through Month 12 | Safety parameters to be assessed: treatment- emergent serious adverse events (SAEs) and adverse events (AEs), AEs leading to treatment discontinuation, abnormal physical exam findings of clinical relevance, abnormal vital signs of clinical relevance, abnormal ECG parameters of clinical relevance, and changes in clinical safety laboratory parameters of potential clinical concern | 12 months | 
| PD assessments of TTR stabilization through Month 12 | Change from baseline in TTR (prealbumin) level (an in vivo measure of TTR stabilization) at Month 12 TTR stabilization as measured in established ex-vivo assays (fluorescent probe exclusion [FPE] and Western blot) at Month 12 in the PK-PD substudy | 12 months | 
| Efficacy by individual components and hierarchical combinations through Month 30 | A hierarchical combination of All-Cause mortality and cumulative frequency of CV-related hospitalization over a 30-month fixed treatment duration A hierarchical combination of All-Cause mortality, cumulative frequency of CV-related hospitalization, and change from baseline in 6MWT over a 30-month fixed treatment duration Change in NT-proBNP from baseline to Month 30 of treatment Cumulative frequency of CV-related hospitalization by Month 30 | 30 months | 
| Efficacy of acoramidis in reducing CV mortality | Total number of deaths adjudicated as being related to cardiovascular causes | 30 months | 
| Incidence of treatment-emergent events | Assessment of incidence of treatment- emergent serious adverse events (SAEs) and adverse events (AEs) | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyloidosis, ATTR-CM, Transthyretin, Amyloid, TTR