Olipudase alfa enzyme replacement therapy for acid sphingomyelinase deficiency (ASMD): sustained improvements in clinical outcomes after 6.5 years of treatment in adults

Abstract

Background: Enzyme replacement therapy with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children and adults. An ongoing, open-label, long-term study (NCT02004704) assessed the safety and efficacy of olipudase alfa in 5 adults with ASMD.

Results: After 6.5 years of treatment, there were no discontinuations, no olipudase-alfa-related serious adverse events, and no new safety signals compared to earlier assessments. Most treatment-emergent adverse events were mild in intensity (1742/1766, 98.6%). Among treatment-related adverse events (n = 657), more than half were considered infusion-associated reactions (n = 403, 61.3%) such as headache, nausea, abdominal pain, arthralgia, pyrexia, and fatigue. No patient developed neutralizing anti-drug antibodies to cellular uptake, and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Improvements (decreases) in spleen and liver volumes progressed through 6.5 years (mean changes from baseline of -59.5% and -43.7%, respectively). There was a mean increase in diffusing capacity of the lung for carbon monoxide from baseline of 55.3%, accompanied by improvements in interstitial lung disease parameters. Lipid profiles at baseline indicated dyslipidemia. All patients had sustained decreases in pro-atherogenic lipid levels and increases in anti-atherogenic lipid levels following olipudase alfa treatment.

Conclusions: Olipudase alfa is the first disease-specific treatment for ASMD. This study demonstrates that long-term treatment with olipudase alfa is well-tolerated and is associated with sustained improvements in relevant disease clinical measures. NCT02004704 registered 26 November 2013, https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1 .

Keywords: Acid sphingomyelinase deficiency; Niemann-Pick disease type B and type A/B; Olipudase alfa; Recombinant human acid sphingomyelinase.

Fig. 1

Assessment of Olipudase Alfa on Spleen Volumes A. Individual patient spleen volumes by years of olipudase alfa treatment. Spleen volumes were calculated by integrating cross-sectional magnetic resonance images and expressed as multiples of normal (MN) where normal spleen volume was assumed to be 0.2% of body weight [18]. Severe and moderate splenomegaly were defined as > 15 and > 5 to ≤ 15MN, respectively [18]. Cutoffs of MN for severity of splenomegaly are indicated by horizontal lines B. Least square (LS) mean percent changes ± SE of the mean in spleen volume from baseline over time. All p values are nominal

Fig. 2

Assessment of Olipudase Alfa on Liver Volumes A. Individual patient liver volumes by years of olipudase alfa treatment. Liver volumes were calculated by integrating cross-sectional magnetic resonance images and expressed as multiples of normal (MN) where normal liver volume was assumed to be 2.5% of body weight [18]. Severe and moderate hepatomegaly were defined as > 2.5 and > 1.25 to ≤ 2.5MN [18], respectively. Cutoffs of MN for severity of hepatomegaly are indicated by horizontal lines B. Least square (LS) mean percent changes ± SE of the mean in liver volume from baseline over time. All p values are nominal

Fig. 3

Diffusing capacity of the lung for carbon monoxide (DL _CO ) adjusted for hemoglobin (Hb) A. Individual patient percent predicted DL_CO values. Cutoffs for impairment are indicated by horizontal lines for individual patient data (> 80% normal/no impairment, > 60% to ≤ 80% mild impairment, 40–60% moderate impairment, and < 40% severe impairment) [21] B. Least square (LS) mean percent change from baseline ± SE over time. All p values are nominal

Fig. 4

Assessment of interstitial lung disease by high-resolution computed tomography (HRCT). Mean HRCT scores over time for ground glass appearance, interstitial lung disease, and reticulo-nodular density. Scoring is based on a 4-point system where 0 = No disease; 1 = Mild (affecting 1–25% of the lung volume); 2 = Moderate (affecting 26–50% of the lung volume); 3 = Severe (affecting 51–100% of the lung volume)

Fig. 5

Ground Glass Appearance HRCT Images and Scores. Images and scores at baseline and through year 6 for the individual with the highest (worst) baseline score

Fig. 6

Plasma Lipid Profiles Over Time. Mean baseline values and mean percent changes from baseline are shown for pro-atherogenic (total cholesterol, LDL cholesterol and triglycerides), and anti-atherogenic l (HDL cholesterol) lipids. Data are shown for timepoints at which all five patients had a complete lipid profile

Fig. 7

Assessment of Bone Mineral Density Over Time. Individual lumbar spinal and femur T-scores