Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy
Conditions
Keywords
TTR, ATTR-PN, Familial ATTR-PN, Amyloidosis, Amyloid, Transthyretin, Polyneuropathy, TTR-mediated amyloidosis, Amyloidosis, hereditary, Familial Amyloid Polyneuropathies, Amyloidosis, Hereditary, Transthyretin-Related
Brief summary
Phase 3 efficacy and safety of acoramidis in subjects with symptomatic Transthyretin Amyloid Polyneuropathy (ATTR-PN)
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.
Interventions
DRUGAcoramidis
TTR stabilizer administered orally twice daily (BID)
Sponsors
Eidos Therapeutics, a BridgeBio company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline to Month 18 in mNIS+7 | 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. |
| Safety: TESAEs will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN) | 60 Months | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) |
| 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) | 60 Months | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) |
| Safety: Adverse Events will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN) | 60 Months | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) |
| 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) | 60 Months | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) |
| 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) | 60 Months | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) |
| 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) | 60 Months | To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline to Month 18 in Norfolk QOL-DN | 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) |
| Change from baseline to Month 18 in mBMI | 18 Months | To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Modified body mass index (mBMI) |
| Change from baseline to Month 18 in COMPASS-31 | 18 Months | To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Composite Autonomic Score (COMPASS-31) |
Outcome results
None listed