study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of ntla-2001 in patients with hereditary transthyretin amyloidosis with polyneuropathy (attrv-pn) and patients with transthyretin amyloidosis-related cardiomyopathy (attr-cm)

Conditions: Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy; Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy; Wild-Type Transthyretin Cardiac Amyloidosis

Summary: this study will be conducted to evaluate the safety, tolerability, pharmacokinetics (pk), and pharmacodynamics (pd) of ntla-2001 in participants with hereditary transthyretin amyloidosis with polyneuropathy (attrv-pn) and participants with hereditary transthyretin amyloidosis with cardiomyopathy (attrv-cm) or wild type cardiomyopathy (attrwt-cm)

for attrv-pn participants, part 1 consists of an open-label, single-ascending dose study, which identifies the dose for evaluation in the cohort expansion of part 2. part 2 will follow as an open-label, dose expansion study to further characterize the activity of ntla-2001, provide an initial assessment of the effect of ntla-2001 on clinical measures of neuropathy and neurological function, and obtain additional safety data. for attr-cm participants, part 1 consists of an open-label, single-ascending dose study, which identifies the dose for evaluation in the cohort expansion of part 2. part 2 will follow as an open-label, dose expansion study to further characterize the activity of ntla-2001, provide an initial assessment of the effect of ntla-2001 on cardiac measures, and obtain additional safety data. all participants who are dosed with ntla-2001 will be offered to participate in a long-term safety monitoring follow-up study via a separate protocol.

Eligibility criteria:
polyneuropathy inclusion criteria: * male and/or female participants 18 to 80 years of age inclusive, at the time of signing the informed consent * diagnosis of polyneuropathy (pn) due to transthyretin (ttr) amyloidosis (attr) * must have a body weight of at least 45 kilograms (kg) at screening visit * lack of access to approved treatments for attr and/or progression of hereditary transthyretin amyloidosis with polyneuropathy (attrv-pn) despite use of approved treatment for attrv-pn polyneuropathy exclusion criteria: * amyloidosis attributable to non-ttr protein, e.g., amyloid light-chain (al) amyloidosis * known leptomeningeal transthyretin amyloidosis * use of any of the following ttr-directed therapy for attr within certain timeframe: 1. patisiran 2. inotersen 3. vutrisiran 4. tafamidis 5. diflunisal 6. doxycycline and/or tauroursodeoxycholic acid 7. any other investigational agent for the treatment of attrv-pn: * other protocol defined inclusion/exclusion criteria may apply cardiomyopathy inclusion criteria (uk only): * male and/or female participants 18 to 90 years of age inclusive, at the time of signing the informed consent * diagnosis of transthyretin (attr) amyloidosis with cardiomyopathy, classified as hereditary attr amyloidosis with cardiomyopathy (attrv-cm) or wild type cardiomyopathy (attrwt-cm). * must have a body weight of at least 45 kilograms (kg) at screening visit * new york heart association (nyha) class i-iii heart failure * at least 1 prior hospitalization for heart failure and/or clinical evidence of heart failure. * able to complete ≥150 meters on the 6-minute walk test (6-mwt) during the screening period. cardiomyopathy exclusion criteria (uk only): * amyloidosis attributable to non-ttr protein, e.g., amyloid light-chain (al) amyloidosis * known leptomeningeal transthyretin amyloidosis * use of any of the following ttr-directed therapy for attr within certain timeframes: 1. patisiran 2. inotersen 3. vutrisiran 4. tafamidis 5. diflunisal 6. doxycycline and/or tauroursodeoxycholic acid 7. investigational ttr stabilizer (e.g., ag-10) * participants with heart failure that in the opinion of the investigator is caused by ischemic heart disease, hypertension, or uncorrected valvular disease and not primarily due to transthyretin amyloid cardiomyopathy. * participants with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (av) nodal or sinoatrial (sa) nodal dysfunction for which a pacemaker is indicated but will not be placed. pacemaker or defibrillator placement, initiation of or change in anti-arrhythmic medication within 28 days prior to study drug administration. * other protocol defined inclusion/exclusion criteria may apply

Keywords: ntla-2001 pharmacokinetics pharmacodynamics neurologic function clustered regularly interspaced short palindromic repeats crispr polyneuropathy attr transthyretin ttr amyloidosis familial amyloid polyneuropathy fap cardiomyopathy