Drug development for exceptionally rare metabolic diseases: challenging but not impossible

Michelle Putzeist,Aukje K Mantel-Teeuwisse,Arno W Hoes,Remco La De Vrueh,Christine C Gispen-De Wied,Hubert Gm Leufkens

doi:10.1186/1750-1172-8-179

Abstract

BackgroundWe studied to what extent the level of scientific knowledge on exceptionally rare metabolic inherited diseases and their potential orphan medicinal products is associated with sponsors deciding to apply for an orphan designation at the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA).MethodsAll metabolic diseases with a genetic cause and prevalence of less than 10 patients per 1 million of the population were selected from the ‘Orphanet database of Rare diseases’. The outcome of interest was the application for an orphan designation at FDA or EMA. The level of publicly available knowledge of the disease and drug candidate before an orphan designation application was defined as whether the physiological function corresponding with the pathologic gene and initiation of the pathophysiological pathway was known, whether an appropriate animal study was identified for the disease, whether preclinical proof of concept was ascertained and the availability of data in humans. Other determinants included in the study were metabolic disease class, the prevalence of the disease, prognosis and time of first description of the disease in the literature. Univariate relative risks (RRs) and 95% confidence intervals (CIs) of an orphan designation application were calculated for each of these determinants. In addition, a multivariate Cox regression analysis was conducted (Forward LR).ResultsIn total, 166 rare metabolic genetic diseases were identified and included in the analysis. For only 42 (25%) of the diseases an orphan designation application was submitted at either FDA or EMA before January 2012. The multivariate analysis identified preclinical proof of concept of a potential medicinal product as major knowledge related determinant associated with an orphan designation application (RRadj 3.9, 95% CI 1.9-8.3) and confirmed that prevalence of the disease is also associated with filing an application for an orphan designation (RRadj 2.8, 95% CI 1.4-5.4).ConclusionFor only one out of four known exceptionally rare metabolic inherited diseases sponsors applied for an orphan designation at FDA or EMA. These applications were found to be associated with the prevalence of the rare disease and the level of available scientific knowledge on the proof of concept linking possible drug candidates to the disease of interest.

Highlights

Rare diseases are a complex and heterogeneous mosaic of an estimated 6000–8000 conditions
For 42 (25%) of the diseases at least one orphan designation application was submitted at either Food and Drug Administration (FDA) or European Medicines Agency (EMA), whereas for the remaining 124 (75%) diseases such an orphan designation application was not submitted before January 2012
The majority of low prevalence rare diseases remain without therapy, the development of medicines for such diseases is considered an unmet medical need

Summary

Introduction

Rare diseases are a complex and heterogeneous mosaic of an estimated 6000–8000 conditions. In the EU, in the first decade more than 850 orphan drug designations have been granted by the European Commission and more than 60 orphan drugs have received marketing authorization [6] Despite this success, it is important to understand that the majority of the estimated 6000–8000 rare diseases has a prevalence of less than 10 patients per 1 million inhabitants (less than 5000 patients in the EU) [7]. An example of an authorized product to treat a low prevalence rare metabolic disease is idursulfase (Elaprase®), an enzyme replacement therapy to treat Hunter syndrome known as mucopolysaccharidosis Type II [10]. Apart from idursulfase, other marketed products for low prevalence rare metabolic diseases are for example nitisinone (Orfadin® for Tyrosinemia type I) and carglumic acid (Carbaglu® for N -acetylglutamate synthetase (NAGS) deficiency). We studied to what extent the level of scientific knowledge on exceptionally rare metabolic inherited diseases and their potential orphan medicinal products is associated with sponsors deciding to apply for an orphan designation at the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA)

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Results

Discussion

Conclusion