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

• ClinicalTrials.gov Identifier: NCT04418024
• Recruitment Status: Withdrawn
• First Posted: June 5, 2020
• Last Update Posted: June 16, 2021
• Sponsor: Eidos Therapeutics, a BridgeBio company
• Information provided by (Responsible Party): Eidos Therapeutics, a BridgeBio company

Study Description

Brief Summary:

See updated study design under NCT04882735. Phase 3 efficacy and safety of AG10 compared with placebo in subjects with symptomatic Transthyretin Amyloid Polyneuropathy (ATTR-PN)

Condition or disease	Intervention/treatment	Phase
Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy	Drug: AG10; Drug: Placebo	Phase 3

Detailed Description:

** See updated study design under ClinicalTrials.gov Identifier NCT04882735. **

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 is researching the investigational drug AG10 800mg (2 tablets) administered orally twice a day. Through the study, Eidos wants to evaluate the efficacy and safety of AG10 in patients with ATTR-PN versus placebo.

This is an 18 month, placebo-controlled study. This means that, during the 18 month study, investigators conducting the research and study participants will not know whether the study participant is receiving AG10 or placebo.

The primary outcome of the study is the difference between AG10 and placebo groups in the Modified Neurologic Impairment Score +7 (mNIS+7) at 18 months of treatment versus baseline.

At the end of 18 months, participants may be eligible to receive investigational AG10, and there is no placebo. This is called an "open label extension." This part of the study may help us better understand the safety related to taking AG10 over a longer period of time.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of AG10 in Subjects With Symptomatic Transthyretin Amyloid Polyneuropathy (ATTRibute-PN Trial)
• Actual Study Start Date: October 21, 2020
• Estimated Primary Completion Date: March 31, 2024
• Estimated Study Completion Date: April 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: AG10 800 mg; TTR stabilizer administered orally twice daily (BID)	Drug: AG10; TTR stabilizer administered orally twice daily (BID); Other Name: Oral AG10
Placebo Comparator: Placebo; Placebo administered orally twice daily (BID)	Drug: Placebo; Non-active control; Other Name: Placebo Oral Tablet

Outcome Measures

Primary Outcome Measures :

1. Change from baseline to Month 18 of treatment in Modified Neuropathy Impairment [ Time Frame: 18 Months ]
   Evaluate the difference between the AG10 and placebo groups in Modified Neuropathy Impairment which is a composite scale that asses,in part, muscle weakness, sensory loss, and decreased muscle stretch reflexes. It is calculated on a scale of 0 to 304 with higher scores indicating a worsening of the disease.

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:

• Be male or female ≥18 to ≤90 years of age;
• Have Stage I or II symptoms (polyneuropathy disability [PND] ≤IIIa) of ATTR-PN and an established diagnosis of ATTR-PN as defined by physical exam 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 randomization. *No genetic testing is needed for subjects who are recipients of domino liver transplants;
• Have an anticipated survival of ≥2 years
• 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, autoimmune disease or monoclonal gammopathy, malignancy, or alcohol abuse;
• Has Vitamin B-12 levels below the lower limit of normal (LLN);
• Has clinical evidence of untreated hyper/hypothyroidism;
• Has leptomeningeal TTR amyloidosis;
• Has Type 1 diabetes;
• Has had Type 2 diabetes for ≥5 years;
• Has active hepatitis B or C or known human immunodeficiency virus (HIV) infection;
• Has NYHA heart failure classification >Class II
• Had a malignancy within 2 years, except for basal or squamous cell carcinoma of
• Is currently undergoing treatment for ATTR-PN with patisiran, inotersen, or other gene silencing agents, marketed drug products lacking a label 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 90 days for patisiran and 180 days for inotersen prior to dosing. Prior to screening, tafamidis, if already prescribed to potential subjects as part of their established background therapy, is allowed at the labeled dosage and administration of 20 mg/day for the treatment of ATTR-PN with, i in the opinion of the Investigator, evidence of disease progression while on tafamidis treatment

Contacts and Locations

Locations

United States, California

Eidos Therapeutics

San Francisco, California, United States, 94104

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: NCT04418024
• Other Study ID Numbers: AG10-333; 2018-004670-10 ( EudraCT Number )
• First Posted: June 5, 2020
• Last Update Posted: June 16, 2021
• Last Verified: June 2021

• 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