Drugs for rare disorders

Abstract

Estimates of the frequencies of rare disorders vary from country to country; the global average defined prevalence is 40 per 100 000 (0.04%). Some occur in only one or a few patients.

However, collectively rare disorders are fairly common, affecting 6–8% of the US population, or about 30 million people, and a similar number in the European Union. Most of them affect children and most are genetically determined. Diagnosis can be difficult, partly because of variable presentations and partly because few clinicians have experience of individual rare disorders, although they may be assisted by searching databases.

Relatively few rare disorders have specific pharmacological treatments (so‐called orphan drugs), partly because of difficulties in designing trials large enough to determine benefits and harms alike. Incentives have been introduced to encourage the development of orphan drugs, including tax credits and research aids, simplification of marketing authorization procedures and exemption from fees, and extended market exclusivity. Consequently, the number of applications for orphan drugs has grown, as have the costs of using them, so much so that treatments may not be cost‐effective. It has therefore been suggested that not‐for‐profit organizations that are socially motivated to reduce those costs should be tasked with producing them.

A growing role for patient organizations, improved clinical and translational infrastructures, and developments in genetics have also contributed to successful drug development.

The translational discipline of clinical pharmacology is an essential component in drug development, including orphan drugs. Clinical pharmacologists, skilled in basic pharmacology and its links to clinical medicine, can be involved at all stages. They can contribute to the delineation of genetic factors that determine clinical outcomes of pharmacological interventions, develop biomarkers, design and perform clinical trials, assist regulatory decision making, and conduct postmarketing surveillance and pharmacoepidemiological and pharmacoeconomic assessments.

‘Rare, adj.

Pronunciation: Brit. /rɛː/, U.S. /rɛ(ə)r/.

Esp. of a thing or things not regarded as members of a class or type: occurring infrequently, encountered only occasionally or at intervals, uncommon.’

Oxford English Dictionary.

Words describing frequencies are difficult to pin down. For example, although one might expect the term ‘always’ to be associated with a 100% probability, studies of healthcare professionals' perceptions have yielded estimates varying from 91% to 100%; similarly, ‘never’, with an expected zero occurrence, is estimated at frequencies of up to 2% 1. In such studies, the terms ‘rare’ and ‘rarely’ have variously been assigned probabilities ranging from 0.5% to 9%.

So, how rare are rare disorders?

Definitions of rare disorders by prevalence

In the Orphanet database, the term ‘rare disorders’ is used to describe rare diseases, malformation syndromes, clinical syndromes, morphological or biological anomalies, and particular clinical presentations 2. The database also contains information on about two dozen supposedly rare adverse drug reactions, mostly with genetic associations, such as the polymorphism in the gene encoding the human solute carrier organic anion transporter family member 1B1 (SLCO1B1) associated with statin‐induced rhabdomyolysis 3, although some of the listed associations are in fact common in the drug‐exposed population, such as the HLA B*5701 polymorphism associated with serious abacavir‐induced rashes 4. Such reactions could be considered rare if the frequency in the whole population (drug‐exposed and non‐exposed) were calculated, but it is usual to calculate the frequencies of adverse drug reactions with respect to the drug‐exposed population only.

For a disorder to be regarded as rare it has to have a very low prevalence, defined in different ways in different countries. In the USA, a rare disorder is defined as one that affects no more than 200 000 individuals, but in Japan the number is 50 000, and in Australia 2000 5, 6. These numbers clearly relate to the population sizes of these countries but, even adjusting for that, the definitions vary from about 10 to 80 per 100 000. The European Community definition is no more than 50 per 100 000 7. The World Health Organization has suggested a frequency of no more than 65–100 per 100 000, and although that seems rather high, it has been adopted in countries such as Brazil and Canada. In a systematic review of 296 definitions of rare diseases, the global average defined prevalence was 40 per 100 000 (0.04%) 8.

However, rare disorders are collectively fairly common: the list published by the Genetic and Rare Diseases Information Center 9 contains about 6000 items, and the Linking Open data for Rare Diseases database 10 about 8500 items, culled from Orphanet 2 and Online Mendelian Inheritance in Man 11; they range from Aagenaes syndrome (lymphoedema and intrahepatic cholestasis 12) to zygomycosis 13. It has been estimated that they affect 6–8% of the US population, or about 30 million people, and a similar number in the European Union 14. Most of them affect children and about 25% are potentially lethal at birth or before 5 years of age. Most of them are genetically determined, about 60% being of autosomal dominant, autosomal recessive, or X‐linked inheritance.

Diagnosis of rare disorders can be difficult, partly because of variable presentations, including common signs and symptoms, which may be mistaken for other disorders, and partly because few, if any, clinicians will have much experience of any of the conditions. However, databases in which rare disorders are coded allow differential diagnosis by entering the clinical features.

Incentives for drug development

Specific treatments are available for relatively few rare disorders. Medicines that are used to treat rare disorders are generally referred to as orphan drugs or products, and the European Commission states that it has authorized 131 orphan medicines for the benefit of patients suffering from rare disorders, and has designated 1459 products as orphan medicinal products 7. The US Food and Drug Administration (FDA) has designated 4016 products to date, of which 565 have been approved and 555 have been withdrawn, including four that were withdrawn after approval 15.

The rarity of a disorder poses problems for drug development. Because of the scarcity of patients, well‐designed clinical trials to determine efficacy can be difficult to perform, and studies large enough to determine serious harms are almost impossible. When no other treatments are available, patients may be willing to risk harms for potential benefits, but the benefit‐to‐harm balance cannot be readily calculated and may in some cases be unfavourable. If it is unlikely that a new medicine will be widely used, drug companies can expect limited financial rewards unless prices are high, in which case treatments may not be cost‐effective.

Incentives have been introduced to encourage the development of orphan drugs 16. After lobbying by the National Organization for Rare Disorders, The Orphan Drug Act was passed in the USA in 1983 17. It was succeeded by similar legislation in Japan (1985 and 1993) 18, Australia (1990) 19, and Singapore (1991) 20. In 2000, the European Commission promulgated Regulation EC 847/2000, which included criteria for designating an orphan drug and definitions of similar medicinal products and clinical superiority 21. The incentives that these regulations provide include tax credits and research aids, simplification of marketing authorization procedures and exemption from fees, and extended market exclusivity 5, 22. As a result, the number of applications for drugs for rare disorders has grown markedly (Figure 1).

Figure 1.

Numbers of products designated as orphan products by the US Food and Drug Administration each year between 1980 and 2016 (top panel) and the cumulative numbers (bottom panel). The data include products that have since been withdrawn, products that have been approved, and four that have been withdrawn after approval; the 2017 data are not included

However, it has been suggested that these incentives are too generous. In a retrospective, propensity score‐matched study of publicly‐listed orphan companies, 86 companies with orphan drug approvals in Europe, the USA, or both were matched with 258 non‐orphan drug companies; the former had a 9.6% average higher return on assets, and for each additional orphan drug sold, the return on assets increased by 11% 23.

Orphan drugs top the list of drugs according to costs 24. For example, the five most expensive medicines (list prices at the time of writing) are glycerol phenylbutyrate for urea cycle disorders ($793 000 per year), cerliponase alfa for infantile neuronal ceroid lipofuscinosis type 2 ($702 000), alglucosidase alfa for Pompe's disease ($626 000), carglumic acid for congenital hyperammonemia ($585 000), and interferon gamma 1‐b for Friedreich's ataxia ($572 000).

There have also been increases in the costs of medicines that were previously used for non‐orphan disorders but which have found a place in the treatment of rare disorders, despite not being cost‐effective for those indications. For example, in a 2010 commentary, it was noted that it cost £160 a year to treat a patient with sickle cell disease using off‐label 500 mg capsules of hydroxycarbamide (hydroxyurea) licensed for chronic myeloid leukaemia, but £14 900 a year using 1 g tablets of hydroxycarbamide licensed as an orphan drug for sickle cell disease; oral ibuprofen for analgesia cost £0.08 per gram, but intravenous ibuprofen for patent ductus arteriosus cost £6575 per gram 25.

It has therefore been suggested that not‐for‐profit organizations that are socially motivated to reduce the costs of orphan drugs should be tasked with producing them 26.

Patient involvement, translational research, and genetics

Besides financial incentives and regulatory easing, other important factors have contributed to successful drug development for rare disorders. These include a growing role for patient organizations, an improved clinical and translational infrastructure, and developments in genetics.

Each year, the National Institutes of Health (NIH) in the USA runs a Rare Disease Day near the end of February, with the slogan ‘Patients & Researchers – Partners for Life’ 27. Rare disease patient communities, often small, are now coming together more readily, thanks to the internet and several overarching patient organizations, such as the US National Organization for Rare Diseases 28. Online communities have made it easier for patients to find specialized centres, and it has become easier for principal investigators and sponsors to find patients who can participate in their studies.

Various translational and clinical infrastructures with special emphasis on rare diseases have developed. They include, in the UK, the Oxford Rare Disease Initiative 29, the Cambridge Rare Disease Network 30, the Centre for Rare Diseases at the University Hospital of Birmingham 31, and Rare Disease UK 32, and, in the USA, the Genetic and Rare Diseases Information Center of the National Center for Advancing Translational Science and their Clinical and Translational Science Awards programmes 33. Besides developing improved methods for conducting clinical studies in patients with rare disorders, these centres, often in conjunction with pharmaceutical companies 34, make various compound libraries available for high throughput screening, which further increases the chances of drug discovery and repurposing of existing drugs 35.

Grant‐giving bodies, such as the UK's Medical Research Council, the European Union, The National Institute for Biomedical Innovation in Japan, and the NIH in the USA, also support the discovery and development of drugs for rare disorders, as do grants from regulatory bodies, such as the FDA's Orphan Drugs Grants Program.

Developments in the field of genetics have reduced the costs of powerful techniques, such as next‐generation sequencing 36, 37 and whole‐genome screening 38, which identify the genetic components in the pathophysiology of many rare disorders, informing drug discovery and development. The genes responsible for about half of the rare monogenic disorders have been identified, and the rest are likely to be identified in the next few years. A few examples of gene‐based discovery and development of drugs for rare disorders are shown in Table 1, well illustrating the heterogeneity both of rare disorders and the medicines that are used to manage them.

Table 1.

Examples of gene‐based discovery and development of drugs for rare disorders

Drug	Disorder	Gene	Reference
Activin A antibody	Fibrodysplasia ossificans progressiva	Activin A receptor type 1 (ACVR1)	39
Alglucosidase alfa,recombinant human	Pompe's disease	Glucosidase alfa, acid (GAA)	40
Ivacaftor + lumacaftor	Some forms of cystic fibrosis	Cystic fibrosis transmembrane conductance regulator (CFTR)	41
Mavoglurant (mGluR5 antagonist)	Fragile X syndrome	Fragile X mental retardation 1 (FMR1)	42, 43
Nonretinoid retinol binding protein 4 antagonists	Ophthalmic Stargardt's disease	ATP binding cassette subfamily A member 4 (ABCA4)	44
Quinidine	Therapy‐resistant potassium sodium‐activated channel subfamily T member (KCNT1)‐positive epilepsies	KCNT1	45

Research into the causes of rare diseases can also lead to the development of drugs for more common diseases. Examples of this include the proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies for more common forms of hypercholesterolaemia 46 and sclerostin antibodies for the treatment of osteoporosis, which have originated from research into the cause of sclerosteosis and van Buchem's disease 47, 48, 49, 50, 51.

Clinical pharmacology and rare disorders

What is the place of the clinical pharmacologist in all of this 52?

The translational discipline of clinical pharmacology is an essential component in drug development, and this includes the development of drugs for rare disorders 53. Figure 2 shows an operational model of translational research, illustrating the various steps in the translational process as two‐way bridges connecting the various parts 54. It recognizes the nonlinear nature of research, the interrelations of the different components of the model and the two‐way processes (bridges in red) that link them, the barrier of cost‐effectiveness (CE, black bars), and the importance of predicting and monitoring beneficial and harmful outcomes.

Figure 2.

An operational model of translational research

Bridge B1 demonstrates the interplay between basic and applied research, in which innovative products or processes are not necessarily generated but which leads, via bridges B2a and B2b, to new knowledge, skills, or understanding. Clinical pharmacologists, trained in the skills of basic pharmacology and its links to clinical medicine 55, have contributed to these processes – for example, in delineating important genetic factors that determine the clinical effects of pharmacological interventions 56 and in developing biomarkers 57.

Bridges B3a and B3b show the aspect of translation that involves the application of new knowledge, skills, and understanding to patient‐oriented research. This usually also involves the use of innovative products that emerge from basic and applied research (bridges B4a, B4b, and B5). Thus, for example, careful design of phase I and phase II studies involving innovative pharmacological agents leads to the pivotal studies that result in marketing authorization and the clinical introduction of novel therapies (bridge B6). These are areas in which clinical pharmacology, including regulatory expertise, is essential 58, 59, 60, 61, 62, especially in the development of innovative trial designs needed for research into rare disorders 63, 64, 65. An example of translational and clinical development of an innovative pharmacological agent for a rare disease is the second‐generation 2'‐methoxyethyl chimeric antisense inhibitor of the molecular transthyretin for transthyretin amyloidosis, with cross‐species and human pharmacokinetic/pharmacodynamic and safety studies feeding into a phase III trial (clinicaltrials.gov number NCT01737398) in patients, currently in progress 66.

In turn, patient‐orientated research, leading to diffusion, dissemination and implementation of innovative products or processes, can yield new insights that require further research, basic and/or applied. For example, an unexpected drug–drug interaction from using a new medicine might prompt in vitro studies of the underlying mechanism, using yeast cells expressing human cytochrome P450 enzymes 67. In addition, incompletely understood observations in patients can stimulate further clinical and translational pharmacology studies into the effects of drugs, as well as the development of systems pharmacology models, as has been described for cholesteryl ester transfer protein inhibitors and drugs based on parathyroid hormone, which in turn may help to optimize treatment 68, 69, 70, 71, 72, 73.

In patient care, clinical pharmacologists can play a role in the implementation of novel proteomic, metabolomic, and genomic technologies, such as the application of next‐generation sequencing in the selection and optimization of pharmacological treatments for rare tumours 74.

The black straps (marked CE) in the model (Figure 2) remind us of the need to assess the cost‐effectiveness of interventions when deciding whether to introduce them into clinical practice. This is an essential part of the scrutiny of orphan products – for example, in relation to value assessments and funding processes 75 – and clinical pharmacologists and pharmacoeconomists have played a leading role in developing the relevant underlying ideas and tools 76, 77.

Bridges B7a and 7b demonstrate the importance of the clinical pharmacological principles of establishing both the balance of benefit‐to‐harm and the balance of two risks – the risk of treating and that of not treating – before prescribing a pharmacological intervention 78, implying all the basic principles of good prescribing 79, 80. An uncertain benefit/harm balance or risk/risk balance underlines the importance of monitoring both for benefits and harms, which should be routine in all cases. Much of pharmacovigilance depends on this 81, 82, 83.

Conclusion

With a complete understanding of the genomic basis of the pathophysiology of most, if not all, monogenic rare disorders, the stage is set for the development of further effective pharmacological interventions to target the major defects or the systems subserved by them. Translational research will be important in bringing such discoveries to fruition in individual patients, and clinical pharmacologists can and should play a substantial role by taking part in the processes at several different stages. Few patients are affected by individual rare disorders but together they represent a large percentage of the population. They need our efforts.

Competing Interests

J.K.A. is President Emeritus, an Honorary Fellow, and Vice‐President Publications of the British Pharmacological Society, Editor of Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions (16th edition, 2015), Chairman of the British Pharmacopoeia Commission's Expert Advisory Group on Drug Nomenclature, and a member of the Editorial Advisory Board of the Adverse Drug Reactions Bulletin. The views expressed in this article are not necessarily shared by these institutions or others associated with them. S.C. is Senior Editor (Reviews) of the British Journal of Clinical Pharmacology. He has no competing interests.

Cremers, S. , and Aronson, J. K. (2017) Drugs for rare disorders. Br J Clin Pharmacol, 83: 1607–1613. doi: 10.1111/bcp.13331.