Continued improvement in disease manifestations of acid sphingomyelinase deficiency for adults with up to 2 years of olipudase alfa treatment: open-label extension of the ASCEND trial

Abstract

Background: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DL_CO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment.

Results: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DL_CO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DL_CO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event.

Conclusion: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691.

Keywords: Acid sphingomyelinase deficiency; Dose escalation; Lung diffusing capacity; Niemann–Pick type A/B; Niemann–Pick type B; Organomegaly; Recombinant human acid sphingomyelinase.

Fig. 1

Patient disposition during the placebo-controlled and open-label extension periods of the ASCEND trial

Fig. 2

Sphingomyelin burden in liver tissue. The percent liver tissue area occupied by sphingomyelin is shown throughout the study during placebo or olipudase alfa treatment periods. Means are shown above and below the lines for the group crossing over to olipudase alfa from placebo and the olipudase alfa group, respectively. Liver tissue was obtained from biopsies at baseline, week 52, and week 104. Liver sphingomyelin burden was assessed by computer morphometry of high-resolution light microscopy imaging of stained tissue

Fig. 3

Liver volume in multiples of normal (MN) and alanine aminotransferase (ALT) during placebo or olipudase alfa treatment periods. A Liver volume over time. Means are shown above and below the lines for the group crossing over to olipudase alfa from placebo and the olipudase alfa group, respectively. The dashed lines indicate hepatomegaly severity cutoffs [26]. B ALT levels over time. Means are shown above and below the lines for the group crossing over to olipudase alfa from placebo and the olipudase alfa group, respectively. The dashed line indicates the upper limit of normal

Fig. 4

Spleen volume in multiples of normal (MN) during placebo or olipudase alfa treatment periods. Means are shown above and below the lines for the group crossing over to olipudase alfa from placebo and the olipudase alfa group, respectively. Splenomegaly severity cutoffs are indicated by the dashed lines [26]

Fig. 5

Percent predicted diffusing  capacity of the lung for carbon monoxide (DL_CO) adjusted for hemoglobin and barometric pressure during placebo or olipudase alfa treatment periods. Means are shown above and below the lines for the group crossing over to olipudase alfa from placebo and the olipudase alfa group, respectively. Percent predicted DL_CO values > 80% were considered normal without impairment, > 60–80% mild impairment, 40–60% moderate impairment, and < 40% severe impairment [29, 30]

Fig. 6

Lung high-resolution computed tomography (HRCT). Illustrative high-resolution computerized tomography image of ground glass opacity, reflecting sphingomyelin-filled infiltrates at baseline and after 1 or 2 years of olipudase alfa treatment

Fig. 7

Pre-infusion plasma lysosphingomyelin levels during placebo or olipudase alfa treatment periods. The dashed line indicates the upper limit of normal. (Note: The increase in mean level at week 104 resulted from multiple missed infusions by two participants.)