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

• ClinicalTrials.gov Identifier: NCT04882735
• Recruitment Status: Withdrawn
• First Posted: May 12, 2021
• Last Update Posted: February 9, 2022
• Sponsor: Eidos Therapeutics, a BridgeBio company
• Information provided by (Responsible Party): Eidos Therapeutics, a BridgeBio company

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy	Drug: Acoramidis	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Estimated Study Start Date: September 2021
• Estimated Primary Completion Date: September 2026
• Estimated Study Completion Date: October 2026

Arms and Interventions

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 Name: AG10

Outcome Measures

Primary Outcome Measures :

1. Change from baseline to Month 18 in mNIS+7 [ Time Frame: 18 Months ]
   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.
2. Safety: TESAEs will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN) [ Time Frame: 60 Months ]
   To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
3. 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) [ Time Frame: 60 Months ]
   To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
4. Safety: Adverse Events will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN) [ Time Frame: 60 Months ]
   To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
5. 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) [ Time Frame: 60 Months ]
   To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
6. 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) [ Time Frame: 60 Months ]
   To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
7. 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) [ Time Frame: 60 Months ]
   To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)

Secondary Outcome Measures :

1. Change from baseline to Month 18 in Norfolk QOL-DN [ Time Frame: 18 Months ]
   To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN)
2. Change from baseline to Month 18 in mBMI [ Time Frame: 18 Months ]
   To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Modified body mass index (mBMI)
3. Change from baseline to Month 18 in COMPASS-31 [ Time Frame: 18 Months ]
   To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Composite Autonomic Score (COMPASS-31)

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Sponsors and Collaborators

Eidos Therapeutics, a BridgeBio company

Investigators

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

More Information

• Responsible Party: Eidos Therapeutics, a BridgeBio company
• ClinicalTrials.gov Identifier: NCT04882735
• Other Study ID Numbers: AG10-334
• First Posted: May 12, 2021
• Last Update Posted: February 9, 2022
• Last Verified: January 2022

• 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

Keywords provided by Eidos Therapeutics, a BridgeBio company:

TTR; ATTR-PN; Familial ATTR-PN; Amyloidosis; Amyloid; Transthyretin; Polyneuropathy; TTR-mediated amyloidosis; Amyloidosis, hereditary; Familial Amyloid Polyneuropathies; Amyloidosis, Hereditary, Transthyretin-Related

Additional relevant MeSH terms:

Polyneuropathies; Amyloid Neuropathies; Amyloid Neuropathies, Familial; Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Amyloidosis, Familial; Metabolism, Inborn Errors