Clinical trial NCT06150716: Orbit Study: A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Intrathecally Administered ION356 in Participants With Pelizaeus Merzbacher Disease (PMD)
Official title: A Phase 1b Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION356 in Patients With Pelizaeus Merzbacher Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Pelizaeus-Merzbacher Disease
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2023-11-29
Enrollment: 24
Sex: MALE
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Up to Week 145
measure: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments
timeFrame: Baseline up to Week 145
measure: Number of Participants With Clinically Significant Change From Baseline in Neurological Examination Findings
timeFrame: Baseline up to Week 145
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Baseline up to Week 145
measure: Number of Participants With Clinically Significant Change From Baseline in Electrocardiography (ECG)
timeFrame: Baseline up to Week 145
measure: Number of Participants With Change From Baseline in Concomitant Medication Use
timeFrame: Baseline up to Week 145
Secondary outcomes:
measure: Maximum Plasma Concentration (Cmax) of ION356
timeFrame: Pre-dose and at multiple points post-dose up to Week 145
measure: Area Under the Concentration-time Curve (AUC) of ION356
timeFrame: Pre-dose and at multiple points post-dose up to Week 145
measure: Plasma Terminal Elimination Half-life (t½) of ION356
timeFrame: Pre-dose and at multiple points post-dose up to Week 145
measure: Plasma Concentration of ION356
timeFrame: Pre-dose and at multiple points post-dose up to Week 145
measure: Cerebrospinal Fluid (CSF) Concentration of ION356
timeFrame: Pre-dose and at multiple points post-dose up to Week 105
measure: Concentration of ION356 Excreted in Urine
timeFrame: Pre-dose and at multiple points post-dose on Week 1 and Week 49
measure: Percent of ION356 Dose Excreted in Urine
timeFrame: Pre-dose and at multiple points post-dose on Week 1 and Week 49
measure: Renal Clearance of ION356
timeFrame: Pre-dose and at multiple points post-dose on Week 1 and Week 49
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Ionis Investigative Site
state: Georgia
city: Philadelphia
country: United States
facility: Ionis Investigative Site
state: Pennsylvania
city: Salt Lake City
country: United States
facility: Ionis Investigative Site
state: Utah
city: Le Kremlin-Bicêtre
country: France
facility: Ionis Investigative Site
city: Göttingen
country: Germany
facility: Ionis Investigative Site
city: Tokyo
country: Japan
facility: Ionis Investigative Site
city: Amsterdam
country: Netherlands
facility: Ionis Investigative Site
Study officials:
References: