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Treatment with pentosan polysulphate in patients with mucopolysaccharidosis type I: Results from an open label, randomized, monocentric phase 2 study
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Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
pathological and behavioral abnormalities, but structural characterization of brain anomalies by neuroimaging has never been conducted. Neuroimaging results of several patients demonstrated that severe cortical atrophy, white matter lesions, and hydrocephalus were common features of the disease. We performed murine magnetic resonance imaging (MRI) studies in order to form corollaries between neuroimaging findings in humans with MPS IIIB and the current mouse model. We conducted MRI in MPS IIIB mice in a cross-sectional, age dependent manner, in order to observe the effect of age on disease progression. Animals were imaged at 3, 6 and 9 months using a gadolinium based contrast agent. T2 weighted images revealed the presence of significant fluid filled regions in the caudate putamen and ventricular spaces of MPS IIIB animals by the age of 6 months, which persisted through nine months. Most changes were observed in the mid- to hindbrain regions primarily in the caudate putamen with mild cortical involvement. T1 weighted images revealed changes in BBB permeability as indicated by a marked increase of the contrast agent extrusion into the CNS in the MPS IIIB animals compared to unaffected Control animals. Evans Blue dye quantitation also revealed significant differences in the amount of dye extrusion into the brain parenchyma of MPS IIIB compared to Control mice which again became evident by six months and persisted through nine months. Our data revealed age dependent differences in CNS pathology and blood brain permeability. Similarly, the human disease displayed increased fluid filled regions. Interestingly, the severe cortical atrophy associated with the human condition was not recapitulated in the murine model regardless of age. doi:10.1016/j.ymgme.2015.12.286
129 Impact of long-term elosulfase alfa treatment on pulmonary function in patients with Morquio syndrome type A Christian J. Hendriksza, Barbara K. Burtonb, Moeen D. AlSayedc, Roberto Giuglianid, Norberto Guelberte, Derralyn Hughesf, Matthew Mealiffeg, John J. Mitchellh, Rossella Parinii, Julian Raimanj, Adam J. Shaywitzg, Peter Slasorg, Martha L. Solano Villarrealk, Fiona Stewartl, Kenneth I. Bergerm, Paul R. Harmatzn, aSalford Royal Foundation NHS Trust, Salford, United Kingdom, bLurie Children’s Hospital & Northwestern University Feinberg School of Medicine, Chicago, IL, United States, c King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia, d Hospital de Clinicas de Porto Alegre, UFRGS & INAGEMP, Porto Alegre, Brazil, eHospital de Niños de Cordoba, Cordoba, Argentina, fRoyal Free London NHS Foundation Trust & UC, London, United Kingdom, gBioMarin Pharmaceutical Inc., Novato, CA, United States, hMontreal Children’s Hospital, Montreal, QC, Canada, iAzienda Ospedaliera San Gerardo, Monza, Italy, jHospital for Sick Children, Toronto, ON, Canada, kFundation l Cardioimfantil, Bogotá, Colombia, Belfast City Hospital, Belfast, NI, m United Kingdom, New York University School of Medicine, New York, NY, United States, nUCSF Benioff Children’s Hospital Oakland, Oakland, CA, United States We present long-term pulmonary function test outcomes from an ongoing, open-label, multi-center, phase 3 extension study assessing the long-term safety and efficacy of elosulfase alfa enzyme replacement therapy (ERT) in patients with Morquio syndrome type A. In part 1 of the extension study, patients who were initially randomized to ERT in the original placebo-controlled 24-week study [1] remained on their regimen (2.0 mg/kg/week or every other week); placebo patients were re-randomized to one of the two treatment regimens. During part 2, all patients received ERT 2.0 mg/kg/week. Pulmonary function was evaluated as a secondary efficacy endpoint. Changes from the original 24-week study [1] baseline to 72 and 120 weeks are
presented. In the 24-week study, non-statistical increases were seen in each dosing group for forced vital capacity (FVC) and maximum voluntary ventilation (MVV) versus placebo [1] and both endpoints continued to improve for the combined patient population during the extension study for up to 120 weeks. MVV increased from baseline by a mean (SE) of 1.78 (0.74) L/min by week 72 and 1.80 (1.04) L/min or 11.04 (4.55) % by week 120. FVC increased from baseline by a mean (SE) of 0.05 (0.01) L by week 72 and 0.08 (0.02) L or 8.6 (1.8) % by week 120. In contrast, matched untreated patients from the MorCAP natural history study [2] showed mean decreases in MVV and FVC over 2 years. In conclusion, long-term ERT causes sustained improvements in pulmonary function in patients with Morquio syndrome type A. References: 1. Hendriksz CJ, Burton B, Fleming TR, et al. J Inherit Metab Dis 2014;37:979-90. 2. Harmatz P, Mengel KE, Giugliani R, et al. Mol Genet Metab 2013;109:54-61. BioMarin Pharmaceutical Inc. sponsored this study.
doi:10.1016/j.ymgme.2015.12.287
130 Treatment with pentosan polysulphate in patients with mucopolysaccharidosis type I: Results from an open label, randomized, monocentric phase 2 study Julia B. Hennermanna, Seyfullah Goekcea, Alexander Solyomb,c, Eugen Mengela, Edward H. Schuchmand, Calogera M. Simonarod, aUniversity Medical Center Mainz, Mainz, Germany, bUniversity of Pecs, Pecs, Hungary, cPlexcera Therapeutics, New York, NY, United States, dIcahn School of Medicine at Mount Sinai, New York, NY, United States Current treatment options for MPS I have limited effects on some organ systems, including the skeletal system. In MPS animal models pentosan polysulphate (PPS) reduces inflammatory markers and glycosaminoglycans (GAG) in tissues and body fluids and improves cartilaginous and osseous pathologies. The goals of this study were to investigate primarily the safety and secondary the clinical effects of PPS treatment in MPS I patients. Four MPS I, i.e., Hurler-Scheie syndrome and Scheie syndrome patients aged 35.6 ± 6.4 years with one male were included in the study. All patients were on enzyme replacement therapy since 9.45 ± 3.75 years. PPS was applied subcutaneously with 1 mg/kg and 2 mg/kg, respectively, weekly for 12 weeks and then biweekly for 12 weeks. The 24-week treatment with PPS was well tolerated by all patients. Laboratory results revealed no signs of hepatopathy or abnormal anticoagulation. Patients receiving 2 mg/kg PPS had higher values for aPTT and INR, as these patients were on additional treatment with phenprocoumon. Urinary GAG concentrations were reduced from 4.13 ± 1.17 mg/mmol at baseline to 2.69 ± 0.36 mg/mmol after 24-week treatment with 1 mg/kg PPS, and from 6.71 ± 0.62 mg/mmol to 2.65 ± 0.09 mg/mmol after 24-week treatment with 2 mg/kg PPS. The pain intensity score was reduced from 4.5 ± 1.77 at baseline to 1.8 ± 0.47 after 24-week treatment with 1 mg/kg PPS; patients with 2 mg/kg PPS had already minimal pain at start of the study (baseline: 2.0 ± 0.35, after 24-week treatment: 1.9 ± 1.59). An improvement in range of motion (ROM) of the lower limbs was noted in 3 out of 4 patients, and an improvement in foot ROM in 1 patient. In conclusion, PPS treatment in a small number of adult patients with MPS I was well tolerated and resulted in clinical significant improvements in GAG excretion, pain intensity and ROM. Therefore, we conclude that PPS may be an effective treatment in MPS I and also other MPS forms.
doi:10.1016/j.ymgme.2015.12.288
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
pathological and behavioral abnormalities, but structural characterization of brain anomalies by neuroimaging has never been conducted. Neuroimaging results of several patients demonstrated that severe cortical atrophy, white matter lesions, and hydrocephalus were common features of the disease. We performed murine magnetic resonance imaging (MRI) studies in order to form corollaries between neuroimaging findings in humans with MPS IIIB and the current mouse model. We conducted MRI in MPS IIIB mice in a cross-sectional, age dependent manner, in order to observe the effect of age on disease progression. Animals were imaged at 3, 6 and 9 months using a gadolinium based contrast agent. T2 weighted images revealed the presence of significant fluid filled regions in the caudate putamen and ventricular spaces of MPS IIIB animals by the age of 6 months, which persisted through nine months. Most changes were observed in the mid- to hindbrain regions primarily in the caudate putamen with mild cortical involvement. T1 weighted images revealed changes in BBB permeability as indicated by a marked increase of the contrast agent extrusion into the CNS in the MPS IIIB animals compared to unaffected Control animals. Evans Blue dye quantitation also revealed significant differences in the amount of dye extrusion into the brain parenchyma of MPS IIIB compared to Control mice which again became evident by six months and persisted through nine months. Our data revealed age dependent differences in CNS pathology and blood brain permeability. Similarly, the human disease displayed increased fluid filled regions. Interestingly, the severe cortical atrophy associated with the human condition was not recapitulated in the murine model regardless of age. doi:10.1016/j.ymgme.2015.12.286
129 Impact of long-term elosulfase alfa treatment on pulmonary function in patients with Morquio syndrome type A Christian J. Hendriksza, Barbara K. Burtonb, Moeen D. AlSayedc, Roberto Giuglianid, Norberto Guelberte, Derralyn Hughesf, Matthew Mealiffeg, John J. Mitchellh, Rossella Parinii, Julian Raimanj, Adam J. Shaywitzg, Peter Slasorg, Martha L. Solano Villarrealk, Fiona Stewartl, Kenneth I. Bergerm, Paul R. Harmatzn, aSalford Royal Foundation NHS Trust, Salford, United Kingdom, bLurie Children’s Hospital & Northwestern University Feinberg School of Medicine, Chicago, IL, United States, c King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia, d Hospital de Clinicas de Porto Alegre, UFRGS & INAGEMP, Porto Alegre, Brazil, eHospital de Niños de Cordoba, Cordoba, Argentina, fRoyal Free London NHS Foundation Trust & UC, London, United Kingdom, gBioMarin Pharmaceutical Inc., Novato, CA, United States, hMontreal Children’s Hospital, Montreal, QC, Canada, iAzienda Ospedaliera San Gerardo, Monza, Italy, jHospital for Sick Children, Toronto, ON, Canada, kFundation l Cardioimfantil, Bogotá, Colombia, Belfast City Hospital, Belfast, NI, m United Kingdom, New York University School of Medicine, New York, NY, United States, nUCSF Benioff Children’s Hospital Oakland, Oakland, CA, United States We present long-term pulmonary function test outcomes from an ongoing, open-label, multi-center, phase 3 extension study assessing the long-term safety and efficacy of elosulfase alfa enzyme replacement therapy (ERT) in patients with Morquio syndrome type A. In part 1 of the extension study, patients who were initially randomized to ERT in the original placebo-controlled 24-week study [1] remained on their regimen (2.0 mg/kg/week or every other week); placebo patients were re-randomized to one of the two treatment regimens. During part 2, all patients received ERT 2.0 mg/kg/week. Pulmonary function was evaluated as a secondary efficacy endpoint. Changes from the original 24-week study [1] baseline to 72 and 120 weeks are
presented. In the 24-week study, non-statistical increases were seen in each dosing group for forced vital capacity (FVC) and maximum voluntary ventilation (MVV) versus placebo [1] and both endpoints continued to improve for the combined patient population during the extension study for up to 120 weeks. MVV increased from baseline by a mean (SE) of 1.78 (0.74) L/min by week 72 and 1.80 (1.04) L/min or 11.04 (4.55) % by week 120. FVC increased from baseline by a mean (SE) of 0.05 (0.01) L by week 72 and 0.08 (0.02) L or 8.6 (1.8) % by week 120. In contrast, matched untreated patients from the MorCAP natural history study [2] showed mean decreases in MVV and FVC over 2 years. In conclusion, long-term ERT causes sustained improvements in pulmonary function in patients with Morquio syndrome type A. References: 1. Hendriksz CJ, Burton B, Fleming TR, et al. J Inherit Metab Dis 2014;37:979-90. 2. Harmatz P, Mengel KE, Giugliani R, et al. Mol Genet Metab 2013;109:54-61. BioMarin Pharmaceutical Inc. sponsored this study.
doi:10.1016/j.ymgme.2015.12.287
130 Treatment with pentosan polysulphate in patients with mucopolysaccharidosis type I: Results from an open label, randomized, monocentric phase 2 study Julia B. Hennermanna, Seyfullah Goekcea, Alexander Solyomb,c, Eugen Mengela, Edward H. Schuchmand, Calogera M. Simonarod, aUniversity Medical Center Mainz, Mainz, Germany, bUniversity of Pecs, Pecs, Hungary, cPlexcera Therapeutics, New York, NY, United States, dIcahn School of Medicine at Mount Sinai, New York, NY, United States Current treatment options for MPS I have limited effects on some organ systems, including the skeletal system. In MPS animal models pentosan polysulphate (PPS) reduces inflammatory markers and glycosaminoglycans (GAG) in tissues and body fluids and improves cartilaginous and osseous pathologies. The goals of this study were to investigate primarily the safety and secondary the clinical effects of PPS treatment in MPS I patients. Four MPS I, i.e., Hurler-Scheie syndrome and Scheie syndrome patients aged 35.6 ± 6.4 years with one male were included in the study. All patients were on enzyme replacement therapy since 9.45 ± 3.75 years. PPS was applied subcutaneously with 1 mg/kg and 2 mg/kg, respectively, weekly for 12 weeks and then biweekly for 12 weeks. The 24-week treatment with PPS was well tolerated by all patients. Laboratory results revealed no signs of hepatopathy or abnormal anticoagulation. Patients receiving 2 mg/kg PPS had higher values for aPTT and INR, as these patients were on additional treatment with phenprocoumon. Urinary GAG concentrations were reduced from 4.13 ± 1.17 mg/mmol at baseline to 2.69 ± 0.36 mg/mmol after 24-week treatment with 1 mg/kg PPS, and from 6.71 ± 0.62 mg/mmol to 2.65 ± 0.09 mg/mmol after 24-week treatment with 2 mg/kg PPS. The pain intensity score was reduced from 4.5 ± 1.77 at baseline to 1.8 ± 0.47 after 24-week treatment with 1 mg/kg PPS; patients with 2 mg/kg PPS had already minimal pain at start of the study (baseline: 2.0 ± 0.35, after 24-week treatment: 1.9 ± 1.59). An improvement in range of motion (ROM) of the lower limbs was noted in 3 out of 4 patients, and an improvement in foot ROM in 1 patient. In conclusion, PPS treatment in a small number of adult patients with MPS I was well tolerated and resulted in clinical significant improvements in GAG excretion, pain intensity and ROM. Therefore, we conclude that PPS may be an effective treatment in MPS I and also other MPS forms.
doi:10.1016/j.ymgme.2015.12.288