An Open-Label Phase II Feasibility Study for the Use of Ublituximab in Adults With Down Syndrome Regression Disorder

An Open-Label Phase II Feasibility Study for the Use of Ublituximab in Adults With Down Syndrome Regression Disorder

The goal of this clinical trial is to evaluate whether the monoclonal antibody ublituximab can treat Down Syndrome Regression Disorder (DSRD) by assessing its safety, tolerability, and preliminary efficacy in affected individuals. This study is conducted in adults aged 18-40 years with Down syndrome who have DSRD and have had an inadequate or partial response to first-line therapies.

The main questions it aims to answer are:

• Does ublituximab demonstrate acceptable safety and tolerability, as measured by treatment-emergent adverse events from baseline through Week 24?
• Does ublituximab lead to improvement in cognitive, neuropsychiatric, motor, and functional outcomes from baseline to Weeks 12 and 24?

This is a single-arm study, so there is no comparison group.

Participants will:

• Receive two intravenous infusions of ublituximab (150 mg on Day 1 and 450 mg on Day 15)
• Attend study visits at Screening, Baseline (Day 1) , Week 2 (Day 15), Week 3, Week 6, Week 12, and Week 24
• Undergo clinical assessments, including neurological and physical exams and safety monitoring labs throughout the study
• Complete cognitive, behavioral, and functional evaluations at Baseline, Week 12, and Week 24
• Provide blood samples for safety monitoring and research biomarker analyses

Inclusion Criteria:

• Age 18 to 40 years, inclusive at time of consent
• Diagnosis of Down syndrome (trisomy 21 or translocation type)
• Diagnosis of possible or probable Down Syndrome Regression Disorder (DSRD) based on 2022 International Consensus Criteria
• History of partial response or non-response to first-line treatment (e.g., lorazepam, SSRIs, corticosteroids, and/or IVIg). Partial response = 10-50% improvement, Non-response = <10% improvement, Based on BFCRS or NPI-Q after 3 months of treatment.
• Ability to attend all study visits with a study partner or legally authorized representative
• Study partner willing to comply with all study procedures
• Willingness to complete required washout periods for medications that may interfere with the study
• Highly effective contraception for reproductive participants and partners of childbearing potential.
• Study partner/LAR sufficiently proficient in English to complete assessments.

Exclusion Criteria:

• Mosaic Down syndrome
• Weight < 40 kg at screening
• Pregnancy or breastfeeding
• Current or past tobacco smoking
• Poor venous access or inability to comply with IV procedures
• Use of IVIg within 8 weeks prior to baseline
• Use of immunosuppressive drugs within 12 weeks prior to baseline
• Prior treatment with anti-CD20 or B-cell therapies within required washout unless B-cell recovery criteria are met
• Other immunosuppressive biologics within 24 months.
• Any prior use of chemotherapeutic agents (e.g., methotrexate, cyclophosphamide)
• History of solid organ transplant
• Recent receipt of blood or plasma products (≤30 days)
• Clinically significant cardiac disease, clotting disorder, or other serious medical condition
• Active or chronic infection of clinical significance (including HBV, HCV, TB, HIV per protocol criteria)
• History of malignancy
• Abnormal screening labs indicating unacceptable risk
• Receipt of live or live-attenuated vaccines within 4 weeks prior to treatment
• Untreated thyroid disease (hypo- or hyperthyroidism)
• History of moyamoya syndrome or stroke
• Wards of the state
• Employees or students of Children's Hospital Los Angeles (CHLA)
• Prior neurosurgical intervention (exceptions for longstanding shunts)
• Current investigational therapy/prohibited medications
• Detailed HBV, HCV, and TB criteria
• Requirement for B-cell recovery >50 cells/μL after prior anti-CD20 therapy.