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

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 a long-term extension (LTE) part of 109 weeks. Eligible participants will receive doses of ION356 during the MAD portion of the study and upon completion will seamlessly transition to the open-label LTE to receive doses of ION356.

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.