Abstract
BackgroundLysosomal 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.MethodsAnalysis of the FDA database for orphan drug designations through descriptive and comparative statistics.ResultsBetween 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.ConclusionsDrug 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.
Highlights
Lysosomal storage disorders are a heterogeneous group of approximately 50 monogenically inherited orphan conditions
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 with no orphan drug designations
In order to account for publication bias, data on registration studies were obtained from the current Food and Drug administration (FDA) approved drug label accessed at http://www.accessdata.fda. gov/scripts/cder/drugsatfda/
Summary
Lysosomal storage disorders are a heterogeneous group of approximately 50 monogenically inherited orphan conditions. Lysosomal storage disorders Lysosomal storage disorders (LSDs) are a clinically heterogeneous group of more than 40 inherited orphan conditions. Their prevalence was determined in various surveys to per 100,000 live births (=1 in 7700) in Australia [1], per 100,000 live births (=1 in 7143) in the Netherlands [2], 7.6 per 100,000 live births 13,158) in British Columbia [3], and 25 per 100,000 live births (=1 in 4000) in Portugal [4] These diseases share a common pathobiochemical leitmotiv: a genetic defect leads to the storage of complex non-metabolized molecules in the lysosome. LSDs are in general multisystemic, Mechler et al Orphanet Journal of Rare Diseases (2015) 10:46 progressive disorders of significant morbidity with decreased life-expectancy that can manifest within a heterogeneous somatic and neurological spectrum such as hydrops fetalis, dysmorphism, dysostosis multiplex, hepatosplenomegaly, central nervous system disease, ophthalmologic, cardiovascular, renal, or cutaneous disease features [5]
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