ABSTRACT
Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal disease characterized by pulmonary dysfunction, hepatosplenomegaly, and dyslipidemia. Olipudase alfa, intravenous-recombinant-human ASM, is in late-stage development (Sanofi Genzyme) for non-central-nervous-system manifestations of ASMD. We report 2-year outcomes for 33/36 ASMD adults with splenomegaly (mean baseline spleen volume: 11.3 multiples of normal [MN]) and respiratory impairment (mean baseline percent-predicted-diffusing capacity for carbon monoxide [DLCO]: 49.3%) who participated in the 1-year double-blind placebo-controlled primary-analysis period [PAP] of the ASCEND trial of olipudase alfa (NCT02004691) and completed a second year in the open-label extension. Patients underwent gradual dose-escalation to 3.0 mg/kg/2-weeks. During the PAP, olipudase-alfa-treated compared to placebo-treated patients (1:1 randomization) had statistically significant increases in DLCO and decreases in spleen and liver volume. One placebo patient withdrew during year-1. In year-2, improvements in former placebo patients paralleled the olipudase-alfa group in the PAP (all values: ANCOVA LS-mean percent change from trial baseline ± SEM): DLCO increased 28.0 ± 6.2% (n = 10);spleen volume decreased 36.0 ± 3.0% (n = 11);liver volume decreased 30.7 ± 2.5% (n = 11). Olipudase-alfa patients who received 2 years of treatment continued improving: DLCO increased 28.5 ± 6.2%, n = 10 (year-1 increase: 22.2 ± 3.4%, n = 17);spleen volume decreased 47.0 ± 2.7%, n = 14 (year-1 decrease: 39.5 ± 2.4%, n = 17), liver volume decreased 33.4 ± 2.2%, n = 14 (year-1 decrease: 27.8 ± 2.5, n = 17). Improvements in dyslipidemia, liver function, liver sphingomyelin clearance, and plasma lyso-sphingomyelin in former placebo patients paralleled those seen in olipudase-alfa patients in the PAP;continuing olipudase-alfa patients maintained these benefits in year-2. Overall, 99% of treatment-emergent adverse events were mild/moderate, with one treatment-related serious adverse event. During year-2, six patients missed ≥1 assessments and one patient discontinued due to COVID-19 travel restrictions;one additional patient discontinued (withdrawal of consent). In summary, during year-2 of ASCEND, crossover-placebo patients improved to a similar extent as olipudase-alfa patients in year-1 and patients continuing on olipudase alfa showed sustained or further improvements.