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Long-term safety and efficacy of intracerebroventricular enzyme replacement therapy with cerliponase alfa in children with CLN2 disease: interim results from an ongoing multicenter, multinational extension study
S120
Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
IVS2+590 CNT, IVS0-12 GNA, IVS4+68 ANG, IVS0-10 CNT, IVS2-81– 77delCAGCC, IVS2-77delC. None of the variants were considered disease causing and their frequency were not appreciably different from the general population (ExAC). We conclude that the general population of patients with heart disease may not contain a substantial number of undiagnosed Fabry patients.
doi:10.1016/j.ymgme.2016.11.309
301 Proof-of-concept studies underlying enzyme replacement therapy for acid ceramidase deficiency Edward H. Schuchmana, Xingxuan Hea, Shaalee Dworskib, Changzhi Zhua, Victor DeAngelisa, Alex Solyomc, Thierry Levaded, Jeffrey A. Medine, Calogera M. Simonaroa, aIcahn School of Medicine at Mount Sinai, NY, NY, United States, bUniversity of Toronto, Toronto, ON, Canada, cEnzyvant, NY, NY, United States, dToulouse-Rangueil Medical School, Toulouse, France, e Medical College of Wisconsin, Milwaukee, WI, United States The deficiency of acid ceramidase (E.C.#3.5.1.23; AC) activity results in two orphan genetic diseases: Farber lipogranulomatosis (OMIM #228000; Farber disease) and spinal muscular atrophy with progressive myoclonic epilepsy (OMIM #159950; SMA-PME). To evaluate the potential of enzyme replacement therapy (ERT) for the treatment of AC deficiency, a knock-in mouse model was used (Alayoubi et al., EMBO Mol. Med., 2013). Recombinant human AC (rhAC) was purified from the media of overexpressing Chinese hamster ovary (CHO) cells and its uptake and bioactivity was confirmed using a human Farber disease cell line and primary chondrocytes from the Farber disease mice. Single injections of rhAC into Farber mice confirmed the activity (reduced tissue ceramides and increased sphingosine), and showed that the treatment was well tolerated up to 50 mg/kg (maximal dose evaluated). Time-course analysis revealed that liver and spleen ceramides remained reduced for at least 1 week post-injection. Repeat dosing (1, 3 and 10 mg/kg) was then carried out once per week, starting at 3 weeks of age. A modest, but significant increase in survival was noted with enzyme treatment, and this could be improved by initiating treatment immediately after birth (3 days). Spleen size, tissue ceramides, macrophage infiltration, and plasma cytokine levels (MCP1) also were all significantly improved by ERT. As expected, tissue sphingosine levels were increased by rhAC treatment, but the increase was transient indicating either rapid conversion to other sphingolipids or degradation. Overall, we conclude that ERT should be considered as a treatment for AC deficiency.
doi:10.1016/j.ymgme.2016.11.310
302 Long-term safety and efficacy of intracerebroventricular enzyme replacement therapy with cerliponase alfa in children with CLN2 disease: interim results from an ongoing multicenter, multinational extension study Angela Schulza, Nicola Specchiob, Paul Gissenc, Emily de los Reyesd, Heather Cahane, Peter Slasore, Temitayo Ajayie, David Jacobye, a University Medical Center Hamburg-Eppendorf, Hamburg, Germany, b Bambino Gesù Children’s Hospital IRCCS, Rome, Italy, cGreat Ormond Street Hospital for Children, London, United Kingdom, dNationwide Children’s Hospital, The Ohio State University, Columbus, OH, United States, e BioMarin Pharmaceutical Inc., Novato, CA, United States
Background. CLN2 disease, a rare, inherited, pediatric, neurodegenerative lysosomal storage disorder caused by TPP1 deficiency, is characterized by seizures, ataxia, language and motor function loss, blindness and early death. A phase 1/2 study (NCT01907087) demonstrated that intracerebroventricular (ICV) infusion of 300 mg cerliponase alfa, a recombinant human TPP1 enzyme, every other week for 48 weeks was associated with attenuation of CLN2 disease progression. This extension study (NCT02485899) assesses the longterm safety and efficacy of ICV-administered cerliponase alfa in children with CLN2 disease for up to 240 weeks. Design. Subjects who completed the phase 1/2 study enrolled in this open-label extension study, and continued receiving 300 mg cerliponase alfa qow. Cumulative data from both studies were used to evaluate long-term safety (assessed by analysis of adverse events (AEs)) and efficacy (assessed by changes in motor and language (ML) functions using the CLN2 clinical rating scale). Results. 24 subjects were initially treated with cerliponase alfa in the phase 1/2 study (9 male, 15 female, mean (SD) age 4.3 years (1.24)); 23 subjects enrolled in the extension study (74 to 124 weeks total exposure). All had AEs; most were Grade 1-2. Common AEs included pyrexia, hypersensitivity and convulsion. Nineteen (79%) subjects had at least one serious AE, which were mostly consistent with neurodegenerative disease in a pediatric population. Significant attenuation of the rate of decline in ML score (mean (95% CI): 0.32 (0.13, 0.52) points/ 48 weeks, pb0.0001) was observed compared with a rate of decline of 2.0 points/48 weeks in untreated patients. The responder (b2 point loss) rate at 81 weeks (87%, p = 0.0002) was unchanged compared to that observed at 48 weeks, suggesting a persistent treatment effect. Conclusions. These data suggest that enzyme replacement therapy with ICV-administered cerliponase alfa has an acceptable safety profile and a sustained effect over time. doi:10.1016/j.ymgme.2016.11.311
303 Characteristics of 27 patients with type 3 Gaucher disease: a descriptive analysis from the Gaucher Outcome Survey Ida Vanessa D Schwartza,b, Ozlem Goker-Alpanc, Priya Kishnanid, Ari Zimrane, Lydie Renaultf, Zoya Panahloof, Patrick Deegang, aHospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, bUniversidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, cLysosomal Disorders Unit and Center for Clinical Trials, O&O Alpan, LLC, Fairfax, VA, United States, dDuke University School of Medicine, Durham, NC, United States, eShaare Zedek Medical Center and the Hebrew University-Hadassah Medical School, Jerusalem, Israel, fShire, Zug, Switzerland, gAddenbrooke's Hospital, Cambridge, United Kingdom The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD)-specific registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status. Patients with neuronopathic type 3 GD (GD3) may show nonneurological manifestations similar to those of type 1 GD. We examined real-world data from GOS for insight into the disease characteristics and management of GD3 patients. The analysis included all GOS patients recorded as GD3. Patient demographics, disease parameters and treatment history were collected. Adverse event (AE) data were collected for patients who received velaglucerase alfa. For GOS patients with GD type data (970/1003), 27/970 (2.8%) were recorded as GD3 (median [range] age at GOS entry 17.4 [0.5-56.3] years, 12 [44.4%] male, 7 [25.9%] splenectomized). Most patients were from the USA (14/27, 51.9%); others were from the UK, Israel, and Brazil. None were Ashkenazi Jewish. The most common GBA1 genotype was L444P/ L444P (13/19, 68.4%). At analysis, 21 patients were on GD treatment
Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
IVS2+590 CNT, IVS0-12 GNA, IVS4+68 ANG, IVS0-10 CNT, IVS2-81– 77delCAGCC, IVS2-77delC. None of the variants were considered disease causing and their frequency were not appreciably different from the general population (ExAC). We conclude that the general population of patients with heart disease may not contain a substantial number of undiagnosed Fabry patients.
doi:10.1016/j.ymgme.2016.11.309
301 Proof-of-concept studies underlying enzyme replacement therapy for acid ceramidase deficiency Edward H. Schuchmana, Xingxuan Hea, Shaalee Dworskib, Changzhi Zhua, Victor DeAngelisa, Alex Solyomc, Thierry Levaded, Jeffrey A. Medine, Calogera M. Simonaroa, aIcahn School of Medicine at Mount Sinai, NY, NY, United States, bUniversity of Toronto, Toronto, ON, Canada, cEnzyvant, NY, NY, United States, dToulouse-Rangueil Medical School, Toulouse, France, e Medical College of Wisconsin, Milwaukee, WI, United States The deficiency of acid ceramidase (E.C.#3.5.1.23; AC) activity results in two orphan genetic diseases: Farber lipogranulomatosis (OMIM #228000; Farber disease) and spinal muscular atrophy with progressive myoclonic epilepsy (OMIM #159950; SMA-PME). To evaluate the potential of enzyme replacement therapy (ERT) for the treatment of AC deficiency, a knock-in mouse model was used (Alayoubi et al., EMBO Mol. Med., 2013). Recombinant human AC (rhAC) was purified from the media of overexpressing Chinese hamster ovary (CHO) cells and its uptake and bioactivity was confirmed using a human Farber disease cell line and primary chondrocytes from the Farber disease mice. Single injections of rhAC into Farber mice confirmed the activity (reduced tissue ceramides and increased sphingosine), and showed that the treatment was well tolerated up to 50 mg/kg (maximal dose evaluated). Time-course analysis revealed that liver and spleen ceramides remained reduced for at least 1 week post-injection. Repeat dosing (1, 3 and 10 mg/kg) was then carried out once per week, starting at 3 weeks of age. A modest, but significant increase in survival was noted with enzyme treatment, and this could be improved by initiating treatment immediately after birth (3 days). Spleen size, tissue ceramides, macrophage infiltration, and plasma cytokine levels (MCP1) also were all significantly improved by ERT. As expected, tissue sphingosine levels were increased by rhAC treatment, but the increase was transient indicating either rapid conversion to other sphingolipids or degradation. Overall, we conclude that ERT should be considered as a treatment for AC deficiency.
doi:10.1016/j.ymgme.2016.11.310
302 Long-term safety and efficacy of intracerebroventricular enzyme replacement therapy with cerliponase alfa in children with CLN2 disease: interim results from an ongoing multicenter, multinational extension study Angela Schulza, Nicola Specchiob, Paul Gissenc, Emily de los Reyesd, Heather Cahane, Peter Slasore, Temitayo Ajayie, David Jacobye, a University Medical Center Hamburg-Eppendorf, Hamburg, Germany, b Bambino Gesù Children’s Hospital IRCCS, Rome, Italy, cGreat Ormond Street Hospital for Children, London, United Kingdom, dNationwide Children’s Hospital, The Ohio State University, Columbus, OH, United States, e BioMarin Pharmaceutical Inc., Novato, CA, United States
Background. CLN2 disease, a rare, inherited, pediatric, neurodegenerative lysosomal storage disorder caused by TPP1 deficiency, is characterized by seizures, ataxia, language and motor function loss, blindness and early death. A phase 1/2 study (NCT01907087) demonstrated that intracerebroventricular (ICV) infusion of 300 mg cerliponase alfa, a recombinant human TPP1 enzyme, every other week for 48 weeks was associated with attenuation of CLN2 disease progression. This extension study (NCT02485899) assesses the longterm safety and efficacy of ICV-administered cerliponase alfa in children with CLN2 disease for up to 240 weeks. Design. Subjects who completed the phase 1/2 study enrolled in this open-label extension study, and continued receiving 300 mg cerliponase alfa qow. Cumulative data from both studies were used to evaluate long-term safety (assessed by analysis of adverse events (AEs)) and efficacy (assessed by changes in motor and language (ML) functions using the CLN2 clinical rating scale). Results. 24 subjects were initially treated with cerliponase alfa in the phase 1/2 study (9 male, 15 female, mean (SD) age 4.3 years (1.24)); 23 subjects enrolled in the extension study (74 to 124 weeks total exposure). All had AEs; most were Grade 1-2. Common AEs included pyrexia, hypersensitivity and convulsion. Nineteen (79%) subjects had at least one serious AE, which were mostly consistent with neurodegenerative disease in a pediatric population. Significant attenuation of the rate of decline in ML score (mean (95% CI): 0.32 (0.13, 0.52) points/ 48 weeks, pb0.0001) was observed compared with a rate of decline of 2.0 points/48 weeks in untreated patients. The responder (b2 point loss) rate at 81 weeks (87%, p = 0.0002) was unchanged compared to that observed at 48 weeks, suggesting a persistent treatment effect. Conclusions. These data suggest that enzyme replacement therapy with ICV-administered cerliponase alfa has an acceptable safety profile and a sustained effect over time. doi:10.1016/j.ymgme.2016.11.311
303 Characteristics of 27 patients with type 3 Gaucher disease: a descriptive analysis from the Gaucher Outcome Survey Ida Vanessa D Schwartza,b, Ozlem Goker-Alpanc, Priya Kishnanid, Ari Zimrane, Lydie Renaultf, Zoya Panahloof, Patrick Deegang, aHospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, bUniversidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, cLysosomal Disorders Unit and Center for Clinical Trials, O&O Alpan, LLC, Fairfax, VA, United States, dDuke University School of Medicine, Durham, NC, United States, eShaare Zedek Medical Center and the Hebrew University-Hadassah Medical School, Jerusalem, Israel, fShire, Zug, Switzerland, gAddenbrooke's Hospital, Cambridge, United Kingdom The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD)-specific registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status. Patients with neuronopathic type 3 GD (GD3) may show nonneurological manifestations similar to those of type 1 GD. We examined real-world data from GOS for insight into the disease characteristics and management of GD3 patients. The analysis included all GOS patients recorded as GD3. Patient demographics, disease parameters and treatment history were collected. Adverse event (AE) data were collected for patients who received velaglucerase alfa. For GOS patients with GD type data (970/1003), 27/970 (2.8%) were recorded as GD3 (median [range] age at GOS entry 17.4 [0.5-56.3] years, 12 [44.4%] male, 7 [25.9%] splenectomized). Most patients were from the USA (14/27, 51.9%); others were from the UK, Israel, and Brazil. None were Ashkenazi Jewish. The most common GBA1 genotype was L444P/ L444P (13/19, 68.4%). At analysis, 21 patients were on GD treatment