Competing for the treasure in exceptions
Authors: Timothy M. Cox
Journal: American Journal of Hematology (2013)

Dr. Samuel Johnson's dictum: “There are few ways in which a man can be more innocently employed than in getting money,” speaks well to therapeutic developments in Gaucher disease. Effective treatments for this ultra-rare disorder are an unparalleled achievement for (amongst other parties), those who inspired the 1983 US Orphan Drug Act; but with five agents licensed, and four already approved, reality far exceeds expectations 1. Often cared for by hematologists, patients with Gaucher disease are scarce (clinical prevalence figures ≈ 1 in 200,000), but this inborn error of glycosphingolipid metabolism is often rewarding to treat. Molecular targeting of acid β-glucocerebrosidase (EC 3.2.1.45) for complementation of the cognate activity that is deficient in the pathologic macrophages of bone marrow and visceral compartments was explored in Dr. Roscoe Brady's laboratory at the National Institutes of Health 2, 3. Clinical translation evolved from a tripartite partnership: the NIH, the embryonic biotech company, Genzyme (and its investors), and the National Gaucher Foundation. The latter, a patient organization, raised funds to mount a clinical trial with just 12 patients 4, the outcome of which proved critical for approval. Hematopoietic stem-cell transplantation, which supplies granulocyte-macrophage-colony-forming units as a source of macrophages competent in glycosphingolipid breakdown, reverses the cytopenias and heptaosplenomegaly with arrest of skeletal injury in Gaucher disease – and identifies the macrophage as a therapeutic target 5. Successful enzyme complementation depended on understanding that mannose receptors mediate incorporation of terminally mannosylated glycoproteins into the endo-lysosomal compartment of macrophages, in which exogenous N-acyl-sphingosyl-1-O-β-d glucosides with varying acyl and sphingosine moieties derived from cell membranes after phagocytosis are hydrolyzed 2, 3, 6. Sequential remodeling of human tissue-derived (alglucerase) and, later, recombinant human acid β-glucocerebrosidase (imiglucerase) using exoglycosidase treatment to reveal core mannose structures, promotes enzyme uptake by macrophage-rich organs 7, 8—as evinced later in living patients with Gaucher disease 9. The first product, alglucerase (Ceredase), derived from placentae, was approved as an orphan agent by the FDA in 1991; a recombinant protein expressed in Chinese hamster ovary cells, imiglucerase (Cerezyme), received marketing approval in 1994. Intravenous infusions of the remodeled glycoproteins correct the anemia, thrombocytopenia, visceromegaly, and growth retardation in infancy; the frequency of new bone complications is decreased and quality of life measures are improved 10. Timely enzyme therapy obviates the need for splenectomy 3—the mainstay of management in the pre-enzyme era but associated with complications including osteonecrosis 11. The safety of enzyme therapy compared with hematopoietic stem-cell transplantation has rendered the latter largely obsolete in Gaucher disease. The 1983 US Orphan Drug Act allows seven years marketing exclusivity for an approved drug 1. Orphan Medicinal Products legislation enacted by the European Commission in 2001 grants orphan drug status for diseases affecting fewer than 1 in 2,000 persons: marketing exclusivity in the EU lasts 10 years 12. Similar legal provisions are in place in Japan, Singapore, and Australia. Despite its salutary disease-modifying effects, and “standard of care” status for the non-neuronopathic manifestations of Gaucher disease, the high costs of this ultra-orphan enzyme therapy have long been controversial. Once approved, pricing for orphan drugs appears to be chiefly the manufacturer's call 13. The founding principle of orphan drug legislation is access to therapy and annual maintenance charges for Ceredase (about $150,000 for an adult), attracted criticism—not least because its development depended on charitable and tax-payer investment. Later, miglustat (Zavesca, Actelion), an iminosugar inhibitor of glycosphingolipid biosynthesis, received FDA approval in 2003 for mild-to-moderate Gaucher disease in the minority of patients for whom parenteral enzyme therapy is not an option 14. This agent costs about $100,000 per annum for the average adult. Notwithstanding the economy of scale of genetically engineered biological agents (and simple compounds), Cerezyme is also very costly. For seven years, the price was protected by Orphan Drug legislation; by 2008, the international market for imiglucerase exceeded 6,000 patients with monopoly revenues of $1,239 bn in a diversified $4.605 bn portfolio. Through charitable access programs, Genzyme commendably donates free drug under compassionate grounds in many countries; however imiglucerase remains beyond reach of many in East Europe, The Balkans, Middle East, Indian subcontinent, Asia including China, South America – and elsewhere. Manufactured at the Allston Landing facility in Massachusetts, the supply of Cerezyme and biologics for other lysosomal diseases unexpectedly shut down in 2009 15. Contamination of three bioreactors by vesivirus 2117, a 7.7 kb single-stranded RNA virus, was identified by Genzyme scientists in June 2009 3, 15. Production restarted at reduced capacity by April 2010 but was insufficient to meet ongoing demand. Early in 2011, Genzyme was purchased by Sanofi for $20.1 billion. The FDA approved a new production facility at Framingham in 2012 and provision for US patients was restored: plans to supply all patients receiving biologics produced by Genzyme–Sanofi are reported to be on schedule in 2013. The global supply crisis of Cerezyme has had far-reaching effects: hitherto, with its former dominant position, unless there were to be a major cost advantage, the therapeutic position of a biosimilar agent was unclear. Three articles in this issue of the American Journal of Hematology confirm that within the anticompetitive orphan framework, competition has a rightful place 16-18. Velaglucerase alfa is acid β-glucocerebrosidase produced by gene-activation in a human fibrosarcoma line (HT-1080) engineered by transkaryotic therapies (TKT) 19. With an enzyme therapy for Fabry disease approved by EMA but not FDA, TKT was taken over by Shire (Human Genetic Therapies) in 2005. To generate the therapeutic product, HT-1080 cells are cultured in the presence of kifunensine, a powerful inhibitor of processing mannosidase I—thus allowing primary biosynthesis of wild-type enzyme decorated by immature high mannose-type N-linked glycan chains for binding to mannose receptors 19-21. Efficacy of velaglucerase alfa was critically assessed in phase 3 clinical trials involving nearly 100 patients with anemia and either thrombocytopenia or organomegaly effectively naïve to therapy 19, 22. In the context of an established market and compassionate use program for Cerezyme, (honorably sustained), suitable subjects for clinical trials in a rare, heterogeneous disease were very scarce. Moreover, exigent regulators now required randomized double-blind controlled, dose-response, and even head-to-head (“non-inferiority”) studies—unusual in orphan diseases. In the event, the FDA and the EMA expeditiously approved velaglucerase alfa (VPRIV) in 2010 for non-neurological Gaucher disease in children and adults. Approval offered an invaluable alternative agent and expanded access. Shire also announced charges for VPRIV at a 15% savings over other commercial therapies in Gaucher disease. In this issue, Zimran et al. 16 report a multicenter, open-label, 12-month study to examine the safety (and efficacy) of velaglucerase alfa in 40 clinically stable patients with Gaucher disease who had previously received imiglucerase and at equal doses. Velaglucerase alfa was apparently well tolerated with most adverse events of mild or moderate severity. Hematologic values and spleen and liver volumes remained stable. Overall, the findings are compatible with those reported in the velaglucerase alfa phase 3 clinical trial program. Of note, one patient developed a grade 2 anaphylactoid reaction shortly after the first infusion and withdrew; antibodies to velaglucerase alfa were not detected using assays carried out and developed by Shire HGT 23. Gonzalez et al. 17 report a multiethnic trial conducted in 25 treatment naïve anemic patients at least 4 years old randomized to receive velaglucerase alfa at two doses (45 units per kg or 60 units per kg) every two weeks—both groups met the primary endpoint, an increase in hemoglobin concentration (2.4 g/dL). In the group receiving 60 units per kg, organ volumes decreased with a significant rise in mean platelet count (> 50 × 109/L); the lower dose induced attenuated responses. As expected, plasma/serum biomarker values reflecting disease activity (chitotriosidase and chemokine, CCL-18) also diminished. Inclusion of six children supports the pediatric indication. In a 9-month, randomized, double-blind, non-inferiority study, Ben Turkia et al. 18 compared velaglucerase alfa with imiglucerase—both given at 60 U/kg every other week in anemic patients aged > 3 years with either thrombocytopenia or organomegaly; in the event, nine were children, seven younger than 7 years old. The primary endpoint was the difference in mean change in hemoglobin concentration between groups, with 15 patients meeting protocol requirements in each arm. The mean treatment difference for hemoglobin concentration from baseline (velaglucerase alfa minus imiglucerase) was 0.14 g/dL (i.e., within the predefined non-inferiority margin of −1.0 g/dL), supporting the conclusion that velaglucerase alfa is not inferior to imiglucerase. No differences in secondary endpoints exceeding predefined fiducial limits occurred, although responses were marginally greater in the imiglucerase group. Two of the original patients treated by intention in this study were misdiagnosed. Eight of 17 in the original velaglucerase alfa group experienced adverse events attributed to the drug by the investigator, including allergic dermatitis (1) and a markedly prolonged activated partial thromboplastin time (1). Six of 17 patients in the original imiglucerase group had attributed adverse events, including severe chills in one. In neither group was any patient discontinued as a result of these events and apparently no patient receiving velaglucerase alfa developed antibodies to either agent; four patients receiving imiglucerase are reported to have IgG antibodies to imiglucerase—again, as determined in the sponsor's laboratory 23. In one case, these antibodies reacted with velaglucerase alfa. Clearly velaglucerase alfa is a credible substitute for imiglucerase, which, marketed as Cerezyme, is still the market lead. VPRIV, a biosimilar, is produced in a state-of-the art facility by innovative technology and short-term clinical studies support the hypothesis that the agent is “non-inferior” (see above); but such is the competitive undercurrent that it is often implied that in safety terms (immune reactions) velaglucerase alfa is preferable. While fully aware that velaglucerase alfa is the wild type human polypeptide sequence and that imiglucerase harbors a point mutation at the C-terminus due to an early cloning artifact (histidine at the penultimate residue, 495, is replaced by arginine, H495R), this reviewer marvels at the lack of agreed criteria and absence of consensus assay facilities for the determination of immunogenicity. Moreover, a ‘in a head-to-head trial between VPRIV and Cerezyme® (imiglucerase), only patients treated with VPRIV experienced statistically significant improvement in lumbar spine bone mineral density at nine months’, has found its way to the courts. In the light of the comparative studies here reported 16, 18 in your reviewer's opinion, beyond supply issues, any putative operational superiority in safety or efficacy terms between these agents will be difficult to prove. Another innovative enzyme preparation, taliglucerase alfa (Elelyso), a variant human acid β-glucocerebrosidase synthesized in carrot cells has been developed by Protalix and Pfizer. Using a plant-specific C-terminal sorting signal the nascent enzyme is targeted to storage vacuoles and displays terminal mannose residues on its complex glycans 24. The manufacturers have claimed greater uptake into macrophages in vitro than imiglucerase, although researchers at Genzyme reported that human enzyme with different oligomannose chain length had paradoxical effects on macrophage uptake; more than two mannose residues appeared to impair ingress. To facilitate secretion of the protein via the vacuolar pathway in plant cells, taliglucerase has unusual sugar sequences, including xylose. In 2012, the enzyme was the first plant-made pharmaceutical to win approval by the FDA; however, it has not so far broken the orphan drug marketing exclusivity granted by the EMA to VPRIV. The unusual niche of Gaucher disease has supported clinical development of eliglustat tartrate—a potent inhibitor of uridine diphosphate-glucose: N-acylsphingosine transferase, the enzyme which catalyzes the first committed step in the biosynthesis of glycosphingolipids. Eliglustat is currently undergoing phase 3 clinical trials by Genzyme–Sanofi 25. With an innovative action, oral inhibitors of substrate biosynthesis not only have the potential to address aspects of Gaucher disease in compartments refractory to enzyme targeting but also other glycosphingolipid disorders. While therapeutic discoveries in the microcosm of Gaucher disease illuminate molecular medicine, the faux anticompetitive environment of orphan legislation has irrevocably transformed clinical development. Bizarrely, the niche market for Cerezyme has incentivized continued diversification and exploration; and has encouraged development of, for example, orally active substrate inhibitors for this disease—arguably the new statins of glycosphingolipid metabolism and with far-reaching clinical implications. The biosimilar targeted enzyme concept became a focus for sustained process innovation and cost improvement, as demonstrated by velaglucerase alfa and taliglucerase alfa. Revealed beyond imagination, however, has been the indispensable value of alternative enzyme preparations in the face of an unprecedented crisis of supply within a monopoly industry: costs merely register competing attractions.