The Discovery of Medicines for Rare Diseases

Abstract

There is a pressing need for new medicines (new molecular entities; NMEs) for rare diseases as few of the 6800 rare diseases (according to the NIH) have approved treatments. Drug discovery strategies for the 102 orphan NMEs approved by the US FDA between 1999 and 2012 were analyzed to learn from past success: 46 NMEs were first in class; 51 were followers; and five were imaging agents. First-in-class medicines were discovered with phenotypic assays (15), target-based approaches (12) and biologic strategies (18). Identification of genetic causes in areas with more basic and translational research such as cancer and in-born errors in metabolism contributed to success regardless of discovery strategy. In conclusion, greater knowledge increases the chance of success and empirical solutions can be effective when knowledge is incomplete.

Challenges and Hurdles to Business as Usual in Drug Development for Treatment of Rare Diseases

“…Analysis of a decade of drug approvals showed that the majority of first‐in‐class medicines were discovered with approaches (phenotypic) that did not require an exact understanding of the target or MMOA, whereas this knowledge contributed to the success of follow‐up drugs in which the mechanism was previously identified . In a separate analysis of approvals of medicines for rare diseases, it was concluded that genetic contributions (25%) were underrepresented with respect to the number of genetic diseases (>80%) . Successful genetic approaches, whereas being fewer than expected based on the number of genetic diseases, were in disease areas with supporting knowledge to facilitate the discovery (e.g., kinases for cancer, enzyme replacement therapy for inborn error of metabolism, and areas in which sufficient knowledge of physiology identified therapeutic opportunities) …”

“…The C1‐esterase‐inhibitor is an inhibitor of plasma kallkrein and regulates the activation of complement and intrinsic coagulation. Kalbitor works by inhibition of the conversion of HMW kininogen to bradykinin and icatibant is a competitive antagonist selective for the bradykinin B2 receptor . Knowledge of the genetic and biochemical pathways facilitated the identification of these treatments.…”

“…6 In a separate analysis of approvals of medicines for rare diseases, it was concluded that genetic contributions (25%) were underrepresented with respect to the number of genetic diseases (>80%). 7 Successful genetic approaches, whereas being fewer than expected based on the number of genetic diseases, were in disease areas with supporting knowledge to facilitate the discovery (e.g., kinases for cancer, enzyme replacement therapy for inborn error of metabolism, and areas in which sufficient knowledge of physiology identified therapeutic opportunities). 7 The consequence of this conclusion is that identification of a genetic association for a disease, by itself, does not provide sufficient molecular details to identify a new specific pharmacological therapy.…”

Incentives for Starting Small Companies Focused on Rare and Neglected Diseases

“…They are also generally characterized by there being over 7000 of them, with only a few hundred having treatments and in some cases these can be incredibly expensive (1). The families affected by these rare diseases are also in most cases highly motivated to raise funds and reach out to researchers and pharma and biotech companies (2).…”

Industrializing rare disease therapy discovery and development

“…There are over 7000 rare diseases, approximately 75% affect children and over 340 currently have treatments. Research for rare diseases has therefore been termed an example of a long-tailed problem 1 in which traditional research has focused on the 20% of genetic conditions (accounting for 80% of all diseases), but at the same time neglecting the other 80% of genetic conditions representing the remaining 20% of all diseases (rare diseases) 2, 3 . The irony here is that rare diseases can in general be readily treated by replacing the gene, protein or stabilizing protein folding etc.…”