Pelizaeus-Merzbacher Disease
Conditions
Brief summary
The primary purpose of this study is to evaluate the safety and tolerability of 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 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.
Interventions
DRUGION356
Administered as intrathecal (IT) injection.
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| 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
| Measure | Time frame |
|---|---|
| Percent of ION356 Dose Excreted in Urine | Pre-dose and at multiple points post-dose on Week 1 and Week 49 |
| Maximum Plasma Concentration (Cmax) of ION356 | Pre-dose and at multiple points post-dose up to Week 145 |
| Renal Clearance of ION356 | Pre-dose and at multiple points post-dose on Week 1 and Week 49 |
| 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 |
Countries
France, Germany, Japan, Netherlands, United States
Contacts
Primary ContactIonis Pharmaceuticals, Inc.
Outcome results
None listed