ION356-CS1: A Phase 1b Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Intrathecally Administered ION356 in Patients with Pelizaeus-Merzbacher Disease

The primary objective of this Phase 1b study is to evaluate the **safety** and **tolerability** of ION356, an intrathecally administered injection, in patients diagnosed with Pelizaeus-Merzbacher Disease. This objective is clinically relevant as it aims to ensure that the treatment is safe for use in this patient population, which is crucial for the progression of the drug development process.

Secondary objectives include:

• Characterizing the cerebrospinal fluid (CSF) and plasma pharmacokinetics (PK) of ascending dose levels of multiple intrathecal administrations of ION356. This will provide insights into the drug's distribution and clearance, which are essential for optimizing dosing regimens.

The clinical trial involves a total of **40 participants** diagnosed with **Pelizaeus-Merzbacher Disease** (PMD). The study population is exclusively male, with an age range from 2 to 17 years. Participants were selected based on a previous diagnosis of PMD, confirmed through genetic testing of the PLP1 gene duplication, and clinical phenotype and brain imaging consistent with PMD. The trial does not include female subjects and focuses on a vulnerable population due to the age and specific health condition of the participants. All participants are required to be able and willing to comply with study requirements, including travel to the study center and participation in necessary procedures and visits. The trial aims to evaluate the safety and tolerability of ION356 in this specific demographic.

The clinical trial is designed to evaluate the **safety** and tolerability of ION356, a new chemical entity, in patients diagnosed with **Pelizaeus-Merzbacher Disease**. This is a Phase 1b study, characterized by a randomized, double-blind, and controlled design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is expected to commence on December 8, 2023, and conclude by September 1, 2029, with the primary objective of assessing the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) throughout the study duration.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a previous diagnosis of Pelizaeus-Merzbacher Disease with genetic confirmation of PLP1 gene duplication, clinical phenotype, and brain imaging consistent with the disease. Eligible participants, males aged 2 to 17 years, will be required to attend regular follow-up visits for comprehensive assessments, including laboratory tests, neurological exams, and vital sign monitoring. The study will also measure ION356 concentrations in plasma and cerebrospinal fluid (CSF) to evaluate pharmacokinetics and pharmacodynamics.

The expected length of participant involvement will span the entire trial duration unless early termination is warranted. Conditions for early termination include the occurrence of significant adverse events or the participant's inability to comply with study requirements. The end-of-study visit will mark the final assessment, ensuring all safety and efficacy data are collected and analyzed. This trial is crucial for understanding the therapeutic potential of ION356 and its future development in treating Pelizaeus-Merzbacher Disease.

The clinical trial involves the administration of the experimental medication **ION356**, which is an **injection** formulated as a **2'-O-(2-methoxyethyl) modified antisense oligonucleotide targeting PLP1 pre-mRNA**. This investigational drug is classified as a New Chemical Entity (NCE) and is developed by Ionis Pharmaceuticals, Inc. The pharmaceutical form of ION356 is an injection, and it is administered via **intrathecal use**. The primary objective of the trial is to evaluate the safety and tolerability of ION356 in patients diagnosed with Pelizaeus-Merzbacher Disease. The dosing schedule, including the specific dosage and frequency of administration, is determined by the study protocol, although specific details are not provided in the source data.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The trial focuses solely on the administration of ION356. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol. The trial does not involve a pediatric formulation, and ION356 is not designated as an orphan drug. The study is designed to assess the pharmacokinetics and pharmacodynamics of the drug, alongside its safety profile.

Efficacy in the clinical trial of ION356 for **Pelizaeus-Merzbacher Disease** will be assessed through both primary and secondary endpoints. The primary endpoints focus on the safety profile of the treatment, including the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) from Day 1 to the final study visit. This will involve monitoring changes from baseline in laboratory assessments such as clinical chemistry, hematology, coagulation in plasma/serum, urinalysis, and cerebrospinal fluid (CSF) safety panel. Additionally, neurological exams, vital signs, ECG, and concomitant medication use will be evaluated.

The secondary endpoints will assess the pharmacokinetics of ION356, specifically its concentrations in plasma and CSF over the course of the study. Key pharmacokinetic parameters include maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), elimination half-life (t½), and both trough (pre-dose) and post-treatment concentrations of ION356 in plasma and CSF. Furthermore, the excretion of ION356 in urine, the percentage of dose excreted, and renal clearance will be measured. These assessments will provide comprehensive data on the drug's behavior in the body, contributing to the overall evaluation of its efficacy.