Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency

Abstract

Background: Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy.

Methods: Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks.

Results: All patients successfully reached 3.0mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4h across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed.

Conclusions: This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD.

Trial registration: ClinicalTrials.gov NCT01722526.

Keywords: Dose escalation; Niemann–Pick disease type B; Nonneuronopathic ASMD; Olipudase alfa; Recombinant human acid sphingomyelinase.

Figure 1. Mean High Sensitivity C-Reactive Protein (hsCRP) Levels Pre- and Post-Infusion from Baseline to Week 16

Arrow indicates when patients escalated to the 3.0 mg/kg dose (3 patients at week 12 and 2 patients at week 14) Post-infusion hsCRP levels remained in the normal range for the remainder of the study (data not shown).

Figure 2. Mean Plasma Ceramide Levels Pre- and Post-Infusion from Baseline to Week 26

Absolute values ± SD.

Figure 3. Exploratory Disease Biomarkers. Mean Percentage Changes in ACE, Chitotriosidase, and CCL18 Levels from Baseline to Week 26

Absolute values ± SD at Baseline and Week 26 are shown in Table 3. ACE = angiotensin converting enzyme; CCL18 = chemokine (C-C motif) ligand 18

Figure 4. Effect of Olipudase Alfa on Liver Sphingomyelin Content and Spleen and Liver Volume after 26 Weeks

A. High-resolution light microscopy (HRLM) images of liver biopsy tissue sections stained with modified toluidine blue (600x) from Patient 2. Arrows indicate sphingomyelin (dark purple) accumulation in lysosomes of hepatocytes (H) and Kupffer cells (K). B. Mean sphingomyelin content in liver quantified using histomorphometric analysis of HLRM at baseline and week 26 using MetaMorph Imaging Processing and Analysis software (Version 6.3; Universal Imaging Corporation). All sphingomyelin identified and measured by this method represents the disease process. The normal value for this parameter in a non-ASMD liver sample is zero. C. By-patient spleen volumes in multiples of normal (MN) at baseline and week 26 (22); D. By-patient liver volumes (MN) at baseline and week 26. (22)

Figure 5. Effect of Olipudase Alfa on Lung Infiltrative Lung Disease and Function

A. High-resolution CT images (Level 2) of lung at baseline and week 26 (Patient 1). The straight arrow in each image refers to reticular changes best seen at the periphery. The block arrow refers to ground glass opacity. Both were improved from baseline to week 26, with only mild residual abnormality at week 26. B. Qualitative assessment of infiltrative lung disease showing the interstitial, reticulonodular, and ground glass appearance components. There were no findings of consolidation, or pleural thickening. Areas of the right and left lungs were evaluated at 4 anatomic levels (1= level of the aortic arch; 2= level of the carina; 3= midway between the tracheal carina and 1 cm above the hemidiaphragm; 4=1 cm above the hemidiaphragm) based on a 4-point scale: 0=no disease; 1=mild disease affecting 1–25% of lung volume (green); 2=moderate, affecting 26–50% of lung volume (yellow); 3=severe, affecting 51–100% of lung volume(red). Imaging data were evaluated by external central readers blinded to patient and time point; C. By-patient percent predicted DLco levels at baseline and week 26. Normal DLco: >80%; Mildly reduced: >60% to ≤80%; Moderately reduced: 40–60%; Severely reduced: <40%

Figure 6. Mean Percentage Changes in Fasting Lipid Profiles from Baseline to Week 26

Absolute values ± SD at baseline and week 26 are shown in Table 3. HDL = high density lipoprotein; LDL = low density lipoprotein; VLDL = very low density lipoprotein