title: Pressure for drug development in lysosomal storage disorders - a quantitative analysis thirty years beyond the US orphan drug act.
abstract: BACKGROUND
  Lysosomal storage disorders are a heterogeneous group of approximately 50 monogenically inherited orphan conditions. A defect leads to the storage of complex molecules in the lysosome, and patients develop a complex multisystemic phenotype of high morbidity often associated with premature death. More than 30 years ago the Orphan Drug Act of 1983 passed the United States legislation intended to facilitate the development of drugs for rare disorders. We directed our efforts in assessing which lysosomal diseases had drug development pressure and what distinguished those with successful development and approvals from diseases not treated or without orphan drug designation.
  
  
  METHODS
  Analysis of the FDA database for orphan drug designations through descriptive and comparative statistics.
  
  
  RESULTS
  Between 1983 and 2013, fourteen drugs for seven conditions received FDA approval. Overall, orphan drug status was designated 70 times for 20 conditions. Approved therapies were enzyme replacement therapies (N = 10), substrate reduction therapies (N = 1), small molecules facilitating lysosomal substrate transportation (N = 3). FDA approval was significantly associated with a disease prevalence higher than 0.5/100,000 (p = 0.00742) and clinical development programs that did not require a primary neurological endpoint (p = 0.00059). Orphan drug status was designated for enzymes, modified enzymes, fusion proteins, chemical chaperones, small molecules leading to substrate reduction, or facilitating subcellular substrate transport, stem cells as well as gene therapies.
  
  
  CONCLUSIONS
  Drug development focused on more common diseases. Primarily neurological diseases were neglected. Small clinical trials with either somatic or biomarker endpoints were successful. Enzyme replacement therapy was the most successful technology. Four factors played a key role in successful orphan drug development or orphan drug designations: 1) prevalence of disease 2) endpoints 3) regulatory precedent, and 4) technology platform. Successful development seeded further innovation.
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, Pediatric Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. konstantin.mechler@zi-mannheim.de.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mechler
authors.affiliation: Clinical Research Program, University of North Carolina Wilmington, Wilmington, NC, USA. wkmountford@gmail.com.
authors.forename: William K
authors.initials: WK
authors.lastname: Mountford
authors.affiliation: Pediatric Neurology and Metabolic Medicine, Center for Rare Diseases, Center for Pediatric and Adolescent Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg, D-69120, Germany. georg.hoffmann@med.uni-heidelberg.de.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: Pediatric Neurology and Metabolic Medicine, Center for Rare Diseases, Center for Pediatric and Adolescent Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg, D-69120, Germany. markus.ries@uni-heidelberg.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Ries
mesh_terms: D017277:Drug Approval / Q000706:statistics & numerical data*; D055808:Drug Discovery; D004345:Drug Industry / Q000191:economics / Q000706:statistics & numerical data*; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000188:drug therapy*; D009965:Orphan Drug Production / Q000331:legislation & jurisprudence*; D035583:Rare Diseases / Q000188:drug therapy; D014481:United States; D014486:United States Food and Drug Administration