Phase 3 Randomized Double-Blind Placebo-Controlled Study of Acoramidis Hydrochloride for Transthyretin Amyloidosis Prevention in Asymptomatic TTR Variant Carriers

The primary objective of this study is to determine the efficacy of **acoramidis** in preventing transthyretin amyloidosis (ATTR), specifically cardiomyopathy (ATTR-CM) or polyneuropathy (ATTR-PN), in asymptomatic carriers of a pathogenic TTR variant who are at risk of developing ATTR but have no clinical evidence of disease at study entry. This is clinically relevant as it aims to intervene early in the disease process, potentially preventing the onset of symptomatic ATTR, which can lead to significant morbidity.

Secondary objectives include:

• Determining the efficacy of acoramidis in preventing cardiomyopathy due to ATTR (ATTR-CM) in asymptomatic carriers with a pathogenic TTR variant.
• Determining the efficacy of acoramidis in preventing polyneuropathy due to ATTR (ATTR-PN) in asymptomatic carriers with a pathogenic TTR variant.
• Assessing the development of ATTR in asymptomatic carriers of a pathogenic TTR variant.
• Determining the efficacy of acoramidis in preventing symptomatic 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.
• Assessing the development of symptomatic ATTR in asymptomatic carriers of a pathogenic TTR variant.
• Evaluating the safety and tolerability of acoramidis administered to asymptomatic carriers of a pathogenic TTR variant.

The clinical trial involves a total of **323 participants** who are asymptomatic carriers of a pathogenic TTR variant, placing them at risk of developing **Transthyretin Amyloidosis**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on their established genotype, confirmed through a medically-genetically indicated test of a TTR gene variant known to be pathogenic. The trial includes individuals who are at risk but exhibit no clinical evidence of the disease at the study's commencement. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use highly effective contraception methods during the study. The trial population is not limited to any specific health status beyond the genetic predisposition to the condition, and it includes a vulnerable population. Key inclusion criteria require participants to be within a specific age range relative to the PADO for their variant, and they must provide informed consent prior to participation.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of **Acoramidis** in preventing **Transthyretin Amyloidosis** in asymptomatic carriers of a pathogenic TTR variant. The trial will involve participants aged 18 to 75 years who meet specific genetic criteria and are at risk of developing the disease. The study will be conducted over an estimated period, with recruitment starting in January 2025 and completion expected by November 2031. Participants will be randomly assigned to receive either Acoramidis or a matching placebo, administered orally in tablet form.

The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor participants' health and response to the treatment, and an end-of-study visit to assess the primary and secondary endpoints. The primary endpoint is the time to development of ATTR, while secondary endpoints include the time to development of ATTR-CM and ATTR-PN, and the proportion of participants experiencing treatment-emergent adverse events. Participants are expected to be involved in the study for a maximum treatment period of 84 days, with conditions for early termination including the development of significant adverse events or withdrawal of consent.

Inclusion criteria require participants to provide informed consent, have a confirmed pathogenic TTR variant, and meet age-related criteria based on their genetic profile. Exclusion criteria are not explicitly detailed in the provided data. The study aims to provide valuable insights into the prevention of Transthyretin Amyloidosis, contributing to the understanding and management of this rare disease. The trial is categorized as a Phase 3 study, aligning with regulatory guidelines for clinical research.

The clinical trial involves the administration of **Acoramidis (AG10)**, an investigational medication designed to prevent Transthyretin Amyloidosis (ATTR) in asymptomatic carriers with a pathogenic TTR variant. **Acoramidis Hydrochloride** is the active substance in this formulation. The pharmaceutical form of Acoramidis is a tablet, and it is administered orally. The maximum daily dose is 1424 mg, with a total maximum dose of 3638320 mg over a treatment period of 84 days. The medication is produced by Eidos Therapeutics, Inc., and is classified as a chemical substance. Participant compliance with the dosing schedule will be monitored throughout the study.

The study also includes the use of a **matching placebo** to maintain the double-blind nature of the trial. The placebo is designed to mimic the appearance and administration route of the Acoramidis tablets, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered orally in the same frequency and form as the active medication, ensuring consistency in the administration process. The use of a placebo is critical in evaluating the efficacy of Acoramidis in preventing the onset of ATTR in the study population.

The efficacy of Acoramidis in preventing **Transthyretin Amyloidosis (ATTR)** will be assessed in a Phase 3, randomized, multicenter, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the time to development of ATTR, specifically ATTR-CM (cardiomyopathy) or ATTR-PN (polyneuropathy), whichever occurs first. Secondary endpoints include the time to development of ATTR-CM and ATTR-PN, the proportion of participants who develop ATTR by the study's completion, the time to development of symptomatic ATTR and ATTR-CM, and the proportion of participants who develop symptomatic ATTR. Additionally, the trial will monitor the proportion of participants experiencing treatment-emergent adverse events (AEs) and serious adverse events (SAEs), AEs leading to treatment discontinuation, and clinically relevant abnormalities in physical examinations, vital signs, ECG parameters, and clinical safety laboratory parameters.