Efficacy and Safety of Acoramidis (AG10) in Subjects With Transthyretin Amyloid Polyneurophathy (ATTRibute-PN)

Study Overview
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Brief Summary
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Phase 3 efficacy and safety of acoramidis in subjects with symptomatic Transthyretin Amyloid Polyneuropathy (ATTR-PN)

Detailed Description
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Transthyretin amyloid polyneuropathy (ATTR-PN), also called Familial Transthyretin-Mediated Amyloid Polyneuropathy (FAP) is a hereditary condition caused by mutations in the TTR gene. It is estimated that around 10,000 people in the world are affected. In ATTR-PN, amyloid builds up in the nerves that detect temperature, pain, and touch. Patients with ATTR-PN can experience a loss of sensation, tingling, numbness, or pain in the hands and feet (also called peripheral neuropathy). In this study Eidos, a BridgeBio Company, is researching the investigational drug acoramidis (AG10) hydrochloride (HCl) 800mg administered orally twice a day. Through the study, Eidos/BridgeBio wants to evaluate the efficacy and safety of acoramidis in patients with ATTR-PN. The primary outcome of the study is to determine the efficacy of acoramidis in the treatment of subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN). At the end of 18 months, participants will be eligible to continue to receive acoramidis to evaluate the long-term safety and tolerability of acoramidis.

Official Title
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A Phase 3, Open-Label, Multicenter, Single-Arm Study to Evaluate the Efficacy and Safety of Acoramidis in Subjects With Symptomatic Transthyretin Amyloid Polyneuropathy (ATTRibute-PN Study)

Conditions
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Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy

Intervention / Treatment
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* Drug: Acoramidis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥18 to ≤90 years of age; Have Stage I or II symptoms (polyneuropathy disability [PND] ≤IIIb) of ATTR-PN and an established diagnosis of ATTR-PN as defined by physical examination findings and/or neurophysiological test findings consistent with the diagnosis of ATTR-PN; Have an NIS of 5 to 130 (inclusive) during Screening; Have a nerve conduction studies (NCS) score (sum of the sural sensory nerve action potential [SNAP], tibial compound muscle action potential (CMAP), ulnar SNAP, ulnar CMAP, and peroneal CMAP) of ≥2 points during Screening. NCS is a component of mNIS+7; Have a mutation consistent with ATTR-PN either documented in medical history or confirmed by genotyping obtained at Screening prior to enrollment. No genetic testing is needed for subjects who are recipients of domino liver transplants; Have an anticipated survival of >2 years in the opinion of the investigator; Have Karnofsky performance status ≥60 %. Exclusion Criteria: Had a prior liver transplantation or is planning to undergo liver transplantation with a wild-type organ graft as treatment for symptomatic ATTR-PN during the study period. Note: Recipients of a domino liver transplant from an ATTR-PN donor who have developed ATTR-PN mediated by their graft are allowed under this protocol, as long as re-transplantation to treat ATTR-PN is not planned during the study period and meets all other eligibility criteria; Has sensorimotor or autonomic neuropathy not related to ATTR-PN; for example, due to autoimmune disease or monoclonal gammopathy, malignancy, or alcohol abuse; Has Vitamin B-12 levels below the lower limit of normal (LLN) at Screening; Has clinical evidence of untreated hyperthyroidism or hypothyroidism; Has leptomeningeal TTR amyloidosis; Has Type 1 diabetes; Has had Type 2 diabetes for ≥5 years; Has a documented case of hepatitis B or C at Screening; Known history of human immunodeficiency virus (HIV) infection; Has NYHA heart failure classification >Class II; Had acute coronary syndrome, uncontrolled cardiac arrhythmia, or a stroke within 90 days prior to Screening; Has estimated glomerular filtration rate (eGFR) by Modification of Diet for Renal Disease (MDRD) formula <30 mL/min/1.73 m2 at Screening; Has abnormal liver function tests at Screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) or total bilirubin >3 × ULN; Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated; Has known hypersensitivity to acoramidis, its metabolites, or formulation excipients. Is currently undergoing treatment for ATTR-PN with tafamidis, or patisiran, inotersen, or other knockdown agents, marketed drug products lacking a labeled indication for ATTR-PN (e.g., diflunisal, doxycycline), natural products or derivatives used as unproven therapies for ATTR-PN (e.g., green tea extract ,tauroursodeoxycholic acid [TUDCA]/ursodiol), within 14 days, or 14 days for tafamidis or 90days for patisiran and 180 days for inotersen prior to dosing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acoramidis HCI 800 mg (two 400mg tablets)<br>TTR stabilizer administered orally twice daily (BID) | Drug: Acoramidis<br>* TTR stabilizer administered orally twice daily (BID)<br>* Other names: AG10;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Month 18 in mNIS+7 | To determine the efficacy of acoramidis in subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) by evaluating the change in Modified Neuropathy Impairment Score +7 (mNIS+7) from baseline to 18 months. | 18 Months | 
| Safety: TESAEs will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN) | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) | 60 Months | 
| Safety: Adverse Events leading to treatment discontinuation will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN) | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) | 60 Months | 
| Safety: Adverse Events will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN) | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) | 60 Months | 
| Safety: Incidence of abnormal physical exam will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN) | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) | 60 Months | 
| Safety: Incidence of abnormal vital signs will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN) | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) | 60 Months | 
| Safety: Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN) | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) | 60 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Month 18 in Norfolk QOL-DN | To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) | 18 Months | 
| Change from baseline to Month 18 in mBMI | To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Modified body mass index (mBMI) | 18 Months | 
| Change from baseline to Month 18 in COMPASS-31 | To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Composite Autonomic Score (COMPASS-31) | 18 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyloidosis, TTR, ATTR-PN, Familial ATTR-PN, Amyloid, Transthyretin, Polyneuropathy, TTR-mediated amyloidosis, Amyloidosis, hereditary, Familial Amyloid Polyneuropathies, Amyloidosis, Hereditary, Transthyretin-Related