Therapeutics
Table 1: Incentives for orphan drug development
from drug development programmes for rare dis- eases has made it clear that the R&D paradigm in this field has very different challenges from that associated with more prevalent diseases. If the development of orphan drugs is to build on the early success associated with rare disease legisla- tion, key stakeholders need to further align on ways to address these challenges.
interest in rare diseases may also be attributed to advances in the knowledge of disease biology and genomics which has made it clear that a number of more prevalent diseases may be categorised into several distinct subsets of disease with unique char- acteristics. We are indeed edging closer to the era of ‘personalised medicine’ and what is learned from drug development for rare diseases may well prove to be applicable to treatments for these sub- sets of patients. This is already starting to be the case for other diseases, such as subsets of different types of cancer.
While there have been significant advances in the field of rare diseases, effective therapies are still not available to more than 95% of the patients suffer- ing from these diseases. In addition, while orphan drug designations have increased, there continues to be only a consistently small number of annual approvals for orphan drugs3-5. So while there have been successes in the development of treatments for diseases such as Fabry Disease, Hunter Syndrome, Gaucher Disease and Pompe Disease, much remains to be achieved to the benefit of patients suffering from rare diseases. Learning
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The major challenges for R&D in the rare dis- ease field stem from the impact of the unique char- acteristics of rare disease patient populations on the clinical development process in rare diseases (Figure 1), and the interface between clinical devel- opment and the regulatory process. Legislation demands that potential therapies demonstrate safe- ty and efficacy in the clinic in order to be approved by regulatory authorities. Generally the final step in this process is two adequately powered Phase III, double-blind, placebo-controlled trials (or a single study with confirmatory evidence), with statistical- ly-significant benefit being demonstrated by an investigative agent compared to placebo in order to be considered appropriate for approval. Increasingly, clinical benefit is also compared to that achieved by a comparator agent representing the current standard of care for a disease. A direct measure of clinical benefit specifically related to disease is generally considered appropriate for approval, such as benefit to the functioning of an organ. For ethical reasons, it is also generally con- sidered appropriate for therapies to be tested in adults before being assessed in the pediatric popu- lation. While these expectations are appropriate and realistic for the majority of common diseases, for drugs under investigation for the treatment of rare diseases these requirements are either very challenging or implausible for technical, practical or ethical reasons.
A fundamental challenge in drug development for the majority of rare diseases is that there is rel- atively little known about the pathophysiology or the natural history of disease; there are usually only a small number of experienced clinical inves- tigators worldwide, and in contrast to higher prevalence diseases there is usually very little sci- entific literature published. For example, a PubMed search demonstrates that while there were close to 6,000 publications in the scientific literature related to arthritis in 2012, there were only 25 related to MPS-II, or Hunter Syndrome – despite the fact that there is an approved therapy for MPS-II. The consequence of this is that there is frequently uncertainty about disease mechanisms in rare diseases, a lack of adequate preclinical models of disease and incomplete knowledge of
Drug Discovery World Spring 2013
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