Olipudase alfa for treatment of acid sphingomyelinase deficiency (ASMD): safety and efficacy in adults treated for 30 months

Melissa P Wasserstein, George A Diaz, Robin H Lachmann, Marie-Hélène Jouvin, Indrani Nandy, Allena J Ji, Ana Cristina Puga, Melissa P Wasserstein, George A Diaz, Robin H Lachmann, Marie-Hélène Jouvin, Indrani Nandy, Allena J Ji, Ana Cristina Puga

Abstract

Olipudase alfa, a recombinant human acid sphingomyelinase (ASM), is an enzyme replacement therapy for the treatment of nonneurologic manifestations of acid sphingomyelinase deficiency (ASMD). This ongoing, open-label, long-term study (NCT02004704) assessed safety and efficacy of olipudase alfa following 30 months of treatment in five adult patients with ASMD. There were no deaths, serious or severe events, or discontinuations during 30 months of treatment. The majority of adverse events were mild and included headache, nausea, and abdominal pain. No patient developed anti-drug antibodies and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Statistically significant reductions in liver (31%) and spleen (39%) volumes were maintained through 30 months of treatment. There was a mean increase in lung diffusing capacity of 35%, and clinically relevant improvements in infiltrative lung disease parameters. Lipid profiles improved in all patients. Improvements in bone mineral density of the spine were observed in some patients. Chitotriosidase in serum and lyso-sphingomyelin in dried blood spots decreased with olipudase alfa treatment, suggesting utility as biomarkers for monitoring treatment efficacy. Olipudase alfa is the first etiology-specific treatment in development for ASMD. This study demonstrates that treatment with olipudase alfa for 30 months is well-tolerated and associated with life-transforming sustained improvements in relevant disease clinical measures.

Conflict of interest statement

Conflict of interest

Melissa P Wasserstein has served as a consultant for Sanofi Genzyme.

George A Diaz declares that he has no conflict of interest.

Robin H Lachmann has received honoraria and support to attend scientific meetings from Sanofi Genzyme.

Marie-Hélène Jouvin, Indrani Nandy, Allena J Ji, and Ana Cristina Puga were employed by Sanofi Genzyme at the time of the study.

Informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

Figures

Fig. 1
Fig. 1
Mean plasma ceramide levels (a), mean lyso-sphingomyelin levels in dried blood spots (DBS) (b), and mean serum chitotriosidase activity (c) at Baseline (BL) and during treatment (30 months) with olipudase alfa. Normal range for plasma ceramide was 1.8–6.5 mg/L. The upper limit of normal for lyso-sphingomyelin in dried blood spots was <69 μg/L, and normal chitotriosidase serum levels were ≤181 nmol/h/mL (note: activity was not corrected for 2 patients heterozygous for a chitotriosidase null mutation)
Fig. 2
Fig. 2
Assessment of olipudase alfa on liver and spleen volume and lung disease. (a) Liver and spleen volumes were calculated by integrating cross-sectional magnetic resonant images and expressed as multiples of normal (MN) where normal spleen volume (L) was assumed to be 0.2% of body weight and normal liver volume (L) to be 2.5% of body weight. (b) Lung disease. By-patient percent predicted DLco, adjusted for hemoglobin (Hb), at baseline and during treatment were calculated from observed values for male and female patients (Crapo and Morris , Macintyre et al 2005). Degree of severity: 80% = lower limit of normal; >60%–79% = mild decrease; 40%–60% = moderate decrease; <40% = severe decrease. HRCT assessment of infiltrative lung disease at baseline and during treatment with olipudase alfa included ground glass appearance (GG), interstitial lung disease (ILD), and reticulonodular density (RD) scored on a 4 point system where 0 = No interstitial lung 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. 3
Fig. 3
Assessment of olipudase alfa on bone marrow burden. Femur. Bone marrow burden changes in the coronal femur of patient 2, (female, 32 years old at baseline). Note the extent of hypointensity of the proximal epiphysis bone marrow at screening in the T1-weighted (a) and T2-weighted (b) images compared with the reduced amount and slightly hypointense diaphyseal bone marrow following 30 months of treatment (T1-weighted, c and T2-weighted, d). Full vertical scale bar, 20 cm. Spine. Bone marrow burden in the sagittal lumbar spine of patient 2. At screening, diffuse infiltration of the bone marrow is observed with T1-weighted isointensity of the non-diseased intervertebral discs (a) and T2-weighted hyperintense signal intensity of presacral fat (b). After 30 months of treatment, the infiltration of the bone marrow remains unchanged (T1-weighted, c) while the presacral fat is improved to slightly hyperintense (T2-weighted, d). Full vertical scale bar, 20 cm
Fig. 3
Fig. 3
Assessment of olipudase alfa on bone marrow burden. Femur. Bone marrow burden changes in the coronal femur of patient 2, (female, 32 years old at baseline). Note the extent of hypointensity of the proximal epiphysis bone marrow at screening in the T1-weighted (a) and T2-weighted (b) images compared with the reduced amount and slightly hypointense diaphyseal bone marrow following 30 months of treatment (T1-weighted, c and T2-weighted, d). Full vertical scale bar, 20 cm. Spine. Bone marrow burden in the sagittal lumbar spine of patient 2. At screening, diffuse infiltration of the bone marrow is observed with T1-weighted isointensity of the non-diseased intervertebral discs (a) and T2-weighted hyperintense signal intensity of presacral fat (b). After 30 months of treatment, the infiltration of the bone marrow remains unchanged (T1-weighted, c) while the presacral fat is improved to slightly hyperintense (T2-weighted, d). Full vertical scale bar, 20 cm

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