Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant

Phase 3

Recruiting

Conditions: Transthyretin Amyloidosis

Interventions: Drug: Acoramidis
Drug: Placebo oral tablet

Registration Number: 2024-513547-82-00

Lead Sponsor: Eidos Therapeutics Inc.

Brief Summary: To determine the efficacy of acoramidis to prevent ATTR (ATTR-CM or ATTR-PN, whichever occurs first) in asymptomatic carriers with a pathogenic TTR variant who are at risk of developing ATTR but have no clinical evidence of disease at study entry

Detailed Description: The AG10-501 ACT-EARLY study is a randomized, multicenter, double-blind, placebo- controlled study of acoramidis for prevention of ATTR (with specific reference to either its cardiomyopathic or polyneuropathic manifestations). Participants will be stratified at randomization.

The study population will be asymptomatic carriers of a known pathogenic TTR gene variant. A participant must be 18 to 75 inclusive years of age, and the age of the participant must be no more than 10 years younger than the predicted age of disease onset (PADO) based either on family history (pedigree analysis) or, if family history is insufficient, based on a TTR Variant Actuarial table from published literature. For example, if PADO for a given individual is found to be 50 years, the age of the participant must be 40 and 75 years inclusive.

Recruitment & Eligibility

Status: Authorised, recruiting

Sex: Not specified

Target Recruitment: 301

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) through a medically-genetically indicated test of a TTR gene variant that is known to be pathogenic confirmed by central laboratory prior to randomization. Participants with rare pathogenic TTR variants documented to be cardiac radionuclide uptake negative (eg, S77Y/p.S97Y, Y114C/p.Y134C, E92K/p.E112K, F64L/p.F84L, or other variant) may be included in the trial, provided the participant can be assessed for the primary ATTR-CM endpoint For further details, please refer to the protocol.
Participant’s age is no more than 10 years (≤ 10) younger than the PADO as determined by pedigree analysis or TTR Variant Actuarial Table for their variant (Scenarios 4A, 4B, or 4C). The participant may be older than PADO. For example, if PADO for a given participant is determined to be 50 years, the age that participant must be is at least 40 years of age (≥ 40) and less than or equal to 75 years of age (≤ 75). Please refer to Genotype Manual for details on calculation of PADO. For further details, please refer to the protocol.
Agree to the use of highly effective contraception: 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 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. b. MALE: 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.
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 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, MI, or ACS
Chronic kidney disease, defined as eGFR ≤ 45 mL/min/1.73 m2, undergoing renal dialysis, or status post kidney transplant.
Abnormal liver function tests at Screening, defined as ALT or AST > 2x ULN or total bilirubin > 2x ULN (or >3x × ULN if known 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 the study drug (acoramidis or placebo to match) or any of the excipients within.
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. A positive urine dipstick pregnancy test will need to be confirmed with a serum test
Evidence of ATTR-PN (including autonomic neuropathy) by SNAC examination or skin biopsy.
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.
Known history of AL amyloidosis or another non-TTR amyloid subtype (eg, ApoA-1, gelsolin).
History of a monoclonal paraprotein or abnormal light chains in serum or urine (ie, 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)
Contraindication to or inability to undergo CMR testing
Presence of condition known to generate false positive myocardial radionuclide uptake with SPECT imaging (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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
acoramidis	Acoramidis	Participants will receive acoramidis 712 mg orally BID (which is equivalent to 800 mg acoramidis HCl BID)
Placebo	Placebo oral tablet	Subjects will receive placebo to match twice daily

Primary Outcome Measures

Name	Time	Method
1. Time to development of ATTR (ATTR-CM or ATTR-PN, whichever occurs first). For further details, please refer to the protocol.		1. Time to development of ATTR (ATTR-CM or ATTR-PN, whichever occurs first). For further details, please refer to the protocol.

Secondary Outcome Measures

Name	Time	Method
1. Time to development of ATTR-CM and ATTR-PN. For further details, please refer to the protocol.		1. Time to development of ATTR-CM and ATTR-PN. For further details, please refer to the protocol.
2. Participants who develop ATTR as defined in the primary endpoint at the time of study completion (yes/no)		2. Participants who develop ATTR as defined in the primary endpoint at the time of study completion (yes/no)
3. Time to development of symptomatic ATTR and ATTR-CM		3. Time to development of symptomatic ATTR and ATTR-CM
4. Participants who develop symptomatic ATTR		4. Participants who develop symptomatic ATTR
5. Proportion of participants with: treatment-emergent AEs and SAEs, AEs leading to treatment discontinuation, abnormal physical examination findings of clinical relevance, abnormal vital signs of clinical relevance, abnormal ECG parameters of clinical relevance, changes in clinical safety laboratory parameters of potential concern		5. Proportion of participants with: treatment-emergent AEs and SAEs, AEs leading to treatment discontinuation, abnormal physical examination findings of clinical relevance, abnormal vital signs of clinical relevance, abnormal ECG parameters of clinical relevance, changes in clinical safety laboratory parameters of potential concern

Trial Locations

Locations (36): Unidade Local De Saude De Santo Antonio E.P.E.
🇵🇹
Porto, Portugal
Unidade Local De Saude De Santa Maria E.P.E.
🇵🇹
Lisbon, Portugal
Centre Hospitalier Universitaire De Rennes
🇫🇷
Rennes, France
Hopital Henri Mondor - 1 rue Gustave Eiffel
🇫🇷
Créteil, France
Bicetre Hospital
🇫🇷
Le Kremlin Bicetre Cedex, France
Centre Hospitalier Universitaire De Toulouse
🇫🇷
Toulouse Cedex 9, France
CHU De Martinique
🇫🇷
Fort De France Cedex, France
Pellegrin Hospital
🇫🇷
Bordeaux, France
Fondazione Toscana Gabriele Monasterio
🇮🇹
Pisa, Italy
Azienda Ospedaliera Universitaria Gaetano Martino Messina
🇮🇹
Messina, Italy
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Unidade Local De Saude De Santo Antonio E.P.E.
🇵🇹Porto, Portugal
Márcio Cardoso
Site contact
915677190
marciocardoso.neurofisiologia@chporto.min-saude.pt