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Longitudinal data from the international registry for Niemann-Pick disease type C (NPC)
Abstracts
the iN cells to investigate potential neurologically relevant pathogenic cascades related to the neuropathic form of MPS II. doi:10.1016/j.ymgme.2013.12.202
191 Longitudinal data from the international registry for Niemann-Pick disease type C (NPC) Marc C. Pattersona, Eugen Mengelb, Frits A. Wijburgc, Marie T. Vanierd, Barbara Schwierine, Audrey Mullere, Harir Drevonf, Merce Pinedag, a Mayo Clinic, Rochester, MN, USA, bVilla Metabolica, University of Mainz, Mainz, Germany, cAcademic Medical Centre, University of Amsterdam, Amsterdam, Netherlands, dINSERM Unit 820, Lyon, France, eActelion Pharmaceuticals Ltd, Allschwil, Switzerland, fNumerus Ltd, Sandhurst, UK, g Hospital Sant Joan de Déu, Barcelona, Spain The international NPC Registry was initiated to evaluate the longterm disease course of NPC in clinical practice. We present data collected between September 2009 and August 2012 for patients who received miglustat continuously between enrolment and last follow-up visit. Patient demographics, disease characteristics and treatment data were collected, and disability status was evaluated using a scale that rated ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Patients were categorised as ‘improved/stable’ if ≥3 out of these 4 domain scores were lower or unchanged between enrolment and last follow-up visit, or as ‘progressed’ if b3 domain scores were lower or unchanged. Overall, 80/190 enrolled patients (mean [SD] age at enrolment 17.8 [11.5] years; 52.5% female) received miglustat continuously throughout the observation period. Mean (SD) exposure was 1.19 (0.69) years. Among 74/80 patients with available data, 10 (14%) patients had early-infantile (aged b2 years), 24 (32%) late-infantile (2 to b6 years), 24 (32%) juvenile (6 to b15 years), and 16 (22%) adolescent/ adult (≥15 years) onset of neurological manifestations. Mean (95%CI) composite disability scores at enrolment and last follow-up visit were 0.39 (0.34, 0.45; N = 75) and 0.45 (0.39, 0.51; N = 76), respectively. A total of 52/72 (72%) patients were categorised as ’improved/stable’; 20/ 72 (28%) were categorised as ‘progressed’. Safety and tolerability findings for miglustat were in line with previous published data. A low proportion of patients had chronic diarrhoea during follow up (7.6%). Disability status was improved or stable in the majority of miglustattreated patients. doi:10.1016/j.ymgme.2013.12.203
192 Longitudinal study of cognition in Niemann-Pick disease type C Marc C. Pattersona, Tanya M. Browna, Michael J. Zaccarielloa, Audrey Thurmb, Forbes D. Porterb, aMayo Clinic, Rochester, MN, USA, bNational Institutes of Health, Bethesda, MD, USA Niemann-Pick disease, type C (NPC) (incidence at conception calculated at 1:100,000) is an atypical lysosomal disease associated with mutations in either of two genes, NPC1 and NPC2, which lead to excess storage of free cholesterol and glycosphingolipids in the CNS and viscera. Affected individuals exhibit progressive dementia, ataxia and vertical supranuclear gaze palsy, with varying degrees of dystonia, cataplexy, spasticity and epilepsy. There is no approved disease-modifying therapy for NPC in the US, but several interventions have shown promise in vitro and in animal models, and in human trials. Progressive cognitive impairment is typical of NPC; prior cross-sectional studies show deficits in recall, executive function, memory, and fluency, with relatively spared
S85
verbal comprehension. We hypothesize that patients with NPC will show a characteristic pattern and steady progression of cognitive impairment, beginning before the onset of other neurologic symptoms or signs. Subjects in the current study are being recruited from patients with a biochemically-proven diagnosis of NPC who regularly attend NIH or Mayo Clinic for research studies or clinical care. They are being administered a set of developmentally appropriate psychometric instruments at annual intervals. Data will be analyzed using descriptive statistics. Preliminary findings in the first ten subjects studied show a pattern of cognitive deficits resembling those perviously reported, and paralleling physical deficits. Supported by U54 NS065768-05. doi:10.1016/j.ymgme.2013.12.204
193 A comparison of pharmacological activity of original and new production lots of BMN 701 using glycogen clearance in a mouse model of Pompe disease Jeff Peng, Rhea Cahayag, Lucy Crockett, Charles A. O'Neill, Jon Lebowitz, Laurie Tsuruda, BioMarin Pharmaceutical Inc, Novato, CA, USA Pompe disease (GSD type II) is a rare neuromuscular disorder caused by deficiency of the enzyme acid α-glucosidase, resulting in accumulation of glycogen in muscle tissues causing progressive muscle weakness, organ failure, and death from cardiac or respiratory failure. A mouse model (Gaatm1Rabn) of Pompe disease containing a disrupted acid α-glucosidase gene recapitulates clinical features of the human disease and has been used to evaluate the efficacy of treatments for glycogen clearance. BMN 701, a novel fusion protein of insulin-like growth factor 2 and acid α-glucosidase (IGF2-GAA), has previously demonstrated improved efficacy in glycogen clearance in the muscle tissues of Gaatm1Rabn mice when compared to rhGAA. This study assessed the relative glycogen clearance activity of different lots of BMN 701 produced from the original and new improved cell lines and manufacturing processes (Clone 35 and Clone 23, respectively). Gaatm1Rabn mice were treated with repeat intravenous bolus administrations of BMN 701 from two different cell lines weekly for four weeks. The heart (left ventricle), diaphragm, quadriceps, psoas, and soleus muscles were then collected and evaluated for glycogen content using an enzymatic assay. Administration of BMN 701 produced by either cell line resulted in a dosedependent reduction in glycogen levels. The glycogen clearance activity of new Clone 23-produced BMN 701 in skeletal muscle was not inferior to lots produced by the Clone 35 cell line and demonstrated superior activity in the heart and diaphragm. In the heart muscle, only Clone 23produced BMN 701 reduced glycogen levels to those indistinguishable from wild-type animals. The results from this study demonstrate that the change in production of BMN 701 to a new cell line resulted in effective glycogen clearance activity similar to previous production lots, and may offer improved pharmacological activity in diaphragm and cardiac muscles.
doi:10.1016/j.ymgme.2013.12.205
194 Podocyturia in Fabry disease: a tool for monitoring renal disorders Ester M. Pereira, Anatalia Labilloy, Adalberto S. da Silva, José T.M. Neto, Semiramis J.H. do Monte, Federal University of Piaui, Teresina, Brazil
the iN cells to investigate potential neurologically relevant pathogenic cascades related to the neuropathic form of MPS II. doi:10.1016/j.ymgme.2013.12.202
191 Longitudinal data from the international registry for Niemann-Pick disease type C (NPC) Marc C. Pattersona, Eugen Mengelb, Frits A. Wijburgc, Marie T. Vanierd, Barbara Schwierine, Audrey Mullere, Harir Drevonf, Merce Pinedag, a Mayo Clinic, Rochester, MN, USA, bVilla Metabolica, University of Mainz, Mainz, Germany, cAcademic Medical Centre, University of Amsterdam, Amsterdam, Netherlands, dINSERM Unit 820, Lyon, France, eActelion Pharmaceuticals Ltd, Allschwil, Switzerland, fNumerus Ltd, Sandhurst, UK, g Hospital Sant Joan de Déu, Barcelona, Spain The international NPC Registry was initiated to evaluate the longterm disease course of NPC in clinical practice. We present data collected between September 2009 and August 2012 for patients who received miglustat continuously between enrolment and last follow-up visit. Patient demographics, disease characteristics and treatment data were collected, and disability status was evaluated using a scale that rated ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Patients were categorised as ‘improved/stable’ if ≥3 out of these 4 domain scores were lower or unchanged between enrolment and last follow-up visit, or as ‘progressed’ if b3 domain scores were lower or unchanged. Overall, 80/190 enrolled patients (mean [SD] age at enrolment 17.8 [11.5] years; 52.5% female) received miglustat continuously throughout the observation period. Mean (SD) exposure was 1.19 (0.69) years. Among 74/80 patients with available data, 10 (14%) patients had early-infantile (aged b2 years), 24 (32%) late-infantile (2 to b6 years), 24 (32%) juvenile (6 to b15 years), and 16 (22%) adolescent/ adult (≥15 years) onset of neurological manifestations. Mean (95%CI) composite disability scores at enrolment and last follow-up visit were 0.39 (0.34, 0.45; N = 75) and 0.45 (0.39, 0.51; N = 76), respectively. A total of 52/72 (72%) patients were categorised as ’improved/stable’; 20/ 72 (28%) were categorised as ‘progressed’. Safety and tolerability findings for miglustat were in line with previous published data. A low proportion of patients had chronic diarrhoea during follow up (7.6%). Disability status was improved or stable in the majority of miglustattreated patients. doi:10.1016/j.ymgme.2013.12.203
192 Longitudinal study of cognition in Niemann-Pick disease type C Marc C. Pattersona, Tanya M. Browna, Michael J. Zaccarielloa, Audrey Thurmb, Forbes D. Porterb, aMayo Clinic, Rochester, MN, USA, bNational Institutes of Health, Bethesda, MD, USA Niemann-Pick disease, type C (NPC) (incidence at conception calculated at 1:100,000) is an atypical lysosomal disease associated with mutations in either of two genes, NPC1 and NPC2, which lead to excess storage of free cholesterol and glycosphingolipids in the CNS and viscera. Affected individuals exhibit progressive dementia, ataxia and vertical supranuclear gaze palsy, with varying degrees of dystonia, cataplexy, spasticity and epilepsy. There is no approved disease-modifying therapy for NPC in the US, but several interventions have shown promise in vitro and in animal models, and in human trials. Progressive cognitive impairment is typical of NPC; prior cross-sectional studies show deficits in recall, executive function, memory, and fluency, with relatively spared
S85
verbal comprehension. We hypothesize that patients with NPC will show a characteristic pattern and steady progression of cognitive impairment, beginning before the onset of other neurologic symptoms or signs. Subjects in the current study are being recruited from patients with a biochemically-proven diagnosis of NPC who regularly attend NIH or Mayo Clinic for research studies or clinical care. They are being administered a set of developmentally appropriate psychometric instruments at annual intervals. Data will be analyzed using descriptive statistics. Preliminary findings in the first ten subjects studied show a pattern of cognitive deficits resembling those perviously reported, and paralleling physical deficits. Supported by U54 NS065768-05. doi:10.1016/j.ymgme.2013.12.204
193 A comparison of pharmacological activity of original and new production lots of BMN 701 using glycogen clearance in a mouse model of Pompe disease Jeff Peng, Rhea Cahayag, Lucy Crockett, Charles A. O'Neill, Jon Lebowitz, Laurie Tsuruda, BioMarin Pharmaceutical Inc, Novato, CA, USA Pompe disease (GSD type II) is a rare neuromuscular disorder caused by deficiency of the enzyme acid α-glucosidase, resulting in accumulation of glycogen in muscle tissues causing progressive muscle weakness, organ failure, and death from cardiac or respiratory failure. A mouse model (Gaatm1Rabn) of Pompe disease containing a disrupted acid α-glucosidase gene recapitulates clinical features of the human disease and has been used to evaluate the efficacy of treatments for glycogen clearance. BMN 701, a novel fusion protein of insulin-like growth factor 2 and acid α-glucosidase (IGF2-GAA), has previously demonstrated improved efficacy in glycogen clearance in the muscle tissues of Gaatm1Rabn mice when compared to rhGAA. This study assessed the relative glycogen clearance activity of different lots of BMN 701 produced from the original and new improved cell lines and manufacturing processes (Clone 35 and Clone 23, respectively). Gaatm1Rabn mice were treated with repeat intravenous bolus administrations of BMN 701 from two different cell lines weekly for four weeks. The heart (left ventricle), diaphragm, quadriceps, psoas, and soleus muscles were then collected and evaluated for glycogen content using an enzymatic assay. Administration of BMN 701 produced by either cell line resulted in a dosedependent reduction in glycogen levels. The glycogen clearance activity of new Clone 23-produced BMN 701 in skeletal muscle was not inferior to lots produced by the Clone 35 cell line and demonstrated superior activity in the heart and diaphragm. In the heart muscle, only Clone 23produced BMN 701 reduced glycogen levels to those indistinguishable from wild-type animals. The results from this study demonstrate that the change in production of BMN 701 to a new cell line resulted in effective glycogen clearance activity similar to previous production lots, and may offer improved pharmacological activity in diaphragm and cardiac muscles.
doi:10.1016/j.ymgme.2013.12.205
194 Podocyturia in Fabry disease: a tool for monitoring renal disorders Ester M. Pereira, Anatalia Labilloy, Adalberto S. da Silva, José T.M. Neto, Semiramis J.H. do Monte, Federal University of Piaui, Teresina, Brazil