A Phase 1/2, Multicenter, Open-Label Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL310 in Pediatric Participants With Hunter Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 47
- 试验地点
- 7
- 主要终点
- Incidence and severity of treatment-emergent adverse events (TEAEs)
研究概览
简要总结
This is a multicenter, multiregional, open-label study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of tividenofusp alfa (DNL310), an investigational central nervous system (CNS)-penetrant enzyme replacement therapy (ERT), designed to treat both the peripheral and CNS manifestations of Mucopolysaccharidosis type II (MPS II; Hunter syndrome).
Participants, whose physicians feel they are deriving benefit, will have the opportunity to be reconsented into a safety extension and then an open-label extension for continued evaluation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Confirmed diagnosis of MPS II
- •Cohort A: Participants aged ≥5 to ≤10 years with neuronopathic MPS II
- •Cohort B: Participants aged ≥1 to ≤18 years with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype
- •Cohort C: Participants aged <4 years with neuronopathic MPS II (this cohort can include participants ≥4 to ≤18 years of age if participant is a blood relative of a participant <4 years of age)
- •Cohort D: Participants aged ≤18 years with non-neuronopathic MPS II or neuronopathic MPS II with preexisting hepatomegaly who have never taken standard-of-care ERT
- •Cohort E: neuronopathic MPS II participants aged ≥6 years at screening, non-neuronopathic MPS II participants <6 or ≥17 years at screening, and neuronopathic MPS II participants ≥1 to ≤18 years at screening with a history of prior haematopoietic stem cell transplantation or gene therapy who have completed at least 48 weeks in Study DNLI-E-0001
- •For participants receiving intravenous iduronate 2-sulfatase (IDS) ERT, tolerated a minimum of 4 months of therapy during the period immediately prior to screening.
排除标准
- •Unstable or poorly controlled medical condition(s) or significant medical or psychological comorbidity or comorbidities that, in the opinion of the investigator, would interfere with safe participation in the trial or interpretation of study assessments
- •Use of any CNS-targeted MPS II ERT within 3 months before study start for participants aged ≥5 years, and within 6 months before study start for participants aged <5 years
- •Use of IDS gene therapy or stem cell therapy at any time (except for participants in Cohort E)
- •Clinically significant thrombocytopenia, other clinically significant coagulation abnormality, or significant active bleeding, or required treatment with an anticoagulant or more than two antiplatelet agents
- •Contraindication for lumbar punctures
- •Have a clinically significant history of stroke, status epilepticus, head trauma with loss of consciousness, or any CNS disease that is not MPS II-related within 1 year of screening
- •Have had a ventriculoperitoneal (VP) shunt placed, or any other brain surgery, or have a clinically significant VP shunt malfunction within 30 days of screening
- •Have any clinically significant CNS trauma or disorder that, in the opinion of the investigator, may interfere with assessment of study endpoints or make participation in the study unsafe
研究组 & 干预措施
Cohort A
Dose escalation followed by a consistent dose level in participants with neuronopathic MPS II
干预措施: tividenofusp alfa (Drug)
Cohort B
A consistent dose level in participants with non-neuronopathic MPS II, neuronopathic MPS II, or unknown phenotype followed by dose escalation in some participants.
干预措施: tividenofusp alfa (Drug)
Cohort C
A consistent dose level in participants with neuronopathic MPS II
干预措施: tividenofusp alfa (Drug)
Cohort D
A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II
干预措施: tividenofusp alfa (Drug)
Cohort E
A consistent dose level in participants with non-neuronopathic MPS II or neuronopathic MPS II
干预措施: tividenofusp alfa (Drug)
结局指标
主要结局
Incidence and severity of treatment-emergent adverse events (TEAEs)
时间窗: 24 weeks, 104 weeks, and 357 weeks
Change from baseline in urine total glycosaminoglycan (GAG) concentrations
时间窗: 24 weeks, 104 weeks, and 357 weeks
Incidence and severity of infusion-related reactions (IRRs)
时间窗: 24 weeks, 104 weeks, and 357 weeks
Change from baseline in concomitant medications
时间窗: 24 weeks, 104 weeks, and 357 weeks
次要结局
- Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score(49 weeks)
- Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores(49 weeks)
- PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum(24 weeks)
- PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum(24 weeks)
- PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum(24 weeks)
- PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum(24 weeks)
- PK parameter: Trough concentration (Cmin) of DNL310 in serum(24 weeks)
- Percentage change from baseline in cerebrospinal fluid (CSF) of heparan sulfate(24 weeks)
- Percentage change from baseline in liver volume(24 weeks and 49 weeks)
- PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of DNL310 in serum(24 weeks)
- Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline(24 weeks)
- PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum(24 weeks)
- Percent change from baseline in urine concentration of heparan sulfate (HS)(24 weeks)
- Participants with liver volume in the normal range(24 weeks and 49 weeks)