Phase 1 Two-Part (Open-label, Single Ascending Dose (Part 1) and Open-label, Single Dose Expansion (Part 2)) 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)
概览
- 阶段
- 1 期
- 干预措施
- NTLA-2001
- 疾病 / 适应症
- 未指定
- 发起方
- Intellia Therapeutics
- 入组人数
- 72
- 试验地点
- 4
- 主要终点
- Number of Participants with Treatment-Emergent Adverse Events
- 状态
- 已完成
- 最后更新
- 3个月前
概览
简要总结
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)
详细描述
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.
研究者
入排标准
入选标准
- •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
排除标准
- •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:
- •Doxycycline and/or tauroursodeoxycholic acid
- •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
研究组 & 干预措施
Polyneuropathy Part 1: NTLA-2001
Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001.
干预措施: NTLA-2001
Polyneuropathy Part 2: NTLA-2001
Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.
干预措施: NTLA-2001
Cardiomyopathy Part 1 (UK only): NTLA-2001
Participants, assigned to one of 2 dose-escalation cohorts, will receive a single dose of NTLA-2001.
干预措施: NTLA-2001
Cardiomyopathy Part 2 (UK only): NTLA-2001
Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.
干预措施: NTLA-2001
Polyneuropathy Follow-on Dosing (PN Part 1 Dose Level 1 Subjects only): NTLA-2001
Participants assigned to the follow-on dosing cohort will receive a subsequent dose of NTLA-2001.
干预措施: NTLA-2001
结局指标
主要结局
Number of Participants with Treatment-Emergent Adverse Events
时间窗: up to Day 730
Number of Participants with Clinically Significant Clinical Laboratory Test Findings
时间窗: up to Day 730
Number of Participants with Clinically Significant Safety Measurements
时间窗: up to Day 730
Percent Change from Baseline in Serum TTR (enzyme-linked immunosorbent assay [ELISA])
时间窗: up to Day 730
Percent Change from Baseline in Serum Prealbumin
时间窗: up to Day 730
Mean Area Under the Plasma Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
时间窗: up to Day 730
Mean Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUCinf) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
时间窗: up to Day 730
Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
时间窗: up to Day 730
Mean Time of the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
时间窗: up to Day 730
Mean Terminal Half-Life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
时间窗: up to Day 730
Mean Apparent Clearance (CL) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
时间窗: up to Day 730
Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA
时间窗: up to Day 730
Change from Baseline in Anti-Drug Antibody to NTLA-2001 and Anti-Cas9 Protein Antibody to Transgene Product Levels
时间窗: up to Day 730
次要结局
- Polyneuropathy only: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage.(up to Day 730)
- Polyneuropathy only: Change from Baseline in Polyneuropathy Disability (PND) Score(up to Day 730)
- Polyneuropathy only: Change from Baseline in Modified Body Mass Index (mBMI)(up to Day 730)
- Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS)(up to Day 730)
- Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7)(up to Day 730)
- Polyneuropathy only: Change from Screening in 10-Meter Walk Test (10-MWT)(up to Day 730)
- Polyneuropathy only: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN)(up to Day 730)
- Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L(up to Day 730)
- Cardiomyopathy only: Change from Baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP)(up to Day 730)
- Cardiomyopathy only: Change from Baseline in hs Troponin T(up to Day 730)
- Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI)(up to Day 730)
- Cardiomyopathy only: Change from Baseline in Echocardiogram(up to Day 730)
- Cardiomyopathy only: Change from Baseline in Cardio-pulmonary exercise test(up to Day 730)
- Cardiomyopathy only: Change from Baseline in 6-Minute Walk Test (6-MWT)(up to Day 730)
- Cardiomyopathy only: Change from Baseline in New York Heart Association (NYHA) Classification(up to Day 730)
- Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ)(up to Day 730)