Contributions
Abstract: EP694
Type: E-Poster Presentation
Session title: Enzymopathies, membranopathies and other anemias
Background
Acid sphingomyelinase deficiency (ASMD) is a rare, debilitating lysosomal storage disease with no approved treatment. Deficient ASM activity results in progressive pulmonary, hepatic, visceral, and hematologic dysfunction across a disease spectrum that includes central nervous system manifestations in the most severe patients. Disease awareness is low and diagnostic delays are common. It may fall to hematologists to evaluate and identify undiagnosed patients. Olipudase alfa (recombinant human ASM) is an enzyme replacement therapy in development for the non-central nervous system manifestations of ASMD.
Aims
Present safety and efficacy outcomes of 2 international clinical trials of dose-escalated olipudase alfa in children and adults with chronic ASMD.
Methods
ASCEND (NCT02004691/Sanofi Genzyme) is a Phase 2/3, multicenter, randomized, 52-week, double-blind, placebo-controlled trial in 36 adults with chronic ASMD randomized 1:1 to receive olipudase alfa or placebo. Independent primary efficacy endpoints were % change in % predicted lung carbon monoxide diffusing capacity (DLCO) and % change in spleen volume (for the USA, combined with change in Splenomegaly Related Score [SRS]) at Week 52. ASCEND-Peds (NCT02292654/Sanofi Genzyme) is a Phase 1/2 multicenter, open-label trial evaluating olipudase alfa in 20 children with chronic ASMD. Primary objective was safety over 64 weeks. Efficacy outcomes at 52 weeks included change in spleen volume, DLCO, and height Z-score. Both trials also evaluated changes in liver volume, platelet count, lipid profile, and biomarkers. Informed consent was obtained.
Results
In ASCEND (adult), least-square mean % change from baseline to Week 52 favored olipudase alfa over placebo for % predicted DLCO (+22.0% vs. +3.0%, p=0.0004), spleen volume (-39.4% vs. +0.5%, p<0.0001), liver volume (-31.7% vs. -1.4%, p<0.0001), and platelets (+16.8% vs. +2.5%, p=0.019), with differences seen by Week 26. SRS decreased in both groups (-8.0 for olipudase vs. -9.3 for placebo at Week 52, p=0.70). Biomarker and lipid profiles improved in olipudase-alfa compared to placebo-treated patients. No patient had a treatment-related serious adverse event or discontinued due to a treatment-emergent adverse event; 35/36 patients continue in an open-label extension.
In ASCEND-Peds (pediatric), splenomegaly and hepatomegaly improved in all patients at Week 52 (mean decrease ±SD: 49.2% ±9.7% and 40.6% ±9.4%, respectively, p<0.0001). Among 9 patients able to perform baseline DLCO testing, mean % predicted DLCO improved by 32.9% ±29.1% (relative change from baseline, p=0.0053). Platelet count improved by a mean ±SD of 34% ± 36% after 52 weeks of olipudase alfa (p=0.0003). Median height Z-score improved from -2.0 to -1.5 (p<0.0001). Biomarker and lipid profiles also improved. Treatment response was similar across age groups (<6 years, 6 to <12 years, 12 to <18 years). Eleven of 20 patients had infusion-associated reactions (mainly urticaria, pyrexia, and/or vomiting). Three patients had treatment-related serious adverse events: transient alanine aminotransferase increases in 1 patient, urticaria and rash in 1 patient, and anaphylactic reaction in 1 patient that was treated with a desensitization protocol. All patients completed the study and continue in an extension trial.
Conclusion
Olipudase alfa was well-tolerated in children and adults and, after 1 year of treatment, resulted in improved lung function, reductions in spleen and liver volumes, improved platelet counts and lipid profiles, reductions in disease biomarkers, and (in children) improved growth.
Keyword(s): Clinical trial, Enzyme replacement therapy, Lysosomal storage disease, Pulmonary
Abstract: EP694
Type: E-Poster Presentation
Session title: Enzymopathies, membranopathies and other anemias
Background
Acid sphingomyelinase deficiency (ASMD) is a rare, debilitating lysosomal storage disease with no approved treatment. Deficient ASM activity results in progressive pulmonary, hepatic, visceral, and hematologic dysfunction across a disease spectrum that includes central nervous system manifestations in the most severe patients. Disease awareness is low and diagnostic delays are common. It may fall to hematologists to evaluate and identify undiagnosed patients. Olipudase alfa (recombinant human ASM) is an enzyme replacement therapy in development for the non-central nervous system manifestations of ASMD.
Aims
Present safety and efficacy outcomes of 2 international clinical trials of dose-escalated olipudase alfa in children and adults with chronic ASMD.
Methods
ASCEND (NCT02004691/Sanofi Genzyme) is a Phase 2/3, multicenter, randomized, 52-week, double-blind, placebo-controlled trial in 36 adults with chronic ASMD randomized 1:1 to receive olipudase alfa or placebo. Independent primary efficacy endpoints were % change in % predicted lung carbon monoxide diffusing capacity (DLCO) and % change in spleen volume (for the USA, combined with change in Splenomegaly Related Score [SRS]) at Week 52. ASCEND-Peds (NCT02292654/Sanofi Genzyme) is a Phase 1/2 multicenter, open-label trial evaluating olipudase alfa in 20 children with chronic ASMD. Primary objective was safety over 64 weeks. Efficacy outcomes at 52 weeks included change in spleen volume, DLCO, and height Z-score. Both trials also evaluated changes in liver volume, platelet count, lipid profile, and biomarkers. Informed consent was obtained.
Results
In ASCEND (adult), least-square mean % change from baseline to Week 52 favored olipudase alfa over placebo for % predicted DLCO (+22.0% vs. +3.0%, p=0.0004), spleen volume (-39.4% vs. +0.5%, p<0.0001), liver volume (-31.7% vs. -1.4%, p<0.0001), and platelets (+16.8% vs. +2.5%, p=0.019), with differences seen by Week 26. SRS decreased in both groups (-8.0 for olipudase vs. -9.3 for placebo at Week 52, p=0.70). Biomarker and lipid profiles improved in olipudase-alfa compared to placebo-treated patients. No patient had a treatment-related serious adverse event or discontinued due to a treatment-emergent adverse event; 35/36 patients continue in an open-label extension.
In ASCEND-Peds (pediatric), splenomegaly and hepatomegaly improved in all patients at Week 52 (mean decrease ±SD: 49.2% ±9.7% and 40.6% ±9.4%, respectively, p<0.0001). Among 9 patients able to perform baseline DLCO testing, mean % predicted DLCO improved by 32.9% ±29.1% (relative change from baseline, p=0.0053). Platelet count improved by a mean ±SD of 34% ± 36% after 52 weeks of olipudase alfa (p=0.0003). Median height Z-score improved from -2.0 to -1.5 (p<0.0001). Biomarker and lipid profiles also improved. Treatment response was similar across age groups (<6 years, 6 to <12 years, 12 to <18 years). Eleven of 20 patients had infusion-associated reactions (mainly urticaria, pyrexia, and/or vomiting). Three patients had treatment-related serious adverse events: transient alanine aminotransferase increases in 1 patient, urticaria and rash in 1 patient, and anaphylactic reaction in 1 patient that was treated with a desensitization protocol. All patients completed the study and continue in an extension trial.
Conclusion
Olipudase alfa was well-tolerated in children and adults and, after 1 year of treatment, resulted in improved lung function, reductions in spleen and liver volumes, improved platelet counts and lipid profiles, reductions in disease biomarkers, and (in children) improved growth.
Keyword(s): Clinical trial, Enzyme replacement therapy, Lysosomal storage disease, Pulmonary