Impact of elosulfase alfa in patients with Morquio syndrome type A who have limited ambulation: An open-label, phase 2 study

Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124

n = 10). The primary endpoints included GAA activity and glycogen content in the tissues, antibody formation, and muscle function. GAA activity was increased and glycogen content was reduced in the heart and skeletal muscles. The AAV-treated mice showed a significantly higher GAA activity in the liver, in comparison with ERT. Both treatments significantly reduced glycogen content of the heart and diaphragm. While ERT provoked anti-GAA antibody formation, there was no detectable antibody response following AAV vector administration. The gastrocnemius mass increased significantly (p b 0.01) by 16% following AAV treatment, and was not increased by ERT. Furthermore, a 40-fold reduced dose of AAV prevented the antibody response against subsequent ERT, demonstrating the use of very low dose gene therapy for immune tolerance induction. Low dose AAV2/8LSPhGAApA could improve the response of patients to subsequent ERT by preventing antibody formation, which would provide a benefit in early phase clinical trials of gene therapy. Gene therapy with AAV2/8LSPhGAApA would increase GAA activity and diminish glycogen buildup in muscle, as well suppressing antibody responses, thereby comparing favorably with ERT in Pompe disease. doi:10.1016/j.ymgme.2015.12.283

126 Impact of elosulfase alfa in patients with Morquio syndrome type A who have limited ambulation: An open-label, phase 2 study Paul R. Harmatza, Andrea Jesterb, Eugen Mengelc, Marsha Treadwella, Barbara K. Burtond, Kenneth I. Bergere, Christian J. Hendrikszf, Tarekegn Geberhiwotg, Zlatko Sisich, Celeste Deckeri, aUCSF Benioff Children's Hospital Oakland, Oakland, CA, United States, bBirmingham Children’s Hospital, Birmingham, United Kingdom, cMainz Medical University, Mainz, Germany, dLurie Children’s Hospital & Northwestern University Feinberg School of Medicine, Chicago, IL, United States, eNew York University School of Medicine, New York, NY, United States, fSalford Royal Foundation NHS Trust, Salford, United Kingdom, gNew Queen Elizabeth Hospital, Birmingham, United Kingdom, hBioMarin Europe Limited, Dublin, Ireland, iBioMarin Pharmaceutical Inc., Novato, CA, United States An open-label, phase 2, multinational study was performed to evaluate efficacy and safety of elosulfase alfa enzyme replacement therapy (ERT) in patients with Morquio syndrome type A aged ≥ 5 years who have limited ambulation (inability to walk ≥30 meters in the 6minute walk test). Patients received elosulfase alfa 2.0 mg/kg/week for 48 weeks. Primary efficacy measures were functional dexterity, pinch/ grip strength, mobility in a modified timed 25-foot walk (mT25FW, in which patients were allowed to crawl, roll, walk on knees), pain, and quality of life. Safety/tolerability of elosulfase alfa was also assessed. Sixteen patients were enrolled; 15 (9.8-42.4 years) received elosulfase alfa, and 12 completed treatment through 48 weeks. All patients had very poor upper extremity function and mobility. Seven patients were unable or refused (e.g. due to pain) to perform the mT25FW. The mT25FW results improved versus baseline in 6 patients and remained stable in 1 patient; 1 patient refused to repeat the test. Other test outcomes varied considerably between patients. This was most likely due to a variety of factors including clinical heterogeneity among patients, difficulties associated with travel to and from testing sites, and challenges with test execution in this severely affected population. Nevertheless, patients who did not show improvements in physical tests mostly indicated improvements in other disease aspects, such as increased energy or better ability to type, lift a cup, comb hair, or stand up without braces. The nature of adverse events (AE) was generally similar to other studies with elosulfase alfa, with the majority of subjects experiencing AE limited to mild or moderate severity. Overall,

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this study demonstrates the considerable challenges in objectively measuring impact of ERT in this very disabled patient population. However, despite their severe impairments, most patients reported subjective benefits from elosulfase alfa ERT. BioMarin Pharmaceutical Inc. sponsored this study. doi:10.1016/j.ymgme.2015.12.284

127 Comparison of echocardiography and cardiac magnetic resonance imaging in the determination of left ventricular mass index in Fabry disease Hassan Hazaria, Israel Belenkiea, Albert Kryskia, James Whitea, Gavin Ouditb, Richard Thompsonb, Tak Funga, Navdeep Dehara, Aneal Khana, a University of Calgary, Calgary, AB, Canada, bUniversity of Alberta, Edmonton, AB, Canada The most common assessment of cardiac involvement in Fabry disease is the left ventricular mass index (LVMI). At clinics in Calgary and Edmonton, patients with Fabry disease have been evaluated using both 2-dimensional transthoracic echocardiography (ECHO), cardiac magnetic resonance imaging (CMR) and significant discrepancies have been noted in the LVMI determination. We therefore did a retrospective review to compare how close the LVMI compare using either technique. Out of 73 patients, 32 had both CMR and ECHO LVMI measurements within a 6 month period. The mean age was 44.3 years (range 17.5-71.0 years) and 47% were male. Eighteen of these patients had sequential LVMI measurements over time. ECHO-derived LVMI was calculated using the American Society of Echocardiography (ASE) formula. CMR LVMI was measured in short-axis. Cross sectional analysis showed that mean ECHO LVMI (97.8 g/m2; SD = 26 g/m2) was greater than CMR LVMI (78.0 g/m2; SD = 22 g/m2) by 25.4% and 95% limits of agreement were computed using Bland-Altman analysis (-15.0, 54.5 g/m2). To account for variability over time within each subject, data were analyzed by generalized estimating equations (GEE), which also revealed a significant difference between LVMI calculated by CMR versus ECHO (p b 0.0001). Our data show that there can be substantial inconsistencies when LVMI is determined using echocardiography. An increased LVMI or a significant interval change can be an indication to start enzyme replacement therapy and is the primary index used to judge the cardiac response to therapy. Echocardiography, which relies on linear measurements and the geometric assumption of the left ventricle as a prolate ellipsoid, may not accurately estimate LV mass with asymmetric regional hypertrophy, as in Fabry disease. We propose that for therapeutic purposes, the CMR should be the preferred imaging method to determine LVMI in Fabry disease. doi:10.1016/j.ymgme.2015.12.285

128 MRI findings reveal corollaries in brain pathology between murine and human MPS IIIB brains Coy Heldermon, Janine Gilkes, University of Florida, Gainesville, FL, United States Mucopolysaccharidoses IIIB (MPS IIIB), is an autosomal recessive lysosomal disease caused by defective production of the enzyme α-Nacetylglucosaminidase causing severe central nervous system (CNS) pathology. The mouse model recapitulates many of the biochemical,