P129: Clinical trial–ready outcomes in MED13L syndrome: Baseline results from a prospective natural history study*

Introduction: Tividenofusp alfa is an investigational iduronate-2-sulfatase fusion protein engineered for CNS and peripheral delivery to address cognitive, behavioral, and somatic disease control in mucopolysaccharidosis type II (MPS II; OMIM 309900).Methods: A single-arm, 24-week, Phase 1/2 study (NCT04251026) with treatment extension enrolled males 18 years with MPS II.Participants received intravenous tividenofusp alfa 15mg/kg weekly with/without dose escalation.Assessments included safety, biomarkers (cerebrospinal fluid [CSF] and urine heparan sulfate [HS], serum neurofilament light chain [sNfL]), hearing, liver volume, cognition (BSID-III), and adaptive behavior (Vineland-3).Safety and efficacy results are reported as of March 28, 2025, with median safety follow-up of 2.6 years.Results: Participants (N=47) ranged from 0.3-12.6years.93.6% were neuronopathic; ~70% had prior enzyme replacement therapy.The most frequently reported treatment-emergent adverse events (TEAEs) were infusion-related reactions (IRRs), occurring in 87.2% of participants; IRRs were generally manageable with standard-of-care pre-medications and declined over time.From baseline, geometric mean CSF HS and urine HS decreased 91.4% and 88.0%, respectively (Week 24), with normalization achieved and maintained in most participants.Geometric mean sNfL, a marker of neuronal damage, decreased 22.8% (Week 49) and 70.0%(Week 104) and normalized in most participants.Mean pure tone average hearing thresholds improved 9.4 dB (Week 24) and 11.4 dB (Week 104).Mean BSID-III cognitive raw score and Vineland-3 adaptive behavior raw composite appeared to increase from baseline to Week 49 and remained higher over time.Conclusion: Tividenofusp alfa treatment was associated with IRRs, a known risk of enzyme replacement therapies.Treatment with tividenofusp alfa reduced CNS and peripheral biomarkers of substrate accumulation and neuronal injury to levels within the range of unaffected children in most patients.Clinical end points also improved.Tividenofusp alfa has the potential to address CNS and somatic manifestations of MPS II.