Open-Label Extension Study Evaluating Long-Term Safety and Efficacy of Ublituximab in Patients with Relapsing Multiple Sclerosis

The primary objective of this study is to evaluate the long-term **safety** and **efficacy** of ublituximab therapy in subjects with **relapsing multiple sclerosis**. This is clinically relevant as it aims to determine the sustained therapeutic benefits and potential adverse effects of ublituximab, a monoclonal antibody targeting CD20, in managing this chronic neurological condition. Understanding the long-term impact of this treatment is crucial for optimizing patient outcomes and guiding clinical decision-making in the management of relapsing multiple sclerosis.

The clinical trial involves a total of **742 participants** diagnosed with **relapsing multiple sclerosis**. The study population includes both male and female subjects, with an age range of 18 to 65 years. Participants were selected based on their completion of specific prior studies, such as the 96-week double-blind TG1101-RMS301 or TG1101-RMS302 study, or the final Week 208 visit of the TG1101-RMS201E study. The trial includes individuals who are considered part of a vulnerable population. Participants are required to be in a general health status that allows them to comply with the study protocol and provide informed consent. Lifestyle considerations such as diet, physical activity, or habits are not specified. The trial aims to evaluate the long-term safety and efficacy of ublituximab therapy in this population.

The clinical trial is designed to evaluate the long-term safety and efficacy of **ublituximab** in subjects with **relapsing multiple sclerosis**. This is a phase 3, open-label extension study, following the completion of prior studies TG1101-RMS301, TG1101-RMS302, or TG1101-RMS201E. The trial employs a non-randomized, open-label design, allowing all eligible participants to receive the investigational product. The study is expected to conclude by September 2027, with recruitment having commenced in June 2020. Participants will be involved in the study for a maximum treatment period of 312 weeks, receiving **ublituximab** via intravenous infusion.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as completion of prior studies and the investigator's assessment of potential benefit from **ublituximab** treatment. Participants must provide written informed consent and agree to comply with the study protocol. Female participants of child-bearing potential and their male partners must consent to use medically acceptable contraception methods. Follow-up visits will occur at regular intervals to assess primary endpoints, including annualized relapse rate, MRI parameters, disability progression, and safety endpoints. These visits will also monitor for any adverse events using the NCI CTCAE v.5.0 grading system.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the long-term impact of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial aims to provide valuable insights into the sustained effects of **ublituximab** on disease activity and progression in individuals with **relapsing multiple sclerosis**.

The clinical trial involves the administration of **ublituximab**, a recombinant chimeric monoclonal antibody targeting CD20, used in the treatment of relapsing forms of multiple sclerosis. Ublituximab is provided as a **concentrate for solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose of ublituximab is 450 mg, with a total maximum dose of 6450 mg over the course of the treatment period, which spans up to 312 days. The pharmaceutical form is specifically designed for infusion, ensuring precise delivery of the active substance. The administration schedule is determined by the study protocol, and compliance is monitored through regular assessments.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The focus remains solely on evaluating the long-term safety and efficacy of ublituximab. Participant compliance is monitored through scheduled visits and assessments to ensure adherence to the dosing regimen and to evaluate the therapeutic outcomes. The study is conducted under the sponsorship of TG Therapeutics, Inc., and the product is identified by the sponsor product code TG-1101.

Efficacy in the clinical trial of ublituximab for **Relapsing Multiple Sclerosis** will be assessed using several primary endpoints. These include the Annualized Relapse Rate (ARR), which is calculated as the number of relapses per subject year, and various MRI parameters such as T1 gadolinium-enhancing lesions, T1 hypointense lesions, T2 lesions, and brain atrophy. Disability progression and improvement will be evaluated through 24-week Confirmed Disability Progression (CDP) and 24-week Confirmed Disability Improvement (CDI), along with the mean change from baseline in the Expanded Disability Status Scale (EDSS) score. The trial will also assess No Evidence of Disease Activity (NEDA), defined as the absence of relapses, MRI activity, and 24-week confirmed disability progression, with the percentage of subjects achieving NEDA being recorded.

Cognition and function will be measured using the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Functional Composite (MSFC), respectively. Safety endpoints will include the reporting and evaluation of all adverse events (AEs) during the treatment period, using the NCI CTCAE v.5.0 grading system. This will encompass the number and severity of infusion-associated events, infectious AEs, and any clinically significant changes in laboratory or vital sign measurements, as well as the incidence of anti-drug antibodies. The trial is designed to provide comprehensive data on the long-term safety and efficacy of ublituximab in subjects with relapsing forms of multiple sclerosis.