Orbit Study: A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Intrathecally Administered ION356 in Participants With Pelizaeus Merzbacher Disease (PMD)

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the safety and tolerability of ION356.

Detailed Description
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This is a Phase 1b, open-label multiple-ascending dose (MAD) study of ION356 in approximately 24 pediatric participants with Pelizaeus-Merzbacher Disease and genetic confirmation of proteolipid protein 1 (PLP1) gene duplication. The study will have 2 parts: a 48-week multiple-ascending dose (MAD) part followed by an open-label long-term extension (LTE) part of 109 weeks. Eligible participants during the MAD portion of the study will receive doses of ION356 and upon completion will seamlessly transition to the open-label LTE to receive doses of ION356.

Official Title
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A Phase 1b, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION356 in Patients With Pelizaeus Merzbacher Disease

Conditions
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Pelizaeus-Merzbacher Disease

Intervention / Treatment
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* Drug: ION356


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Participant's parent or legally accepted representative can provide informed consent, attend all scheduled study visits, provide feedback regarding the participant's symptoms, and can comply with all study requirements. Diagnosis of PMD with genetic confirmation of PLP1 gene duplication. Clinical phenotype and brain imaging consistent with a diagnosis of PMD. Male between the ages of 2 and 17 years, inclusive, at the time of informed consent. Able and willing to meet all study requirements (in the opinion of the Investigator), including travel to Study Center, procedures, measurements, and visits. Exclusion Criteria Clinically significant abnormalities in medical history, laboratory tests or physical examination. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator. Any contraindication or unwillingness to undergo magnetic resonance imaging (MRI). Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of the investigational agent, whichever is longer. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid) within 4 months of Screening if a single dose was received, or within 12 months of Screening if multiple doses were received. This exclusion does not apply to vaccines (both messenger ribonucleic acid [mRNA] and viral vector vaccines). History of gene therapy or cell transplantation, or any experimental brain surgery. Current obstructive hydrocephalus. Known brain or spinal disease or previous spinal surgery that would interfere with the lumbar puncture (LP) process, CSF circulation, or safety assessment. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during the study. Have any other conditions, which, in the opinion of the Investigator, would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the study.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: ION356 Dose A<br>Participants will receive ION356 intrathecally at Dose A in the MAD Period, followed by ION356 Dose A in the LTE Period. | Drug: ION356<br>* Administered as intrathecal (IT) injection.<br>|
| Experimental: Cohort B: ION356 Dose B<br>Participants will receive ION356 intrathecally at Dose B in the MAD Period, followed by ION356 Dose B in the LTE Period. | Drug: ION356<br>* Administered as intrathecal (IT) injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs |  | Up to Week 145 | 
| Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments |  | Baseline up to Week 145 | 
| Number of Participants With Clinically Significant Change From Baseline in Neurological Examination Findings |  | Baseline up to Week 145 | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs |  | Baseline up to Week 145 | 
| Number of Participants With Clinically Significant Change From Baseline in Electrocardiography (ECG) |  | Baseline up to Week 145 | 
| Number of Participants With Change From Baseline in Concomitant Medication Use |  | Baseline up to Week 145 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of ION356 |  | Pre-dose and at multiple points post-dose up to Week 145 | 
| Area Under the Concentration-time Curve (AUC) of ION356 |  | Pre-dose and at multiple points post-dose up to Week 145 | 
| Plasma Terminal Elimination Half-life (t½) of ION356 |  | Pre-dose and at multiple points post-dose up to Week 145 | 
| Plasma Concentration of ION356 |  | Pre-dose and at multiple points post-dose up to Week 145 | 
| Cerebrospinal Fluid (CSF) Concentration of ION356 |  | Pre-dose and at multiple points post-dose up to Week 105 | 
| Concentration of ION356 Excreted in Urine |  | Pre-dose and at multiple points post-dose on Week 1 and Week 49 | 
| Percent of ION356 Dose Excreted in Urine |  | Pre-dose and at multiple points post-dose on Week 1 and Week 49 | 
| Renal Clearance of ION356 |  | Pre-dose and at multiple points post-dose on Week 1 and Week 49 |