A Phase 3 Study of ALXN2060 in Japanese Participants With Symptomatic ATTR-CM

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.

• ALXN2060 (Drug), also known as AG10, Acoramidis: ALXN2060 tablets will be administered twice daily at a dose of 800 milligrams.

Primary outcomes

• 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 outcomes

• 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.

Sex: All

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.

Participant flow

Outcome results

• Part A: Change From Baseline To Month 12 Of Treatment In Distance Walked During The Six-minute Walk Test (6MWT) (Primary), Least squares mean, meters: ALXN2060 -3.86 +/- 9.182
• Parts A and B: Number of Cardiovascular (CV)-Related Hospitalizations Over A 30-month Period (Primary), Mean, CV-related hospitalizations: ALXN2060 0.1329 (0.0511 to 0.3457)
• Parts A and B: Change From Baseline In Distance Walked During The 6MWT (Secondary), Least squares mean, meters: ALXN2060 -29.54 +/- 9.316
• Parts A and B: Change From Baseline In The Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) (Secondary), Least squares mean, scores on a scale: ALXN2060 0.94 +/- 2.779
• Parts A and B: Number of Participants With Treatment-emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation (Secondary), Count of participants, Participants: ALXN2060 25
• Parts A and B: Change From Baseline In Serum Transthyretin (TTR) Concentration (Secondary), Least squares mean, milligrams (mg)/deciliter (dL): ALXN2060 9.73 +/- 0.886
• Parts A and B: Change From Baseline In TTR Stabilization (Secondary), Median, percentage stabilization: ALXN2060 97.15 (94.45 to 100.05)
• All-cause Mortality (ACM) Over A 30-month Period (Primary), Count of participants, Participants: ALXN2060 0

Adverse events

Time frame: Up to approximately Month 57

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2023-09-11)
• Statistical Analysis Plan (PDF, 2023-03-27)