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Continued Clinical Improvements in Adults with Acid Sphingomyelinase Deficiency after 3-5 Years of Olipudase Alfa Treatment: Final ASCEND Trial Results

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Enzyme Replacement Therapy
  • Secondary Categories:
    • Enzyme Replacement Therapy
Introduction:
Acid sphingomyelinase deficiency (ASMD) is a rare, debilitating lysosomal storage disease characterized by pulmonary dysfunction, hepatosplenomegaly, and dyslipidemia. The first disease-specific treatment – olipudase alfa, IV recombinant-human ASM – is now approved for non-CNS manifestations of ASMD in >50 countries. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD (NCT02004691/Sanofi), olipudase-alfa-treated patients compared to placebo-treated patients (1:1 randomization) had statistically significant increases in %-predicted diffusing capacity for carbon monoxide (DLCO) and decreases in spleen and liver volume. We report long-term outcomes of the ASCEND trial. 



 

Methods:
Thirty-five of 36 patients continued in the open-label trial extension during which all patients received olipudase alfa (1 placebo patient withdrew during year 1). Results (all mean±SD) are reported by time on olipudase alfa; baseline values are prior to receiving active treatment.  Change from baseline values are reported using the last assessment value after at least 3 years of treatment.

Results:
All patients underwent olipudase alfa dose escalation (≥14 weeks) to a target dose of 3.0 mg/kg/2 weeks; dose was subsequently adjusted as needed due to adverse events and/or missed infusions. Overall, 29 patients completed the extension; median time on olipudase alfa was 4 years. One withdrawal was due to a related adverse event (rash); all others were unrelated to treatment (other/withdrawal of consent: three; COVID-19 travel restrictions: one; pregnancy: one). Time on olipudase alfa was 4.2±1.0 years; compliance was 90%±13%. Most patients had one or more missed assessment due to travel issues or laboratory closures related to the COVID-19 pandemic. At treatment baseline (n=35), patients had impaired pulmonary function (%-predicted DLCO: 49.6%±10.9%, evidence of ground glass opacities), hepatosplenomegaly (spleen volume: 11.5±4.5 multiples of normal [MN]; liver volume: 1.5±0.4 MN), dyslipidemia (HDL cholesterol: 22±8 mg/dL, LDL cholesterol: 142±32 mg/dL, triglycerides: 83±34 mg/dL); elevated liver transaminases (alanine aminotransferase [ALT]: 41±27  IU/L and aspartate aminotransferase [AST]: 42±29 IU/L), and mild thrombocytopenia (platelet count: 113±34 x 109 /L).  Mean levels of the ASMD disease biomarker plasma lyso-sphingomyelin were 45x the upper limit of normal and all patients had histologic evidence of sphingomyelin storage in liver (30.11%±11.63% tissue occupied by sphingomyelin). All measures of disease burden improved with olipudase alfa treatment. Percent-predicted DLCO increased in almost all patients along with complete or near complete clearance of ground glass opacities; all patients had improved hepatosplenomegaly, and liver transaminases normalized in most patients.  At the final assessment (3-5Y on olipudase alfa, mean ± SD), %-predicted DLCO improved by 37%±29% (n=25); mean spleen volume decreased by 58%±10% (n=31); mean liver volume decreased by 37%±11% (n=31); HDL cholesterol increased by 100%±64% (n=32); LDL cholesterol decreased by 27%±24% (n=32); triglycerides decreased by 29%±39% (n=32); mean high-resolution computed tomography  ground glass appearance score decreased by 98%±7% (n=22); ALT decreased by 31%±41% (n=32), AST decreased by 27%±40% (n=32) and platelet count improved by 28%±32% (n=32). Some treatment effects were achieved within the first year and sustained with long-term treatment (normalization of proatherogenic lipids and liver transaminases, clearance of ground glass opacities and liver sphingomyelin, substantial reduction in lyso-sphingomyelin) while others continued to show incremental improvement with time on olipudase alfa (DLCO, spleen and liver volumes, HDL cholesterol). No new safety issues emerged during the trial extension; overall, 98% of treatment-emergent adverse events were mild/moderate, with 1 treatment-related serious adverse event (extrasystole in patient with history of cardiomyopathy). 

Conclusion:
Adults with ASMD showed sustained or continuing improvement in key clinical outcomes after 3-5 years of olipudase alfa treatment. These results are consistent with what was observed in an earlier open-label Phase 1b trial in 5 adults and an open-label phase 1/2 trial in 20 children with ASMD.

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