Cardiac Magnetic Resonance and Echocardiography Study with Acoramidis in Participants with Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

Prior treatment

• History within the previous 6 months of nonreversible cardiomyopathy (eg, reversible cardiomyopathy examples include Takotsubo cardiomyopathy, viral cardiomyopathy, ischemic mitral regurgitation), untreated or uncontrolled cardiac arrhythmia.
• Undergoing renal dialysis or status post kidney transplant.
• Participation in another investigational clinical study within 30 days prior to screening or within 5 half-lives of any non-ATTR investigational agent, whichever is longer. Participation in observational and/or registry studies must be discussed with the medical monitor prior to study entry.
• Major surgery as defined by the investigator within the past 3 months or planned during the next 12 months.
• Acute myocardial infarction, acute coronary syndrome or coronary revascularization, or experienced stroke or transient ischemic attack within 90 days prior to screening.
• NYHA Class III/IV at screening. NYHA definitions are provided in Appendix 3. - NOTE: Recent cardiovascular hospitalization for heart failure or urgent heart failure visit allowed as long as the participant has been clinically stable for at least 6 weeks prior to screening, as per investigator’s judgement.
• Prior or current treatment with acoramidis.

Other illness

• Current or planned implantation of a cardiac implantable electronic device (eg, pacemaker, implantable cardiac defibrillator).
• Known HIV infection; active hepatitis B or C (participants with resolved or cured infection are eligible for enrollment).
• Malignancy within 5 years or ongoing malignancy, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
• Known hypersensitivity to acoramidis or any of the excipients within the study drug.
• Any condition that, in the opinion of the investigator or medical monitor, would preclude compliance with the study protocol, such as a history of substance abuse, alcoholism, or a psychiatric condition.
• Likely to undergo heart transplantation within 12 months from screening.

Lab values

• Current treatment with calcium channel blockers with conduction system effects (eg, 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.
• Abnormal liver function tests at screening, defined as ALT or AST >2× ULN or total bilirubin >2× ULN (or >3× ULN if known Gilbert’s Syndrome).
• Female participants who are pregnant or breastfeeding. Females must agree to discontinue breastfeeding before study drug is administered. A negative serum pregnancy test must be confirmed during screening for WOCBP. A negative dipstick urine pregnancy test is also required on Day 1 prior to dosing, and at every in-clinic visit for WOCBP. A positive urine dipstick pregnancy test will need to be confirmed with a serum test.
• In the judgment of the investigator or medical monitor, has any clinically relevant ongoing medical condition or laboratory abnormality or other condition that might jeopardize the participant’s safety, increase the participant’s risk from participation, interfere with the study, or confound study results.
• NAC Stage 3 at screening (ie, eGFR <45 mL/min/1.73m² and NT-proBNP >3000 pg/mL).

Age

• Estimated life expectancy <2 years.

Other

• Inability to perform or contraindication to CMR procedure (eg, severe claustrophobia, weight or body girth exceeds limits of the CMR machine).
• Hemodynamic instability.
• Confirmed diagnosis of AL amyloidosis at screening.

• Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent.
• Participant heart failure condition has been clinically stable for at least 6 weeks prior to screening, as per investigator’s judgement.
• NT-proBNP level ≥300 and <6,000 pg/mL at screening.
• eGFR ≥40 mL/min/1.73m² at screening.
• Agree to the use of highly effective contraception if participant is either a WOCBP or is a male who has not had a vasectomy and is sexually active with a WOCBP: a. FEMALE: WOCBP (defined as all women physiologically capable of becoming pregnant) who engage in heterosexual intercourse must agree to use a highly effective method of contraception from the signing of the ICF and continuing for 30 days after the last dose of study drug (Section 8.5.6). b. MALE: A male participant who has not had a vasectomy and is sexually active with a WOCBP must agree to a double-barrier method of birth control during the study and continue for 30 days after the last dose of study drug. Males must agree to refrain from sperm donation for a minimum of 30 days post the last dose of study drug.
• Participant must be willing and able to give signed informed consent for participation in the study. Informed consent must be obtained prior to initiation of study procedures.
• Have an established diagnosis of ATTR-CM warranting treatment with a targeted ATTR-CM therapy, as per investigator’s assessment. Diagnosis of ATTR-CM should be confirmed by the investigator prior to screening and will have been established either: • noninvasively by grade 2 or 3 endomyocardial uptake on radionuclide bone scan imaging and exclusion of light-chain amyloidosis OR • with endomyocardial biopsy with confirmatory TTR amyloid typing.
• Participant has TTR genetic testing already performed prior to screening (with documented results).
• CMR and TTE with strain performed at screening deemed adequate by the Central CMR and Central Cardiac Echocardiography Laboratories, respectively, to serve as baseline assessments for quantitative analysis of key imaging parameters (LVEF, LVSVi, LVGLS, LVMi for both imaging modalities; ECV for CMR).
• LV wall (interventricular septum or LV posterior wall) thickness ≥12 mm at screening by TTE with strain.
• LVEF >35% at screening - NOTE (IC7 and IC8): A TTE with strain should be scheduled at or shortly after the initial screening visit and sent to the Central Cardiac Echocardiography Laboratory for confirmation of eligibility criteria (LVEF, LV wall thickness).
• 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 heart failure that required or require ongoing treatment with a diuretic.
• NYHA Class I/II at screening. NYHA definitions are provided in Appendix 3.