A Randomized, Double-Blind, Placebo-Controlled, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple-Doses of AOC 1001 Administered Intravenously to Adult Myotonic Dystrophy Type 1 (DM1) Patients
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 39
- 试验地点
- 8
- 主要终点
- Frequency of Treatment Emergent Adverse Events (TEAEs)
研究概览
简要总结
AOC 1001-CS1 is a randomized, double-blind, placebo-controlled, Phase 1/2 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple-doses of AOC 1001 Administered Intravenously to Adult Myotonic Dystrophy Type 1 (DM1) patients (MARINA).
Part A is a single dose design with 1 cohort (dose level). In Part A, the patient duration is 6 months as the treatment period is 1 day followed by a 6 month follow-up period.
Part B is a multiple-ascending dose design with 2 cohorts (dose levels). In Part B, the patient duration is 6 months as the treatment period is 3 months followed by a 3 month follow-up period.
研究设计
- 研究类型
- 干预性
- 分配方式
- 随机
- 干预模型
- 序贯
- 主要目的
- 治疗
- 盲法
- 四盲 (受试者、医护人员、研究者、结局评估者)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- Genetic diagnosis of DM1 (CTG repeat length ≥ 100)
- Clinician assessed signs of DM1
- Ability to walk independently (orthoses and ankle braces allowed) for at least 10 meters at screening
- Key
排除标准
- Diabetes that is not adequately controlled
- BMI > 35 kg/m2
- Uncontrolled hypertension
- Congenital DM1
- History of tibialis anterior (TA) biopsy within 3 months of Day 1 or planning to undergo TA biopsies during study period
- Recently treated with an investigational drug
- Treatment with anti-myotonic medication within 14 days of Day 1
- Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Part B Multiple Ascending Dose: Placebo
Saline will be administered three times.
干预措施: Placebo (Drug)
Part A Single Dose: Placebo
Saline will be administered once.
干预措施: Placebo (Drug)
Part A Single Dose: AOC 1001 Dose Level 1
AOC 1001 will be administered once.
干预措施: AOC 1001 (Drug)
Part B Multiple Ascending Dose: AOC 1001 Dose Levels 2 & 3
AOC 1001 will be administered three times.
干预措施: AOC 1001 (Drug)
方案终点
主要结局
Frequency of Treatment Emergent Adverse Events (TEAEs)
时间窗: Through study completion, up to Day 183
Cumulative number of participants with treatment emergent adverse events at the end of study.
Frequency of treatment emergent adverse events (TEAEs)
时间窗: Through study completion, up to Day 183
次要结局
- Plasma PK Parameters(Day 1)
- Plasma Pharmacokinetic (PK) Parameters(Day 1)
- Urine Pharmacokinetic (PK) Parameters(Day 1)
- Change From Baseline in DMPK mRNA Knockdown(Day 43 (participants treated with 1 mg/kg) and Day 92 (participants treated with 2 mg/kg and 4 mg/kg))
- Absolute Change From Baseline in 4 Gene Spliceopathy(Day 43 (participants treated with 1 mg/kg) and Day 92 (participants treated with 2 mg/kg and 4 mg/kg))
- AOC 1001 Concentration Levels in Plasma, Urine, and Muscle Tissue(Up to Day 43)
- Change and percentage change from baseline in DMPK mRNA knockdown(Through study completion, up to Day 183)
- Change and percentage change from baseline in Spliceopathy(Through study completion, up to Day 183)
- Urine pharmacokinetic (PK) parameters(Through study completion, up to Day 183)
- AOC 1001 levels in muscle tissue(Through study completion, up to Day 183)
- Plasma pharmacokinetic (PK) parameters(Through study completion, up to Day 183)
试验结果
结果已于 2026-09-28 在 ClinicalTrials.gov 公示。 在 ClinicalTrials.gov 查看
受试者流程
入组 39 人 · 完成 37 人
主要终点
Frequency of Treatment Emergent Adverse Events (TEAEs)
Participants · 时间窗: Through study completion, up to Day 183
| Part A Single Dose: 1 mg/kg AOC 1001 （n=6） | Part A Single Dose: Placebo （n=2） | Part B Multiple Dose: 2 mg/kg AOC 1001 （n=9） | Part B Multiple Dose: 4 mg/kg AOC 1001 （n=13） | Part B Multiple Dose: Pooled Placebo （n=8） |
|---|---|---|---|---|
| 6 | 1 | 9 | 13 | 7 |
其他终点（8）
Plasma PK Parameters
ng/mL · Standard Deviation · 时间窗: Day 1
| Part A Single Dose: 1 mg/kg AOC 1001 （n=6） | Part B Multiple Dose: 2 mg/kg AOC 1001 （n=9） | Part B Multiple Dose: 4 mg/kg AOC 1001 （n=13） |
|---|---|---|
| 23600 (3610) | 50400 (9380) | 101000 (19200) |
All subjects who received any amount of study drug and provided a sufficient number of plasma sample(s) for PK analysis.
Plasma Pharmacokinetic (PK) Parameters
hours · Full Range · 时间窗: Day 1
| Part A Single Dose: 1 mg/kg AOC 1001 （n=6） | Part B Multiple Dose: 2 mg/kg AOC 1001 （n=9） | Part B Multiple Dose: 4 mg/kg AOC 1001 （n=13） |
|---|---|---|
| 0.542 (0.47–0.60) | 1.707 (0.72–4.77) | 2.204 (1.07–7.73) |
All subjects who received any amount of study drug and provided a sufficient number of plasma sample(s) for PK analysis
Plasma Pharmacokinetic (PK) Parameters
hours · Standard Deviation · 时间窗: Day 1
| Part A Single Dose: 1 mg/kg AOC 1001 （n=6） | Part B Multiple Dose: 2 mg/kg AOC 1001 （n=9） | Part B Multiple Dose: 4 mg/kg AOC 1001 （n=12） |
|---|---|---|
| 28.42 (2.82) | 40.61 (9.69) | 49.60 (6.08) |
all subjects who receive any amount of study drug and provide a sufficient number of plasma sample(s) for PK analysis
Plasma Pharmacokinetic (PK) Parameters
h*ng/mL · Standard Deviation · 时间窗: Day 1
| Part A Single Dose: 1 mg/kg AOC 1001 （n=6） | Part B Multiple Dose: 2 mg/kg AOC 1001 （n=9） | Part B Multiple Dose: 4 mg/kg AOC 1001 （n=13） |
|---|---|---|
| 850000 (137000) | 2470000 (629000) | 5490000 (1570000) |
All subjects who received any amount of study drug and provided a sufficient number of plasma sample(s) for PK analysis.
Urine Pharmacokinetic (PK) Parameters
percent of total siRNA component · Standard Deviation · 时间窗: Day 1
| Part A Single Dose: 1 mg/kg AOC 1001 （n=6） | Part B Multiple Dose: 2 mg/kg AOC 1001 （n=9） | Part B Multiple Dose: 4 mg/kg AOC 1001 （n=13） |
|---|---|---|
| 3.724 (0.747) | 4.216 (2.084) | 4.308 (2.087) |
All subjects who received any amount of study drug and provided a sufficient number of plasma sample(s) for PK analysis
Change From Baseline in DMPK mRNA Knockdown
% change · Standard Error · 时间窗: Day 43 (participants treated with 1 mg/kg) and Day 92 (participants treated with 2 mg/kg and 4 mg/kg)
| Part A Single Dose: 1 mg/kg AOC 1001 （n=5） | Part B Multiple Dose: 2 mg/kg AOC 1001 （n=9） | Part B Multiple Dose: 4mg/kg AOC 1001 （n=9） | Pooled Placebo （n=9） |
|---|---|---|---|
| -46.36 (8.85) | -44.39 (3.80) | -36.81 (6.34) | 1.46 (11.17) |
All subjects who received any amount of study drug and had a baseline PD assessment and at least 1 post-baseline PD assessment.
Absolute Change From Baseline in 4 Gene Spliceopathy
percent · Standard Error · 时间窗: Day 43 (participants treated with 1 mg/kg) and Day 92 (participants treated with 2 mg/kg and 4 mg/kg)
| Part A Single Dose: 1 mg/kg AOC 1001 （n=5） | Part B Multiple Dose: 2 mg/kg AOC 1001 （n=9） | Part B Multiple Dose: 4mg/kg AOC 1001 （n=9） | Pooled Placebo （n=9） |
|---|---|---|---|
| -3.13 (8.39) | -16.72 (7.65) | -15.81 (10.30) | -6.97 (9.68) |
All subjects who received any amount of study drug and had a baseline pharmacodynamic assessment and at least 1 post-baseline pharmacodynamic assessment.
AOC 1001 Concentration Levels in Plasma, Urine, and Muscle Tissue
nM · Standard Error · 时间窗: Up to Day 43
| 分类 | Part A Single Dose: 1 mg/kg AOC 1001 （n=6） | Part B Multiple Dose: 2 mg/kg AOC 1001 （n=9） | Part B Multiple Dose: 4 mg/kg AOC 1001 （n=13） |
|---|---|---|---|
| Plasma siDMPK.19: first dose, end of Infusion | 1749 (109.26) | 3670.18 (236.29) | 7234.72 (415.56) |
| Plasma siDMPK.19: first dose, 1 hour post-infusion | 1623.12 (86.83) | 3632.49 (246.59) | 7281.03 (365.77) |
| Plasma siDMPK.19: first dose, 2 hours post infusion | 1596.32 (89.48) | 3410.50 (276.98) | 7050.49 (379.32) |
| Plasma siDMPK.19: first dose, 6 hours post infusion | 1379.38 (102.25) | 3018.71 (243.95) | 6419.49 (399.580) |
| Plasma siDMPK.19: first dose, 24 hours post infusion | 841.88 (56.13) | 2052.98 (148.097) | 4666.17 (301.02) |
| Plasma siDMPK.19: first dose, 8 days post infusion | 38.18 (10.16) | 152.66 (27.95) | 465.92 (41.74) |
| Plasma siDMPK.19: first dose, 15 days post infusion | 0.46 (0.18) | 9.46 (8.79) | 44.01 (17.99) |
| Plasma siDMPK.19: first dose, 29 days post infusion | 0.00 (0.00) | 0.11 (0.06) | 0.69 (0.14) |
| Plasma siDMPK.19: first dose, 43 days post infusion | 0.00 (0.00) | 0.00 (0.00) | 0.05 (0.03) |
| Urine siDMPK.19: first dose, 0-6 hours post infusion | 55.38 (26.22) | 256.64 (73.72) | 196.331 (38.415) |
| Urine siDMPK.19: first dose, 6-12 hours | 227.91 (53.89) | 419.66 (82.97) | 653.42 (100.98) |
| Urine siDMPK.19: first dose, 12-24 hours | 161.79 (26.95) | 387.46 (113.47) | 648.11 (109.66) |
| Muscle siDMPK.19: first dose, Day 43 (1 mg/kg) or 92 (2 mg/kg and 4 mg/kg) | 0.085 (0.054) | 0.424 (0.159) | 1.414 (0.417) |
All subjects who received any amount of study drug and provided a sufficient number of plasma sample(s) for PK analysis.
安全性
| 组别 | 严重不良事件 | 死亡 |
|---|---|---|
| Part A Single Dose: 1 mg/kg AOC 1001 | 0 / 6 | 0 / 6 |
| Part A Single Dose: Placebo | 0 / 2 | 0 / 2 |
| Part B Multiple Dose: 2 mg/kg ACO 1001 | 1 / 9 | 0 / 9 |
| Part B Multiple Dose: 4 mg/kg AOC 1001 | 1 / 13 | 0 / 13 |
| Part B Multiple Dose: Pooled Placebo | 0 / 8 | 0 / 8 |
最常见的严重不良事件（人数）
| 事件 | Part A Single Dose: 1 mg/kg AOC 1001 | Part A Single Dose: Placebo | Part B Multiple Dose: 2 mg/kg ACO 1001 | Part B Multiple Dose: 4 mg/kg AOC 1001 | Part B Multiple Dose: Pooled Placebo |
|---|---|---|---|---|---|
| Thalmus haemorrhage | 0 / 6 | 0 / 2 | 0 / 9 | 1 / 13 | 0 / 8 |
| Respiratory Failure | 0 / 6 | 0 / 2 | 1 / 9 | 0 / 13 | 0 / 8 |
数值为申办方在 ClinicalTrials.gov 公示的原始数据，未经重新计算；括号内为公示的离散度（如 95% 置信区间）。
相关文献
- 相关文献（PubMed 关联）Johnson NE, Tai LJ, Hamel JI, Day JW, Statland JM, Soltanzadeh P, Subramony SH, Thornton CA, Arnold WD, Wicklund M, Freimer ML, Eichinger K, Dekdebrun J, Chen CY, Goel V, McEvoy B, Zhu Y, Hughes SG, Ackermann EJ, Levin AA. An Antibody-Oligonucleotide Conjugate for Myotonic Dystrophy Type 1. N Engl J Med. 2026 Feb 19;394(8):763-772. doi: 10.1056/NEJMoa2407326. PubMed 41707138
研究者
研究点 (8)
标识符
- NCT 编号
- NCT05027269
- 其他研究编号
- AOC 1001-CS1
日期
- 首次提交
- (5年前)
- 首次发布
- (5年前)
- 主要完成日期
- (3年前)
- 研究完成日期
- (3年前)
- 最近核实
- (29天前)
- 最近更新
- (前天)
监管与共享
- FDA 监管药物
- 是
- FDA 监管器械
- 否
- 个体参与者数据共享计划
- 否
- 是否有结果
- 是