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1Astellas Pharma US Inc., Deerfield, Illinois, USA; 2Pfizer Inc., New York, New York, USA. Correspondence: J Vincent (john.vincent@pfizer.com)

doi:10.1038/clpt.2012.97

Rare Diseases: The Bane of Modern Society and the Quest for CuresN Azie1 and J Vincent2

The enormous progress in the development of drugs for rare diseases may be attributed to advances in genomic technology, molecular profiling, improved target and biomarker selection, an improved understanding of the natural history and pathophysiology of several orphan diseases, use of integrated quantitative analysis techniques in drug development, and a favorable regulatory climate, but major challenges still remain. most rare diseases manifest during childhood; about 30% of affected children die before their fifth birthday, and the health and economic burden on survivors can be tremendous.1

Orphan diseases, rare diseases, and orphan drugsThe terms “orphan diseases” and “rare diseases” are commonly used interchangeably worldwide and have been defined as “any disease or condition that affects a small percentage of the population.” There are currently no universally accepted criteria used to identify or define a disease condition as rare. Some definitions are based on prevalence and others on factors such as existence of adequate treatment and impact on the affected patient. The US Rare Diseases Act of 2002 defines rare disease strictly according to prevalence, as does Japan. The European Commission on Public Health defines rare diseases as “life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them.”2 The definition of “low prevalence” varies between countries but usually ranges from 1/1,000 to 1/200,000.3

The alternative term “orphan disease” is used in reference to a combination of the paucity of treatment availability, lack of resources, and severity of disease.3

According to EURORDIS (Rare Diseases Europe), there are as many as 5,000 to 7,000 distinct rare diseases, and approximately 350 million people worldwide live with such a disease. Approximately 30 million of these individuals live in the United States2—as many as 1 in 10 Americans suffers from a rare disease.4 The prevalence is not uniform in all populations because a disease that is rare in one country could be relatively common in another country, as is seen with some genetic diseases and infectious diseases. An example of a genetic disease with this characteristic is cystic fibrosis, which is uncommon in Asia but relatively common in Europe and in populations of European descent. Similarly, the founder effect can result in a high concentration within certain

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Replacement therapies for loss-of-function mutations are used in the treatment of hemophilia, some inherited metabolic disorders in which recombinant enzymes are used, immunodeficiency, a1-antitrypsin deficiency, and gene therapy (J. Woodcock, personal communication). Complex pharmacological manipulations may be necessary for some difficult replacement targets, such as dystrophin, because of exon skipping in the dystrophin molecule (C.T. Dollery, personal communication). From the rarest genetic disease, ribose-5-phosphate isomerase deficiency, to amyotrophic lateral sclerosis, Huntington’s disease, myasthenia gravis, lipoprotein lipase deficiency, and numerous other orphan diseases, notable progress has been made toward finding efficacious drugs. Progress in the development of stable and scalable adeno-associated viral (AAV)-derived vector and the AAV-manufacturing platform that may be applied to a large number of orphan diseases caused by faulty genes might facilitate treatment of these conditions, if this technique is found to be devoid of the adverse effects of earlier vectors. Advances in understanding the molecular basis of disease, new therapies, and new and more efficient devices have improved the prospects for the management of these previously difficult-to-treat diseases.

Cancers make up a large percentage of orphan diseases for which there is active ongoing research, but infectious diseases have the capacity to do more harm in nonimmune populations. With mass movements of populations caused by national disasters, wars, and travel, the prospects for disease transmission are high. A disease that is considered an orphan disease today because of low prevalence could become an epidemic tomorrow. New rare diseases are discovered every week and many have

populations of a disease that is ordinarily rare in most of the world. An example is familial hypercholesterolemia, which has a relatively high prevalence in parts of Canada, the Middle East, and South Africa. Many infectious diseases are rare in the developed countries, although they commonly occur in communities in less developed countries. Some of these diseases are prevalent in the poorer regions of the world, where they may even be endemic. In Finland, about 40 rare diseases with a higher prevalence in their population constitute the Finnish disease heritage.5

Epidemiology and treatment optionsMany orphan diseases are genetic in origin and consequently are chronic. Others are cancers, autoimmune diseases, or degenerative and proliferative diseases, or caused by infections and infestations. Genetic causes commonly arise from mechanisms that include gain-of-function mutations, loss-of-function polymorphism, and gene misexpression, deletion, transposition, or insertion.6 For example, imatinib inhibits the tyrosine kinase enzyme ABL in chronic myeloid leukemia cells that are chronically activated by the Philadelphia chromosome transposition. HER2, a member of the human epidermal growth factor receptor family of tyrosine kinases, is overactive in about 40% of breast cancers, and trastuzumab is active against its extracellular domain. Other examples include the use of Herceptin (trastuzumab) and Gleevec (imatinib mesylate) in cancer chemotherapy because they target gain-of-function changes.

However, pharmacotherapy has difficulty in replacing lost function (C.T. Dollery, personal communication). Although loss-of-function mutations are more common, they are less readily amenable to pharmacotherapy.

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of patients could be seen as a challenge for any drug development program, but Woodcock frames this as an enrichment scenario in which nonresponders are eliminated, leaving a population with a high probability of showing a treatment effect of great magnitude, consequently decreasing the sample size and costs and, maybe, mitigating one of the major ethical concerns for orphan drug development. In essence, a drug development program that targets a subset of a broader disease can improve efficiency. The increased magnitude of response seen in this population may reflect the exclusion of potential nonresponders and enrichment of the study population for a greater probability of success because orphan diseases self-select the study population.

Kesselheim10 discusses the ethics of orphan drug development in a Commentary. He raises the important consideration that patients with rare diseases may feel that they are in the best position to assess the risk–benefit relationship and may therefore accept the inherent risks even if these drugs do not undergo the rigorous empirical testing that conventional pharmaceutical agents do. Although this is certainly a theoretical concern, there is no evidence that marketing authorization has been withdrawn by regulatory agencies for many more drugs approved for orphan diseases as compared with drugs approved for more common diseases because of adverse effects.11 The question of cost is a major challenge, and the typical concept of “value proposition” is not tenable in this context. Patients with orphan diseases did not bring these conditions on themselves. All efforts must be made to allay any sense of guilt and self-pity, and they must not be made to bear any disproportionate costs. As Aronson appropriately puts it, “If an orphan drug is one used to treat a rare disease, a rare disease is one that is

no treatments available. Frightful as this concept may be, it is real. Consequently, close collaboration and cooperation are necessary between the advanced countries of the world where these diseases are very rare and the poorer countries with a high prevalence. In addition, in vitro fertilization by sperm obtained from sperm banks may yet turn out to have unintended consequences as a source for propagating rare genetic diseases despite currently available screening procedures. Currently, about 350 orphan drugs have been approved for sale in the United States, and this number will increase with time.7

Public advocacy and pharma collaborationNumerous advocacy groups such as the National Organization for Rare Disorders, the Global Genes Project, the Children’s Rare Disease Network, the Abetalipoproteinemia Collaboration Foundation, the Zellweger Baby Support Network, and the Friedreich’s Ataxia Research Alliance have been founded to advocate for patients suffering from rare diseases, with a particular emphasis on diseases that afflict children.8 Key orphan drug developers, including Synageva BioPharma, Genzyme, Swedish Orphan Biovitrum, Shire, GlaxoSmithKline, Pfizer, and Novartis, have established units devoted to the discovery and development of orphan drugs. These pharmaceutical companies work with national bodies such as the US National Organization for Rare Disorders, the National Institutes of Health, and EURORDIS to advance this field by means of joint congresses, lectures, and symposia.

In this issue of CPTThis issue is devoted to orphan disease and orphan drugs. In her Macroscopy,9 Woodcock provides an insight into orphan diseases and the direction of drug development for them. The small number

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to this technique.14 Several examples of successful use of this approach are described here.

Orfali et al.15 provide an interesting perspective in their contribution on the similarities and differences between clinical development programs for rare and common diseases. Package inserts are not peer-reviewed documents, but they provide a summary of the trials that form the basis for regulatory approval even if they are underreported relative to the overall trials in a drug development program. They also often contain information referenced in peer-reviewed publications. By comparing the details of the studies listed against these programs, one can confirm that, although the numbers of studies of and patients on drugs approved for orphan indications are smaller than those for common diseases, the proportions of randomized studies, placebo-controlled end-point trials, and, in some cases, the development times, are similar. In some ways, this observation may confirm Woodcock’s assertion that the subjects with rare diseases constitute an enriched population such that drug development in this population gains the time lost in recruitment during the trial from the robust outcomes.

In his State of the Art piece, Ian Phillips16 offers insights into the progress in the advanced platforms of gene therapy, gene modification, and gene correction for the treatment of orphan diseases. In addition, the potential benefits from stem cell research are discussed. This review also provides a summary of orphan drug development endeavors that leverage the current state of knowledge in this field. As stated earlier, although a majority of orphan diseases are genetic, infectious and infestation-related diseases contribute to rare diseases in this country. Barry et al.17 reviewed a group of endemic parasitic and related infections, known as the neglected

not cost-effective to treat,” although it is a moral imperative for society to provide access to disease-management tools for these patients.5

Academic institutions have seen increased activity in the development of drugs for orphan diseases. Coles and Cloyd review the role of academic institutions in this area of scientific inquiry and observe that this interest parallels that of the major pharmaceutical companies, now that the era of blockbuster products has passed.12 Aspects of this line of inquiry that are particularly appealing to academia include faster development timelines, lower research and development expenses, a higher likelihood of clinical and regulatory success, opportunities for premium pricing, lower marketing costs, and lower risks of generic competition. Academic institutions, by virtue of their workforce disposition, have the option of several models of drug development, including a disease-focused model, a drug/biologic discovery model, a development-focused model, and an industry collaboration–partnership model.

One of the major challenges of orphan drugs is control of the cost of drug development. Lesko13 discusses the use of quantitative analysis to guide orphan drug development. The integration of drug–disease modeling and the use of simulation (quantitative analysis) to guide choice of doses, targets, and treatment outcomes speed development timelines. The ability to use quantitative analysis to predict doses for various age groups or disease-severity groups eliminates the need for additional studies, thereby reducing costs. This approach is increasingly being used by pharmaceutical companies to improve the drug development process, and the orphan drug arena is particularly amenable

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project in determining gene function: insights from model organisms. Cell 86, 521–529 (1996).

7. Clinuvel. Orphan drug designation (ODD) information <http://www.clinuvel.com/en/pharmaceutical-development/orphan-drug-designation>.

8. Armstrong, W. Pharma’s orphans. PharmExec.com <http://www.pharmexec.com/pharmexec/Strategy/Pharmas-Orphans/ArticleStandard/Article/detail/670568> (1 May 2010).

9. Woodcock, J. The future of orphan drug development. Clin. Pharmacol. Ther. 92, 146–148 (2012).

10. Kesselheim, A.S. Ethical considerations in orphan drug approval and use. Clin. Pharmacol. Ther. 92, 153–155 (2012).

11. Hudson, I. & Breckenridge, A. The challenges of orphan drugs and orphan diseases: real and imagined. Clin. Pharmacol. Ther. 92, 151–153 (2012).

12. Coles, L.D. & Cloyd, J.C. The role of academic institutions in the development of drugs for rare and neglected diseases. Clin. Pharmacol. Ther. 92, 193–202 (2012).

13. Lesko, L.J. Quantitative analysis to guide orphan drug development. Clin. Pharmacol. Ther. 92, 258–261 (2012).

14. Bashaw, E.D. et al. Clinical pharmacology as a corner-stone of orphan drug development. Nat. Rev. Drug Discov. 10, 795–796 (2011).

15. Orfali, M. et al. Raising orphans: how clinical development programs of drugs for rare and common diseases are different. Clin. Pharmacol. Ther. 92, 262–264 (2012).

16. Ian Phillips, M. Gene, stem cell, and future therapies for orphan diseases. Clin. Pharmacol. Ther. 92, 182–192 (2012).

17. Barry, M.A., Bezek, S., Serpa, J.A., Hotez, P.J. & Woc-Colburn, L. Neglected infections of poverty in Texas and the rest of the United States: management and treatment options. Clin. Pharmacol. Ther. 92, 170–181 (2012).

infections of poverty, that are prevalent along the Gulf Coast and in southern Texas. These infections are characterized by their chronic nature, disabling features, and disproportionate impact on the poor.

We can conclude that, although recent advances in science, technology, and medical research, coupled with a growing attention focused on identifying root causes and developing appropriate therapies, are encouraging, rare diseases remain an ongoing challenge.

CONFLICT OF INTERESTThe authors declared no conflict of interest.

© 2012 ASCPT

1. Yaneva-Deliverska, M. Rare diseases and genetic discrimination. J. IMAB–Annu. Proc. (Scientific Papers) 17, 116–119 (2011).

2. European Commission. Useful information on rare diseases from an EU perspective <http://ec.europa.eu/health/ph_information/documents/ev20040705_rd05_en.pdf>.

3. Rare Diseases Act of 2002 (Public Law 107-280) <http://history.nih.gov/research/downloads/PL107-280.pdf>.

4. Duffy, A. Rare diseases’ troubling questions. Cobourg Daily Star (Ontario), 25 January 2002.

5. Aronson, J.K. Editor’s view. Rare diseases and orphan drugs. Br. J. Clin. Pharmacol. 61, 243–245 (2006).

6. Miklos, G.L.G. & Rubin, G.M. The role of the genome