Rare diseases are serious, chronically and/or progressively disabling, and can be life-limiting and life-threatening. According to the US National Institutes of Health (NIH), there are close to 7,000 described rare diseases. In the United States a disease is considered to be ‘rare’if it affects fewer than 200,000 individuals, and in the European Union it is defined as having a prevalence of fewer than 5 in 10,000 people. Some rare diseases have less than a dozen known cases, whereas others are more common, such as multiple sclerosis, cystic fibrosis and Duchenne muscular dystrophy1. Collectively, these disorders affect 6–7% of the population in the developed world. However, compared to indications such as diabetes or atherosclerosis, a given rare disease represents a very small market opportunity for the biopharmaceutical industry; a small market is generally viewed as unattractive for drug companies. In 1983 the Orphan Drug Act (ODA) was approved in the United States to promote the development of treatments for rare diseases. This legislation created economic incentives for the industry, such as 7 years of market exclusivity, tax credits for certain development costs and application fee waivers. Subsequently, similar regulations were passed in Japan, Australia and the European Union2. The ODA is considered to be highly successful: in the 1970s there were only 10 approved drugs for rare diseases but since 1983 more than 2,500 small molecules and biologics have been designated as orphan drugs, with more than 390 achieving marketing approval (FIG. 1). Currently, there are 460 medicines in clinical trials for a variety of rare diseases (FIG. 2). Rare oncology indications represent the largest segment and account for over 30% of the pipeline and all orphan drug approvals (FIG. 3). Most of the orphan drugs on the market have been approved for a single indication, but close to 50 compounds have received regulatory clearance in multiple rare diseases. With seven separate orphan drug approvals, imatinib (Gleevec; Novartis) is one of the most commercially successful drugs for treating rare diseases. Sales of imatinib reached US $4.65 billion in 2011. In 2006–2008, 16 orphan therapeutics made the top 200 list for US drug sales, with annual sales ranging from $200 million to over $2 billion. It is now widely recognized that rare diseases provide attractive niche opportunities for biopharmaceutical companies. Orphan drugs offer advantages such as faster development timelines, lower research and development expenses, a higher likelihood of clinical and regulatory success, premium pricing, lower marketing costs and a lower risk of generic competition. According to the Tufts Center for the Study of Drug Development, companies reported that 22% of their programmes designated as orphan drugs led to approvals between 2000 and 2009, whereas clinical approval success rate for mainstream drugs was 16%. Overall, in the past few years, medicines for rare conditions accounted for over 35% of the new drugs approved by the US Food and Drug Administration (FDA). Despite recent successes, less than 10% of patients afflicted with rare diseases are treated today, and the unmet medical need remains high1. Most of these conditions represent significant development challenges that are due to several factors, including large heterogeneity in disease pathophysiology, poorly understood natural histories of disease progression, limited availability of patients to conduct clinical trials, large heterogeneity in treatment effects, lack of biomarkers to predict outcomes, uncertainties in the appropriate end points and duration of treatment, and typically a lack of …