- Email: [email protected]
Development of an algorithm to facilitate diagnosis of Gaucher disease
Abstracts / Molecular Genetics and Metabolism 126 (2019) S17–S156
231 Long term biomarker analysis to assess cardiac involvement in Fabry disease Lauren M. Mason, Renuka Limgala, Ozlem Goker-Alpan, Lysosomal & Rare Disorders Research & Treatment Center, Fairfax, VA, United States In Fabry disease (FD), α-galactosidaseA deficiency leads to the accumulation of globotriaosylceramide (GL-3), triggering a pathologic cascade that causes progressive damage to multiple organs, including the heart. Disease heterogeneity and lack of meaningful short term clinical endpoints are the major obstacles in managing patients with FD. While disease onset occurs in early childhood, the diagnosis is typically made only after life-threatening cardiac, renal or cerebrovascular complications in the fourth to fifth decade of life. Therefore, clinically significant markers are necessary for early detection of specific organ involvement and monitoring FD progression. In current study, 80 patients with FD (33M:50F -80 yr, mean age: 36 yr) were seen between 2010-2018. 25 patients (13 M:12F 372 yr, mean age: 51 yr) were diagnosed with cardiomyopathy (LVPWd (cm)N1.0 and/or LVMI (g/m2) (M)N 81 and (F)N61), and 7 to have severe cardiac disease (LVPWdN1.5 and LVMI (M)N91 and (F)N 69). Three females with mild/moderate involvement had extensive cardiac fibrosis. Median treatment duration was 10 years among the treated (19/25). All but one with severe cardiac disease, were treated for 10 years or more. Glycolipid biomarkers, plasma lyso-GL3, plasma GL3 and urine GL3, and cardiac specific markers, high-sensitive troponins, BNP and Galectin 3 levels were compared to organ involvement. Plasma lyso-GL3 was found to be significantly higher in the cohort with severe cardiac involvement (p=0.0086). This difference was more prominent in females (p=0.0025). Troponin I and Troponin T were significantly elevated in all patients with Fabry related cardiomyopathy (pb0.0001, p=0.0062 respectively). BNP was elevated in patients with severe cardiomyopathy (pb0.0001). This information is important clinically because it shows that organ damage continues despite intervention later in FD. Disease progression once triggered, continues even in patients under long-term therapy. Early treatment in FD is critical to prevent irreversible end organ damage.
doi:10.1016/j.ymgme.2018.12.247
232 FACTs Fabry gene therapy clinical trial: Two-year data Jeffrey A. Medina,b, Aneal Khanc, Ju Huangb, Dwayne Barberb, C. Anthony Rupard, Christiane Auray-Blaise, Graeme Fraserf, Daniel H. Fowlerg, Armand Keatingb, Michael L. Westh, Ronan Foleyf, aMedical College of Wisconsin, Milwaukee, WI, United States, bUniversity Health Network, Toronto, ON, Canada, cUniversity of Calgary, Calgary, AB, Canada, dWestern University, London, ON, Canada, eUniversite de Sherbrooke, Sherbrooke, QC, Canada, fMcMaster University, Hamilton, ON, Canada, gRapa Therapeutics, Rockville, MD, United States, h Dalhousie University, Halifax, NS, Canada Fabry disease is due to a deficiency in alpha-galactosidase A (agal A) activity. Enzyme therapy is used to treat Fabry disease although the cost is high and biweekly infusions are required longterm. We have shown that when a-gal A is overexpressed in cells, a portion of the hydrolase is secreted and can be taken up and used functionally by unmodified bystander cells. Based on this concept,
S99
and building on extensive preclinical data we generated previously, we have launched a multi-center, phase I clinical trial in Canada using gene transfer to treat men with Fabry disease of the classical phenotype (clinicaltrials.gov#NCT02800070) and to determine the feasibility and safety of this procedure. The protocol involves mobilization of Fabry patient hematopoietic stem/progenitor cells (HSPCs), ex vivo recombinant lentivirus-mediated gene transfer of a codon-optimized human a-gal A cDNA into those cells, and infusion of the transduced HSPCs into minimally ablated autologous recipients. The first Fabry patient received a single dose of vectortransduced cells in January 2017. Since then two other Fabry patients have also received the transduced cell product (with more patients in the queue). With regards to safety - no serious adverse events have occurred in any Fabry patient in our trial to date. We now report results for patient 1 at two years post-infusion of the transduced cells. We tracked a-gal A activity in leukocytes and plasma, vector copy number in peripheral blood and bone marrow cells, antibody titers in plasma, and changes to enzyme substrates and catabolites in both plasma and urine. Results show durable engraftment and persistence of vector-transduced HSPCs in this Fabry patient that are functionally enabled to produce a-gal A continually. This protocol appears to be feasible and safe however, application to other patients and long-term effectiveness are still to be studied
doi:10.1016/j.ymgme.2018.12.248
233 Development of an algorithm to facilitate diagnosis of Gaucher disease Atul Mehtaa, Oliver Rivero-Ariasb, Magy Abdelwahabc, Samantha Campbella, Annabel McMillana, David Kuterd, aRoyal Free Hospital, London, United Kingdom, bNuffield Department of Population Health, Oxford, United Kingdom, cCairo University Paediatric Hospital, Cairo, Egypt, dMassachusetts General Hospital, Boston, MA, United States Collating the opinions of 22 global experts, the Gaucher Earlier Diagnosis Consensus (GED-C) initiative determined which risk factors are potential indicators of Gaucher disease (GD). The aim is to create an algorithm based on these risk factors that can differentiate possible GD from other diseases in which such factors occur. A feasibility study was conducted to assess whether patients in three disease groups (liver disease [LD] haematologic malignancy [HM] immune thrombocytopenic purpura [ITP] N=25 per group) who had similar risk factors to GD patients (N=25) could inform development of this algorithm. Pearson's chi-squared test was used in all comparisons. Family history of GD was only associated with GD (n=8 overall, pb0.001). Jewish ancestry was more frequent with GD than LD (n=9 vs n=0 p=0.006) but differences between GD and either HM (n=5) or ITP (n=4) were non-significant. More patients with GD and LD had splenomegaly (n=17, both) than did patients with HM (n=4) or ITP (n=0 overall, pb0.001), and significantly more patients with GD had hepatomegaly (n=14) than did patients with LD (n=3), HM (n=1) or ITP (n=0 overall, pb0.001). Bone pain was more frequent with GD (n=17) than with LD (n=0), HM (n=2), or ITP (n=0 overall, pb0.001), and hyperferritinaemia was also more frequent with GD (n=14 versus LD [n=7], HM [n=5], ITP [n=5] overall, p=0.004). Thrombocytopenia affected more patients with ITP (n=25) than with GD (n=14 p=0.002) and was more severe with ITP than GD (pb0.001). Fewer patients with HM (n=9)
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Abstracts / Molecular Genetics and Metabolism 126 (2019) S17–S156
than GD were thrombocytopenic (p=0.038) the difference between LD (n=22) and GD was non-significant. More patients with LD (n=19) than GD (n=9) had gammopathy (pb0.001) compared with GD, no other differences in gammopathy were significant, nor were any differences in incidence of anaemia. Collectively, these betweendisease differences suggest that development of a GD algorithm may be feasible.
doi:10.1016/j.ymgme.2018.12.249
234 Influence of enzyme replacement therapy on the evolution of ocular manifestationsin a cohort of Fabry disease patients Langis Michauda, aFreeline Therapeutics, Stevenage, United Kingdom Purpose: To compare evolution of ocular manifestations of Fabry patients between those on ERT and those without ERT Methods: Observational study conducted between 2012 and 2017. Subjects were seen on an annual basis and ocular manifestations were assessed. Testing included: slit lamp (anterior segment), threshold visual field (FDT), corneal biomechanics (hysteresis and resistance factor), intraocular pressure, dilated fundus examination. Results: 28 patients completed the study after 5 years. Among them, 18 (10 hemizygotes and 8 hétérozygotes) received algaside alpha or beta prior and during the study. Another group of 10 heterozygotes, not taking ERT, were also included. A few clinical findings did not evolve: conjunctival, retinal and upper lid vessels tortuosity, and cornea verticilata. Many others increased in prevalence and/or severity: micro-aneurysms, corneal haze, anterior and posterior sub-capsular cataracts. Hemizygotes on ERT showed increased signs at baseline vs others. Heterozygotes on ERT showed a marked evolution of ocular manifestations over time, especially for the presence of microaneurysms. All patients under ERT demonstrated evolution over time. Conclusion: ERT does not influence the prevalence and the progression of ocular manifestations over time, compared with subjects not treated. Heterozygotes on ERT progressed more and, after 5 years, were at the same level than hemizygotes on ERT for a majority of clinical findings.
doi:10.1016/j.ymgme.2018.12.250
235 Liver directed AAV gene therapy to treat Gaucher disease Carlos J. Mirandaa, Jenny McIntoshb, Azadeh Kiaa, Miriam Canavesea, Jonathan Foleya, Doyoung Leeb, Paniz Hosseinia, Jey Jeyakumara, Rose Sheridana, Romuald Corbaua, Amit C. Nathwania, aFreeline Therapeutics, Stevenage, United Kingdom, bUniversity College London, London, United Kingdom Gaucher disease (GD) is characterised by the deposition of glucocerebroside in cells of the macrophage-monocyte system caused by impaired production of the enzyme beta-glucocerebrosidase (GCase). Over the past 20 years, enzymatic replacement therapy (ERT) was developed as the standard of care for GD. However, since it requires continuous treatment (every other week infusions), it results in a high cumulative cost for this type of therapy, and more importantly in a significant patient treatment burden. Over the same period, gene
therapy has emerged as a very promising avenue of treatment for various monogenic genetic disorders, allowing sustained levels of transgene expression upon a single treatment. We hypothesised that liver-directed gene therapy could be used to ameliorate GD disease. For this purpose, we used an adeno-associated viral vector (AAV) to drive the expression of human GBA gene in the liver of mice. Four weeks after a single injection we observed a steady and dose-dependent elevation of GCase in the bloodstream of treated mice. Upon tissue analysis, noticeable uptake of human GCase was observed in organs affected in GD such as spleen, lung and bone marrow. Marker analysis performed in spleen tissue showed positive staining for human GCase in macrophages. Further improvement in our AAV constructs, obtained by applying rational design and codon optimisation algorithms, has allowed us to achieve an additional five-fold increase in GCase circulating in the bloodstream, resulting in increased uptake by macrophages. Overall, these data show that upon a single injection of a liver-expression-directed AAV vector it is possible to achieve elevation of GCase in the bloodstream that results in greater GCase bioavailability compared to current ERT. Therefore, this approach offers enhanced therapeutic potential for the treatment of GD.
doi:10.1016/j.ymgme.2018.12.251
236 Two years of efficacy of oral eliglustat in treatment-naïve and switch patients enrolled in the International Collaborative Gaucher Group Gaucher registry Pramod K. Mistrya, Manisha Balwanib, Joel Charrowc, Priya Kishnanid, Claus Niederaue, Monica R. McClainf, aYale University School of Medicine, New Haven, CT, United States, bIcahn School of Medicine at Mount Sinai, New York, NY, United States, cNorthwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States, dDuke University, Durham, NC, United States, eKatholische Kliniken Oberhausen, Oberhausen, Germany, f Sanofi Genzyme, Cambridge, MA, United States Eliglustat (Cerdelga, Sanofi Genzyme) is a first-line oral substrate reduction therapy for adults with Gaucher disease type 1 (GD1) with extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (N90% of patients). Clinical trials have demonstrated long-term clinical improvement in all major disease manifestations in treatment-naïve patients and long-term stability in patients switching from enzyme-replacement therapy (ERT). We report real-world data from treatment-naïve and ERT-switch patients enrolled in the International Collaborative Gaucher Group Gaucher (ICGG) Registry (NCT00358943/Sanofi Genzyme) who were treated with eliglustat for ≥1 year. Of 400 eliglustat-treated patients in the Registry as of July 2018, 238 had baseline and 2-year data (±1 year) for ≥1 key disease parameter: 15 treatment-naïve (0 splenectomized) and 223 switch (43 splenectomized). Overall, 213 were from the United States, the first country to approve eliglustat. In treatment-naïve patients, mean hemoglobin improved from 12.5 to 13.8 g/dL (p=0.004 n=14) mean platelet count improved from 113 to 158 x109/L (p=0.0002 n=13) mean spleen volume decreased from 9.4 to 4.2 multiples of normal (MN) (p=0.01, n=5), and mean liver volume was unchanged: 1.2 vs 1.1 MN (non-significant, n=5). In non‑splenectomized-switch patients, mean hemoglobin remained normal: 14.3 vs 14.1 g/dL (p=0.01, n=169) mean platelet count remained normal: 181 vs 184 x109/L (non-significant, n=169) mean spleen volume decreased from 2.9 to 2.5 MN (p=0.002, n=63), and
231 Long term biomarker analysis to assess cardiac involvement in Fabry disease Lauren M. Mason, Renuka Limgala, Ozlem Goker-Alpan, Lysosomal & Rare Disorders Research & Treatment Center, Fairfax, VA, United States In Fabry disease (FD), α-galactosidaseA deficiency leads to the accumulation of globotriaosylceramide (GL-3), triggering a pathologic cascade that causes progressive damage to multiple organs, including the heart. Disease heterogeneity and lack of meaningful short term clinical endpoints are the major obstacles in managing patients with FD. While disease onset occurs in early childhood, the diagnosis is typically made only after life-threatening cardiac, renal or cerebrovascular complications in the fourth to fifth decade of life. Therefore, clinically significant markers are necessary for early detection of specific organ involvement and monitoring FD progression. In current study, 80 patients with FD (33M:50F -80 yr, mean age: 36 yr) were seen between 2010-2018. 25 patients (13 M:12F 372 yr, mean age: 51 yr) were diagnosed with cardiomyopathy (LVPWd (cm)N1.0 and/or LVMI (g/m2) (M)N 81 and (F)N61), and 7 to have severe cardiac disease (LVPWdN1.5 and LVMI (M)N91 and (F)N 69). Three females with mild/moderate involvement had extensive cardiac fibrosis. Median treatment duration was 10 years among the treated (19/25). All but one with severe cardiac disease, were treated for 10 years or more. Glycolipid biomarkers, plasma lyso-GL3, plasma GL3 and urine GL3, and cardiac specific markers, high-sensitive troponins, BNP and Galectin 3 levels were compared to organ involvement. Plasma lyso-GL3 was found to be significantly higher in the cohort with severe cardiac involvement (p=0.0086). This difference was more prominent in females (p=0.0025). Troponin I and Troponin T were significantly elevated in all patients with Fabry related cardiomyopathy (pb0.0001, p=0.0062 respectively). BNP was elevated in patients with severe cardiomyopathy (pb0.0001). This information is important clinically because it shows that organ damage continues despite intervention later in FD. Disease progression once triggered, continues even in patients under long-term therapy. Early treatment in FD is critical to prevent irreversible end organ damage.
doi:10.1016/j.ymgme.2018.12.247
232 FACTs Fabry gene therapy clinical trial: Two-year data Jeffrey A. Medina,b, Aneal Khanc, Ju Huangb, Dwayne Barberb, C. Anthony Rupard, Christiane Auray-Blaise, Graeme Fraserf, Daniel H. Fowlerg, Armand Keatingb, Michael L. Westh, Ronan Foleyf, aMedical College of Wisconsin, Milwaukee, WI, United States, bUniversity Health Network, Toronto, ON, Canada, cUniversity of Calgary, Calgary, AB, Canada, dWestern University, London, ON, Canada, eUniversite de Sherbrooke, Sherbrooke, QC, Canada, fMcMaster University, Hamilton, ON, Canada, gRapa Therapeutics, Rockville, MD, United States, h Dalhousie University, Halifax, NS, Canada Fabry disease is due to a deficiency in alpha-galactosidase A (agal A) activity. Enzyme therapy is used to treat Fabry disease although the cost is high and biweekly infusions are required longterm. We have shown that when a-gal A is overexpressed in cells, a portion of the hydrolase is secreted and can be taken up and used functionally by unmodified bystander cells. Based on this concept,
S99
and building on extensive preclinical data we generated previously, we have launched a multi-center, phase I clinical trial in Canada using gene transfer to treat men with Fabry disease of the classical phenotype (clinicaltrials.gov#NCT02800070) and to determine the feasibility and safety of this procedure. The protocol involves mobilization of Fabry patient hematopoietic stem/progenitor cells (HSPCs), ex vivo recombinant lentivirus-mediated gene transfer of a codon-optimized human a-gal A cDNA into those cells, and infusion of the transduced HSPCs into minimally ablated autologous recipients. The first Fabry patient received a single dose of vectortransduced cells in January 2017. Since then two other Fabry patients have also received the transduced cell product (with more patients in the queue). With regards to safety - no serious adverse events have occurred in any Fabry patient in our trial to date. We now report results for patient 1 at two years post-infusion of the transduced cells. We tracked a-gal A activity in leukocytes and plasma, vector copy number in peripheral blood and bone marrow cells, antibody titers in plasma, and changes to enzyme substrates and catabolites in both plasma and urine. Results show durable engraftment and persistence of vector-transduced HSPCs in this Fabry patient that are functionally enabled to produce a-gal A continually. This protocol appears to be feasible and safe however, application to other patients and long-term effectiveness are still to be studied
doi:10.1016/j.ymgme.2018.12.248
233 Development of an algorithm to facilitate diagnosis of Gaucher disease Atul Mehtaa, Oliver Rivero-Ariasb, Magy Abdelwahabc, Samantha Campbella, Annabel McMillana, David Kuterd, aRoyal Free Hospital, London, United Kingdom, bNuffield Department of Population Health, Oxford, United Kingdom, cCairo University Paediatric Hospital, Cairo, Egypt, dMassachusetts General Hospital, Boston, MA, United States Collating the opinions of 22 global experts, the Gaucher Earlier Diagnosis Consensus (GED-C) initiative determined which risk factors are potential indicators of Gaucher disease (GD). The aim is to create an algorithm based on these risk factors that can differentiate possible GD from other diseases in which such factors occur. A feasibility study was conducted to assess whether patients in three disease groups (liver disease [LD] haematologic malignancy [HM] immune thrombocytopenic purpura [ITP] N=25 per group) who had similar risk factors to GD patients (N=25) could inform development of this algorithm. Pearson's chi-squared test was used in all comparisons. Family history of GD was only associated with GD (n=8 overall, pb0.001). Jewish ancestry was more frequent with GD than LD (n=9 vs n=0 p=0.006) but differences between GD and either HM (n=5) or ITP (n=4) were non-significant. More patients with GD and LD had splenomegaly (n=17, both) than did patients with HM (n=4) or ITP (n=0 overall, pb0.001), and significantly more patients with GD had hepatomegaly (n=14) than did patients with LD (n=3), HM (n=1) or ITP (n=0 overall, pb0.001). Bone pain was more frequent with GD (n=17) than with LD (n=0), HM (n=2), or ITP (n=0 overall, pb0.001), and hyperferritinaemia was also more frequent with GD (n=14 versus LD [n=7], HM [n=5], ITP [n=5] overall, p=0.004). Thrombocytopenia affected more patients with ITP (n=25) than with GD (n=14 p=0.002) and was more severe with ITP than GD (pb0.001). Fewer patients with HM (n=9)
S100
Abstracts / Molecular Genetics and Metabolism 126 (2019) S17–S156
than GD were thrombocytopenic (p=0.038) the difference between LD (n=22) and GD was non-significant. More patients with LD (n=19) than GD (n=9) had gammopathy (pb0.001) compared with GD, no other differences in gammopathy were significant, nor were any differences in incidence of anaemia. Collectively, these betweendisease differences suggest that development of a GD algorithm may be feasible.
doi:10.1016/j.ymgme.2018.12.249
234 Influence of enzyme replacement therapy on the evolution of ocular manifestationsin a cohort of Fabry disease patients Langis Michauda, aFreeline Therapeutics, Stevenage, United Kingdom Purpose: To compare evolution of ocular manifestations of Fabry patients between those on ERT and those without ERT Methods: Observational study conducted between 2012 and 2017. Subjects were seen on an annual basis and ocular manifestations were assessed. Testing included: slit lamp (anterior segment), threshold visual field (FDT), corneal biomechanics (hysteresis and resistance factor), intraocular pressure, dilated fundus examination. Results: 28 patients completed the study after 5 years. Among them, 18 (10 hemizygotes and 8 hétérozygotes) received algaside alpha or beta prior and during the study. Another group of 10 heterozygotes, not taking ERT, were also included. A few clinical findings did not evolve: conjunctival, retinal and upper lid vessels tortuosity, and cornea verticilata. Many others increased in prevalence and/or severity: micro-aneurysms, corneal haze, anterior and posterior sub-capsular cataracts. Hemizygotes on ERT showed increased signs at baseline vs others. Heterozygotes on ERT showed a marked evolution of ocular manifestations over time, especially for the presence of microaneurysms. All patients under ERT demonstrated evolution over time. Conclusion: ERT does not influence the prevalence and the progression of ocular manifestations over time, compared with subjects not treated. Heterozygotes on ERT progressed more and, after 5 years, were at the same level than hemizygotes on ERT for a majority of clinical findings.
doi:10.1016/j.ymgme.2018.12.250
235 Liver directed AAV gene therapy to treat Gaucher disease Carlos J. Mirandaa, Jenny McIntoshb, Azadeh Kiaa, Miriam Canavesea, Jonathan Foleya, Doyoung Leeb, Paniz Hosseinia, Jey Jeyakumara, Rose Sheridana, Romuald Corbaua, Amit C. Nathwania, aFreeline Therapeutics, Stevenage, United Kingdom, bUniversity College London, London, United Kingdom Gaucher disease (GD) is characterised by the deposition of glucocerebroside in cells of the macrophage-monocyte system caused by impaired production of the enzyme beta-glucocerebrosidase (GCase). Over the past 20 years, enzymatic replacement therapy (ERT) was developed as the standard of care for GD. However, since it requires continuous treatment (every other week infusions), it results in a high cumulative cost for this type of therapy, and more importantly in a significant patient treatment burden. Over the same period, gene
therapy has emerged as a very promising avenue of treatment for various monogenic genetic disorders, allowing sustained levels of transgene expression upon a single treatment. We hypothesised that liver-directed gene therapy could be used to ameliorate GD disease. For this purpose, we used an adeno-associated viral vector (AAV) to drive the expression of human GBA gene in the liver of mice. Four weeks after a single injection we observed a steady and dose-dependent elevation of GCase in the bloodstream of treated mice. Upon tissue analysis, noticeable uptake of human GCase was observed in organs affected in GD such as spleen, lung and bone marrow. Marker analysis performed in spleen tissue showed positive staining for human GCase in macrophages. Further improvement in our AAV constructs, obtained by applying rational design and codon optimisation algorithms, has allowed us to achieve an additional five-fold increase in GCase circulating in the bloodstream, resulting in increased uptake by macrophages. Overall, these data show that upon a single injection of a liver-expression-directed AAV vector it is possible to achieve elevation of GCase in the bloodstream that results in greater GCase bioavailability compared to current ERT. Therefore, this approach offers enhanced therapeutic potential for the treatment of GD.
doi:10.1016/j.ymgme.2018.12.251
236 Two years of efficacy of oral eliglustat in treatment-naïve and switch patients enrolled in the International Collaborative Gaucher Group Gaucher registry Pramod K. Mistrya, Manisha Balwanib, Joel Charrowc, Priya Kishnanid, Claus Niederaue, Monica R. McClainf, aYale University School of Medicine, New Haven, CT, United States, bIcahn School of Medicine at Mount Sinai, New York, NY, United States, cNorthwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States, dDuke University, Durham, NC, United States, eKatholische Kliniken Oberhausen, Oberhausen, Germany, f Sanofi Genzyme, Cambridge, MA, United States Eliglustat (Cerdelga, Sanofi Genzyme) is a first-line oral substrate reduction therapy for adults with Gaucher disease type 1 (GD1) with extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (N90% of patients). Clinical trials have demonstrated long-term clinical improvement in all major disease manifestations in treatment-naïve patients and long-term stability in patients switching from enzyme-replacement therapy (ERT). We report real-world data from treatment-naïve and ERT-switch patients enrolled in the International Collaborative Gaucher Group Gaucher (ICGG) Registry (NCT00358943/Sanofi Genzyme) who were treated with eliglustat for ≥1 year. Of 400 eliglustat-treated patients in the Registry as of July 2018, 238 had baseline and 2-year data (±1 year) for ≥1 key disease parameter: 15 treatment-naïve (0 splenectomized) and 223 switch (43 splenectomized). Overall, 213 were from the United States, the first country to approve eliglustat. In treatment-naïve patients, mean hemoglobin improved from 12.5 to 13.8 g/dL (p=0.004 n=14) mean platelet count improved from 113 to 158 x109/L (p=0.0002 n=13) mean spleen volume decreased from 9.4 to 4.2 multiples of normal (MN) (p=0.01, n=5), and mean liver volume was unchanged: 1.2 vs 1.1 MN (non-significant, n=5). In non‑splenectomized-switch patients, mean hemoglobin remained normal: 14.3 vs 14.1 g/dL (p=0.01, n=169) mean platelet count remained normal: 181 vs 184 x109/L (non-significant, n=169) mean spleen volume decreased from 2.9 to 2.5 MN (p=0.002, n=63), and