NTLA-2001 in Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Intellia Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

17 Aug 2021 → 12 Sep 2025

Decision date (initial)

2024-08-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Intellia Therapeutics, Inc.

External identifiers

EU CT number

2024-511170-69-00

EudraCT number

2020-002034-32

ClinicalTrials.gov

NCT04601051

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy, Pharmacodynamic, Dose response

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.

Secondary objectives 2

1. Part 1 and Part 2: To evaluate the effect of NTLA-2001 on clinical measures of neurologic function in subjects with ATTRv-PN.
2. Follow-on Dosing Sub-study: To evaluate the effect of a 55 mg dose of NTLA-2001 on clinical measures of neurologic function in subjects with ATTRv-PN who previously received a 0.1 mg/kg dose of NTLA-2001.

Conditions and MedDRA coding

Hereditary Transthyretin Amyloidosis with Polyneuropathy (ATTRv-PN)

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut, European Medicines Agency, Infarmed, Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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.

Exclusion criteria 1

1. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Safety assessments, immunogenicity assessments, pharmacokinetic assessments, pharmacodynamic assessments

Secondary endpoints 1

1. Polyneuropathy assessments

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Intellia Therapeutics Inc.

Sponsor organisation

Intellia Therapeutics Inc.

Address

40 Erie Street

City

Cambridge

Postcode

02139-4254

Country

United States

Scientific contact point

Organisation

Intellia Therapeutics Inc.

Contact name

Adia Leung

Public contact point

Organisation

Intellia Therapeutics Inc.

Contact name

Adia Leung

Third parties 7

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 25 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications