Symptomatic Transthyretin Amyloid Cardiomyopathy
Conditions
Brief summary
This prospective study is designed to evaluate the efficacy, safety, and tolerability of ALXN2060 (also known as AG10), as well as to establish its pharmacokinetic and pharmacodynamic profile in Japanese participants with symptomatic ATTR-CM administered on a background of stable heart failure therapy.
Detailed description
Participants will receive ALXN2060 for 12 months (Part A). Following the last visit (Month 12) of Part A, participants will continue the study in Part B, which will last for an additional 18 months (30 months from Day 1), during which all participants will continue to receive oral treatment with ALXN2060. Following completion of Month 30 assessments in Part B, participants will be offered the opportunity to continue to receive ALXN2060 in the Extension Period, which will last until ALXN2060 is approved in Japan or for up to 24 additional months, whichever occurs first.
Interventions
DRUGALXN2060
ALXN2060 tablets will be administered twice daily at a dose of 800 milligrams.
Sponsors
Alexion Pharmaceuticals, Inc.
Eidos Therapeutics, a BridgeBio company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Established diagnosis of ATTR-CM with either wild-type TTR or a variant TTR genotype. 2. History of heart failure evidenced by at least 1 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 pressures or heart failure symptoms that required or requires ongoing treatment with a diuretic. 3. New York Heart Association Class I-III symptoms due to ATTR-CM. 4. On stable doses of cardiovascular medical therapy. 5. Completed ≥ 150 meters on the 6MWT on 2 tests prior to Day 1. 6. Left ventricular (LV) wall (interventricular septum or LV posterior wall) thickness ≥ 12 millimeters. 7. Biomarkers of myocardial wall stress: N-terminal pro-brain-type natriuretic pep (NT-proBNP) level ≥ 300 picograms/milliliter (pg/mL).
Exclusion criteria
1. Acute myocardial infarction, acute coronary syndrome or coronary revascularization, or experienced stroke or transient ischemic attack within 90 days prior to screening. 2. Hemodynamic instability at screening. 3. Likely to undergo heart transplantation within a year of screening. 4. Current treatment with marketed drug products and other investigational agents for the treatment of ATTR-CM. 5. Current treatment with calcium channel blockers with conduction system effects (for example, verapamil, diltiazem). The use of dihydropyridine calcium channel blockers is allowed. 6. Confirmed diagnosis of light-chain (AL) amyloidosis. 7. Biomarkers of myocardial wall stress: NT-ProBNP ≥ 8,500 pg/mL. 8. Measure of kidney function, estimated glomerular filtration rate by Modification of Diet in Renal Disease formula \< 30 mL/minute/1.73 meters squared.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Change From Baseline To Month 12 Of Treatment In Distance Walked During The Six-minute Walk Test (6MWT) | Baseline, Month 12 | The 6MWT measures how far a participant can walk in 6 minutes. Change from baseline was calculated as the difference between the distance walked during the 6MWT at 12 months and the distance walked during the 6MWT at baseline. To determine the baseline, at least 2 6MWTs were conducted \> 24 hours to ≤ 3 weeks apart prior to the first dose of ALXN2060. The baseline 6MWT is the average of the total distance walked by participants for the 2 qualifying 6MWTs that met all the protocol-defined criteria. Least squares mean change from baseline data were adjusted for baseline measures and visits. |
| Parts A and B: Number of Cardiovascular (CV)-Related Hospitalizations Over A 30-month Period | 30 months | CV-related hospitalization was defined as the mean number of CV-related hospitalizations per participant per year over a 30-month period. CV-related hospitalizations were also reported as adverse events and were reviewed and adjudicated by an independent Clinical Events Committee (CEC). |
| All-cause Mortality (ACM) Over A 30-month Period | 30 months | ACM was assessed as time from the date of first initiation of study treatment to the date of death during a 30-month period, and was analyzed using Kaplan-Meier analysis. Data are reported for the number of participants with ACM over the 30-month period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts A and B: Change From Baseline In Distance Walked During The 6MWT | Baseline, Months 6, 9, 18, 24 and 30 | The 6MWT measures how far a participant can walk in 6 minutes. Change from baseline was calculated as the difference between the distance walked during the 6MWT at specified timepoints and the distance walked during the 6MWT at baseline. To determine the baseline, at least 2 6MWTs were conducted \> 24 hours to ≤ 3 weeks apart prior to the first dose of ALXN2060. The baseline 6MWT is the average of the total distance walked by participants for the 2 qualifying 6MWTs that met all the protocol-defined criteria. Least squares mean change from baseline data were adjusted for baseline measures and visits. |
| Parts A and B: Change From Baseline In The Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | Baseline, Months 6, 9, 12, 18, 24 and 30 | The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life in participants with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life. The overall summary score ranged from 0-100, with higher scores indicating better health status. Data presented are for change from baseline to specified timepoints. Least squares mean change from baseline data were adjusted for baseline measures and visits. |
| Parts A and B: Number of Participants With Treatment-emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | Up to Month 30 | A treatment-emergent AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention that occurred after first dose. A treatment-emergent SAE was defined as any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or was a congenital anomaly/birth defect that occurred after first dose. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Baseline, pre-dose on Days 14, 28 and Months 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30 | Least squares mean change from baseline derived from with visits and baseline serum TTR as a covariate. Other covariates were included as needed. |
| Parts A and B: Change From Baseline In TTR Stabilization | Baseline, Pre-dose Days 14, 28 and Months 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30 | TTR stabilization was measured using fluorescent probe exclusion (FPE). Data presented are for change from baseline in FPE percentage stabilization. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ALXN2060 Participants received ALXN2060 twice daily (bid) for 12 months (Part A). Following the Month 12 visit, participants continued to receive ALXN2060 bid for an additional 18 months (up to 30 months from Day 1, \[Part B\]). Following the completion of Month 30 assessments, participants were offered the opportunity to continue into the Extension Period for up to 30 additional months or until ALXN2060 could be provided via an Alexion post study access program (as allowed by local laws and regulations), whichever occurred first. The Extension Period of the study is ongoing. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | ALXN2060 |
|---|---|
| Age, Continuous | 76.5 years STANDARD_DEVIATION 6.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 25 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 25 |
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 17 / 25 |
Outcome results
Primary
All-cause Mortality (ACM) Over A 30-month Period
ACM was assessed as time from the date of first initiation of study treatment to the date of death during a 30-month period, and was analyzed using Kaplan-Meier analysis. Data are reported for the number of participants with ACM over the 30-month period.
Time frame: 30 months
Population: Measured in the Full Analysis Set, which included all participants who have received at least 1 dose of ALXN2060.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ALXN2060 | All-cause Mortality (ACM) Over A 30-month Period | 0 Participants |
Primary
Part A: Change From Baseline To Month 12 Of Treatment In Distance Walked During The Six-minute Walk Test (6MWT)
The 6MWT measures how far a participant can walk in 6 minutes. Change from baseline was calculated as the difference between the distance walked during the 6MWT at 12 months and the distance walked during the 6MWT at baseline. To determine the baseline, at least 2 6MWTs were conducted \> 24 hours to ≤ 3 weeks apart prior to the first dose of ALXN2060. The baseline 6MWT is the average of the total distance walked by participants for the 2 qualifying 6MWTs that met all the protocol-defined criteria. Least squares mean change from baseline data were adjusted for baseline measures and visits.
Time frame: Baseline, Month 12
Population: Measured in the Full Analysis Set, which included all participants who have received at least 1 dose of ALXN2060. Number of participants analyzed = number of participants evaluable for the outcome measure at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ALXN2060 | Part A: Change From Baseline To Month 12 Of Treatment In Distance Walked During The Six-minute Walk Test (6MWT) | -3.86 meters | Standard Error 9.182 |
Primary
Parts A and B: Number of Cardiovascular (CV)-Related Hospitalizations Over A 30-month Period
CV-related hospitalization was defined as the mean number of CV-related hospitalizations per participant per year over a 30-month period. CV-related hospitalizations were also reported as adverse events and were reviewed and adjudicated by an independent Clinical Events Committee (CEC).
Time frame: 30 months
Population: Measured in the Full Analysis Set, which included all participants who have received at least 1 dose of ALXN2060.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ALXN2060 | Parts A and B: Number of Cardiovascular (CV)-Related Hospitalizations Over A 30-month Period | 0.1329 CV-related hospitalizations |
Secondary
Parts A and B: Change From Baseline In Distance Walked During The 6MWT
The 6MWT measures how far a participant can walk in 6 minutes. Change from baseline was calculated as the difference between the distance walked during the 6MWT at specified timepoints and the distance walked during the 6MWT at baseline. To determine the baseline, at least 2 6MWTs were conducted \> 24 hours to ≤ 3 weeks apart prior to the first dose of ALXN2060. The baseline 6MWT is the average of the total distance walked by participants for the 2 qualifying 6MWTs that met all the protocol-defined criteria. Least squares mean change from baseline data were adjusted for baseline measures and visits.
Time frame: Baseline, Months 6, 9, 18, 24 and 30
Population: Measured in the Full Analysis Set, which included all participants who have received at least 1 dose of ALXN2060. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. Number analyzed = participants evaluable for this outcome measure at the specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| ALXN2060 | Parts A and B: Change From Baseline In Distance Walked During The 6MWT | Month 6 | -29.54 meters | Standard Error 9.316 |
| ALXN2060 | Parts A and B: Change From Baseline In Distance Walked During The 6MWT | Month 9 | -23.12 meters | Standard Error 11.61 |
| ALXN2060 | Parts A and B: Change From Baseline In Distance Walked During The 6MWT | Month 24 | -24.89 meters | Standard Error 8.534 |
| ALXN2060 | Parts A and B: Change From Baseline In Distance Walked During The 6MWT | Month 30 | -36.20 meters | Standard Error 10.798 |
| ALXN2060 | Parts A and B: Change From Baseline In Distance Walked During The 6MWT | Month 18 | -26.27 meters | Standard Error 12.532 |
Secondary
Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration
Least squares mean change from baseline derived from with visits and baseline serum TTR as a covariate. Other covariates were included as needed.
Time frame: Baseline, pre-dose on Days 14, 28 and Months 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30
Population: Measured in the Full Analysis Set, which included all participants who have received at least 1 dose of ALXN2060. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. Number analyzed = participants evaluable for this outcome measure at the specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Day 14, Predose | 9.73 milligrams (mg)/deciliter (dL) | Standard Error 0.886 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Day 28, Predose | 9.13 milligrams (mg)/deciliter (dL) | Standard Error 1.256 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Month 3, Predose | 10.64 milligrams (mg)/deciliter (dL) | Standard Error 1.056 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Month 6, Predose | 9.61 milligrams (mg)/deciliter (dL) | Standard Error 0.847 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Month 9, Predose | 11.16 milligrams (mg)/deciliter (dL) | Standard Error 0.744 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Month 12, Predose | 11.80 milligrams (mg)/deciliter (dL) | Standard Error 1.157 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Month 15, Predose | 10.79 milligrams (mg)/deciliter (dL) | Standard Error 1.347 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Month 18, Predose | 10.12 milligrams (mg)/deciliter (dL) | Standard Error 1.253 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Month 21, Predose | 9.23 milligrams (mg)/deciliter (dL) | Standard Error 0.704 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Month 24, Predose | 11.06 milligrams (mg)/deciliter (dL) | Standard Error 0.848 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Month 27, Predose | 9.57 milligrams (mg)/deciliter (dL) | Standard Error 1.02 |
| ALXN2060 | Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration | Month 30, Predose | 9.36 milligrams (mg)/deciliter (dL) | Standard Error 1.28 |
Secondary
Parts A and B: Change From Baseline In The Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS)
The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life in participants with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life. The overall summary score ranged from 0-100, with higher scores indicating better health status. Data presented are for change from baseline to specified timepoints. Least squares mean change from baseline data were adjusted for baseline measures and visits.
Time frame: Baseline, Months 6, 9, 12, 18, 24 and 30
Population: Measured in the Full Analysis Set, which included all participants who have received at least 1 dose of ALXN2060. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. Number analyzed = participants evaluable for this outcome measure at the specified timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| ALXN2060 | Parts A and B: Change From Baseline In The Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | Month 6 | 0.94 scores on a scale | Standard Error 2.779 |
| ALXN2060 | Parts A and B: Change From Baseline In The Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | Month 9 | -1.73 scores on a scale | Standard Error 3.291 |
| ALXN2060 | Parts A and B: Change From Baseline In The Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | Month 12 | 2.71 scores on a scale | Standard Error 2.766 |
| ALXN2060 | Parts A and B: Change From Baseline In The Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | Month 18 | -5.34 scores on a scale | Standard Error 3.747 |
| ALXN2060 | Parts A and B: Change From Baseline In The Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | Month 24 | -0.68 scores on a scale | Standard Error 3.029 |
| ALXN2060 | Parts A and B: Change From Baseline In The Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | Month 30 | -6.97 scores on a scale | Standard Error 3.755 |
Secondary
Parts A and B: Change From Baseline In TTR Stabilization
TTR stabilization was measured using fluorescent probe exclusion (FPE). Data presented are for change from baseline in FPE percentage stabilization.
Time frame: Baseline, Pre-dose Days 14, 28 and Months 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30
Population: Measured in the Full Analysis Set, which included all participants who have received at least 1 dose of ALXN2060. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. Number analyzed = participants evaluable for this outcome measure at the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Day 14, Predose | 97.15 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Day 28, Predose | 97.29 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Month 3, Predose | 99.09 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Month 12, Predose | 100.89 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Month 15, Predose | 97.65 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Month 18, Predose | 96.75 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Month 21, Predose | 101.30 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Month 24, Predose | 102.60 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Month 27, Predose | 102.65 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Month 30, Predose | 95.60 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Month 6, Predose | 98.56 percentage stabilization |
| ALXN2060 | Parts A and B: Change From Baseline In TTR Stabilization | Month 9, Predose | 96.47 percentage stabilization |
Secondary
Parts A and B: Number of Participants With Treatment-emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation
A treatment-emergent AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention that occurred after first dose. A treatment-emergent SAE was defined as any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, or was a congenital anomaly/birth defect that occurred after first dose. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Up to Month 30
Population: Measured in the Safety Set, which included all participants who have received at least 1 dose of ALXN2060.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ALXN2060 | Parts A and B: Number of Participants With Treatment-emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | Treatment-emergent AE | 25 Participants |
| ALXN2060 | Parts A and B: Number of Participants With Treatment-emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | Treatment-emergent SAE | 12 Participants |
| ALXN2060 | Parts A and B: Number of Participants With Treatment-emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs Leading to Treatment Discontinuation | 2 Participants |