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

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Ionis Pharmaceuticals

Status and phase

Phase 1


Pelizaeus-Merzbacher Disease


Drug: ION356

Study type


Funder types



2022-502432-39 (EudraCT Number)

Details and patient eligibility


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

Full 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.


24 estimated patients




2 to 17 years old


No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose




Interventional model

Sequential Assignment


None (Open label)

24 participants in 2 patient groups

Cohort A: ION356 Dose A
Experimental group
Participants will receive ION356 intrathecally at Dose A in the MAD Period, followed by ION356 Dose A in the LTE Period.
Drug: ION356
Cohort B: ION356 Dose B
Experimental group
Participants will receive ION356 intrathecally at Dose B in the MAD Period, followed by ION356 Dose B in the LTE Period.
Drug: ION356

Trial contacts and locations



Central trial contact

Ionis Pharmaceuticals, Inc.

Data sourced from clinicaltrials.gov

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