- Email: [email protected]
29 Clinical benefit of enzyme replacement therapy (ERT) in mucopolysaccharidosis II (MPS II, Hunter syndrome)
S18
Abstracts / Molecular Genetics and Metabolism 92 (2007) S11–S34
Fabry disease is caused by a cellular deficiency of the lysosomal alpha-galactosidase A. This results in multi-organ dysfunction with neurological disease resulting from a systemic vasculopathy and stroke. A knock-out (KO) mouse model is available for Fabry disease. We hypothesized that enzyme replacement therapy (ERT) acts as a specific alteration of the disease state to reveal novel pathophysiological insight in Fabry disease. Using a combination of gene expression arrays and tandem mass spectrometry (MS–MS) in the KO model and in pediatric patient PBMCs and serum we identified a series of Fabry disease markers including neuronal apoptosis inhibitory protein (NAIP) and alpha-2 antiplasmin. The KO model either treated with and enzyme replacement therapy or not, and wild-type control, followed by examination of gene expression in the heart, aorta and liver and. Such data indicated extensive cellular pathway dysregulation in Fabry. RPGRIP1 was the highest ranked statistically in all three organs and its splice variants responded in a unique way to alpha-galactosidase A. ERT tended to not only normalize gene expression, e.g., reducing the over-expression of securin, but also specifically modified gene expression in each tissue. From significantly expressed and multiple comparison corrected (false discovery rate) genes, correlational expression networks were derived followed by structural equation model (SEM) analysis. This allowed examination of a priori hypotheses concerning the cellular basis of Fabry glycolipidopathy. Utilizing a system biology approach we demonstrate enhanced understanding of Fabry pathophysiology together with a basis for directed therapeutic target selection. doi:10.1016/j.ymgme.2007.08.032
28 Safety and efficacy of laronidase in young, severe patients with mucopolysaccharidosis I Michael Beck a, J.E. Wraith b, R. Lane c, A. van der Ploeg d, E. Shapiro e, N. Guffon f, a University Hospital Mainz, Mainz, Germany, b Manchester, UK, c London, UK, d Rotterdam, The Netherlands, e Minneapolis, USA, f Lyon, France Objective: To evaluate the safety and efficacy of laronidase therapy in young, severely affected patients with mucopolysaccharidosis I (MPS I). Methods: This was a 1-year, open-label study of laronidase in 16 Hurler and 4 Hurler-Scheie patients aged <5 years (mean 2.9) who had not undergone bone marrow transplantation. All patients were to receive weekly infusions of 100 U/kg laronidase. The dose was increased to 200 U/kg in four patients for the last 26 weeks because urinary glycosaminoglycan (uGAG) levels were above 200 mcg/mg creatinine at Week 22. Results: Laronidase was well tolerated at both doses. The majority of adverse events were related to MPS I. Two patients died of laronidaseunrelated causes. Seven patients experienced 33 infusion-associated reactions (e.g., pyrexia, chills) that were mostly mild and easily managed. Pharmacokinetic parameters were similar to those observed in older, attenuated patients studied earlier. All patients developed IgG antibodies to laronidase. uGAG levels declined sharply, and were reduced by 61.3% at Week 52. Robust uGAG reductions occurred in patients with low antibody titers or receiving 200 U/kg. Hepatomegaly substantially improved and left ventricular hypertrophy was less frequent at final visit (from 50% to 15%). Sleep disorders improved/stabilized in 10/15 patients. Cognitive function tests showed improvement in the Hurler-Scheie and younger Hurler patients (<2.5 years). Investigators reported overall clinical status as improved in 17/18 patients. Conclusions: Laronidase was safe and well-tolerated, and showed evidence of clinical benefit in young and severe MPS I patients. doi:10.1016/j.ymgme.2007.08.033
29 Clinical benefit of enzyme replacement therapy (ERT) in mucopolysaccharidosis II (MPS II, Hunter syndrome)
Christine Eng a, J. Muenzer b, E. Wraith c, M. Beck d, R. Giugliani e, P. Harmatz f, A. Vellodi g, R. Martin h, U. Ramaswami i, M. Calikoglu b, S. Vijayaraghavan b, A. Puga e, B. Ulbrich h, M. Shinawi f, M. Cleary f, S. Wendt d, a Baylor College of Medicine, Houston, TX, USA, b University of North Carolina, Chapel Hill, NC, USA, c Royal Manchester Children’s Hospital, MA, UK, d Childrens Hospital University of Mainz, Mainz, Rhineland-Palatinat, Germany, e University of Cincinnati Medical Center, Cinncinati, OH, USA, f Children’s Hospital & Research Center Oakland, Oakland, CA, USA, g Stanford University School of Medicine, Stanford, CA, USA, h Washington University School of Medicine, St. Louis, MO, USA, i Cambridge University Hospitals, Cambridge, UK In this double-blind trial, ERT with idursulfase, produced in genetically engineered human cells, was tested for its ability to improve function in MPS II. Patients (N = 96) were randomized to placebo or idursulfase at a dose of 0.5 mg/kg, IV, administered either weekly or every other week (EOW) for 1 year. After 1 year, patients in the weekly and EOW group exhibited significant improvements compared to placebo in the primary efficacy outcome, a composite endpoint comprising change in percent predicted forced vital capacity (%FVC) and distance walked in 6 min (P = .0049, weekly; P = .0416, EOW). Compared to placebo, the weekly dosing group increased the distance walked by 37 m (P = .0131) and the absolute FVC by 160 mL (P = .0011). Mean responses were meaningfully larger in the weekly vs EOW dosing groups for these and other secondary endpoints. Idursulfase was well tolerated. IgG antibodies were detected in 46.9% of patients in each idursulfase group, but did not appear to influence efficacy of ERT. Two-year safety data will be presented. These results support the use of weekly infusions of idursulfase in the treatment of MPS II. doi:10.1016/j.ymgme.2007.08.034
30 Long term safety and efficacy of enzyme replacement therapy for MPS VI (Maroteaux–Lamy syndrome) Paul Harmatz, Children’s Hospital Oakland, Oakland, CA, USA MPS VI is a rare, life-threatening lysosomal storage disease. ERT has shown positive results in three clinical studies and received FDA approval as galsulfase (NaglazymeÒ). Efficacy and safety will be reported for the Phase 1–3 and Phase 3 Extension study (72–240 weeks on galsulfase) with focus on growth, resolution of pubertal delay, and antibody response to galsulfase. Study updates will be presented for the ongoing Clinical Surveillance Program (CSP) and ASB-008: A Phase 4 Multicenter, Openlabel, Randomized, Two Dose Level Study of NaglazymeÒ (galsulfase) in infants with Maroteaux–Lamy syndrome (MPS VI). Finally, future initiatives including intra-articular Naglazyme to prevent or treat disease in large weight bearing joints and intra-thecal Naglazyme to prevent or treat spinal cord compression will be summarized. doi:10.1016/j.ymgme.2007.08.035
31 Hippocampal functions in MPS I: A pilot study of memory encoding and visual spatial function Elsa Shapiro a, Kendra Bjoraker b, Kate Delaney b, Chester Whitley b, a University of Minnesota, Minneapolis, MN, USA, b Department of Pediatrics Neuropsychological development and brain function in attenuated MPS I, Hurler Scheie and Scheie syndromes, are unknown. A previous clinical study of 4 such patients indicated slow cognitive development, poor memory encoding, and poor visual spatial ability despite ERT. It is not known if the slowed rate is stable or is a signal of adolescent/adult cognitive decline. Previous studies of severe MPS I (Hurler) show cognitive slowing and then decline. With hematopoietic stem cell transplant
Abstracts / Molecular Genetics and Metabolism 92 (2007) S11–S34
Fabry disease is caused by a cellular deficiency of the lysosomal alpha-galactosidase A. This results in multi-organ dysfunction with neurological disease resulting from a systemic vasculopathy and stroke. A knock-out (KO) mouse model is available for Fabry disease. We hypothesized that enzyme replacement therapy (ERT) acts as a specific alteration of the disease state to reveal novel pathophysiological insight in Fabry disease. Using a combination of gene expression arrays and tandem mass spectrometry (MS–MS) in the KO model and in pediatric patient PBMCs and serum we identified a series of Fabry disease markers including neuronal apoptosis inhibitory protein (NAIP) and alpha-2 antiplasmin. The KO model either treated with and enzyme replacement therapy or not, and wild-type control, followed by examination of gene expression in the heart, aorta and liver and. Such data indicated extensive cellular pathway dysregulation in Fabry. RPGRIP1 was the highest ranked statistically in all three organs and its splice variants responded in a unique way to alpha-galactosidase A. ERT tended to not only normalize gene expression, e.g., reducing the over-expression of securin, but also specifically modified gene expression in each tissue. From significantly expressed and multiple comparison corrected (false discovery rate) genes, correlational expression networks were derived followed by structural equation model (SEM) analysis. This allowed examination of a priori hypotheses concerning the cellular basis of Fabry glycolipidopathy. Utilizing a system biology approach we demonstrate enhanced understanding of Fabry pathophysiology together with a basis for directed therapeutic target selection. doi:10.1016/j.ymgme.2007.08.032
28 Safety and efficacy of laronidase in young, severe patients with mucopolysaccharidosis I Michael Beck a, J.E. Wraith b, R. Lane c, A. van der Ploeg d, E. Shapiro e, N. Guffon f, a University Hospital Mainz, Mainz, Germany, b Manchester, UK, c London, UK, d Rotterdam, The Netherlands, e Minneapolis, USA, f Lyon, France Objective: To evaluate the safety and efficacy of laronidase therapy in young, severely affected patients with mucopolysaccharidosis I (MPS I). Methods: This was a 1-year, open-label study of laronidase in 16 Hurler and 4 Hurler-Scheie patients aged <5 years (mean 2.9) who had not undergone bone marrow transplantation. All patients were to receive weekly infusions of 100 U/kg laronidase. The dose was increased to 200 U/kg in four patients for the last 26 weeks because urinary glycosaminoglycan (uGAG) levels were above 200 mcg/mg creatinine at Week 22. Results: Laronidase was well tolerated at both doses. The majority of adverse events were related to MPS I. Two patients died of laronidaseunrelated causes. Seven patients experienced 33 infusion-associated reactions (e.g., pyrexia, chills) that were mostly mild and easily managed. Pharmacokinetic parameters were similar to those observed in older, attenuated patients studied earlier. All patients developed IgG antibodies to laronidase. uGAG levels declined sharply, and were reduced by 61.3% at Week 52. Robust uGAG reductions occurred in patients with low antibody titers or receiving 200 U/kg. Hepatomegaly substantially improved and left ventricular hypertrophy was less frequent at final visit (from 50% to 15%). Sleep disorders improved/stabilized in 10/15 patients. Cognitive function tests showed improvement in the Hurler-Scheie and younger Hurler patients (<2.5 years). Investigators reported overall clinical status as improved in 17/18 patients. Conclusions: Laronidase was safe and well-tolerated, and showed evidence of clinical benefit in young and severe MPS I patients. doi:10.1016/j.ymgme.2007.08.033
29 Clinical benefit of enzyme replacement therapy (ERT) in mucopolysaccharidosis II (MPS II, Hunter syndrome)
Christine Eng a, J. Muenzer b, E. Wraith c, M. Beck d, R. Giugliani e, P. Harmatz f, A. Vellodi g, R. Martin h, U. Ramaswami i, M. Calikoglu b, S. Vijayaraghavan b, A. Puga e, B. Ulbrich h, M. Shinawi f, M. Cleary f, S. Wendt d, a Baylor College of Medicine, Houston, TX, USA, b University of North Carolina, Chapel Hill, NC, USA, c Royal Manchester Children’s Hospital, MA, UK, d Childrens Hospital University of Mainz, Mainz, Rhineland-Palatinat, Germany, e University of Cincinnati Medical Center, Cinncinati, OH, USA, f Children’s Hospital & Research Center Oakland, Oakland, CA, USA, g Stanford University School of Medicine, Stanford, CA, USA, h Washington University School of Medicine, St. Louis, MO, USA, i Cambridge University Hospitals, Cambridge, UK In this double-blind trial, ERT with idursulfase, produced in genetically engineered human cells, was tested for its ability to improve function in MPS II. Patients (N = 96) were randomized to placebo or idursulfase at a dose of 0.5 mg/kg, IV, administered either weekly or every other week (EOW) for 1 year. After 1 year, patients in the weekly and EOW group exhibited significant improvements compared to placebo in the primary efficacy outcome, a composite endpoint comprising change in percent predicted forced vital capacity (%FVC) and distance walked in 6 min (P = .0049, weekly; P = .0416, EOW). Compared to placebo, the weekly dosing group increased the distance walked by 37 m (P = .0131) and the absolute FVC by 160 mL (P = .0011). Mean responses were meaningfully larger in the weekly vs EOW dosing groups for these and other secondary endpoints. Idursulfase was well tolerated. IgG antibodies were detected in 46.9% of patients in each idursulfase group, but did not appear to influence efficacy of ERT. Two-year safety data will be presented. These results support the use of weekly infusions of idursulfase in the treatment of MPS II. doi:10.1016/j.ymgme.2007.08.034
30 Long term safety and efficacy of enzyme replacement therapy for MPS VI (Maroteaux–Lamy syndrome) Paul Harmatz, Children’s Hospital Oakland, Oakland, CA, USA MPS VI is a rare, life-threatening lysosomal storage disease. ERT has shown positive results in three clinical studies and received FDA approval as galsulfase (NaglazymeÒ). Efficacy and safety will be reported for the Phase 1–3 and Phase 3 Extension study (72–240 weeks on galsulfase) with focus on growth, resolution of pubertal delay, and antibody response to galsulfase. Study updates will be presented for the ongoing Clinical Surveillance Program (CSP) and ASB-008: A Phase 4 Multicenter, Openlabel, Randomized, Two Dose Level Study of NaglazymeÒ (galsulfase) in infants with Maroteaux–Lamy syndrome (MPS VI). Finally, future initiatives including intra-articular Naglazyme to prevent or treat disease in large weight bearing joints and intra-thecal Naglazyme to prevent or treat spinal cord compression will be summarized. doi:10.1016/j.ymgme.2007.08.035
31 Hippocampal functions in MPS I: A pilot study of memory encoding and visual spatial function Elsa Shapiro a, Kendra Bjoraker b, Kate Delaney b, Chester Whitley b, a University of Minnesota, Minneapolis, MN, USA, b Department of Pediatrics Neuropsychological development and brain function in attenuated MPS I, Hurler Scheie and Scheie syndromes, are unknown. A previous clinical study of 4 such patients indicated slow cognitive development, poor memory encoding, and poor visual spatial ability despite ERT. It is not known if the slowed rate is stable or is a signal of adolescent/adult cognitive decline. Previous studies of severe MPS I (Hurler) show cognitive slowing and then decline. With hematopoietic stem cell transplant