Ublituximab in Pediatric Participants with Relapsing forms of Multiple Sclerosis (RMS)

This clinical trial evaluates ublituximab in pediatric patients aged 10 to less than 18 years with relapsing forms of multiple sclerosis (RMS). The study is divided into three parts with distinct primary objectives. In Part A, the primary objectives are to assess the pharmacokinetics and relative bioavailability of ublituximab, as well as to evaluate the pharmacodynamics of ublituximab in this patient population. Part B aims to establish the non-inferiority of ublituximab compared with fingolimod in children with RMS aged 10 years and older. Part C focuses on evaluating the long-term safety and efficacy of ublituximab in pediatric participants with RMS. These objectives are clinically relevant as they address the need for therapeutic options in pediatric RMS, a population with limited treatment data, and seek to determine whether ublituximab provides comparable benefit to an established therapy while characterizing its pharmacological profile and long-term tolerability in younger patients.

The secondary objectives include:

• Part A: To assess the safety, tolerability, and efficacy of ublituximab in patients aged 10 to less than 18 years with RMS

• Part B: To assess the safety, tolerability, and efficacy of ublituximab in patients aged 10 to less than 18 years with RMS

This clinical trial enrolled approximately 200 participants diagnosed with **relapsing multiple sclerosis**. The study population consisted of **pediatric patients** aged **10 to less than 18 years** at the time of randomization. Both **male and female participants** were included in the trial. Participants were required to have documented disease activity, including at least one relapse in the previous 12 months, or at least two relapses in the previous 24 months with specific **MRI** findings such as **gadolinium-enhancing lesions** on T1-weighted imaging or new T2 lesions compared to prior imaging. Eligible participants had an **Expanded Disability Status Scale (EDSS)** score between 0 and 5.5, inclusive, and demonstrated neurologic stability for at least 30 days prior to screening. Participants were required to have completed their locally recommended **vaccination schedule** and show evidence of immunity to **varicella-zoster virus**, mumps, measles, rubella, diphtheria, tetanus, and pertussis. **B cell counts** had to fall within a specified range at baseline. Female participants of **child-bearing potential** were required to have a negative pregnancy test and agree to use medically acceptable contraception throughout the study period and for a specified duration after the last dose of study medication. Similarly, fertile male participants who were sexually active with women of child-bearing potential were required to use barrier contraception during the treatment period and for a defined follow-up period.

This is a Phase 2/Phase 3 clinical trial evaluating **ublituximab** in pediatric participants aged 10 to less than 18 years with **relapsing forms of multiple sclerosis**. The trial is structured in three sequential parts (Part A, Part B, and Part C) with distinct objectives and designs. Part A is designed to assess the **pharmacokinetics** and relative bioavailability of ublituximab, as well as its **pharmacodynamics**, specifically evaluating the percentage of patients achieving a defined level of **CD19+ B cell** depletion. Part B aims to establish **non-inferiority** of ublituximab compared with **fingolimod** in children with relapsing multiple sclerosis. Part C is a long-term extension phase designed to evaluate the safety and efficacy of ublituximab in pediatric participants.

The investigational medicinal products include ublituximab administered as a **concentrate for solution for infusion** via **intravenous infusion**, with a maximum daily dose of 450 mg and a maximum total dose of 5250 mg over a treatment period of up to 240 weeks. The comparator is fingolimod, provided as a hard **capsule** for **oral** administration, with a maximum daily dose of 0.5 mg and a maximum total dose of 335.5 mg over a treatment period of up to 96 weeks. Fingolimod has been overencapsulated to maintain blinding of study treatment. Matching **placebo** formulations are utilized for both ublituximab and fingolimod to ensure appropriate blinding throughout the study.

Participants eligible for enrollment must be aged 10 to less than 18 years at randomization and have a confirmed diagnosis of relapsing multiple sclerosis according to the 2017 Revised McDonald Criteria. Key inclusion criteria include evidence of disease activity, defined as at least one relapse in the previous 12 months, or at least two relapses in the previous 24 months with at least one **gadolinium-enhancing lesion** on T1-weighted brain **MRI** within the previous 12 months, or at least one new T2 lesion or gadolinium-enhancing T1 lesion compared to a prior MRI conducted within 12 months. Participants must have an **Expanded Disability Status Scale** score between 0 and 5.5 inclusive at screening, demonstrate neurologic stability for at least 30 days prior to screening and between screening and the first treatment visit, and have **B cell** counts within a specified range. Participants must have completed their locally recommended vaccination schedule and have documented evidence of immunity to **varicella-zoster virus**, mumps, measles, rubella, diphtheria, tetanus, and pertussis at screening. Female participants of childbearing potential must have a negative serum pregnancy test and agree to use medically acceptable contraception throughout the study period and for 20 weeks after the last dose of ublituximab or intravenous placebo, or 8 weeks after the last dose of fingolimod or oral placebo, whichever is later. Male participants who are sexually active with women of childbearing potential must agree to use condoms during the same timeframe. Written informed consent from legal representatives and age-appropriate assent from participants are required before any study-specific procedures. Eligibility for Part C requires completion of Part A (Week 24 visit) or Part B (Week 96 visit).

The primary endpoints for Part A include the percentage of patients with CD19+ B cell counts at a defined level. For Part C, the primary endpoints focus on safety, including the incidence and severity of **adverse events** graded according to the **NCI CTCAE** version 5.0, and assessment of suicidal ideation using the **Columbia-Suicide Severity Rating Scale**. Secondary endpoints for Part A include safety assessments (incidence and severity of adverse events and suicidal ideation) and pharmacological evaluations, such as serum concentrations of ublituximab and the percentage of participants with **anti-drug antibodies** to ublituximab. For Part B, secondary endpoints include safety assessments identical to Part A, as well as pharmacological parameters including calculated pharmacokinetic parameters of ublituximab, CD19+ B cell counts, and the percentage of participants with treatment-emergent anti-drug antibodies to ublituximab.

The estimated recruitment start date for the trial is November 10, 2025, with an estimated completion date of September 2, 2032. Participant involvement varies depending on the trial part, with Part A extending to 24 weeks, Part B extending to 96 weeks, and Part C providing long-term follow-up. Conditions that may lead to early termination from the study are not explicitly specified in the provided data.

The experimental medication ublituximab is administered as a concentrate for solution for infusion via intravenous infusion. The active substance is ublituximab, a protein classified as a monoclonal antibody. The sponsor product code for this investigational medicinal product is TG-1101, with alternative designations including UTX, LFB-R603, and TGTX1101. The maximum daily dose amount is 450 mg, with a maximum total dose amount of 5250 mg over a treatment period of up to 240 weeks. This product is manufactured by TG Therapeutics, Inc.

The comparator treatment fingolimod is provided as a hard capsule for oral administration. The active substance is fingolimod, a chemical compound. The maximum daily dose amount is 0.5 mg, with a maximum total dose amount of 335.5 mg administered over a treatment period of up to 96 weeks. The drug has been overencapsulated to maintain blinding of the study treatment.

A placebo formulation matching ublituximab is utilized in the study to maintain blinding. This placebo is designated as Ublituximab Placebo and contains no active pharmaceutical ingredient.

An additional placebo formulation matching fingolimod is employed in the trial. This placebo is designated as Fingolimod placebo and contains no active pharmaceutical ingredient, serving to preserve the blind for the oral treatment arm.

Efficacy will be assessed in Part A through the evaluation of the percentage of patients achieving CD19+ B cell levels at a defined threshold. In Part B, efficacy assessment will focus on establishing non-inferiority of ublituximab compared with fingolimod in pediatric patients with relapsing forms of multiple sclerosis. Part C will evaluate the long-term efficacy of ublituximab in pediatric participants with relapsing forms of multiple sclerosis. The treatment period extends up to 96 weeks for Part B and up to 240 weeks for the extended treatment phase. CD19+ B cell counts will be measured as part of the pharmacodynamic assessments to evaluate the biological response to treatment. Participants must complete Part A at the Week 24 visit or Part B at the Week 96 visit to be eligible for enrollment in Part C, which will provide extended efficacy data over the long-term treatment period.