efficacy and safety of acoramidis (ag10) in subjects with transthyretin amyloid polyneurophathy (attribute-pn)

Conditions: Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy

Summary: phase 3 efficacy and safety of acoramidis in subjects with symptomatic transthyretin amyloid polyneuropathy (attr-pn)

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.

Eligibility 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.

Keywords: ttr attr-pn familial attr-pn amyloidosis amyloid transthyretin polyneuropathy ttr-mediated amyloidosis amyloidosis, hereditary familial amyloid polyneuropathies amyloidosis, hereditary, transthyretin-related