Participants

Thirty-five individuals who completed the placebo-controlled primary analysis period of the ASCEND trial continued in the open-label trial extension, including 17 of 18 individuals crossing over to olipudase alfa from placebo and all 18 participants from the original olipudase alfa group (Fig. 1). Baseline characteristics at study screening are shown in Table 1.

Fig. 1

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

Table 1 Demographics and baseline characteristics for all participants

Thirty-three of 35 participants completed year 2 of the open-label extension period. One participant withdrew due to COVID-19 travel restrictions, and another withdrew consent (Fig. 1). Furthermore, some individuals had missing efficacy evaluations during the extension period due to the COVID-19 pandemic and prolonged restriction of access to pulmonary function testing and radiological assessments (Note: there was no impact of the COVID-19 pandemic during the primary analysis period as the last visit was in October 2019).

Olipudase alfa treatment

Sixteen of the 17 individuals who crossed over to olipudase alfa from placebo reached the 3 mg/kg target dose of olipudase alfa during year 2, while one maintained a maximum dose of 2 mg/kg due to multiple missed infusions resulting from adverse events unrelated to study drug. All those from the initial olipudase alfa group received 3 mg/kg olipudase alfa dose during year 2. Some participants had periodic dose reductions or interruptions, sometimes requiring restarting the dose escalation. Among those completing year 2, six participants missed four or more infusions during year 2. The missed infusions resulted from COVID-19 pandemic issues for four of the six individuals. The mean ± SD treatment compliance during the extension period for those not impacted and those impacted by the COVID-19 pandemic was 92.7 ± 9.0% and 87.7 ± 14.9%, respectively. Data are not reported separately for individuals with missed infusions.

Efficacy analysesSphingomyelin accumulation in liver

Computer morphometry of high-resolution light microscopy images determined the mean ± SD percent tissue area occupied by sphingomyelin at baseline to be 28.5 ± 11.7% and 30.5 ± 9.7% in the original olipudase alfa and placebo groups, respectively (Fig. 2). Sphingomyelin clearance in liver biopsy samples was nearly complete after 1 year of olipudase alfa treatment within the former placebo group (mean ± SD percent tissue area occupied by sphingomyelin 1.6 ± 0.8%; LS mean ± SE percent change from baseline − 93.3 ± 5.0%). Within the group receiving olipudase alfa treatment for 2 years, the LS mean ± SE percent change from baseline was − 98.4 ± 2.0% (mean ± SD percent tissue area occupied by sphingomyelin 0.45 ± 0.6% at year 2).

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

Hepatomegaly

Mean liver volume at baseline indicated moderate hepatomegaly, which improved with olipudase alfa treatment (Fig. 3A). Within the former placebo group, the LS mean ± SE percent change from baseline was -30.7 ± 2.5% after 1 year of olipudase alfa treatment (mean ± SD 1.6 ± 0.5 MN at baseline to 1.1 ± 0.3 MN at 1 year) while the decrease in liver volume for those receiving olipudase alfa for 2 years (mean ± SD 1.4 ± 0.3MN at baseline and 0.95 ± 0.1 MN at year 2; LS mean ± SE percent change from baseline − 33.4 ± 2.2%) was slightly improved relative to year 1 (LS mean ± SE percent change from baseline -27.8 ± 2.5%) [10].

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

Individual liver volumes over time are shown in Supplemental Material Fig. 1A. Liver volumes improved with olipudase alfa treatment in all individuals, with most values in the mild category by 1 year of olipudase alfa treatment among those whose baseline values were moderate (18/23). One individual with severe hepatomegaly at baseline was in the moderate category after 1 year of treatment, with a decrease from baseline of 40% (3 MN to 1.8 MN).

Lipid profiles

Mean baseline levels for antiatherogenic and proatherogenic lipids and lipoproteins were below and above normal limits, respectively [10] (Additional file 1: Table S1). Additional file 1: Table S1 lists the mean observed values and percent changes from baseline over time. Within the former placebo group, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) LS mean ± SE percent changes from baseline were 59.8 ± 9.7% and − 27.5 ± 6.8%, respectively, after 1 year of treatment. Within the group continuing to receive olipudase alfa, HDL-C and LDL-C LS mean ± SE percent change from baseline were 64.4 ± 10.5% and − 23.0 ± 7.1%, respectively, after 2 years of treatment. Results were similar for other plasma lipoproteins and lipids, where levels of proatherogenic parameters (total cholesterol, triglycerides, apolipoprotein B, very low-density lipoprotein cholesterol, non-HDL-C) decreased, and levels of the antiatherogenic parameter apolipoprotein A1 increased (Additional file 1: Table S1).

Pre-infusion plasma transaminase levels

Mean ± SD transaminase levels at baseline were elevated (ALT: 44.7 ± 30.8 for the placebo group and 40.8 ± 28.3 IU/L for the olipudase alfa group (ULN 36 IU/L), reflecting increased levels for 50% of individuals (18/36 with levels > 36 IU/L). Levels improved over time with olipudase alfa treatment. The mean ± SD ALT after 1 year of olipudase alfa treatment for the former placebo group was 17.3 ± 6.8 (LS mean ± SE percent change from baseline − 45.2 ± 9.1%) and was 19.7 ± 8.5 IU/L (LS mean ± SE percent change from baseline − 32.0 ± 10.2%) after 2 years of olipudase alfa (Fig. 3B), and only one individual had an ALT level > 36 IU/L. Results were similar for AST (data not shown).

Splenomegaly

Mean baseline spleen volume reflected moderate to severe splenomegaly and decreased with olipudase alfa treatment (Fig. 4). Within the former placebo group, the LS mean ± SE percent change from baseline was − 35.9 ± 3.0% with 1 year of olipudase alfa treatment (mean ± SD spleen volume 11.2 ± 3.8 MN at baseline versus 7.7 ± 2.9 MN at 1 year). The LS mean percent change from baseline was − 47.0 ± 2.7% for the group receiving olipudase alfa for 2 years (11.7 ± 4.9 MN at baseline versus 6.1 ± 2.7MN at year 2) and reflected further improvement compared to year 1 (LS mean percent change from baseline − 39.5 ± 2.4%) [10].

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]

Individual spleen volumes over time are shown in Supplemental Material Fig. 1B. Spleen volumes improved with olipudase alfa treatment in all individuals by 6 months of olipudase alfa treatment. At their last assessment while receiving olipudase alfa, eight individuals improved from severe to moderate splenomegaly, and 11 improved from moderate to mild.

Thrombocytopenia

Mean baseline platelet counts reflected mild thrombocytopenia with a broad range of values from 63.6 to 207 × 109/L [10]. Within the former placebo group, mean ± SD platelet counts increased from 115.6 ± 36.3 × 109/L at baseline to 140.0 ± 50.8 × 109/L after 1 year of olipudase alfa (range 76–245 × 109/L; LS mean ± SE percent change from baseline 21.7 ± 6.4%). Among those with 2 years of olipudase alfa treatment, platelet counts increased from a mean ± SD of 107.2 ± 26.9 × 109/L at baseline to 133.6 ± 29.6 × 109/L at year 2 (range 95–199.5 × 109/L; LS mean ± SE percent change from baseline 24.9 ± 6.9%).

Pulmonary endpoints

Figure 5 shows the mean percent predicted DLCO over time. The mean baseline percent predicted DLCO indicated moderate impairment of the diffusing capacity of the lung [10]. Within the former placebo group, the mean ± SD percent predicted DLCO improved with 1 year of olipudase alfa treatment from 48.5 ± 10.8% at baseline to 61.9 ± 11.4% at year 1 (LS mean ± SE percent change from baseline 28.0 ± 6.2%). Within the group with 2 years of olipudase alfa treatment, the mean ± SD percent predicted DLCO improved from 49.4 ± 11.0% at baseline to 66.8 ± 15.4% at year 2 (LS mean ± SE percent change from baseline 28.5 ± 6.2%) and reflected continued improvement from the increase reported at year 1 (LS mean ± SE percent change from baseline 22.2 ± 3.4%) [10].

Fig. 5

Percent predicted diffusing  capacity of the lung for carbon monoxide (DLCO) 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 DLCO values > 80% were considered normal without impairment, > 60–80% mild impairment, 40–60% moderate impairment, and < 40% severe impairment [29, 30]

Individual percent predicted DLCO values over time are shown in Supplemental Material Fig. 1C. Among 10 individuals with 2 years of olipudase alfa treatment, impairment improved to mild or none for all but one individual with the most severe value at baseline. Individuals from the placebo group receiving olipudase alfa for 6 months to 1 year showed improved percent predicted DLCO over time.

The mean lung imaging HRCT scores at baseline for ground glass appearance reflected mild ILD [10], and mean scores improved (decreased) over time with olipudase alfa treatment (Table 2). An illustrative HRCT image from an individual with 2 years of olipudase alfa treatment (Fig. 6) shows clearance of ground glass opacities at year 1 that is maintained at year 2.

Table 2 Lung high-resolution computed tomography (HRCT) scores for ground glass appearanceFig. 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

Biochemical marker levels

Plasma levels of the sphingomyelin metabolite lyso-sphingomyelin were elevated at baseline in all participants (mean ± SD: 474 ± 199 μg/L in the placebo group and 384 ± 194 μg/L in the olipudase alfa group; overall range 157–830 μg/L; ULN 10 μg/L). Pre-infusion levels steadily decreased and stabilized after 6 months of olipudase alfa treatment (Fig. 7). The increase in the mean level observed at week 104 resulted from multiple missed olipudase alfa infusions by two participants within the group.

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.)

Treatment-emergent adverse events and other safety assessments

The treatment-emergent adverse event profile during olipudase alfa treatment is summarized in Table 3. Most events were mild or moderate in severity (572/584, 97.9%). No event led to permanent treatment discontinuation or study withdrawal. Among 13 serious events reported for ten participants, one event of extrasystoles in an individual with previously documented cardiomyopathy was considered possibly treatment-related. There were 151 events considered possibly related to treatment (Table 3). The most common related adverse event was headache among 10/35 individuals (28.6%), and most were categorized as IARs (53/59 events; Table 3). Among the 101 events classified as IARs, most (63/101, 62%) were reported in the first 6 months of treatment, and none were reported after 18 months. Four individuals had multiple transient increases in liver transaminases, and all resolved.

Table 3 Overview of treatment-emergent adverse events during treatment with olipudase alfa (1 year of treatment for those in the former placebo group crossing over to olipudase alfa and 2 years of treatment for the original olipudase alfa group)

No individual developed neutralizing anti-drug IgG antibodies that interfered with ASM enzyme cellular uptake through 2 years of olipudase alfa treatment. One individual had transient positivity for neutralizing antibodies that inhibited ASM catalytic activity after 1 year of olipudase alfa treatment without apparent impact on clinical responses.