Evaluation of Fosigotifator Sodium Tromethamine in Adult and Pediatric Patients with Vanishing White Matter Disease: A Phase 1b/2 Open-Label Study

The primary objective of this study is to evaluate the **safety** and **tolerability** following the administration of Fosigotifator in adult and pediatric subjects with Vanishing White Matter (VWM) disease during the Safety Evaluation Period. Additionally, the study aims to assess the pharmacokinetics (PK) of A-1684909, the pharmacologically active compound, following multiple doses of Fosigotifator, which is a prodrug, in the same patient population. These objectives are clinically relevant as they aim to establish the foundational safety profile and pharmacokinetic behavior of Fosigotifator, which is crucial for determining its potential therapeutic application in VWM disease.

Secondary objectives include evaluating the safety and tolerability of Fosigotifator during the Maintenance Dose Period and the Follow-up Period in both adult and pediatric subjects with VWM disease. This further assessment is important to ensure the long-term safety and manageability of the treatment regimen.

The clinical trial involves a total of **13 participants** diagnosed with **Vanishing White Matter disease**. The study population includes both male and female subjects, with age groups spanning from infants as young as 6 months to adults aged 18 years and older. Participants are categorized into cohorts based on age: Cohort 1 and 1b include individuals aged 18 years and above, Cohort 2 includes those aged 12 to less than 18 years, Cohort 3 includes children aged 6 to less than 12 years, and Cohort 4 includes infants and young children aged 6 months to less than 6 years. The trial population was selected based on a confirmed clinical and molecular diagnosis of Vanishing White Matter disease, with MRI findings consistent with the condition. Participants must have a designated caregiver to assist with assessments and comply with the study protocol. Both male and female participants of reproductive potential are required to use contraceptive methods during the study and for a specified period after the final dose of the study drug. The trial includes a vulnerable population, as it involves pediatric subjects and individuals with cognitive impairments. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **Phase 1b/2 open-label study** to evaluate the safety, tolerability, pharmacokinetics, and exploratory efficacy of **Fosigotifator** in adult and pediatric subjects diagnosed with **Vanishing White Matter disease**. The trial will involve multiple cohorts, categorized by age, to assess the effects of the investigational product, ABBV-CLS-7262, administered in the form of film-coated granules via the oral route. The study is expected to commence on January 15, 2024, and conclude by December 27, 2026, with an estimated duration of approximately three years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific inclusion criteria, such as age and a confirmed diagnosis of Vanishing White Matter disease. The trial will include regular follow-up visits to monitor safety and pharmacokinetic parameters, with key assessments scheduled at baseline, Week 12, Week 48, and Week 96. The end-of-study visit will occur at Week 197, where final evaluations will be conducted, including assessments of adverse events (AEs) and serious adverse events (SAEs), vital signs, electrocardiograms (ECGs), and clinical laboratory tests.

The expected length of participant involvement will vary depending on the cohort, with the longest duration extending up to the end-of-study visit at Week 197. Conditions that may lead to early termination from the study include the development of cognitive impairment that prevents informed consent, significant adverse events, or any other protocol-defined criteria. The study aims to provide comprehensive data on the safety and pharmacokinetics of Fosigotifator, contributing to the understanding of its potential therapeutic benefits for individuals with Vanishing White Matter disease.

The clinical trial involves the administration of the experimental medication **ABBV-CLS-7262**, which is formulated as **film-coated granules**. The active substance in this medication is **sodium ({(2S)-1,4-bis[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[2.2.2]octan-2-yl}oxy)methyl hydrogen phosphate-2-amino-2-(hydroxymethyl)propane-1,3-diol (1/1/1)**. This compound is chemically synthesized and is administered orally. The frequency and specific dosage of administration are not detailed in the provided data. The medication is not a pediatric formulation and is designated as an orphan drug with the designation number 22-9013. The pharmaceutical development and production are attributed to Calico Life Sciences.

Another formulation of the experimental medication, also under the code **ABBV-CLS-7262**, contains the active substance **fosigotifator sodium tromethamine**. This formulation is similarly presented as **film-coated granules** and is administered orally. The compound is a small molecule, chemically synthesized, and is not specifically formulated for pediatric use. The orphan drug designation is consistent with the previous formulation, and the development is credited to AbbVie Deutschland GmbH & Co. KG.

Throughout the trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The study focuses on evaluating the safety, tolerability, and pharmacokinetics of the active compound in subjects with Vanishing White Matter Disease. Participant compliance monitoring and specific dosing schedules are not detailed in the available data.

The efficacy of the investigational product, **Fosigotifator**, in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the measurement of plasma concentrations of the pharmacologically active compound, A-1684909, at pre-specified visits from Baseline up to Week 96 for all cohorts. Additionally, cerebrospinal fluid (CSF) concentrations of A-1684909 will be evaluated at Week 12, Week 48, and Week 96. Plasma pharmacokinetic (PK) parameters of A-1684909, such as Cmax, Tmax, AUC0-24h, Ctrough, and t1/2, will be assessed following dosing at Visit 4 (Study Day 14) for Cohorts 1 and 1b.

Secondary endpoints will focus on the assessment of adverse events (AEs) and serious adverse events (SAEs) at the last visit (Week 197), as well as the monitoring of vital signs, electrocardiograms (ECGs), clinical laboratory tests, and suicidality up to the last visit (Week 197). These endpoints are designed to provide a comprehensive evaluation of the safety and tolerability of Fosigotifator in subjects with Vanishing White Matter Disease over the course of the study.