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

A Phase 1b Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION356 in Patients With Pelizaeus Merzbacher Disease

The primary purpose of this study is to evaluate the safety and tolerability of ION356.

Study Overview

• Status: Not yet recruiting
• Conditions: Pelizaeus-Merzbacher Disease
• Intervention / Treatment: Drug: ION356

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ionis Pharmaceuticals, Inc.; Phone Number: (844) 387-9520; Email: IonisPelizaeusMerzbacherStudy2@clinicaltrialmedia.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria

1. 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.
2. Diagnosis of PMD with genetic confirmation of PLP1 gene duplication.
3. Clinical phenotype and brain imaging consistent with a diagnosis of PMD.
4. Male between the ages of 2 and 17 years, inclusive, at the time of informed consent.
5. 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

1. Clinically significant abnormalities in medical history, laboratory tests or physical examination.
2. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator.
3. Any contraindication or unwillingness to undergo magnetic resonance imaging (MRI).
4. 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.
5. 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).
6. History of gene therapy or cell transplantation, or any experimental brain surgery.
7. Current obstructive hydrocephalus.
8. Known brain or spinal disease or previous spinal surgery that would interfere with the lumbar puncture (LP) process, CSF circulation, or safety assessment.
9. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during the study.
10. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: November 21, 2023
• First Submitted That Met QC Criteria: November 21, 2023
• First Posted (Actual): November 29, 2023

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Demyelinating Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Leukoencephalopathies; Hereditary Central Nervous System Demyelinating Diseases; Pelizaeus-Merzbacher Disease
• Other Study ID Numbers: ION356-CS1; 2022-502432-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No