Orphan Drugs

  • Maurizio Scarpa
  • Cinzia Bellettato
  • Christina Lampe
Living reference work entry


Pharmacological research and biotechnology sciences have always been focused at developing new therapeutic strategies capable of modifying diseases’ natural history and improving patients’ quality of life all around the world. Nevertheless, many diseases are still lacking specific therapies, and this is particularly true for the so-called orphan diseases where the terms orphan is used to designate diseases that affect only small numbers of individuals. Due to their relatively low prevalence, these diseases are not considered economically appealing and viable under ordinary marketing conditions by pharmaceutical companies. Moreover, developing a new medicine is extremely challenging due to the related high costs and low rate of success. To overcome these problems, special orphan drug legislations have been introduced across the globe in order to encourage and stimulate the research, the development, and the approval of drugs capable to treat rare diseases. The advent of orphan drug legislations has marked an important milestone in pharmacological development and has raised hope for the most neglected patients such as those affected by neuronopathic lysosomal storage diseases (LSDs). These disorders are in fact chronic progressive diseases that have a devastating impact on the patient and family. Being characterized by high morbidity and mortality, they still constitute a big challenge for the therapeutic area. Many of orphan drugs available today can in fact almost reverse the natural history of the disease in peripheral organs (i.e., enzyme replacement therapy) but unfortunately, due to the presence of the blood–brain barrier (BBB), are still unable to effectively reach the central nervous system to stop the disease lethal progression. This chapter will discuss in detail these issues, evaluating the advancements in the field that have already been done and that have led to the marketing approval for several orphan drugs for LSDs. An analysis of their strength and weaknesses will be done, and a description of the most important innovative initiatives using different approaches to specifically deliver molecules across the BBB will be performed.


Enzyme Replacement Therapy Fabry Disease Gauche Disease Orphan Drug Pompe Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References and Further Reading

  1. Alegra T, Vairo F, de Souza MV, Krug BC, Schwartz IV (2012) Enzyme replacement therapy for Fabry disease: a systematic review and meta-analysis. Genet Mol Biol 35(Suppl 4):947–954PubMedCentralCrossRefPubMedGoogle Scholar
  2. Appelqvist H, Waster P, Kagedal K, Ollinger K (2013) The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol 5(4):214–226CrossRefPubMedGoogle Scholar
  3. Bali RK, Bos L, Gibbons MC, Ibell SR (2013) Rare diseases in the age of health 2.0. Springer, HeidelbergGoogle Scholar
  4. Bellettato CM, Scarpa M (2010) Pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis 33(4):347–362CrossRefPubMedGoogle Scholar
  5. Biegstraaten M, van Schaik IN, Aerts JM, Hollak CE (2008) ‘Non-neuronopathic’ Gaucher disease reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher disease patients and a systematic review of the literature. J Inherit Metab Dis 31(3):337–349CrossRefPubMedGoogle Scholar
  6. Braun MM, Farag-El-Massah S, Xu K, Coté TR (2010) Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years. Nat Rev Drug Dis 9:519–522Google Scholar
  7. Braunlin E, Rosenfeld H, Kampmann C, Johnson J, Beck M, Giugliani R, Guffon N, Ketteridge D, Sa Miranda CM, Scarpa M et al (2013) Enzyme replacement therapy for mucopolysaccharidosis VI: long-term cardiac effects of galsulfase (Naglazyme(R)) therapy. J Inherit Metab Dis 36(2):385–394PubMedCentralCrossRefPubMedGoogle Scholar
  8. Byrne BJ, Falk DJ, Clement N, Mah CS (2012) Gene therapy approaches for lysosomal storage disease: next-generation treatment. Hum Gene Ther 23(8):808–815PubMedCentralCrossRefPubMedGoogle Scholar
  9. Calias P (2012) Drug delivery to the CNS. Drug Deliv Transl Res 2(3):143–144CrossRefPubMedGoogle Scholar
  10. Calias P, Banks WA, Begley D, Scarpa M, Dickson P (2014) Intrathecal delivery of protein therapeutics to the brain: a critical reassessment. Pharmacol Ther 144(2):114–122CrossRefPubMedGoogle Scholar
  11. Chien YH, Hwu WL, Lee NC (2013) Pompe disease: early diagnosis and early treatment make a difference. Pediatr Neonatol 54(4):219–227CrossRefPubMedGoogle Scholar
  12. Cox TM (2006) Biomarkers in lysosomal storage diseases. In: Mehta A, Beck M, Sunder-Plassmann G (eds) Fabry disease: perspectives from 5 years of FOS. Oxford PharmaGenesis, OxfordGoogle Scholar
  13. Cox TM, Cachon-Gonzalez MB (2012) The cellular pathology of lysosomal diseases. J Pathol 226(2):241–254CrossRefPubMedGoogle Scholar
  14. Cox-Brinkman J, van Breemen MJ, van Maldegem BT, Bour L, Donker WE, Hollak CE, Wijburg FA, Aerts JM (2008) Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III. J Inherit Metab Dis 31(6):745–752CrossRefPubMedGoogle Scholar
  15. da Silva EM, Strufaldi MW, Andriolo RB, Silva LA (2014) Enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II (Hunter syndrome). Cochrane Database Syst Rev 1, CD008185PubMedGoogle Scholar
  16. de Ru MH, Boelens JJ, Das AM, Jones SA, van der Lee JH, Mahlaoui N, Mengel E, Offringa M, O’Meara A, Parini R et al (2011) Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J Rare Dis 6:55PubMedCentralCrossRefPubMedGoogle Scholar
  17. Dear JW, Lilitkarntakul P, Webb DJ (2006) Are rare diseases still orphans or happily adopted? The challenges of developing and using orphan medicinal products. Br J Clin Pharmacol 62(3):264–271PubMedCentralCrossRefPubMedGoogle Scholar
  18. Decker C, Yu ZF, Giugliani R, Schwartz IV, Guffon N, Teles EL, Miranda MC, Wraith JE, Beck M, Arash L et al (2010) Enzyme replacement therapy for mucopolysaccharidosis VI: growth and pubertal development in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase. J Pediatr Rehabil Med 3(2):89–100PubMedCentralPubMedGoogle Scholar
  19. Development IoMUCoARDRaOP (2010) Rare diseases and orphan products: accelerating research and development. National Academies Press (US), Washington, DCGoogle Scholar
  20. El Dib RP, Nascimento P, Pastores GM (2013) Enzyme replacement therapy for Anderson-Fabry disease. Cochrane Database Syst Rev 2, CD006663PubMedGoogle Scholar
  21. Fellgiebel A, Gartenschlager M, Wildberger K, Scheurich A, Desnick RJ, Sims K (2014) Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease. Cerebrovasc Dis 38:448–456. S. Karger AG, Basel, SwitzerlandGoogle Scholar
  22. Feltmate K, Janiszewski PM, Gingerich S, Cloutier M (2015) Delayed access to treatments for rare diseases: who’s to blame? Respirology 20(3):361–369CrossRefPubMedGoogle Scholar
  23. Ferraz MJ, Kallemeijn WW, Mirzaian M, Herrera Moro D, Marques A, Wisse P, Boot RG, Willems LI, Overkleeft HS, Aerts JM (2014) Gaucher disease and Fabry disease: new markers and insights in pathophysiology for two distinct glycosphingolipidoses. Biochim Biophys Acta 1841(5):811–825CrossRefPubMedGoogle Scholar
  24. Fox JE, Volpe L, Bullaro J, Kakkis ED, Sly WS (2015) First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient. Mol Genet Metab 114(2):203–208CrossRefPubMedGoogle Scholar
  25. Franco P (2013) Orphan drugs: the regulatory environment. Drug Discov Today 18(3–4):163–172CrossRefPubMedGoogle Scholar
  26. Germain DP, Giugliani R, Hughes DA, Mehta A, Nicholls K, Barisoni L, Jennette CJ, Bragat A, Castelli J, Sitaraman S et al (2012) Safety and pharmacodynamic effects of a pharmacological chaperone on alpha-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies. Orphanet J Rare Dis 7:91PubMedCentralCrossRefPubMedGoogle Scholar
  27. Gieselmann V (1995) Lysosomal storage diseases. Biochim Biophys Acta 1270:103–136CrossRefPubMedGoogle Scholar
  28. Gieselmann V (2006) Cellular pathophysiology of lysosomal storage diseases. In: Mehta A, Beck M, Sunder-Plassmann G (eds) Fabry disease: perspectives from 5 years of FOS. Oxford PharmaGenesis, OxfordGoogle Scholar
  29. Graul AI, Cruces E, Stringer M (2015) The year’s new drugs & biologics, 2014: Part I. Drugs Today (Barc) 51(1):37–87. United States: 2015 Prous Science, S.A.U. or its licensorsGoogle Scholar
  30. Grubb JH, Vogler C, Levy B, Galvin N, Tan Y, Sly WS (2008) Chemically modified beta-glucuronidase crosses blood–brain barrier and clears neuronal storage in murine mucopolysaccharidosis VII. Proc Natl Acad Sci U S A 105:2616–2621PubMedCentralCrossRefPubMedGoogle Scholar
  31. Grubb JH, Vogler C, Sly WS (2010) New strategies for enzyme replacement therapy for lysosomal storage diseases. Rejuvenation Res 13(2–3):229–236PubMedCentralCrossRefPubMedGoogle Scholar
  32. Haddley K (2014) Elosulfase alfa. Drugs Today (Barc) 50(7):475–483. United States: 2014 Prous Science, S.A.U. or its licensorsGoogle Scholar
  33. Haffner M, Torrent-Farnell J, Maher PD (2008) Does orphan drug legislation really answer the needs of patients? Lancet 371:2041–2044CrossRefPubMedGoogle Scholar
  34. Harmatz P, Ketteridge D, Giugliani R, Guffon N, Teles EL, Miranda MC, Yu ZF, Swiedler SJ, Hopwood JJ (2005) Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): results after 48 weeks in a phase 2 open-label clinical study of recombinant human N-acetylgalactosamine 4-sulfatase. Pediatrics 115:e681–e689CrossRefPubMedGoogle Scholar
  35. Harmatz P, Giugliani R, Schwartz I, Guffon N, Teles EL, Miranda MC, Wraith JE, Beck M, Arash L, Scarpa M et al (2006) Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. J Pediatr 148:533–539CrossRefPubMedGoogle Scholar
  36. Hawkins-Salsbury JA, Reddy AS, Sands MS (2011) Combination therapies for lysosomal storage disease: is the whole greater than the sum of its parts? Hum Mol Genet 20(R1):R54–R60PubMedCentralCrossRefPubMedGoogle Scholar
  37. Heemstra HE, de Vrueh RL, van Weely S, Buller HA, Leufkens HG (2008) Predictors of orphan drug approval in the European Union. Eur J Clin Pharmacol 64(5):545–552PubMedCentralCrossRefPubMedGoogle Scholar
  38. Hendriksz CJ, Harmatz P, Beck M, Jones S, Wood T, Lachman R, Gravance CG, Orii T, Tomatsu S (2013) Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA. Mol Genet Metab 110(1–2):54–64PubMedCentralCrossRefPubMedGoogle Scholar
  39. Hendriksz CJ, Burton B, Fleming TR, Harmatz P, Hughes D, Jones SA, Lin SP, Mengel E, Scarpa M, Valayannopoulos V et al (2014) Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J Inherit Metab Dis 37(6):979–990PubMedCentralCrossRefPubMedGoogle Scholar
  40. Hernberg-Stahl E, Reljanovic M (2013) Orphan drugs: understanding the rare disease market and its dynamics. Elsevier Science, CambridgeCrossRefGoogle Scholar
  41. Hollak CE, Aerts JM, Ayme S, Manuel J (2011) Limitations of drug registries to evaluate orphan medicinal products for the treatment of lysosomal storage disorders. Orphanet J Rare Dis 6:16PubMedCentralCrossRefPubMedGoogle Scholar
  42. Jameson E, Jones S, Wraith JE (2013) Enzyme replacement therapy with laronidase (Aldurazyme((R))) for treating mucopolysaccharidosis type I. Cochrane Database Syst Rev 11, CD009354PubMedGoogle Scholar
  43. Kirkegaard T (2013) Emerging therapies and therapeutic concepts for lysosomal storage diseases. Expert Opin Orphan Drugs 1(5):385–404CrossRefGoogle Scholar
  44. Kishnani PS, Beckemeyer AA (2014) New therapeutic approaches for Pompe disease: enzyme replacement therapy and beyond. Pediatr Endocrinol Rev 12(Suppl 1):114–124PubMedGoogle Scholar
  45. Kizhner T, Azulay Y, Hainrichson M, Tekoah Y, Arvatz G, Shulman A, Ruderfer I, Aviezer D, Shaaltiel Y (2015) Characterization of a chemically modified plant cell culture expressed human alpha-Galactosidase-A enzyme for treatment of Fabry disease. Mol Genet Metab 114(2):259–267CrossRefPubMedGoogle Scholar
  46. Klein AD, Futerman AH (2013) Lysosomal storage disorders: old diseases, present and future challenges. Pediatr Endocrinol Rev 11(Suppl 1):59–63PubMedGoogle Scholar
  47. Lampe C, Bellettato CM, Karabul N, Scarpa M (2013) Mucopolysaccharidoses and other lysosomal storage diseases. Rheum Dis Clin North Am 39(2):431–455CrossRefPubMedGoogle Scholar
  48. Lampe C, Atherton A, Burton BK, Descartes M, Giugliani R, Horovitz DD, Kyosen SO, Magalhaes TS, Martins AM, Mendelsohn NJ et al (2014a) Enzyme replacement therapy in mucopolysaccharidosis II patients under 1 year of age. JIMD Rep 14:99–113PubMedCentralCrossRefPubMedGoogle Scholar
  49. Lampe C, Bosserhoff AK, Burton BK, Giugliani R, de Souza CF, Bittar C, Muschol N, Olson R, Mendelsohn NJ (2014b) Long-term experience with enzyme replacement therapy (ERT) in MPS II patients with a severe phenotype: an international case series. J Inherit Metab Dis 37(5):823–829PubMedCentralCrossRefPubMedGoogle Scholar
  50. Lavandeira A (2002) Orphan drugs: legal aspects, current situation. Haemophilia 8(3):194–198CrossRefPubMedGoogle Scholar
  51. Lyseng-Williamson KA (2014a) Elosulfase Alfa: a review of its use in patients with mucopolysaccharidosis type IVA (Morquio A syndrome). BioDrugs 28(5):465–475CrossRefPubMedGoogle Scholar
  52. Lyseng-Williamson KA (2014b) Miglustat: a review of its use in Niemann-Pick disease type C. Drugs 74(1):61–74CrossRefPubMedGoogle Scholar
  53. Martinez-Pardo M (2001) Orphan drugs and metabolic disorders. Rev Neurol 33(3):220–225PubMedGoogle Scholar
  54. Meekings KN, Williams CS, Arrowsmith JE (2012) Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discov Today 17(13–14):660–664CrossRefPubMedGoogle Scholar
  55. Melnikova I (2012) Rare diseases and orphan drugs. Nat Rev Drug Discov 11(4):267–268CrossRefPubMedGoogle Scholar
  56. Muenzer J (2011) Overview of the mucopolysaccharidoses. Rheumatology 50(Suppl 5):v4–v12CrossRefPubMedGoogle Scholar
  57. Ortolano S, Vieitez I, Navarro C, Spuch C (2014) Treatment of lysosomal storage diseases: recent patents and future strategies. Recent Pat Endocr Metab Immune Drug Discov 8(1):9–25CrossRefPubMedGoogle Scholar
  58. Parenti G (2009) Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics. EMBO Mol Med 1(5):268–279PubMedCentralCrossRefPubMedGoogle Scholar
  59. Parenti G, Pignata C, Vajro P, Salerno M (2013) New strategies for the treatment of lysosomal storage diseases (review). Int J Mol Med 31(1):11–20PubMedGoogle Scholar
  60. Parenti G, Fecarotta S, la Marca G, Rossi B, Ascione S, Donati MA, Morandi LO, Ravaglia S, Pichiecchio A, Ombrone D et al (2014) A chaperone enhances blood alpha-glucosidase activity in Pompe disease patients treated with enzyme replacement therapy. Mol Ther 22:2004–2012CrossRefPubMedGoogle Scholar
  61. Pastores GM, Gupta P (2013) Orphan drug development. Pediatr Endocrinol Rev 11(Suppl 1):64–67PubMedGoogle Scholar
  62. Platt FM, Lachmann RH (2009) Treating lysosomal storage disorders: current practice and future prospects. Biochim Biophys Acta 1793(4):737–745CrossRefPubMedGoogle Scholar
  63. Platt FM, Boland B, van der Spoel AC (2012) The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J Cell Biol 199:723–734PubMedCentralCrossRefPubMedGoogle Scholar
  64. Pryde DC, Palmer MJ (2014) Orphan drugs and rare diseases. Royal Society of Chemistry, CambridgeCrossRefGoogle Scholar
  65. Putzeist M, Mantel-Teeuwisse AK, Wied CC, Hoes AW, Leufkens HG, de Vrueh RL (2013) Drug development for exceptionally rare metabolic diseases: challenging but not impossible. Orphanet J Rare Dis 8:179PubMedCentralCrossRefPubMedGoogle Scholar
  66. Rombach SM, Smid BE, Bouwman MG, Linthorst GE, Dijkgraaf MG, Hollak CE (2013) Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain. Orphanet J Rare Dis 8:47PubMedCentralCrossRefPubMedGoogle Scholar
  67. Rombach SM, Smid BE, Linthorst GE, Dijkgraaf MG, Hollak CE (2014) Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta-analysis: effectiveness of ERT in different disease stages. J Inherit Metab Dis 37(3):341–352CrossRefPubMedGoogle Scholar
  68. Sands MS (2014) Mucopolysaccharidosis type VII: a powerful experimental system and therapeutic challenge. Pediatr Endocrinol Rev 12(Suppl 1):159–165PubMedGoogle Scholar
  69. Sanford M, Lo JH (2014) Elosulfase alfa: first global approval. Drugs 74(6):713–718CrossRefPubMedGoogle Scholar
  70. Scarpa M, Bellettato CM, Lampe C, Begley DJ (2015) Neuronopathic lysosomal storage disorders: approaches to treat the central nervous system. Best Pract Res Clin Endocrinol Metab 29(2):159–171Google Scholar
  71. Scarpa M, Almassy Z, Beck M, Bodamer O, Bruce IA, De Meirleir L, Guffon N, Guillen-Navarro E, Hensman P, Jones S et al (2011) Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis 6:72PubMedCentralCrossRefPubMedGoogle Scholar
  72. Schlander M, Beck M (2009) Expensive drugs for rare disorders: to treat or not to treat? The case of enzyme replacement therapy for mucopolysaccharidosis VI. Curr Med Res Opin 25(5):1285–1293CrossRefPubMedGoogle Scholar
  73. Stolk P, Willemen MJ, Leufkens HGM (2006) Rare essentials: drugs for rare diseases as essential medicines. Bull World Health Organ 84:745–751PubMedCentralCrossRefPubMedGoogle Scholar
  74. Talele SS, Xu K, Pariser AR, Braun MM, Farag-El-Massah S, Phillips MI, Thompson BH, Cote TR (2010) Therapies for inborn errors of metabolism: what has the orphan drug act delivered? Pediatrics 126(1):101–106CrossRefPubMedGoogle Scholar
  75. Tomanin R, Zanetti A, D’Avanzo F, Rampazzo A, Gasparotto N, Parini R, Pascarella A, Concolino D, Procopio E, Fiumara A et al (2014) Clinical efficacy of enzyme replacement therapy in paediatric Hunter patients, an independent study of 3.5 years. Orphanet J Rare Dis 9:129PubMedCentralCrossRefPubMedGoogle Scholar
  76. Valayannopoulos V, Nicely H, Harmatz P, Turbeville S (2010) Mucopolysaccharidosis VI. Orphanet J Rare Dis 5:5PubMedCentralCrossRefPubMedGoogle Scholar
  77. van der Meijden JC, Gungor D, Kruijshaar ME, Muir AD, Broekgaarden HA, van der Ploeg AT (2014) Ten years of the international Pompe survey: patient reported outcomes as a reliable tool for studying treated and untreated children and adults with non-classic Pompe disease. J Inherit Metab Dis 38(3):495–503Google Scholar
  78. van Dussen L, Biegstraaten M, Hollak CE, Dijkgraaf MG (2014) Cost-effectiveness of enzyme replacement therapy for type 1 Gaucher disease. Orphanet J Rare Dis 9:51PubMedCentralCrossRefPubMedGoogle Scholar
  79. Wastfelt M, Fadeel B, Henter JI (2006) A journey of hope: lessons learned from studies on rare diseases and orphan drugs. J Intern Med 260(1):1–10CrossRefPubMedGoogle Scholar
  80. Westermark K, Holm BB, Soderholm M, Llinares-Garcia J, Riviere F, Aarum S, Butlen-Ducuing F, Tsigkos S, Wilk-Kachlicka A, N’Diamoi C et al (2011) European regulation on orphan medicinal products: 10 years of experience and future perspectives. Nat Rev Drug Discov 10(5):341–349CrossRefPubMedGoogle Scholar
  81. Wraith JE (2006) Limitations of enzyme replacement therapy: current and future. J Inherit Metab Dis 29(2–3):442–447CrossRefPubMedGoogle Scholar
  82. Wraith JE, Jones S (2014) Mucopolysaccharidosis type I. Pediatr Endocrinol Rev 12(Suppl 1):102–106PubMedGoogle Scholar
  83. Young-Gqamana B, Brignol N, Chang HH, Khanna R, Soska R, Fuller M, Sitaraman SA, Germain DP, Giugliani R, Hughes DA et al (2013) Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients. PLoS One 8:e57631PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Maurizio Scarpa
    • 1
    • 2
    • 3
  • Cinzia Bellettato
    • 3
  • Christina Lampe
    • 1
    • 3
  1. 1.Center of Rare DiseasesHorst Schmidt KlinikWiesbadenGermany
  2. 2.Department of PediatricsUniversity of PadovaPadovaItaly
  3. 3.Brains for Brain FoundationPadovaItaly

Personalised recommendations