Clinical Trials

Inclusion Criteria:

• Participants must be willing and able to give a signed informed consent for study procedures. Informed consent must be obtained prior to initiation of study procedures.
• Male or female ≥ 18 to ≤ 75 years of age inclusive when signing the informed consent. The minimum age requirement will comply with local regulatory requirements.
• Participants must have an established genotype (hetero- or homozygosity) of a TTR gene variant that is known to be pathogenic (eg, V30M/pV50M, V122I/pV142I, T60A/pT80A, or all other pathogenic TTR variants) confirmed by the central laboratory prior to randomization.

Participants with rare pathogenic TTR variant documented to be cardiac radionuclide uptake negative (eg, S77Y/p.S97Y, Y114C/p.Y134C, E92K/p.E112K, I68L/p.I88L, F64L/p.F84L, or other variant) may be included in the trial, provided the participant can be assessed for the primary ATTR-CM endpoint with:

• Echocardiography with strain suggestive of cardiac amyloidosis and an endomyocardial biopsy with confirmatory TTR amyloid typing
• OR
• CMR suggestive of cardiac amyloidosis AND an endomyocardial biopsy with confirmatory TTR amyloid typing

In these rare TTR variants documented to be cardiac radionuclide uptake negative, screening echocardiography with strain and CMR must be essentially normal (ie, not suggestive of ATTR-CM) according to the Investigator.

• Participant’s age is ≤ 10 years younger than the PADO as determined by pedigree analysis or TTR Variant Actuarial Table for their variant (Scenarios 4A, 4B, or 4C). For example, if PADO is 50 years, the age of the participant must be ≥ 40 years (see Table 5). Please refer to Genotype Manual for details on calculation of PADO.
  •  If on pedigree analysis, the participant has an established family history (in at least TWO affected relatives) with documented ATTRv due to the same pathogenic TTR variant, PADO should be based on the MEDIAN age of ATTRv diagnosis onset within their kindred. See Genotype Manual for details on determination of pedigreebased PADO.
  • OR
  • If on pedigree analysis, the participant has a family history in ONLY ONE affected relative with documented ATTRv due to the same pathogenic TTR variant, the older of the two values between the age of that affected relative and the age listed in the TTR Variant Actuarial Table (Genotype Manual) should be assigned as the PADO. See Genotype Manual for further details on determination of actuarial table-based PADO.
  • OR
  • If the participant has NO family history from which to determine PADO, the TTR Variant Actuarial Table should be used to determine PADO. See Genotype Manual for further details on determination of actuarial table-based PADO.
• Women of childbearing potential (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 beginning before a radionuclide cardiac amyloid imaging with SPECT is performed during the Screening period and continuing for 30 days after the last dose of study drug. Female participants using oral contraceptives must agree to use an additional birth control method. While not considered highly effective, a double-barrier method is also considered acceptable. A male participant who has not had a vasectomy and is sexually active with a female of childbearing potential must agree to use 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 the study drug.

Exclusion Criteria:

• Myocardial radionuclide uptake of Grade 1 to Grade 3 on planar imaging with confirmation by SPECT imaging.
• Evidence of ATTR-PN (including autonomic neuropathy) by SNAC examination or skin biopsy.
• Known history of AL amyloidosis or another non-TTR amyloid subtype [eg, apolipoprotein A-1 (ApoA-1), gelsolin].
• History of a monoclonal paraprotein or abnormal light chains in serum or urine (ie, monoclonal gammopathy of undetermined significance, MGUS) in which AL has not been ruled out.
• Pre-existing diagnosis of axonal neuropathy from a non-amyloid cause (eg, established diagnosis of diabetic peripheral neuropathy, presence of alcohol-related neuropathy)
• Presence of a TTR variant known to be phenotypically protective (eg, T119M, R104H)
• Current or past treatment with patisiran, inotersen, or tafamidis within 3 months. Current treatment with any ATTR-oriented on- or off-label or over the counter (OTC) product within 1 month (eg, green tea extract, diflunisal, doxycycline, tauroursodeoxycholic acid, ursodeoxycholic acid), any second-generation TTR knockdown agent within 6 months (eg, vutrisiran, eplontersen), or any monoclonal antibody TTR amyloid depleter agent within 12 months.
• Contraindication to or inability to undergo CMR testing
• Presence of condition known to generate false positive myocardial radionuclide uptake with SPECT (eg, ApoA-1 amyloidosis, chronic hydroxychloroquine use).
• Comorbidity or condition that is likely to result in a life expectancy of < 10 years based on clinical judgment of the Investigator.
• Clinical evidence of untreated hyperthyroidism or hypothyroidism.
• History of type 1 diabetes.
• Known active hepatitis B or C (participants with resolved or cured infection are eligible for enrollment).
• Known human immunodeficiency virus (HIV) infection.
• 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, stroke, myocardial infarction (MI), or acute coronary syndrome (ACS).
• Chronic kidney disease, defined as estimated glomerular filtration rate (eGFR) ≤ 45 mL/min/1.73 m2 , undergoing renal dialysis, or status post kidney transplant.
• Abnormal liver function tests at Screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x upper limit of normal (ULN) or total bilirubin > 2x ULN (or >3x × ULN if Gilbert’s Disease).
• Malignancy within 3 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 its excipients.
• Female participants who are pregnant or breastfeeding. Females must agree to discontinue breastfeeding before study drug is administered. At Screening, a negative serum pregnancy test must be confirmed at a maximum of 14 days prior to first dose. A negative dipstick urine pregnancy test is also required before any radionuclide cardiac amyloid imaging with SPECT, on Day 1 prior to dosing, and at every In-clinic Visit for WOCBP (Section 1.5). 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.
• Participation in another investigational clinical trial within 30 days prior to Screening or within 5 half-lives of any non-ATTR investigational agent (or within the timeframe specified in Exclusion Criterion #7 for ATTR investigational agents) whichever is longer. Participation in observational and/or registry studies must be discussed with the Medical Monitor.
• 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.
• Major surgery as defined by the Investigator within the past 3 months or planned during the next 12 months.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 07/24/2024. Questions regarding updates should be directed to the study team contact.