P027: Genetic landscape of ALPL and other genes impacting alkaline phosphatase variation in the UK Biobank

Introduction: Tividenofusp alfa is an investigational iduronate-2-sulfatase fusion protein engineered for CNS delivery to address cognitive and behavioral decline in mucopolysaccharidosis type II (MPS II; OMIM 309900) while optimizing somatic disease control.Methods: A single-arm, 24-week, phase 1/2 study (NCT04251026) with extension enrolled males 18 years with MPS II.Participants received 15 mg/kg tividenofusp alfa with or without prior dose escalation via weekly intravenous infusion.Biomarker endpoints included cerebrospinal fluid (CSF) heparan sulfate (HS), serum neurofilament light chain (NfL), and urine HS.Clinical endpoints included safety assessment, cognitive measures (Bayley Scales of Infant and Toddler Development, third edition [BSID-III]/Kaufman Assessment Battery for Children, second edition [KABC-II]), adaptive behavior, auditory brainstem responses, and abdominal imaging.Interim data from 1 March 2024, except serum NfL and urine HS (1 September 2023 cutoff), are summarized.Results: Participants (N=43) had a median (range) age of 4.7 (0.3-12.6) years; 93.0% were neuronopathic and 65.1% had prior enzyme replacement therapy (ERT).As expected for ERT, a majority reported infusion-related reactions, which were manageable and decreased in frequency over time.Mean CSF HS was reduced 90.9% from baseline to Week 24; reductions were sustained through Weeks 49 (-90.4%),104 (-91.1%) and 153 (-89.3%),all p<0.0001, most below the upper limit of the normal range.Mean urine HS was reduced 84.6% from baseline to Week 24; reductions were sustained through Weeks 49 (-86.5%),104 (-78.2%) and 129 (-80.1%),all p<0.0001.Serum NfL (geometric mean) was significantly reduced by Week 61 (-41.1%), with further reduction at Weeks 104 (-70.4%) and 129 (-81.5%;all within normal range), all p0.0001.As of the last visit, 67.6% of participants had improved/unchanged cognitive (BSID-III/ KABC-II) age equivalent scores relative to baseline, including nearly all participants aged <4 years at treatment initiation.Updated results will be presented.Conclusion: Treatment with tividenofusp alfa was well tolerated, resulted in substantial sustained reductions in CSF and urine HS, lowered serum NfL, and improved or unchanged cognitive (BSID-III/KABC-II) age equivalent scores in males 18 years with MPS II.