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Successful Within-Patient Dose Escalation of Olipudase Alfa in Acid Sphingomyelinase Deficiency

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Successful Within-Patient Dose Escalation of Olipudase Alfa in Acid Sphingomyelinase Deficiency Molecular Genetics and Metabolism 116 (2015) 88–97 Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency☆ Melissa P. Wasserstein a, Simon A. Jones b,HandreanSoranc,GeorgeA.Diaza, Natalie Lippa a,BethL.Thurbergd, Kerry Culm-Merdek e,EliasShamiyehe, Haig Inguilizian f,GeraldF.Coxg, Ana Cristina Puga g,⁎ a Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA b Manchester Centre for Genomic Medicine, St. Mary's Hospital, CMFT, University of Manchester, Manchester, UK c Cardiovascular Trials Unit, Central Manchester University Hospital, Manchester, UK d Pathology, Genzyme, a Sanofi company, Cambridge, MA, USA e Clinical and Experimental Pharmacology, Sanofi, Bridgewater, NJ, USA f Global Safety, Genzyme, a Sanofi company, Cambridge, MA, USA g Clinical Development, Genzyme, a Sanofi company, Cambridge, MA, USA article info abstract Article history: Background: Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme Received 14 April 2015 replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann–Pick Disease (NPD) A and B]. This Received in revised form 27 May 2015 open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escala- Accepted 27 May 2015 tion to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which Available online 30 May 2015 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 Keywords: olipudase alfa intravenously every 2 weeks for 26 weeks. Olipudase alfa Recombinant human acid sphingomyelinase Results: All patients successfully reached 3.0 mg/kg without serious or severe adverse events. One patient repeat- Dose escalation ed a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) Nonneuronopathic ASMD were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nau- Niemann–Pick disease type B sea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersen- sitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4 h 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. © 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction severe systemic manifestations, including hepatosplenomegaly, liver dysfunction, infiltrative lung disease, thrombocytopenia, anemia, and Acid sphingomyelinase deficiency [ASMD; Niemann–Pick dis- bone disease. In the most severe form with acute neuronopathic disease ease (NPD) types A and B] is a rare lysosomal storage disorder that (NPD A), patients have little to no residual ASM activity, with onset of affects 0.25–.40 per 100,000 births depending on NPD subtype [1, systemic manifestations, failure-to-thrive, and rapidly progressive neu- 2]. Mutations in the SMPD1 gene encoding the lysosomal enzyme rodegeneration during infancy, and death by 3 years of age [4].Incon- acid sphingomyelinase (ASM) result in the accumulation of trast, patients with chronic nonneuronopathic ASMD (NPD B) have sphingomyelin primarily within reticuloendothelial cells and hepato- higher residual ASM activity and variable ages of onset from infancy cytes of affected patients [3]. Sphingomyelin accumulation produces to adulthood. Systemic manifestations are heterogeneous and include hepatosplenomegaly, pancytopenia, infiltrative lung disease, and a pro-atherogenic lipid profile. Growth restriction during childhood and delayed puberty are common manifestations [5–7]. Patients with NPD ☆ Trial registration: Clintrials.gov trial registration # NCT01722526. B may have a normal lifespan; however, some die prematurely from ⁎ Corresponding author at: Genzyme, a Sanofi company, 500 Kendall St., Cambridge, MA, USA. pulmonary or liver disease, or from hemorrhage, including splenic E-mail address: [email protected] (A.C. Puga). rupture [5]. http://dx.doi.org/10.1016/j.ymgme.2015.05.013 1096-7192/© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). M.P. Wasserstein et al. / Molecular Genetics and Metabolism 116 (2015) 88–97 89 There are no approved, etiology-based therapies for ASMD. Intrave- which they were monitored for at least 3 h post-infusion. Patients nous administration of enzyme replacement therapy (ERT) with who experienced adverse events greater than mild in severity were to olipudase alfa (recombinant human acid sphingomyelinase), has repeat the same dose or receive a reduced dose at the next infusion. shown promising results in the ASM knock-out (ASMKO) mouse with Dose escalation could only proceed if adverse events were mild or dose-dependent reductions in tissue sphingomyelin levels up to absent. 3.0 mg/kg [8,9]. Doses up to 3.0 mg/kg were able to reduce sphingomyelin levels in hard to reach target tissues, including lung. 2.3. Outcome measures High doses (≥10.0 mg/kg), however, caused severe toxicity character- ized by systemic inflammation and cardiovascular shock. Concomitant Safety was the primary objective and assessments included physical elevations in plasma ceramide and cytokine levels in ASMKO animals, examinations and vital signs, cardiac evaluations, clinical laboratory along with the absence of toxicity in normal mice administered up to tests, safety biomarkers [ceramide, high-sensitivity C-reactive protein 30 mg/kg olipudase alfa, suggested that the observed toxicity in the (hsCRP), interleukin (IL)-6, IL-8], liver function [aspartate aminotrans- ASMKO mice was a result of rapid production of sphingomyelin ferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl catabolite(s) rather than a nonspecific drug reaction. Consistent with transferase (GGT)], immune responses, continuous monitoring of treat- this hypothesis, the high-dose toxicity could be completely prevented ment emergent adverse events (TEAEs) and infusion associated reac- by prior treatment of ASMKO mice with several low doses of olipudase tions (IARs), and histopathological evaluations of liver biopsy samples. alfa to gradually debulk accumulated sphingomyelin [9]. Secondary objectives included pharmacodynamic and pharmacoki- Olipudase alfa is in clinical development for treatment of the system- netic assessments of olipudase alfa. Pharmacodynamic parameters in- ic (nonneurological) manifestations of ASMD, as the enzyme is unable cluded measurement of plasma sphingomyelin, and ceramide levels to cross the blood–brain barrier. A phase 1 single-ascending-dose by liquid chromatography-tandem mass spectrometry (LC/MS/MS) study of olipudase alfa in adult patients with NPD B identified and liver sphingomyelin content by both LC/MS/MS and computer- 0.6 mg/kg as the maximum tolerated first dose [10]. The dose-limiting assisted morphometric analysis of hepatic histopathology (MetaMorph toxicity manifested as hyperbilirubinemia in a patient later diagnosed Imaging Processing and Analysis software (Version 6.3; Universal Imag- with Gilbert syndrome who received a dose of 1.0 mg/kg. At ing Corporation)) [11]. Serial blood samples for pharmacokinetic evalu- doses ≥ 0.3 mg/kg, constitutional symptoms (e.g., pyrexia, myalgia, ations were collected at doses ≥0.3 mg/kg before and immediately after and nausea) and changes in inflammatory mediators (e.g., C-reactive infusion plus 1, 4, 8, 12, 24, 48, and 72 h after infusion. Plasma concen- protein and cytokines) began 12 to 24 h postinfusion and were consis- trations of olipudase alfa were determined using a validated enzyme tent with an acute phase response triggered by the innate immune sys- linked immunosorbent assay (ELISA) at Genzyme. tem [10]. This is in contrast to the typical hypersensitivity-type, Exploratory efficacy outcomes included quantitative measurement infusion-associated reactions (IARs), e.g., pyrexia, rash, urticaria, chills, of spleen and liver volumes using abdominal MRI; qualitative assess- and chest tightness, observed with other ERTs that develop in some pa- ment of infiltrative lung disease using high-resolution computed to- tients after several infusions, and which are often associated with the mography (HRCT) [12] and chest x-ray; and pulmonary function tests formation of antibodies against the infused protein. (PFT) using American Thoracic Society guidelines [13]. Fasting lipid pro- The unique adverse drug reactions to olipudase alfa, which were dose- files included measurement of total cholesterol (TC), low density lipo- dependent and attributable to the rapid production of sphingomyelin
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