Drug Evaluation 5 Drug Evaluation 2015/05/28 Velaglucerase alfa in the treatment of Gaucher disease type 1: an update Clin. Invest. (Lond.) Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused K Nicole Weaver1, Gregory by deficiency of the enzyme acidβ -glucosidase. Enzyme replacement therapy is A Grabowski1 & Thomas A the standard of care for the treatment of GD type I. Currently, three preparations, Burrow*,1 1 including imiglucerase (Cerezyme®, Genzyme Corporation, MA, USA), taliglucerase Cincinnati Children’s Hospital Medical Center, Division of Human Genetics, ® ® alfa (Elelyso , Pfizer Inc., NY, USA) and velaglucerase alfa (VPRIV , Shire Human Genetic 3333 Burnet Avenue, MLC 4006, Therapies Inc., Dublin, Ireland), are commercially available. Here, we will review the Cincinnati, OH 45229-43039, USA recent literature addressing the safety and efficacy of velaglucerase, particularly *Author for correspondence: as compared with the other enzyme replacement therapy products, as well as the [email protected] treatment of GD type 1 with velaglucerase alfa. Keywords: anemia • enzyme replacement therapy • Gaucher disease • hepatomegaly • lysosomal storage disease • splenomegaly • thrombocytopenia • velaglucerase alfa Background GD types 2 and 3 have variably progressive Gaucher disease (GD), an autosomal reces- primary CNS manifestations in addition to sively inherited lysosomal storage disease, is the visceral signs observed in GD type 1. caused by mutations in the gene-encoding While individuals of all ages with GD type 1 acid β-glucosidase, GBA1. Insufficient activ- may develop disease signs and require treat- ity of this enzyme results in accumulation of ment, onset of GD type 2 is in infancy and glucosyl ceramide (GL-1) and other gluco- neurologic progression occurs rapidly, result- sphingolipids in visceral tissue. Their accu- ing in death in early childhood. GD type 3 mulation predominantly in cells of mono- has a more slowly progressive primary neu- cyte/macrophage origin lead to the majority rologic course. While the major clinical fea- of visceral manifestations. The worldwide tures of GD type 1 can be attributed to accu- 6 incidence of GD is estimated to be one in mulation of Gaucher cells, the pathogenesis 111,111. [1] . Three variants of GD are clas- of neurologic abnormalities in the neurono- sically described. Type 1, a variant that does pathic forms of GD are likely more complex, not manifest early onset rapid neuronopathic for example, related to inflammation, toxic- 2015 involvement, is the most commonly diag- ity of storage material, ultimately leading to nosed in the Western world, while the neu- neuronal death [1] . Although these classical ronopathic variants (types 2 and 3) appear to variants provide a useful clinical nosology, be the most prevalent worldwide [1] . types 2 and 3 variants represent a continuum The accumulation of ‘Gaucher cells,’ of phenotypes unified by the similar CNS glucosylceramide-engorged macrophages, pathogenesis of neuronal death [2]. in the liver, spleen and bone marrow leads Recombinant, exogenously produced acid to the primary clinical manifestations of β-glucosidase has been available since the type 1 disease, including hematologic (ane- early 1990s for intravenous administration mia, thrombocytopenia), visceral (hepa- (enzyme replacement therapy [ERT]) to tomegaly and splenomegaly) and skeletal patients with GD type I. The initial thera- (osteoporosis, lytic lesions and bone pain). peutic (alglucerase) and its successor (imiglu- part of 10.4155/CLI.15.19 © 2015 Future Science Ltd Clin. Invest. (Lond.) (2015) 5(6), 543–549 ISSN 2041-6792 543 Drug Evaluation Weaver, Grabowski & Burrow cerase) were/are manufactured to contain glycan struc- and early Phase III trials demonstrated that safety and tures with exposed mannose residues to allow their efficacy of velaglucerase are similar to imiglucerase recognition and internalization by macrophages via in adults and children, although seroconversion rates the mannose receptor. Although not approved for use with imiglucerase appear greater (seroconversion of 1% in patients with neuronopathic variants of GD, ERT for velaglucerase vs ~15% for imiglucerase) [9,10]. Both does have positive effects on visceral manifestations drugs are effective and have similar profiles of increas- of GD type 3 [3]. The blood–brain barrier prevents ing hemoglobin concentration and platelet counts, enzyme entry into the CNS, therefore, it is ineffec- and reducing liver and spleen volumes in children and tive at reversing or stabilizing the primary neurologic adults with type 1 GD. Like imiglucerase, velaglu- m anifestations [1] . cerase has a proportional dose-sensitive response, with Three ERT products are commercially available greater improvement in clinical parameters noted at and approved by the US FDA and EMA, among higher dosing [9]. other countries, for treatment of GD type 1 in all age The importance of having multiple products avail- groups: imiglucerase (Cerezyme®, Genzyme Corpora- able for ERT of a disease was emphasized by the 2009 tion, MA, USA), velaglucerase alfa (VPRIV®, Shire global shortage of imiglucerase. This article serves as Human Genetic Therapies Inc., Dublin, Ireland) and an update to Burrow and Grabowski’s 2011 review taliglucerase alfa (Elelyso®, Pfizer Inc., NY, USA). article, which addressed velaglucerase alfa treatment of Although conceptually similar, differences in produc- GD type 1 [9]. Key themes of clinically oriented pub- tion and structures of the products exist. Imiglucerase lications published since 2011 include safety and effi- is produced in Chinese hamster ovary cells engineered cacy of switching from imiglucerase to velaglucerase; to overexpress a recombinant analog of human acid safety and efficacy of velaglucerase as compared with β-glucosidase, velaglucerase alfa is produced in a imiglucerase; evaluation of the effect of velaglucerase human fibrosarcoma cell line to overexpress the endog- on GD-related bone disease and safety and efficacy of enous GBA1 using gene-activation technology and velaglucerase in pregnant woman afflicted by GD. taliglucerase is produced in carrot root cells expressing recombinant human glucocerebrosidase [4,5]. Related Safety & efficacy of switching from to these differences in production, the glycan chain imiglucerase to velaglucerase compositions of the three enzymes are distinct. Imi- The Early Access Program to velaglucerase in Israel glucerase contains short chain core mannose residues, was started in 2009 in response to the impending which are exposed via in vitro exoglycosidase treat- global shortage of imiglucerase. A retrospective study ment after expression and purification. Velaglucerase examined the safety and efficacy of velaglucerase contains longer chain high-mannose residues cre- in 71 patients [11] . All 71 were included in the safety ated by incorporation of a mannosidase I inhibitor report, but only 44 were included in efficacy evalua- (kifunensine) during cell culture. Like imiglucerase, tion because the remaining 27 were either on therapy taliglucerase contains a shorter chain of mannose resi- for less than 6 months or had not had follow-up evalu- dues, but it does not require postproduction modifi- ations at appropriate times. The cohort of 44 included cation for mannose exposure as plants naturally have five adult patients who were treatment-naive, three mannose-terminated glycoproteins [4–6]. The amino who had been off imiglucerase for 2–3 years and 36 acid sequences of the three enzymes are also distinct. patients (ten who were <16 years old) who were pre- Velaglucerase has an identical sequence to the natural viously treated with imiglucerase. Among the 36 pre- human protein, but imiglucerase and taliglucerase dif- viously treated patients, the duration without imiglu- fer at amino acid residue 495, with histidine replac- cerase therapy ranged from 0 (14 patients) to 9 months ing the natural arginine [5]. Taliglucerase also contains (one patient). The cohort of 27 included three patients an additional two amino acids at the N-terminus and who were withdrawn from taliglucerase trials due to seven amino acids at the C-terminus [5]. allergic reactions. Overall, two drug-related adverse Studies comparing velaglucerase and imiglucerase events (AEs) were described: One was an allergic reac- have demonstrated that the enzymatic properties are tion during the first infusion in a patient who previ- essentially identical, drug elimination is similar and in ously had an allergic reaction to taliglucerase, and vitro kinetic parameters and pH denaturation are also who was positive for IgG antibodies to velaglucerase. similar [4–8]. The two drugs performed similarly with The patient continued to use velaglucerase alfa with regards to half-life and efficacy in the mouse model of premedication. The other was a putatively fixed drug GD, and both showed comparable dose and duration- eruption on the chin of a switchover patient that dependent effect on the disappearance of Gaucher resolved spontaneously and never reappeared despite cells and glucosylceramide clearance. Phase I/II trials continued use of velaglucerase alfa. Improvements in 544 Clin. Invest. (Lond.) (2015) 5(6) future science group Velaglucerase alfa in the treatment of Gaucher disease type 1: an update Drug Evaluation the mean hemoglobin concentration, platelet count were no dose reductions in the Elstein study, 22 of and spleen and liver volumes were noted in both swi-