- Email: [email protected]
99. Long-term clinical trial with miglustat in Niemann-Pick disease type C
Abstracts / Molecular Genetics and Metabolism 96 (2009) S12–S47 was similar in patients from NA (2.5 [2.0] years) and from ROW (1.9 [1.6] years), but diagnosis was delayed by 1.3 (1.8) years in NA compared with 2.1 (2.7) years in ROW. The most frequently observed mutations were missense (49% in NA and 43% in ROW). Similar symptoms were present in patients from NA and ROW: typical facial features (82% in NA); hepatosplenomegaly (78%); joint stiffness (74%); otitis (67%); hernia (66%); and enlarged tongue (61%). The median number of surgeries was 3 (min/ max, 0–13) for NA and 2 (0–17) for ROW. The most frequent surgeries in NA were ear tubes (63% of patients from NA), adenoidectomy (55%), hernioplasty (43%), and tonsillectomy (42%). Conclusion: Information on patients with Hunter syndrome from NA in HOS suggests similar patient demography and symptoms to patients from ROW. The delay in diagnosis is greater in ROW compared to NA. The burden of illness in Hunter patients is severe with significant multiple impairment of organs and systems and frequent need for surgical interventions. doi:10.1016/j.ymgme.2008.11.095
95. Podocyte injury and GL-3 accumulation are progressive in Fabry disease Behzad Najafiana, Marie-Claire Gublerb, Chester Whitleya, Michael Mauera, aUniversity of Minnesota, Minneapolis, MN, USA, bHopital Necker-Enfants Malades Introduction: Fabry disease is predominantly known through its vascular lesions. However, natural history of its renal complications is poorly understood. We studied glomerular lesions in biopsies from Fabry patients using quantitation of structural parameters by unbiased stereology. Methods: Renal biopsies from 8 (M/F = 6/2) Fabry patients [4–35 (median 15) years old] were studied by electron microscopy. Fractional volumes of GL-3 inclusions per podocytes [Vv (Inc/PC)], mesangial [Vv (Inc/Mes)] and endothelial cells [Vv (Inc/ Endo)], foot process width (FPW) and %endothelial fenestration were estimated. Six normal living kidney donors were used as controls. Results: Three patients had detectable proteinuria (max. 0.75 g/day). FPW was greater (p = 0.009) in Fabry patients (5,761,130 nm) than controls (406,134 nm) with no overlap between the groups. FPW increased progressively with age (r = 0.87, p = 0.005). Similarly, there was a trend for progressive increase of Vv(Inc/PC) with age (r = 0.67, p = 0.07). This trend when excluding a 13 years old female with minimal Fabry lesions, was statistically significance (r = 0.75, p = 0.05). The three oldest patients (15, 19 and 35 years old) had the greatest, but almost identical Vv(Inc/PC) values (0.46, 0.47 and 0.46). There was no relationship between Vv(Inc/PC) and Vv(Inc/ Mes) or Vv(Inc/Endo). However, Vv(Inc/Mes) and Vv(Inc/Endo) were significantly correlated (r = 0.90; p = 0.003). There was no relationship between age and Vv(Inc/Mes) or Vv(Inc/Endo). Also, glomerular endothelial fenestration was significantly reduced in Fabry patients (4119%) compared to controls (5316%). Conclusion: Our preliminary data suggest that podocyte injury occurs early in Fabry disease and is progressive with age. Podocyte GL-3 accumulation is similarly progressive with age, but may reach to a plateau at older ages. Reduced endothelial fenestration, first described here, could be a manifestation of endothelial injury in Fabry disease. Careful quantitation of Fabry lesions is required for the proper development of structural/functional relationships and end points for clinical trials. doi:10.1016/j.ymgme.2008.11.096
96. Canavan disease treatment using glyceryltriacetate Aryan Namboodiria, C. Madhavaraoa, P. Aruna, S. Moga, N. Grunberga, W. Gahlb, Y. Aniksterc, J. Moffetta, aUniformed Services University, Bethesda, MD, USA, bNational Institutes of Health, cSafra Children Hospital, Sheba Medical Center Canavan disease (CD) is a neurodegenerative genetic disorder caused by defects in aspartoacylase (ASPA). ASPA catalyzes the deacetylation of N-acetylaspartate (NAA), an abundant nervous system-specific amino acid derivative. Our central hypothesis is that CD pathology results primarily from inadequate myelin lipid synthesis caused by a deficiency in the supply of NAA-derived acetate. Previously, we examined acetate levels and myelin-associated lipid synthesis in the murine model of CD (ASPA/), and found that brain acetate levels were decreased almost 80%, and certain myelin associated lipids were reduced by approximately 1/3. Subsequently we found that oral administration of glyceryltriacetate (GTA) can increase acetate levels in the brain over 15-fold within 1 h of administration, indicating that GTA could be used to prevent the severe acetate deficiency in CD. We tested the acetate deficiency hypothesis by studying the effectiveness and tolerability of GTA using the tremor rat model of CD. Tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 to 14, and at 5.8 g/kg from day 15 to 23 and thereafter, in food (7.5%) and water (5%). Performance of the treated tremor rats improved significantly in rotarod balancing as well as in locomotion tests after about 8 weeks of
S33
treatment. Further, no toxicity was detectable, and no histopathological lesions were noted in any organ examined. doi:10.1016/j.ymgme.2008.11.097
97. Autophagy dysfunction in Alzheimer s disease and other late-age onset neurodegenerative diseases Ralph Nixon, Orangeburg, NY, United States, Nathan Kline Institute, New York University School of Medicine Primary lysosomal dysfunction in congenital lysosomal storage disorders is well known to cause severe neurodegenerative phenotypes associated with accumulations of lysosomes and autophagic vacuoles (AVs). Recently, the number of recognized inherited adult-onset neurodegenerative diseases that are caused by proteins that regulate protein sorting and degradation within the endocytic and autophagic pathways has grown considerably. I will briefly discuss examples of neurodegenerative diseases across the lifespan characterized by prominent autophagic-lysosomal dysfunction, which may share mechanisms of neurodegeneration related to degradative failure and lysosomal destabilization. I will highlight Alzheimer’s disease (AD) as a disease within this group and discuss how the genes and other risk factors promoting this disease contribute to progressive lysosomal system dysfunction and neuronal cell death. Our recent studies indicate that neuronal macroautophagy is constitutively active and that clearance of autophagic substrates is exceptionally efficient in healthy neurons. Impaired autophagosome clearance rather than autophagy induction most likely accounts for the extensive autophagic-lysosomal pathology observed in sporadic AD. This research was supported by the National Institute on Aging. doi:10.1016/j.ymgme.2008.11.098
98. Small molecule therapies for neurologic manifestations of LSD in humans Marc Patterson, Mayo Clinic, Rochester, MN, United States The treatment of LSDs was revolutionized by the introduction of enzyme replacement therapy (ERT) in the last decade of the 20th century. ERT has proven effective in reversing or ameliorating most of the non-neurologic manifestations of these diseases, but in general has not influenced the progression of neurologic disease. Small molecule therapies are under development to fill this therapeutic hiatus. Chaperone (or enzyme enhancement) therapy is currently under investigation for Pompe, Fabry and Gaucher disease; substrate reduction therapy is approved for Gaucher disease and is under investigation in Niemann-Pick disease, type C. Preclinical studies have indicated potential for molecules targeting downstream effectors of neurologic injury, including inflammation, apoptosis, calcium maldistribution and mistrafficking of macromolecules. Chaperone therapy is aimed at substantially correcting the primary deficiency, and in subjects with appropriate mutations, has the potential to reverse the phenotype. In contrast, the other interventions are directed at mechanisms downstream of the primary mutation, and in theory (and practice) have more modest effects. Combination therapies with small molecules targeting multiple pathways have shown additive or synergistic effects in animal models. Translation of these promising findings to clinical studies is challenging for several reasons. In many LSDs, the pool of likely participants is small, and enrolling a sufficient number of subjects to adequately power a traditional randomized controlled trial may not be feasible. Even if subjects are available, acceptable study endpoints may not be defined; in many LSDs there are no well established markers of neurologic progression. Innovative solutions including small clinical trials, N of 1 studies and metabolomic’ approaches to identification of biomarkers are promising responses to this conundrum. The rise of personalized medicine highlights these problems in the broader population and the challenges they pose for both regulatory authorities and investigators. doi:10.1016/j.ymgme.2008.11.099
99. Long-term clinical trial with miglustat in Niemann-Pick disease type C Marc Pattersona, Darlenn Vecchiob, Elizabeth Jacklinc, Ed Wraithc, aMayo Clinic, Rochester, USA, Rochester, MN, United States, bColumbia University, New York, USA, c Royal Manchester Children s Hospital, UK Introduction: Niemann-Pick disease type C (NP-C) is an invariably progressive neurological disorder. The clinical trial, OGT 918-007, indicated that miglustat slowed
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disease progression in NP-C patients following 24 months of treatment. We report final, long-term data from this trial. Methods: Patients aged e12 years who completed a 12-month, open-label, randomised trial (miglustat 200 mg t.i.d. vs. standard care) and 12-month, open-label miglustat extension were offered miglustat treatment up to 66 months. Results: Sixteen out of 19 patients (84.2%) continued with treatment (mean SD age 22.6 9.4 years; 44% female). The numbers of patients completing 36, 42, 48 and 66 Months were 15 (93.7%), 11 (68.7%), 9 (56.2%) and 2 (12.5%), respectively. Median (range) treatment duration was 1465 (825–2056) days. At last assessment, swallowing capacity (in 14 evaluable patients) was improved or stable in 11 (78.6%) patients (with water), 12 (85.7%) patients (with puree), and 13 (92.8%) patients (with both soft lumps and cookies). Ambulation Index (in 12 evaluable patients) remained stable in 8 (66.7%) patients (mean change [95% CI], +0.6 [ 0.2, +1.4]). Diarrhoea and weight decrease were each recorded in 50.0% of patients overall, compared with 87.5% and 75.0%, respectively, during the first 24 months. Mean SD (range) weight change from baseline to last value was +0.56 1 8.10 kg (9.3 to +21.0 kg). Three patients discontinued; none because of adverse events. Conclusions: The data indicate that the effect of miglustat on disease stability observed in the initial phase of the study could be sustained over the long term.
clinical course of NPC, and to identify clinical, neuropsychological and laboratory markers of disease burden and progression. Hypothesis: Patients with NPC will demonstrate a specific pattern of neurocognitive deficits that will be present prior to development of significant neurological deficits and that will correlate with disease progression. Methods: Subjects will be recruited from participants in studies at two network sites the NIH Clinical Center and Mayo Clinic. NPC patients enrolled in the current NIH NPC observational study will be recruited into the neurocognitive study that will be performed at the Kennedy Krieger Institute (KKI) in Baltimore. Patients are evaluated every 6–12 months in the NIH study, neurocognitive testing will be done every 12 months. NPC patients participating in the miglustat study will be seen every 12 months at Mayo Clinic, where neurocognitive evaluation will be performed using the same instruments as are employed at KKI. The neurocognitive phenotype of Niemann Pick disease type C will be defined using age and functionally appropriate instruments to assess the following domains: intelligence, visuospatial abilities, memory (verbal visual, working, non-verbal working), visual-spatial construction, language, motor, attention/executive function, adaptive and behavioral/emotional. Data will be analyzed using descriptive statistics.
doi:10.1016/j.ymgme.2008.11.100
doi:10.1016/j.ymgme.2008.11.102
100. A multicentre retrospective survey of miglustat in patients with NiemannPick type C disease
102. Genz-112638, an investigational oral treatment for Gaucher disease type 1: Preliminary Phase 2 clinical trial results
Marc Pattersona, Merci Pinedab, Fridiric Sedelc, Eugen Mengeld, Wuh-Liang Hwue, Marianne Rohrbachf, Brubo Bembig, Christoph Korenkeh, Cicile Luzyi, Peter Schieberi, Ruben Giorginoi, Ed Wraithj, aMayo Clinic, Rochester, MN, USA, Rochester, MN, USA, b Hospital Sant Joan de Deu, Barcelona, Spain, cHopital Pitii Salpjtrihre, Paris, France, d University of Mainz, Mainz, Germany, eNational Taiwan University Hospital, Taipei, Taiwan, fKinderspital, Zurich, Switzerland, gRegional Coordinator Centre for Rare Diseases, University Hospital, Udine, Italy, hElisabeth Kinderkrankenhaus, Oldenburg, Germany, i Actelion Pharmaceuticals Ltd, Allschwil, Switzerland, jRoyal Manchester Children’s Hospital, Manchester, UK
Judith Peterschmitta, Elena Lukinab, Nora Watmanc, Elsa Arreguind, Maryam Banikazemie, Gregory Pastorese, Marcelo Iastrebnerf, Marta Dragoskyf, Hanna Rosenbaumg, Ari Zimranh, Fanny O’Briena, Sharon Smitha, Ana Cristina Pugaa, a Genzyme Corporation, Cambridge, MA, USA, bRussian Academy of Medical Sciences, c Hospital Ramos Mejia, dInstituto Mexicano del Seguro Social Hospital de Especialidades, e New York University, fInstituto Argentino de Diagnostico y Tratamiento, gRambam Medical Center, hSha’are Zedek Medical Center
Introduction: Niemann-Pick disease type C (NP-C) is a progressive neurological disorder. The clinical trial, OGT-918-007, indicated that miglustat is able to slow disease progression in patients with NP-C. Here we present the final results from a multinational, retrospective survey assessing neurological disease progression in NP-C patients treated with miglustat. Methods: NP-C patients prescribed miglustat in 25 selected expert centres were included. Treating physicians were asked to complete a questionnaire on patient demographics, treatment history, disease progression and general health. A diseasespecific disability scale was used to evaluate dysphagia, dystonia, ataxia and dysarthria severity at diagnosis, treatment initiation and last visit. Results: In total, 66 patients were included (mean SD age: 9.7 7.6 years at diagnosis, 12.8 9.5 years at miglustat initiation). Mean SD time interval between diagnosis and treatment initiation was 3.1 3.4 years. Median (range) miglustat exposure was 533 (18 1646) days. Most patients remained stable or were improved after miglustat treatment as regards to dysphagia (51/63; 80.9%), dystonia (48/63; 76.2%), ataxia (49/64; 76.5%) and dysarthria (47/61; 77.0%). Of 65 evaluable patients, 49 (75.4%) were classified as good responders (if at least 3 out of 4 disability scale parameters were stable/improved). In physician global assessments, 22/60 (36.7%) evaluable patients improved in general health, and 43/58 (74.1%) evaluable patients experienced excellent, good or fair benefit. Conclusions: Miglustat appears to have a clinically relevant beneficial effect on neurological disease progression in patients with NP-C. doi:10.1016/j.ymgme.2008.11.101
Introduction: Genz-112638 is a novel oral small molecule inhibitor of glucosylceramide synthase under development for the treatment of Gaucher disease type 1 (GD1). An open-label Phase 2 clinical study of the efficacy, safety, and pharmacokinetics of Genz-112638 in patients with GD1 has recently completed 52-week follow-up. Methods: This clinical trial of Genz-112638, given 50 or 100 mg bid orally, treated 26 adults with GD1 (16F:10M; mean age 34 years, range 18–60; all Caucasian) at 7 sites in 5 countries. Patients were to have splenomegaly (volumee10 normal) and either thrombocytopenia (platelets 45,000–100,000/mm3) or anemia (hemoglobin 8–10 g/dL, female; 8–11 g/dL, male). None received enzyme replacement or substrate reduction therapy in the prior 12 months. The composite primary efficacy endpoint is based on improvements in e2 of the 3 main parameters: spleen volume (15%), hemoglobin level (+0.5 g/dL) or platelet count (+15%) after 52 weeks of treatment. Liver volume, chitotriosidase, glucosylceramide are also assessed. Patients continue to be treated and monitored long-term. Results: To date, Week 52 data are available for up to 20 patients; 4 others withdrew prematurely and 2 are ongoing. The composite primary endpoint was met by 19 of the 20 patients. Mean (1SD) changes from baseline to Week 52 were: hemoglobin +1.6 (11.35) g/dL; platelet count +43.6% (137.59%); spleen and liver volume (multiples of normal) 40.2% (110.44%) and 15.8% (110.39%), respectively; and chitotriosidase 49.9% (120.75%). Plasma glucosylceramide levels normalized after 4 weeks in all patients. Genz-112638 was well tolerated with an acceptable safety profile. As of June 2008, 7 adverse events in 6 patients have been reported as related; all were mild and transient. Conclusions: Preliminary data from this Phase 2 study indicate that Genz-112638 may be a safe, effective, and convenient oral therapy for patients with GD1. Clinical development of Genz-112638 is proceeding, and Phase 3 studies are planned. doi:10.1016/j.ymgme.2008.11.103
101. Longitudinal study of cognition in subjects with Niemann-Pick disease, type C Marc Pattersona, Forbes Porterb, Rebecca Vaurioc, Tanya Browna, aMayo Clinic, Rochester, MN, USA, bNational Institutes of Health, cThe Hugo W. Moser Research Institute at Kennedy Krieger, Inc. Introduction: Niemann-Pick disease, type C (NPC) is a pan-ethnic, autosomal recessive lysosomal storage disease with an incidence of 1/150,000. Because of the devastating effects of this illness on patients and families, the public health burden of this disease is disproportionate to its prevalence. Most patients experience a progressive dementia accompanied by vertical supranuclear gaze palsy ataxia, dysarthria, dysphagia, dystonia and in some cases, epilepsy and cataplexy. Several potential human therapeutic agents have been studied invitro and in animal models of NPC. Before human therapeutic trials can be pursued, it is essential to define the
103. Bilateral coordination in children with Hurler and Hunter syndrome Dawn Phillipsa, Dawn Phillipsa, Maria Escolarb, aDivision of Physical Therapy, School of Medicine, UNC at Chapel Hill, Chapel Hill, NC, USA, bCenter for Development and Learning, UNC at Chapel Hill Children with MPS I (Hurler Syndrome) and MPS II (Hunter Syndrome) are living longer lives due to medical treatment advances,such as hematopoietic stem cell transplantation and enzyme replacement therapy. The Peabody Developmental Motor Scales II has been used to document gross motor delay in children with MPS through 6 years of age but little has been documented on the motor ability of the older child with MPS. The purpose of this report is to describe the bilateral coordination of 10
95. Podocyte injury and GL-3 accumulation are progressive in Fabry disease Behzad Najafiana, Marie-Claire Gublerb, Chester Whitleya, Michael Mauera, aUniversity of Minnesota, Minneapolis, MN, USA, bHopital Necker-Enfants Malades Introduction: Fabry disease is predominantly known through its vascular lesions. However, natural history of its renal complications is poorly understood. We studied glomerular lesions in biopsies from Fabry patients using quantitation of structural parameters by unbiased stereology. Methods: Renal biopsies from 8 (M/F = 6/2) Fabry patients [4–35 (median 15) years old] were studied by electron microscopy. Fractional volumes of GL-3 inclusions per podocytes [Vv (Inc/PC)], mesangial [Vv (Inc/Mes)] and endothelial cells [Vv (Inc/ Endo)], foot process width (FPW) and %endothelial fenestration were estimated. Six normal living kidney donors were used as controls. Results: Three patients had detectable proteinuria (max. 0.75 g/day). FPW was greater (p = 0.009) in Fabry patients (5,761,130 nm) than controls (406,134 nm) with no overlap between the groups. FPW increased progressively with age (r = 0.87, p = 0.005). Similarly, there was a trend for progressive increase of Vv(Inc/PC) with age (r = 0.67, p = 0.07). This trend when excluding a 13 years old female with minimal Fabry lesions, was statistically significance (r = 0.75, p = 0.05). The three oldest patients (15, 19 and 35 years old) had the greatest, but almost identical Vv(Inc/PC) values (0.46, 0.47 and 0.46). There was no relationship between Vv(Inc/PC) and Vv(Inc/ Mes) or Vv(Inc/Endo). However, Vv(Inc/Mes) and Vv(Inc/Endo) were significantly correlated (r = 0.90; p = 0.003). There was no relationship between age and Vv(Inc/Mes) or Vv(Inc/Endo). Also, glomerular endothelial fenestration was significantly reduced in Fabry patients (4119%) compared to controls (5316%). Conclusion: Our preliminary data suggest that podocyte injury occurs early in Fabry disease and is progressive with age. Podocyte GL-3 accumulation is similarly progressive with age, but may reach to a plateau at older ages. Reduced endothelial fenestration, first described here, could be a manifestation of endothelial injury in Fabry disease. Careful quantitation of Fabry lesions is required for the proper development of structural/functional relationships and end points for clinical trials. doi:10.1016/j.ymgme.2008.11.096
96. Canavan disease treatment using glyceryltriacetate Aryan Namboodiria, C. Madhavaraoa, P. Aruna, S. Moga, N. Grunberga, W. Gahlb, Y. Aniksterc, J. Moffetta, aUniformed Services University, Bethesda, MD, USA, bNational Institutes of Health, cSafra Children Hospital, Sheba Medical Center Canavan disease (CD) is a neurodegenerative genetic disorder caused by defects in aspartoacylase (ASPA). ASPA catalyzes the deacetylation of N-acetylaspartate (NAA), an abundant nervous system-specific amino acid derivative. Our central hypothesis is that CD pathology results primarily from inadequate myelin lipid synthesis caused by a deficiency in the supply of NAA-derived acetate. Previously, we examined acetate levels and myelin-associated lipid synthesis in the murine model of CD (ASPA/), and found that brain acetate levels were decreased almost 80%, and certain myelin associated lipids were reduced by approximately 1/3. Subsequently we found that oral administration of glyceryltriacetate (GTA) can increase acetate levels in the brain over 15-fold within 1 h of administration, indicating that GTA could be used to prevent the severe acetate deficiency in CD. We tested the acetate deficiency hypothesis by studying the effectiveness and tolerability of GTA using the tremor rat model of CD. Tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 to 14, and at 5.8 g/kg from day 15 to 23 and thereafter, in food (7.5%) and water (5%). Performance of the treated tremor rats improved significantly in rotarod balancing as well as in locomotion tests after about 8 weeks of
S33
treatment. Further, no toxicity was detectable, and no histopathological lesions were noted in any organ examined. doi:10.1016/j.ymgme.2008.11.097
97. Autophagy dysfunction in Alzheimer s disease and other late-age onset neurodegenerative diseases Ralph Nixon, Orangeburg, NY, United States, Nathan Kline Institute, New York University School of Medicine Primary lysosomal dysfunction in congenital lysosomal storage disorders is well known to cause severe neurodegenerative phenotypes associated with accumulations of lysosomes and autophagic vacuoles (AVs). Recently, the number of recognized inherited adult-onset neurodegenerative diseases that are caused by proteins that regulate protein sorting and degradation within the endocytic and autophagic pathways has grown considerably. I will briefly discuss examples of neurodegenerative diseases across the lifespan characterized by prominent autophagic-lysosomal dysfunction, which may share mechanisms of neurodegeneration related to degradative failure and lysosomal destabilization. I will highlight Alzheimer’s disease (AD) as a disease within this group and discuss how the genes and other risk factors promoting this disease contribute to progressive lysosomal system dysfunction and neuronal cell death. Our recent studies indicate that neuronal macroautophagy is constitutively active and that clearance of autophagic substrates is exceptionally efficient in healthy neurons. Impaired autophagosome clearance rather than autophagy induction most likely accounts for the extensive autophagic-lysosomal pathology observed in sporadic AD. This research was supported by the National Institute on Aging. doi:10.1016/j.ymgme.2008.11.098
98. Small molecule therapies for neurologic manifestations of LSD in humans Marc Patterson, Mayo Clinic, Rochester, MN, United States The treatment of LSDs was revolutionized by the introduction of enzyme replacement therapy (ERT) in the last decade of the 20th century. ERT has proven effective in reversing or ameliorating most of the non-neurologic manifestations of these diseases, but in general has not influenced the progression of neurologic disease. Small molecule therapies are under development to fill this therapeutic hiatus. Chaperone (or enzyme enhancement) therapy is currently under investigation for Pompe, Fabry and Gaucher disease; substrate reduction therapy is approved for Gaucher disease and is under investigation in Niemann-Pick disease, type C. Preclinical studies have indicated potential for molecules targeting downstream effectors of neurologic injury, including inflammation, apoptosis, calcium maldistribution and mistrafficking of macromolecules. Chaperone therapy is aimed at substantially correcting the primary deficiency, and in subjects with appropriate mutations, has the potential to reverse the phenotype. In contrast, the other interventions are directed at mechanisms downstream of the primary mutation, and in theory (and practice) have more modest effects. Combination therapies with small molecules targeting multiple pathways have shown additive or synergistic effects in animal models. Translation of these promising findings to clinical studies is challenging for several reasons. In many LSDs, the pool of likely participants is small, and enrolling a sufficient number of subjects to adequately power a traditional randomized controlled trial may not be feasible. Even if subjects are available, acceptable study endpoints may not be defined; in many LSDs there are no well established markers of neurologic progression. Innovative solutions including small clinical trials, N of 1 studies and metabolomic’ approaches to identification of biomarkers are promising responses to this conundrum. The rise of personalized medicine highlights these problems in the broader population and the challenges they pose for both regulatory authorities and investigators. doi:10.1016/j.ymgme.2008.11.099
99. Long-term clinical trial with miglustat in Niemann-Pick disease type C Marc Pattersona, Darlenn Vecchiob, Elizabeth Jacklinc, Ed Wraithc, aMayo Clinic, Rochester, USA, Rochester, MN, United States, bColumbia University, New York, USA, c Royal Manchester Children s Hospital, UK Introduction: Niemann-Pick disease type C (NP-C) is an invariably progressive neurological disorder. The clinical trial, OGT 918-007, indicated that miglustat slowed
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Abstracts / Molecular Genetics and Metabolism 96 (2009) S12–S47
disease progression in NP-C patients following 24 months of treatment. We report final, long-term data from this trial. Methods: Patients aged e12 years who completed a 12-month, open-label, randomised trial (miglustat 200 mg t.i.d. vs. standard care) and 12-month, open-label miglustat extension were offered miglustat treatment up to 66 months. Results: Sixteen out of 19 patients (84.2%) continued with treatment (mean SD age 22.6 9.4 years; 44% female). The numbers of patients completing 36, 42, 48 and 66 Months were 15 (93.7%), 11 (68.7%), 9 (56.2%) and 2 (12.5%), respectively. Median (range) treatment duration was 1465 (825–2056) days. At last assessment, swallowing capacity (in 14 evaluable patients) was improved or stable in 11 (78.6%) patients (with water), 12 (85.7%) patients (with puree), and 13 (92.8%) patients (with both soft lumps and cookies). Ambulation Index (in 12 evaluable patients) remained stable in 8 (66.7%) patients (mean change [95% CI], +0.6 [ 0.2, +1.4]). Diarrhoea and weight decrease were each recorded in 50.0% of patients overall, compared with 87.5% and 75.0%, respectively, during the first 24 months. Mean SD (range) weight change from baseline to last value was +0.56 1 8.10 kg (9.3 to +21.0 kg). Three patients discontinued; none because of adverse events. Conclusions: The data indicate that the effect of miglustat on disease stability observed in the initial phase of the study could be sustained over the long term.
clinical course of NPC, and to identify clinical, neuropsychological and laboratory markers of disease burden and progression. Hypothesis: Patients with NPC will demonstrate a specific pattern of neurocognitive deficits that will be present prior to development of significant neurological deficits and that will correlate with disease progression. Methods: Subjects will be recruited from participants in studies at two network sites the NIH Clinical Center and Mayo Clinic. NPC patients enrolled in the current NIH NPC observational study will be recruited into the neurocognitive study that will be performed at the Kennedy Krieger Institute (KKI) in Baltimore. Patients are evaluated every 6–12 months in the NIH study, neurocognitive testing will be done every 12 months. NPC patients participating in the miglustat study will be seen every 12 months at Mayo Clinic, where neurocognitive evaluation will be performed using the same instruments as are employed at KKI. The neurocognitive phenotype of Niemann Pick disease type C will be defined using age and functionally appropriate instruments to assess the following domains: intelligence, visuospatial abilities, memory (verbal visual, working, non-verbal working), visual-spatial construction, language, motor, attention/executive function, adaptive and behavioral/emotional. Data will be analyzed using descriptive statistics.
doi:10.1016/j.ymgme.2008.11.100
doi:10.1016/j.ymgme.2008.11.102
100. A multicentre retrospective survey of miglustat in patients with NiemannPick type C disease
102. Genz-112638, an investigational oral treatment for Gaucher disease type 1: Preliminary Phase 2 clinical trial results
Marc Pattersona, Merci Pinedab, Fridiric Sedelc, Eugen Mengeld, Wuh-Liang Hwue, Marianne Rohrbachf, Brubo Bembig, Christoph Korenkeh, Cicile Luzyi, Peter Schieberi, Ruben Giorginoi, Ed Wraithj, aMayo Clinic, Rochester, MN, USA, Rochester, MN, USA, b Hospital Sant Joan de Deu, Barcelona, Spain, cHopital Pitii Salpjtrihre, Paris, France, d University of Mainz, Mainz, Germany, eNational Taiwan University Hospital, Taipei, Taiwan, fKinderspital, Zurich, Switzerland, gRegional Coordinator Centre for Rare Diseases, University Hospital, Udine, Italy, hElisabeth Kinderkrankenhaus, Oldenburg, Germany, i Actelion Pharmaceuticals Ltd, Allschwil, Switzerland, jRoyal Manchester Children’s Hospital, Manchester, UK
Judith Peterschmitta, Elena Lukinab, Nora Watmanc, Elsa Arreguind, Maryam Banikazemie, Gregory Pastorese, Marcelo Iastrebnerf, Marta Dragoskyf, Hanna Rosenbaumg, Ari Zimranh, Fanny O’Briena, Sharon Smitha, Ana Cristina Pugaa, a Genzyme Corporation, Cambridge, MA, USA, bRussian Academy of Medical Sciences, c Hospital Ramos Mejia, dInstituto Mexicano del Seguro Social Hospital de Especialidades, e New York University, fInstituto Argentino de Diagnostico y Tratamiento, gRambam Medical Center, hSha’are Zedek Medical Center
Introduction: Niemann-Pick disease type C (NP-C) is a progressive neurological disorder. The clinical trial, OGT-918-007, indicated that miglustat is able to slow disease progression in patients with NP-C. Here we present the final results from a multinational, retrospective survey assessing neurological disease progression in NP-C patients treated with miglustat. Methods: NP-C patients prescribed miglustat in 25 selected expert centres were included. Treating physicians were asked to complete a questionnaire on patient demographics, treatment history, disease progression and general health. A diseasespecific disability scale was used to evaluate dysphagia, dystonia, ataxia and dysarthria severity at diagnosis, treatment initiation and last visit. Results: In total, 66 patients were included (mean SD age: 9.7 7.6 years at diagnosis, 12.8 9.5 years at miglustat initiation). Mean SD time interval between diagnosis and treatment initiation was 3.1 3.4 years. Median (range) miglustat exposure was 533 (18 1646) days. Most patients remained stable or were improved after miglustat treatment as regards to dysphagia (51/63; 80.9%), dystonia (48/63; 76.2%), ataxia (49/64; 76.5%) and dysarthria (47/61; 77.0%). Of 65 evaluable patients, 49 (75.4%) were classified as good responders (if at least 3 out of 4 disability scale parameters were stable/improved). In physician global assessments, 22/60 (36.7%) evaluable patients improved in general health, and 43/58 (74.1%) evaluable patients experienced excellent, good or fair benefit. Conclusions: Miglustat appears to have a clinically relevant beneficial effect on neurological disease progression in patients with NP-C. doi:10.1016/j.ymgme.2008.11.101
Introduction: Genz-112638 is a novel oral small molecule inhibitor of glucosylceramide synthase under development for the treatment of Gaucher disease type 1 (GD1). An open-label Phase 2 clinical study of the efficacy, safety, and pharmacokinetics of Genz-112638 in patients with GD1 has recently completed 52-week follow-up. Methods: This clinical trial of Genz-112638, given 50 or 100 mg bid orally, treated 26 adults with GD1 (16F:10M; mean age 34 years, range 18–60; all Caucasian) at 7 sites in 5 countries. Patients were to have splenomegaly (volumee10 normal) and either thrombocytopenia (platelets 45,000–100,000/mm3) or anemia (hemoglobin 8–10 g/dL, female; 8–11 g/dL, male). None received enzyme replacement or substrate reduction therapy in the prior 12 months. The composite primary efficacy endpoint is based on improvements in e2 of the 3 main parameters: spleen volume (15%), hemoglobin level (+0.5 g/dL) or platelet count (+15%) after 52 weeks of treatment. Liver volume, chitotriosidase, glucosylceramide are also assessed. Patients continue to be treated and monitored long-term. Results: To date, Week 52 data are available for up to 20 patients; 4 others withdrew prematurely and 2 are ongoing. The composite primary endpoint was met by 19 of the 20 patients. Mean (1SD) changes from baseline to Week 52 were: hemoglobin +1.6 (11.35) g/dL; platelet count +43.6% (137.59%); spleen and liver volume (multiples of normal) 40.2% (110.44%) and 15.8% (110.39%), respectively; and chitotriosidase 49.9% (120.75%). Plasma glucosylceramide levels normalized after 4 weeks in all patients. Genz-112638 was well tolerated with an acceptable safety profile. As of June 2008, 7 adverse events in 6 patients have been reported as related; all were mild and transient. Conclusions: Preliminary data from this Phase 2 study indicate that Genz-112638 may be a safe, effective, and convenient oral therapy for patients with GD1. Clinical development of Genz-112638 is proceeding, and Phase 3 studies are planned. doi:10.1016/j.ymgme.2008.11.103
101. Longitudinal study of cognition in subjects with Niemann-Pick disease, type C Marc Pattersona, Forbes Porterb, Rebecca Vaurioc, Tanya Browna, aMayo Clinic, Rochester, MN, USA, bNational Institutes of Health, cThe Hugo W. Moser Research Institute at Kennedy Krieger, Inc. Introduction: Niemann-Pick disease, type C (NPC) is a pan-ethnic, autosomal recessive lysosomal storage disease with an incidence of 1/150,000. Because of the devastating effects of this illness on patients and families, the public health burden of this disease is disproportionate to its prevalence. Most patients experience a progressive dementia accompanied by vertical supranuclear gaze palsy ataxia, dysarthria, dysphagia, dystonia and in some cases, epilepsy and cataplexy. Several potential human therapeutic agents have been studied invitro and in animal models of NPC. Before human therapeutic trials can be pursued, it is essential to define the
103. Bilateral coordination in children with Hurler and Hunter syndrome Dawn Phillipsa, Dawn Phillipsa, Maria Escolarb, aDivision of Physical Therapy, School of Medicine, UNC at Chapel Hill, Chapel Hill, NC, USA, bCenter for Development and Learning, UNC at Chapel Hill Children with MPS I (Hurler Syndrome) and MPS II (Hunter Syndrome) are living longer lives due to medical treatment advances,such as hematopoietic stem cell transplantation and enzyme replacement therapy. The Peabody Developmental Motor Scales II has been used to document gross motor delay in children with MPS through 6 years of age but little has been documented on the motor ability of the older child with MPS. The purpose of this report is to describe the bilateral coordination of 10