NTLA-2001 in Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN)
- Conditions
- Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN)
- Interventions
- Registration Number
- 2024-511170-69-00
- Lead Sponsor
- Intellia Therapeutics Inc.
- Brief Summary
Part 1 and Part 2:
To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of NTLA-2001 in patients with ATTRv-PN
Follow-on Dosing Sub-study:
To evaluate the safety, tolerability, PK, and PD of a 55 mg dose of NTLA-2001 in subjects with ATTRv-PN who previously received a 0.1 mg/kg
dose of NTLA-2001.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- Ongoing, recruitment ended
- Sex
- Not specified
- Target Recruitment
- 15
Subjects must meet the following inclusion criteria: 1. Male and/or female subjects 18 to 80 years of age inclusive, at the time of signing the informed consent. 2. Diagnosis of PN due to TTR amyloidosis (ATTR) based on all of the following: a. Documented TTR mutation (i.e., whole TTR gene sequencing information). b. Clinical diagnosis of sensorimotor peripheral neuropathy. c. Neuropathy Impairment Score (NIS) ≥ 5 and ≤ 130 during Screening. d. Polyneuropathy Disability (PND) score ≤ 3b. 3. Must have a body weight of at least 45 kg at Screening visit. 4. Subjects must meet the following laboratory criteria during Screening: a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (see exception for Gilbert’s Syndrome below), and international normalized ratio (INR) ≤ upper limit of normal (ULN) range at Screening. b. For subjects with a history of Gilbert’s Syndrome, total bilirubin ≤ 2 × ULN at Screening. c. Estimated glomerular filtration rate (eGFR) > 45 mL/min/1.73m2 as measured by the Modification of Diet in Renal Disease equation at Screening. d. Platelet count ≥ 100,000 cells/mm3 at Screening. e. Within laboratory reference range or deemed clinically non significant by the investigator: activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen, and D dimer levels at Screening. f. N terminal prohormone of brain natriuretic peptide (NT proBNP) < 2,000 pg/mL during Screening. g. Low density lipoprotein (LDL) cholesterol < 200 mg/dL at Screening, with or without pharmacotherapy. h. Vitamin A ≥ lower limit of normal (LLN) at Screening. i. Thyroid-stimulating hormone (TSH) values within the normal range at Screening. 5. Subjects must be willing to limit alcohol consumption to 1 alcoholic drink per day during Screening and through 28 days after treatment with NTLA 2001. 6. Lack of access to approved treatments for transthyretin amyloidosis (Criterion A) and/or progression of ATTRv PN despite use of approved treatment for ATTRv PN (Criterion B). Criterion A: Lack of access to approved treatments for ATTRv PN defined as one or more of the following: • ATTRv PN-directed therapy not approved in subject’s geographic region. • Subject unable to receive treatment approved for ATTRv PN (e.g., intolerance or other medical reasons, financial reasons, and/or other reasons). Criterion B: Progression of ATTRv PN symptoms per the investigator assessment despite approved treatment for ATTRv PN for at least 6 months and meeting any two of the following criteria: • Increase in Polyneuropathy Disability (PND) score ≥ 1 point. • Increase in Neuropathy Impairment Score (NIS) ≥ 5 points. • Decrease in Modified Body-Mass Index (mBMI) ≥ 25 kg/m2 × g/L. • One of the following: • Decrease in 6 minute walk test ≥ 30 meters. • Decrease in 10 meter walk test ≥ 0.1 meter/second. • Increase in Timed Get Up and Go test ≥ 15% Note: In Part 1, subjects with a history of treatment with TTR lowering therapy (i.e., patisiran, inotersen) will be excluded. In Part 2, up to 6 subjects with progression of ATTRv PN symptoms despite treatment with TTR lowering therapy will be able to be dosed with NTLA 2001. 7. A female subject must be: • Postmenopausal or Surgically sterile. Please see protocol for further inclusion criteria.
Subjects must not meet any of the following exclusion criteria: 1. Amyloidosis attributable to non TTR protein, e.g., amyloid light-chain (AL) amyloidosis. 2. Known leptomeningeal transthyretin amyloidosis. 3. Subjects who have known hypersensitivity to any lipid nanoparticles (LNP) component or who have previously received LNP and experienced any treatment related laboratory abnormalities or AE listed below: • ALT or AST > 3 × ULN if baseline was normal or > 3 × baseline if baseline was above normal after receiving an LNP containing product. • INR, aPTT or D dimer > 1.5 × ULN if baseline was normal or > 1.5 × Baseline if baseline was above normal after receiving an LNP containing product. • Any LNP treatment-related AE classified as CTCAE Grade 3 or higher. • Infusion-related reaction (IRR) to an LNP containing product requiring treatment or discontinuation of infusion; NOTE: slowing of the infusion rate to mitigate an infusion-related reaction is not considered exclusionary. • Any LNP treatment-related AE which in the opinion of the investigator should be exclusionary. 4. Use of any of the following TTR directed therapy for ATTR within the specified timeframe: • Patisiran (small interfering ribonucleic acid [siRNA] therapeutic formulated LNP): o Part 1: prior history of use. o Part 2: last dose administered less than 60 days prior to study drug administration. • Inotersen (antisense oligonucleotide [ASO]): o Part 1: prior history of use. o Part 2: last dose administered less than 160 days prior to study drug administration. • Vutrisiran (investigational siRNA therapeutic GalNAc conjugate): prior history of use. • Tafamidis (TTR stabilizer): subject must be on stable dose for a minimum of 14 days. • Diflunisal (TTR stabilizer): last dose administered less than 3 days prior to study drug dosing. • Doxycycline and/or tauroursodeoxycholic acid (TTR matrix solvent): last dose administered less than 14 days of study drug dosing. • Any other investigational agent for the treatment of ATTRv PN: last dose administered less than 30 days or 5 half-lives, whichever is longer, prior to study drug dosing. 5. Other known causes of sensorimotor or autonomic neuropathy (e.g., diabetic neuropathy, autoimmune disease-associated neuropathy, etc.). 6. Type 1 diabetes mellitus or diagnosis of Type 2 diabetes mellitus for ≥ 5 years. 7. Current or prior New York Heart Association (NYHA) class III or IV symptoms due to heart failure or worsening of heart failure symptoms within 90 days prior to or during Screening. 8. Within 6 months of planned NTLA 2001 infusion, any history of myocardial infarction, unstable angina, severe aortic stenosis, symptomatic mitral regurgitation, Mobitz II atrioventricular block, third degree heart block, symptomatic ventricular arrhythmia, symptomatic bradycardia, or newly recognized ventricular tachycardia, cerebral ischemia, symptomatic peripheral vascular disease, pulmonary emboli, deep vein thrombosis, abnormal carotid ultrasound, abnormal coronary perfusion study, or aneurysm under imaging surveillance. For history of the above more than 6 months prior to the planned NTLA 2001 infusion, subject will require formal evaluation by her/his managing medical specialist to document that medical management has been optimized and that the patient’s current health status would be deemed safe to proceed with the equivalent of intermediate risk, non-cardiac surgery. In addition, cardiovascular hospitalization or invasive procedure within 90 days prior to or during Screening will also be exclusionary. 9. Anticipated invasive cardiovascular procedure (e.g., coronary stent, pacemaker placement, etc.) within 28 days after study drug administration. 10. Unable or unwilling to take Vitamin A supplementation. Please refer to protocol for further exclusion criteria.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Polyneuropathy Part 1: NTLA-2001 NTLA-2001 Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001. Cardiomyopathy Part 2 (UK only): NTLA-2001 NTLA-2001 Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001. Polyneuropathy Part 2: NTLA-2001 NTLA-2001 Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001. Polyneuropathy Follow-on Dosing (PN Part 1 Dose Level 1 Subjects only): NTLA-2001 NTLA-2001 Participants assigned to the follow-on dosing cohort will receive a subsequent dose of NTLA-2001. Cardiomyopathy Part 1 (UK only): NTLA-2001 NTLA-2001 Participants, assigned to one of 2 dose-escalation cohorts, will receive a single dose of NTLA-2001.
- Primary Outcome Measures
Name Time Method Safety assessments, immunogenicity assessments, pharmacokinetic assessments, pharmacodynamic assessments Safety assessments, immunogenicity assessments, pharmacokinetic assessments, pharmacodynamic assessments
- Secondary Outcome Measures
Name Time Method Polyneuropathy assessments Polyneuropathy assessments
Trial Locations
- Locations (2)
Assistance Publique Hopitaux De Paris
🇫🇷Le Kremlin-Bicetre, France
Region Vaesterbotten
🇸🇪Umea, Sweden
Assistance Publique Hopitaux De Paris🇫🇷Le Kremlin-Bicetre, FranceDavid AdamsSite contact+33145212711david.adams@aphp.fr