Pressure for drug development in lysosomal storage disorders – a quantitative analysis thirty years beyond the US orphan drug act

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.

Ultra‐orphan lysosomal storage diseases: A cross‐sectional quantitative analysis of the natural history of alpha‐mannosidosis

“…Velmanase alfa is currently licensed in the European Union “for patients with mild to moderate alpha‐mannosidosis for treating effects of the disease that do not involve the brain (non‐neurological effects)” (https://www.ema.europa.eu/en/medicines/human/EPAR/lamzede). This drug labeling acknowledges that enzyme replacement therapy does not cross the blood‐brain barrier and would not be expected to cure the neurological disease associate with alpha‐mannosidosis, which may result in incomplete treatment of CNS manifestations. In addition, there might be various levels of yet‐to‐be defined “limited window of opportunity for early intervention” which might result either in prevention, disease stability, or reversibility, or modifying morbidity and premature mortality.…”

Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives

“…In spite of the constant debate surrounding this issue, the success of such legislation in driving drug development for LDs must not be undermined. However, even with these incentives, LDs with a very low incidence or those that display primarily neurological symptoms, which are currently untreatable, have been faced with a low “development pressure”, probably due to a lower chance of success [64]. …”

Disease awareness or subtle product placement? Orphan diseases featured in the television series “House, M.D.” - a cross-sectional analysis

“…Second, more prevalent orphan diseases may be more likely to be depicted in a TV series. Previous literature has shown that an orphan drug development is more likely in the more prevalent orphan diseases [48]. Third, the real benefit of such "product placement" is questionable as orphan drugs will only be of therapeutic interest for a very small portion of the television series' viewership.…”