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

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)

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

Study Overview

• Status: Withdrawn
• Conditions: Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy
• Intervention / Treatment: Drug: Acoramidis

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acoramidis HCI 800 mg (two 400mg tablets); TTR stabilizer administered orally twice daily (BID)	Drug: Acoramidis; TTR stabilizer administered orally twice daily (BID); Other Names: AG10

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Eidos Therapeutics, a BridgeBio company
• Investigators: Study Director: Mark McGovern, RN, CCRN, Eidos Therapeutics, a BridgeBio company

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2021
• Primary Completion (Anticipated): September 1, 2026
• Study Completion (Anticipated): October 1, 2026

Study Registration Dates

• First Submitted: April 29, 2021
• First Submitted That Met QC Criteria: May 6, 2021
• First Posted (Actual): May 12, 2021

Study Record Updates

• Last Update Posted (Actual): February 9, 2022
• Last Update Submitted That Met QC Criteria: January 26, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: TTR; Amyloidosis; Polyneuropathy; Transthyretin; Amyloid; TTR-mediated amyloidosis; Amyloidosis, Hereditary, Transthyretin-Related; Familial Amyloid Polyneuropathies; ATTR-PN; Familial ATTR-PN; Amyloidosis, hereditary
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Proteostasis Deficiencies; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Amyloidosis, Familial; Amyloidosis; Polyneuropathies; Amyloid Neuropathies; Amyloid Neuropathies, Familial
• Other Study ID Numbers: AG10-334

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes