The term orphan drug is a formal regulatory term used to describe a drug product that has been granted orphan status by a regulatory agency. Orphan designation is reserved for medicines that are intended to treat diseases with prevalence below the threshold set for rare diseases, which in the US is any disease or condition affecting fewer than 200 000 people. In Europe, a condition is considered rare if it affects fewer than 1 in 2000 people. There is considerable diversity among conditions defined as rare and they include neurological conditions, infectious diseases, rare cancers, autoimmune disorders, respiratory, muscle and blood disorders and a wide range of inherited genetic disorders. It has been estimated that there are more than 7000 rare diseases known but only around 5% of these have therapies available and the unmet medical need within rare diseases remains high. Across the thousands of highly heterogeneous rare diseases that are known, there is no unifying classification that links them all, with the exception that they affect a relatively small number of people, and the vast majority have no effective therapy available. Outside of the rare disease field, there is considerable misconception and misunderstanding surrounding rare diseases and orphan drugs; what these terms mean, what is classed as an orphan drug, what this designation entails and how many orphan drugs exist for which rare diseases. This chapter seeks to clear up these misconceptions and make clear to the reader what the terms orphan drug and rare disease mean, and detail the breadth of research, drugs and clinical activity taking place in this important field.
1.1 Orphan Drugs
An orphan drug or orphan medicine is a formal regulatory term used to describe a drug product that has been granted orphan status by a regulatory agency. Orphan designation is reserved for medicines that will treat diseases with prevalence below the threshold set for rare diseases, and may have additional factors such as the lack of availability of alternative treatments. The word ‘orphan’, from the Greek word orphanus for a child that has lost a parent,1 is taken from the ground-breaking legislation in the USA enshrined in the Orphan Drug Act of 1983,2–6 designed to stimulate the development of pharmaceutical products that target rare diseases, which were at the time largely neglected as they affected relatively few people.
1.2 Rare Diseases
There is considerable diversity among conditions that are defined as rare diseases and include neurological conditions, infectious diseases, rare cancers, autoimmune disorders, respiratory disorders, muscle disorders, blood disorders and a wide range of inherited genetic disorders. It has been estimated that there are more than 7000 rare diseases known,7 but only around 5% of these have therapies available8,9 and the unmet medical need across the breadth of rare diseases remains high. Over 80% of rare diseases are genetic in origin.10 Most of these are caused by defects in a single gene (that may be dominant or recessive), but some rare diseases are caused by multiple gene defects or a multitude of factors. Fifty percent of all rare diseases affect children and 85% are classified as serious or life-threatening. Some rare diseases may only affect literally a handful of individuals around the world, while others may affect hundreds of thousands of patients. In the developed world alone, rare diseases are thought to affect some 6% of the population, with estimates of more than 25 million North Americans and more than 30 million Europeans affected by a rare disease. Across the thousands of highly heterogeneous rare diseases that are known, there is no unifying classification that links them all, with the exception that they affect a relatively small number of people.
There is no single, widely accepted definition for rare diseases. In the USA, rare diseases are defined as any disease or condition affecting fewer than 200 000 people.11 In Europe, a condition is considered rare if it affects fewer than 1 in 2000 people12 and in Japan 1 in 50 000.13 There are a few diseases that affect more than 200 000 people where certain subpopulations that carry a particular disease fall below the prevalence threshold for a rare disease.
1.3 Developing an Orphan Drug
Developing drugs to treat rare diseases poses many unique challenges. Designing and conducting clinical trials is constrained, as there is usually little understanding or information about the natural progression of the disease to inform end point selection.8 Many rare diseases do not have clearly identifiable symptoms and investigators often have difficulty identifying and enrolling a large number of patients. Basic tools, such as validated animal models, may not exist. Small sample sizes pose statistical hurdles. These challenges increase the uncertainty that a research programme will lead to a new therapy, resulting in historically less investment into these therapies. An interesting example was raised by Tambuyzer,8 who highlighted that for Gaucher disease patients in Germany, only around 5% of all possible patients are being treated despite treatments being available for more than 15 years. This example also highlights the difficulties of obtaining accurate prevalence data for rare diseases, and how variable different sources of these data are. Certain rare diseases are also known to have very different prevalence rates in different populations and geographical regions, for example the glycogen storage disease Pompe disease, which can range in prevalence from 1 in 200 000 in Caucasians to as much as 1 in 14 000 in African Americans.14
In recognition of these specific issues facing drug development for rare diseases, many governments around the world have developed orphan drug regulations to support those working to develop new products intended for the diagnosis, prevention or treatment of rare conditions. While provisions vary from country to country, the key incentives created under various orphan drug regulations generally include marketing exclusivity, which prevents similars from competing with the original approved product during the exclusive period but is in no way intended to create a monopoly if clinical differentiation can be demonstrated. For example, several small molecule treatments (imatinib, dasatinib and nilotinib) have been approved in parallel for chronic myeloid leukaemia. There is also support for sponsors taking their orphan drug through the regulatory approval process in the form of fee waivers, additional scientific advice and expedited review. Some regulations also include research grants or R&D tax credits.
These incentives have successfully increased drug development activities within the orphan drug space. Orphan drugs can offer faster development timelines, lower R&D costs, lower marketing costs and lower risk of generic competition. An analysis has suggested that orphan drug approval rates were greater than those of mainstream drugs, and the proportion of overall new drug approvals in recent years that are orphan drugs has steadily grown.15
1.4 The Orphan Drug Act
The USA passed the first legislation of this type when the Orphan Drug Act of 1983 was signed into law.5 Similar legislation has been created in Australia, Europe, Japan and Singapore, with Canada and Russia set to introduce their own regulatory frameworks in the near future. The Orphan Drug Act sought to encourage development of drugs, diagnostics and vaccines intended to improve the treatment options for rare diseases by designating them as an orphan drug.
Orphan drug designation does not imply that a medicine is safe, effective or legal to develop and manufacture, but simply that the sponsor qualifies for certain benefits in the course of the drug development process.16
In the USA, the Office of Orphan Products Development (OOPD) within the Food and Drug Administration (FDA) grants an orphan designation to any product that is indicated for a rare disease as per the above definition.17 Orphan designation may be granted at any point through the drug development process. An orphan-designated product may subsequently gain market approval only if data derived from clinical trials demonstrate the safety and efficacy of the product. Orphan designation confers certain benefits to a sponsor; 50% tax credits for clinical development costs, exemption from application user fees, subsidies for conducting clinical trials and market exclusivity for 7 years. These incentives have clearly made a significant impact on rare disease drug development. In the decade leading up to the Orphan Drug Act being passed, only 10 products for rare diseases received marketing approved while in the period since, more than 10 products have received marketing approval every year, and to date some 430 orphan products for rare diseases have been approved.18 The OOPD also administers a related programme that is intended to stimulate the development of medical devices that are intended for use in the treatment or diagnosis of a rare disease.19
The Orphan Drug Act is widely accepted as having been hugely successful in driving R&D into rare diseases.20 In Figure 1.1, the number of orphan drug designations made by the OOPD since the adoption of the Orphan Drug Act in 1983 in the USA is illustrated, along with the number of orphan drugs that received market authorisation. The number of designations has increased markedly in the last decade to an average of well over 100 per year, reflective of generally increased interest from R&D companies in rare diseases. However, one can also see that the number of market authorisation approvals in the same period has remained relatively constant, and in fact relatively constant going back to the previous decade also, which at first glance may look like diminished, or at best flat, productivity.
Orphan drug designations and market authorizations granted by year in the USA since 1983. Data obtained from the US FDA OOPD website.18 Data from 2013 is only partial data, correct up to and including May 2013.
Orphan drug designations and market authorizations granted by year in the USA since 1983. Data obtained from the US FDA OOPD website.18 Data from 2013 is only partial data, correct up to and including May 2013.
Using the data set charted in Figure 1.1, over the entire period 1984–2013, 15% of all designations resulted in an approved product. Year on year, overall approval rates as a proportion of designations was plotted in Figure 1.2 and is relatively flat, with a peak towards the end of the last decade.
Approval rates in the USA as a proportion of orphan drug designations. Data obtained from the US FDA OOPD website.18 Data from 2013 is only partial data, correct up to and including May 2013.
Approval rates in the USA as a proportion of orphan drug designations. Data obtained from the US FDA OOPD website.18 Data from 2013 is only partial data, correct up to and including May 2013.
This picture is of course atypical in a period where overall drug approval rates have fallen, and therefore the proportion of orphan drugs being approved as a percentage of overall drug approvals is actually rising and appear to have higher approval rates than more mainstream drug applications in recent years.15
1.5 Outside of the USA
In the European Union, the Committee for Orphan Medicinal Products (COMP) is responsible for reviewing requests for drug products being given an orphan medicinal product (OMP) designation that are being developed for the purpose of treating a rare disease.21 Compounds that are given this designation are then assessed by the Committee for Medicinal Products for Human Use (CHMP) to receive formal market authorisation should they have demonstrable efficacy and safety. In Europe, the incentives for drugs that have been designated as having orphan status include 10 years of market exclusivity, grants for conducting clinical trials and fee reductions for requests made to the European Medicines Agency (EMA). The OMP legislation came into force in 2000, the same year the COMP was established.22,23
Several other countries also now have dedicated legislation, development incentives and approvals procedures for rare disease treatments, including Japan, Australia and Singapore.
1.6 Thirty Years on from the Orphan Drug Act
Since these regulations were established, the number of licensed therapies for rare diseases has increased markedly. Since 1983, there have been some 400 orphan product approvals in the USA now available for use by patients around the world, compared to just 10 orphan drugs approved in the previous decade.24 Focusing on the last decade only, the number of drug approvals has been both high (in total more than 180) and consistent and appears set to continue this trend into the future (Figure 1.3).
FDA orphan drug approvals by year in the last decade. Data obtained from the US FDA OOPD website.18 Data from 2013 is only partial data, correct up to and including May 2013.
FDA orphan drug approvals by year in the last decade. Data obtained from the US FDA OOPD website.18 Data from 2013 is only partial data, correct up to and including May 2013.
In Europe, within the same period of time, more than 65 orphan drug products have been granted market authorisation since the EU orphan drug legislation was enacted (Figure 1.4).
EU orphan drug approvals by year in the last decade. Data obtained from the US FDA OOPD website.18 Data from 2013 is only partial data, correct up to and including May 2013.
EU orphan drug approvals by year in the last decade. Data obtained from the US FDA OOPD website.18 Data from 2013 is only partial data, correct up to and including May 2013.
These regulatory guidelines can therefore be described as very successfully stimulating orphan drug development. However, the Orphan Drug Act and its sister regulations in other regions have sparked some controversy, not least through the advent of blockbuster orphans.24,25 These are drugs that generate annual revenues of at least several hundred million dollars through high per unit cost, sometimes in excess of $100 000 per patient per year or by widespread use of the drug outside of its primary orphan indication. Some studies have identified orphan drugs that generate significantly more revenue through off-label use than for any orphan indication.26
Most orphan drugs are approved for a single indication only, but now almost 50 drugs have been approved for multiple rare diseases. One of the most commercially successful orphan drugs is imatinib (Gleevec), with sales in excess of $4.5 billion in 2011 and seven separate orphan drug approvals. Indeed, in 2006–2008, no less than 16 orphan drugs made the top 200 list of best-selling drugs in the USA with annual sales in the range $200 million to $2 billion,27 and fuels the perception that orphan drugs can be economically viable and offer attractive business opportunities for biomedical drug development organisations.28 It should be borne in mind, however, that each market authorisation requires separate clinical trials for each additional indication added to a product, which needs to be paid for by the sponsor. It is also clear that for small market sizes and first-in-class medicines, a sponsor needs to embark on a R&D programme in the knowledge that their investment can be recouped, which does imply higher drug pricing, without which many of the products invented to date may never have come to market. It should also be highlighted that the legislation as it applies to orphan drug development makes no explicit provision for enhancing basic research into rare diseases, their diagnosis or which diseases receive drug development attention in which order.
1.7 Drug Repurposing
A crucial aspect of drug development activity for rare diseases has been the repurposing of existing drugs that had previously received marketing approval for a more common disease. This is particularly important as previously approved compounds will already have completed pre-clinical toxicity testing and been deemed to have demonstrated pharmacological activity in another disease indication. The OOPD has recently published data on the FDA website that details all 97 drugs that have an orphan designation and have previously been approved for a more mainstream indication.29 In addition, the same resource details the 71 drugs that are orphan-designated and have received previous market authorisation for another rare disease, and the 36 drugs that have an orphan designation and have been previously approved for both orphan and mainstream indications. Taken together, all drugs that have been previously approved for any disease indication by a regulatory authority offers a significant resource for rare disease research, having cleared many of the hurdles that often lead to attrition in the drug development process. There are more than 200 drugs that have a current orphan drug designation and benefit from market authorisation for some disease indication, but of course this is but a small fraction of the totality of approved drugs that could have some utility against a rare disease.
An example of a drug that was approved for a mainstream indication and subsequently approved for a rare disease is sildenafil from Pfizer (as Viagra, approved for the treatment of male erectile dysfunction in 1998), which was approved for the treatment of pulmonary arterial hypertension in 2005 as Revatio. Examples of drugs that were initially launched as orphan drugs and then were repurposed for broader indications include rituximab from Genentech (as Rituxan, initially approved for the treatment of non-Hodgkin lymphomas in 1997) and epoetin alpha from Amgen (as Epogen initially approved for the treatment of anaemia in 1989).27
An interesting example of a drug that was never intended for use as a human therapeutic is nitisinone, which was developed originally as a herbicide. Nitisinone is a 4-hydroxyphenyl pyruvate oxidase inhibitor that interrupts the formation of excess tyrosine in the blood and helps to prevent liver damage in children with hereditary tyrosinemia.30
1.8 Treatments and Modalities
The breadth and diversity of rare diseases makes all therapeutic modalities potentially applicable. Of the currently approved orphan drugs, many are small molecules, but others include, for example, monoclonal antibodies or enzyme replacement therapy (ERT) that at the time of approval were considered to be highly innovative.31,32 A wide range of experimental therapies based on the next generation of novel and innovative technologies that are especially well suited to gene defects include anti-sense oligonucleotides, RNA interference and stem cell-based therapies. Applications of all of these technologies to the treatment of rare diseases are illustrated below.
1.8.1 Small Molecules
The vast majority of rare disease treatments available today are small molecules, and mirrors the research focus of most mainstream disease indications across the industry. It seems likely that this trend will continue, particularly where a specific distribution feature of a rare disease (a neurological disease, for example) or an intolerance to other modalities (for example the use of the small molecule miglustat for the treatment of metabolic disorders where ERTs are poorly tolerated) dictates that small molecule options are best suited. The origins of the small molecule agents that are currently approved as a rare disease treatment again mirrors those of more mainstream small molecule drugs, and include phenotypic screens, high-throughput single target screens and natural product semi-synthesis as well as drug repurposing.
An interesting example of how small molecule therapies (and their delivery methods) have evolved through the years comes from the portfolio of approved products for the treatment of pulmonary arterial hypertension. The first agent approved was the vasodilating prostaglandin derivative epoprostenol, which had to be administered by IV injection. This was followed by the small molecule endothelin receptor antagonists, for example bosentan, which are taken orally. More recently, synthetic derivatives of prostaglandins have been developed using advances in formulation and drug delivery, for example the inhaled iloprost.
1.8.2 Antibody Therapies
Therapeutic monoclonal antibodies (mAbs) are large heterodimeric molecules composed of a heavy and a light chain that offer exquisite selectivity for their intended biological target. mAbs do not readily cross the blood–brain barrier or cell membranes, and as such are suitable for extracellular, non-central targets. Initially, murine mAbs were manufactured using hybridoma technology, but due to toxicity and variable immunologic response have since been replaced by other, more human versions.
Chimeric mAbs are murine-based in which the mAb constant region is replaced by a human equivalent. Chimeric mAb drugs include infliximab, a mAb that targets tumour necrosis factor and decreases intestinal inflammation in Crohn's disease.
Humanised mAbs are human antibody-based, in which murine hypervariable regions are grafted on. Example products of this type that have been developed for rare diseases include Soliris, for the treatment of paroxysmal nocturnal haemoglobinuria.
Human mAbs are produced by vaccinating transgenic mice, which contain human genes, with the antigen of choice, leading to the production of fully human mAbs. An example is Ilaris®, which is approved for the treatment of cryopyrin-associated periodic syndrome.
1.8.3 Therapeutic Proteins
Protein therapies aim to deliver a protein that is either absent or depleted in a disease state. Most often this is an endogenous protein, for example human growth hormone (marketed as Somatropin) that stimulates cell production and growth in conditions such as growth hormone disorders and paediatric growth disorders. More recent examples include Amgen's Neupogen, a granulocyte colony-stimulating factor analogue that is used to stimulate neutrophil production in patients with neutropenia.
1.8.4 Enzyme Replacement Therapies
Enzyme replacement therapies (ERTs) are the regular injection of a native or a recombinant enzyme to patients throughout their lives to mitigate for a lack or dysfunction of an endogenous enzyme. Lysosomal storage disorders are especially suitable for this type of therapy as they are caused by a deficiency in a single enzyme and respond well to ERT. Initially, the replacement enzymes were isolated from human organs, but enzyme yields were often low and ultimately recombinant versions were developed. Manufacture of the recombinant enzymes is often expensive and this is reflected in the high annual treatment cost of ERT which commonly exceeds $100 000 per patient per year. Successful ERT applications include Fabry disease, Gaucher disease and Hunter syndrome.
The Medical Research Council is funding research at the University of London into mitochondrial neurogastrointestinal encephalomyopathy (MNGIE),33 which is caused by a defect in the gene that produces the enzyme thymidine phosphorylase, and leads to mitochondrial dysfunction, muscle defects and a malfunctioning central nervous system. Only 200 cases of MNGIE have been identified worldwide. A new ERT is being developed using erythrocyte encapsulated thymidine phosphorylase (EE-TP) in which TP is introduced directly into a patient's red blood cells. The University of London, in partnership with Orphan Technologies, is continuing to develop the approach following the demonstration of efficacy in a small pilot study.
1.8.5 Gene Therapies
Diseases that are caused by single or multiple gene changes make them technically attractive to genetic or cell-based therapies to correct the malfunctioning gene(s). A number of innovative gene therapies have been developed for rare diseases which at a top level involves the use of a viral vector to deliver either a DNA cassette containing the missing gene to be expressed or an anti-sense or interfering RNA molecule to silence an overexpressing gene. In many ways the viral vector delivery system is critical to the success of the approach. The viruses of choice are adeno-associated viruses (AAVs), which are small human parvoviruses. They are single-stranded DNA viruses that can be delivered in high titres to both dividing and non-dividing cells and very effectively integrate into the host genome. Most importantly, they are safe and non-pathogenic, and can produce an effect that lasts for years. This is the vector used in uniQure's Glybera, the first ever gene therapy product to be approved in the EU34 as a treatment for lipoprotein lipase deficiency (LPL) through intramuscular expression of lipoprotein lipase.35 Contrast this with some of the false starts for gene therapy in which adenoviruses caused massive immune reaction or lentiviruses induced leukaemias in patients. Now, several gene therapy trials are under way for rare diseases, including alpha-1 antitrypsin deficiency, age-related macular degeneration, glioblastoma, Leber congenital amaurosis and Duchenne muscular dystrophy (DMD), and the results of these trials are eagerly anticipated.36
Recently, Sangamo Biosciences has reported the successful application of their in vivo protein replacement platform to modulate levels of the coagulation protein, Factor VIII, to offer a potential therapeutic approach to haemophilia.37 This approach is based on zinc-finger DNA-binding protein genome editing technology, which enables the precise insertion of a replacement Factor VIII gene into the albumin gene, thereby allowing high and stable expression of Factor VIII in the liver following a single systemic treatment in a mouse model. Other monogenic diseases that are being targeted by the Sangamo technology include sickle cell anaemia, Gaucher disease and beta thalassaemia.
Sarepta Therapeutics has reported on a potential new treatment for DMD using an anti-sense oligonucleotide AVI-4658 (Eteplirsen) in a small patient study. AVI-4658 is a phosphoramidate morpholino-oligomer that interacts with and then silences the long dystrophin exon 51 gene and enables expression of a shorter but functional dystrophin protein in DMD patients. AVI-4658 is well tolerated in dystrophic mice, normal mice and in non-human primates and has shown efficacy in Phase 2 clinical trials.38
1.8.6 Cell Therapies
Pluripotent stem cells are derived from adult somatic cells and can be induced (induced pluripotent stem cells, iPSCs) to take on the properties of human embryonic stem cells (hESCs); potentially this therapeutic approach could have a massive impact on rare disease research. Stem cells have the unique ability to renew themselves continuously and could be applied to the supply of native-like cell types for screening purposes, used to repair mutated systems caused by a rare disease before being transplanted back into the patient or directly targeting disease-producing cell types (e.g. the so-called cancer stem cells). Several reports have been made of the manufacture of iPSCs from rare disease patients including those for Gaucher disease, DMD, Huntington's disease and Hurler syndrome, but to date no iPSC clinical trial has been initiated. Several stem cell trials are, however, under way for a number of rare diseases using stem cells derived from bone marrow, for example retinitis pigmentosa, age-related macular degeneration and sickle cell disease. The biotechnology company Bluebird Bio has clinical stage assets based on genetically altered haematopoietic stem cells for the treatment of adrenoleukodystrophy and beta thalassaemia.39
Another viable approach involves the application of gene-altered stem cells as a combination of both gene and cell therapies that allows components of both technologies to operate. For example, altered stem cells have been used to express Factor VIII in a mouse model of haemophilia.
Finally, micro RNAs (miRNAs) are short, non-coding RNAs that function as gene regulators and can control the switching on and off of genes within stem cells. This is being applied in experimental approaches to regulating gene switching and elucidating the role of miRNAs in primarily monogenic rare diseases. miRNAs can also be detected in blood and could offer a simple biomarker for certain rare diseases. Santaris Pharma A/S is a drug development company that specialises in the discovery and development of RNA-based therapies using its locked nucleic acid (LNA) platform and reportedly has been looking into the application of its technology to rare genetic disorders.40
1.9 Orphan Drugs and the Diseases they are Used to Treat
In the above sections, the numbers of orphan drugs that have been approved and/or designated as orphan drugs have been presented along with the modalities that have been or are being researched within the rare disease field. In this section, examples of what the orphan drugs actually are, when they were approved, which modality they concern and which rare disease they are used to treat is now detailed. In Table 1.1, a range of orphan drug examples are shown that have been approved in the EU and/or the USA along with their target indication.
Example orphan drugs and the rare diseases they are intended to treat.a
| Active principle | Trade name | Year of approval | Indication | Product class | Market authorization holder |
|---|---|---|---|---|---|
| Somatropin | Nutropin | 1985 (USA) | Growth failure due to lack of growth hormone | Protein | Genentech |
| Clofazimine | Lamprene | 1986 (USA) | Lepromatous leprosy | Small molecule | Novartis |
| Etidronate | Didronel | 1987 (USA) | Hypercalcaemia of malignancy | Small molecule | MGI Pharma |
| Epoetin alpha | Epogen | 1989 (USA) | Anaemia | Protein | Amgen |
| 2007 (EU) | |||||
| Eflornithine | Ornidyl | 1990 (USA) | Treatment of Trypanosoma brucei | Small molecule | Hoechst Marion Roussel |
| Baclofen | Lioresal | 1992 (USA) | Treatment of intractable spasticity | Small molecule | Medtronic |
| Felbamate | Felbatol | 1993 (USA) | Lennox–Gastaut syndrome | Small molecule | Wallace Laboratories |
| Imiglucerase | Cerezyme | 1994 (USA) | Gaucher disease | ERT | Genzyme |
| Filgrastim | Neupogen | 1994 (USA) | Severe chronic neutropenia | Protein | Amgen |
| Riluzole | Rilutek | 1995 (USA) | Amyotrophic lateral sclerosis | Small molecule | Rhone-Poulenc Rorer |
| Clonidine | Duraclon | 1996 (USA) | Cancer pain | Small molecule | Roxane Laboratories |
| Tobramycin | Tobi | 1997 (USA) | Bronchopulmonary infections | Small molecule | Novartis |
| Infliximab | Remicade | 1998 (USA) | Crohn's disease | mAb | Centocor |
| Temozolomide | Temodar | 1999 (USA) | Malignant glioma | Small molecule | Schering Plough |
| Arsenic trioxide | Trisenox | 2000 (USA) | Acute promyelocytic leukaemia | Small molecule | Cephalon |
| Agalsidase beta | Fabrazyme | 2001 (EU) | Fabry disease | ERT | Genzyme |
| 2003 (USA) | |||||
| Agalsidase alpha | Replagal | 2001 (EU) | Fabry disease | ERT | Shire HGT |
| Imatinib | Glivec | 2001 (EU) | Chronic myeloid leukaemia | Small molecule | Novartis |
| 2001 (USA) | |||||
| Bosentan | Tracleer | 2002 (EU) | Pulmonary arterial hypertension | Small molecule | Actelion |
| 2001 (USA) | |||||
| Miglustat | Zavesca | 2002 (EU) | Gaucher disease | Small molecule | Actelion |
| 2003 (USA) | |||||
| Laronidase | Aldurazyme | 2003 (EU) | Mucopolysaccharidosis I | ERT | Genzyme |
| 2003 (USA) | |||||
| Cladribine | Litak | 2004 (EU) | Hairy cell leukaemia | Small molecule | Lipomed |
| Nitisinone | Orfadin | 2005 (EU) | Hereditary tyrosinaemia type 1 | Small molecule | Swedish Orphan International AB |
| 2002 (USA) | |||||
| Ziconotide | Prialt | 2005 (EU) | Chronic pain | Peptide | Elan Pharma |
| 2004 (USA) | |||||
| Sildenafil | Revatio | 2005 (EU) | Pulmonary arterial hypertension | Small molecule | Pfizer |
| 2005 (USA) | |||||
| Galsulfase | Naglazyme | 2006 (EU) | Mucopolysaccharidosis VI | ERT | BioMarin |
| 2005 (USA) | |||||
| Sunitinib | Sutent | 2006 (EU) | Metastatic renal cell carcinoma | Small molecule | Pfizer |
| 2006 (USA) | |||||
| Sitaxentan | Thelin | 2006 (EU) | Idiopathic pulmonary arterial hypertension | Small molecule | Encysive |
| Dasatinib | Sprycel | 2006 (EU) | Chronic myeloid leukaemia | Small molecule | Bristol-Myers Squibb |
| 2006 (USA) | |||||
| Stiripentol | Diacomit | 2007 (EU) | Severe myoclonic epilepsy in infancy | Small molecule | Biocodex |
| Idursulfase | Elaprase | 2007 (EU) | Hunter's syndrome (Mucopolysaccharidosis II) | ERT | Shire HGT |
| 2006 (USA) | |||||
| Betaine | Cystadane | 2006 (EU) | Homocystinuria | Small molecule | Orphan Europe |
| Lenalidomide | Revlimid | 2007 (EU) | Multiple myeloma | Small molecule | Celgene |
| 2006 (USA) | |||||
| Eculizumab | Soliris | 2007 (EU) | Paroxysmal nocturnal haemoglobinuria | mAb | Alexion |
| 2007 (USA) | |||||
| Trabectedin | Yondelis | 2007 (EU) | Soft tissue sarcoma | Small molecule | PharmaMar |
| Temsimorilus | Torisel | 2007 (EU) | Renal cell carcinoma | Small molecule | Pfizer |
| 2007 (USA) | |||||
| Icatibant | Firazyr | 2008 (EU) | Angioedema | Small molecule | Jerini |
| 2011 (USA) | |||||
| Sapropterin | Kuvan | 2008 (EU) | Hyperphenyl-alaninaemia | Small molecule | BioMarin |
| 2007 (USA) | |||||
| Azacytidine | Vidaza | 2008 (EU) | Myelodysplastic syndromes | Small molecule | Celgene |
| 2004 (USA) | |||||
| Romiplostim | Nplate | 2008 (EU) | Chronic immune thrombocytopenia | Protein | Amgen |
| 2008 (USA) | |||||
| Everolimus | Afinitor | 2009 (EU) | Renal cell carcinoma | Small molecule | Novartis |
| 2009 (USA) | |||||
| Plerixafor | Mozobil | 2009 (EU) | Mobilize progenitor stem cells prior to stem cell transplantation | Small molecule | Genzyme |
| 2008 (USA) | |||||
| Rilonacept | Arcalyst | 2009 (EU) | CAPS | Protein | Regeneron |
| 2008 (USA) | |||||
| Canakinumab | Ilaris | 2009 (EU) | CAPS | mAb | Novartis |
| 2009 (USA) | |||||
| Ofatumumab | Arzerra | 2010 (EU) | Chronic lymphocytic leukaemia | mAb | GSK |
| 2009 (USA) | |||||
| Eltrombopag | Revolade | 2010 (EU) | Idiopathic thrombocytopenic purpura | Small molecule | GSK |
| 2008 (USA) | |||||
| Velaglucerase alpha | Vpriv | 2010 (EU) | Gaucher disease Type 1 | ERT | Shire HGT |
| 2010 (USA) | |||||
| Cinacalcet | Sensipar | 2011 (USA) | Severe hypercalcaemia | Small molecule | Amgen |
| Crizotinib | Xalkori | 2011 (USA) | Metastatic non-small cell lung cancer | Small molecule | Pfizer |
| Clobazam | Onfi | 2011 (USA) | Lennox–Gastaut syndrome | Small molecule | Lundbeck |
| Ruxolitinib | Jakafi | 2012 (EU) | Myelofibrosis | Small molecule | Incyte |
| 2011 (USA) | |||||
| Ivacaftor | Kalydeco | 2012 (EU) | Cystic fibrosis | Small molecule | Vertex |
| 2011 (USA) | |||||
| Mifepristone | Korlym | 2011 (USA) | Cushing's syndrome | Small molecule | Corcept Therapeutics |
| Lomitapide | Juxtapid | 2012 (USA) | Familial hypercholesterolemia | Small molecule | Aegerion Pharmaceuticals |
| Alipogene | Glybera | 2012 (EU) | Lipoprotein lipase deficiency | Gene therapy | uniQure |
| Pomalidomide | Pomalyst | 2013 (USA) | Multiple myeloma | Small molecule | Celgene |
| Tocilizumab | Actemra | 2013 (USA) | Juvenile idiopathic arthritis | mAb | Genentech |
| Nimodipine | Nymalize | 2013 (USA) | Subarachnoid haemorrhage | Small molecule | Intercell |
| Active principle | Trade name | Year of approval | Indication | Product class | Market authorization holder |
|---|---|---|---|---|---|
| Somatropin | Nutropin | 1985 (USA) | Growth failure due to lack of growth hormone | Protein | Genentech |
| Clofazimine | Lamprene | 1986 (USA) | Lepromatous leprosy | Small molecule | Novartis |
| Etidronate | Didronel | 1987 (USA) | Hypercalcaemia of malignancy | Small molecule | MGI Pharma |
| Epoetin alpha | Epogen | 1989 (USA) | Anaemia | Protein | Amgen |
| 2007 (EU) | |||||
| Eflornithine | Ornidyl | 1990 (USA) | Treatment of Trypanosoma brucei | Small molecule | Hoechst Marion Roussel |
| Baclofen | Lioresal | 1992 (USA) | Treatment of intractable spasticity | Small molecule | Medtronic |
| Felbamate | Felbatol | 1993 (USA) | Lennox–Gastaut syndrome | Small molecule | Wallace Laboratories |
| Imiglucerase | Cerezyme | 1994 (USA) | Gaucher disease | ERT | Genzyme |
| Filgrastim | Neupogen | 1994 (USA) | Severe chronic neutropenia | Protein | Amgen |
| Riluzole | Rilutek | 1995 (USA) | Amyotrophic lateral sclerosis | Small molecule | Rhone-Poulenc Rorer |
| Clonidine | Duraclon | 1996 (USA) | Cancer pain | Small molecule | Roxane Laboratories |
| Tobramycin | Tobi | 1997 (USA) | Bronchopulmonary infections | Small molecule | Novartis |
| Infliximab | Remicade | 1998 (USA) | Crohn's disease | mAb | Centocor |
| Temozolomide | Temodar | 1999 (USA) | Malignant glioma | Small molecule | Schering Plough |
| Arsenic trioxide | Trisenox | 2000 (USA) | Acute promyelocytic leukaemia | Small molecule | Cephalon |
| Agalsidase beta | Fabrazyme | 2001 (EU) | Fabry disease | ERT | Genzyme |
| 2003 (USA) | |||||
| Agalsidase alpha | Replagal | 2001 (EU) | Fabry disease | ERT | Shire HGT |
| Imatinib | Glivec | 2001 (EU) | Chronic myeloid leukaemia | Small molecule | Novartis |
| 2001 (USA) | |||||
| Bosentan | Tracleer | 2002 (EU) | Pulmonary arterial hypertension | Small molecule | Actelion |
| 2001 (USA) | |||||
| Miglustat | Zavesca | 2002 (EU) | Gaucher disease | Small molecule | Actelion |
| 2003 (USA) | |||||
| Laronidase | Aldurazyme | 2003 (EU) | Mucopolysaccharidosis I | ERT | Genzyme |
| 2003 (USA) | |||||
| Cladribine | Litak | 2004 (EU) | Hairy cell leukaemia | Small molecule | Lipomed |
| Nitisinone | Orfadin | 2005 (EU) | Hereditary tyrosinaemia type 1 | Small molecule | Swedish Orphan International AB |
| 2002 (USA) | |||||
| Ziconotide | Prialt | 2005 (EU) | Chronic pain | Peptide | Elan Pharma |
| 2004 (USA) | |||||
| Sildenafil | Revatio | 2005 (EU) | Pulmonary arterial hypertension | Small molecule | Pfizer |
| 2005 (USA) | |||||
| Galsulfase | Naglazyme | 2006 (EU) | Mucopolysaccharidosis VI | ERT | BioMarin |
| 2005 (USA) | |||||
| Sunitinib | Sutent | 2006 (EU) | Metastatic renal cell carcinoma | Small molecule | Pfizer |
| 2006 (USA) | |||||
| Sitaxentan | Thelin | 2006 (EU) | Idiopathic pulmonary arterial hypertension | Small molecule | Encysive |
| Dasatinib | Sprycel | 2006 (EU) | Chronic myeloid leukaemia | Small molecule | Bristol-Myers Squibb |
| 2006 (USA) | |||||
| Stiripentol | Diacomit | 2007 (EU) | Severe myoclonic epilepsy in infancy | Small molecule | Biocodex |
| Idursulfase | Elaprase | 2007 (EU) | Hunter's syndrome (Mucopolysaccharidosis II) | ERT | Shire HGT |
| 2006 (USA) | |||||
| Betaine | Cystadane | 2006 (EU) | Homocystinuria | Small molecule | Orphan Europe |
| Lenalidomide | Revlimid | 2007 (EU) | Multiple myeloma | Small molecule | Celgene |
| 2006 (USA) | |||||
| Eculizumab | Soliris | 2007 (EU) | Paroxysmal nocturnal haemoglobinuria | mAb | Alexion |
| 2007 (USA) | |||||
| Trabectedin | Yondelis | 2007 (EU) | Soft tissue sarcoma | Small molecule | PharmaMar |
| Temsimorilus | Torisel | 2007 (EU) | Renal cell carcinoma | Small molecule | Pfizer |
| 2007 (USA) | |||||
| Icatibant | Firazyr | 2008 (EU) | Angioedema | Small molecule | Jerini |
| 2011 (USA) | |||||
| Sapropterin | Kuvan | 2008 (EU) | Hyperphenyl-alaninaemia | Small molecule | BioMarin |
| 2007 (USA) | |||||
| Azacytidine | Vidaza | 2008 (EU) | Myelodysplastic syndromes | Small molecule | Celgene |
| 2004 (USA) | |||||
| Romiplostim | Nplate | 2008 (EU) | Chronic immune thrombocytopenia | Protein | Amgen |
| 2008 (USA) | |||||
| Everolimus | Afinitor | 2009 (EU) | Renal cell carcinoma | Small molecule | Novartis |
| 2009 (USA) | |||||
| Plerixafor | Mozobil | 2009 (EU) | Mobilize progenitor stem cells prior to stem cell transplantation | Small molecule | Genzyme |
| 2008 (USA) | |||||
| Rilonacept | Arcalyst | 2009 (EU) | CAPS | Protein | Regeneron |
| 2008 (USA) | |||||
| Canakinumab | Ilaris | 2009 (EU) | CAPS | mAb | Novartis |
| 2009 (USA) | |||||
| Ofatumumab | Arzerra | 2010 (EU) | Chronic lymphocytic leukaemia | mAb | GSK |
| 2009 (USA) | |||||
| Eltrombopag | Revolade | 2010 (EU) | Idiopathic thrombocytopenic purpura | Small molecule | GSK |
| 2008 (USA) | |||||
| Velaglucerase alpha | Vpriv | 2010 (EU) | Gaucher disease Type 1 | ERT | Shire HGT |
| 2010 (USA) | |||||
| Cinacalcet | Sensipar | 2011 (USA) | Severe hypercalcaemia | Small molecule | Amgen |
| Crizotinib | Xalkori | 2011 (USA) | Metastatic non-small cell lung cancer | Small molecule | Pfizer |
| Clobazam | Onfi | 2011 (USA) | Lennox–Gastaut syndrome | Small molecule | Lundbeck |
| Ruxolitinib | Jakafi | 2012 (EU) | Myelofibrosis | Small molecule | Incyte |
| 2011 (USA) | |||||
| Ivacaftor | Kalydeco | 2012 (EU) | Cystic fibrosis | Small molecule | Vertex |
| 2011 (USA) | |||||
| Mifepristone | Korlym | 2011 (USA) | Cushing's syndrome | Small molecule | Corcept Therapeutics |
| Lomitapide | Juxtapid | 2012 (USA) | Familial hypercholesterolemia | Small molecule | Aegerion Pharmaceuticals |
| Alipogene | Glybera | 2012 (EU) | Lipoprotein lipase deficiency | Gene therapy | uniQure |
| Pomalidomide | Pomalyst | 2013 (USA) | Multiple myeloma | Small molecule | Celgene |
| Tocilizumab | Actemra | 2013 (USA) | Juvenile idiopathic arthritis | mAb | Genentech |
| Nimodipine | Nymalize | 2013 (USA) | Subarachnoid haemorrhage | Small molecule | Intercell |
One can see from the table that through the 30 years of orphan drug approvals, a range of therapeutic modalities are represented and a large cross-section of the industry are represented as sponsors of orphan drug development programmes. A large range of rare diseases have been served by the drug approvals shown in the table, but when one considers the breadth of total rare disease space (>7000), the products shown in the table only cover a tiny percentage of all rare diseases.
1.10 Rare Diseases and their Prevalence
In Table 1.2, we have focused this time on rare diseases, and attempted to classify them using similar criteria to those applied by the PhRMA resource.31 Once again, we have not attempted to be exhaustive but highlighted several rare diseases of differing origins and causative links, where known, for illustrative purposes. It is important to point out that the prevalence data compiled in the table was obtained from several sources, including Orphanet,41 Eurordis42 and is quite variable, most likely because accurate figures in many cases are lacking.
Selected rare diseases, their prevalence and causative link where known.
| Disease | Estimated prevalence per 100 000 | Causative link |
|---|---|---|
| Lysosomal storage disorders | ||
| Fabry disease | 1.8 | Alpha-galactosidase A |
| Pompe disease | 1 | Alpha-1,4-glucosidase |
| Hunter's syndrome | 1 | Iduronate-2-sulfatase deficiency |
| Gaucher disease | 1 | Glucocerebrosidase |
| Niemann-Pick disease | 2.5 | NPC |
| Tay–Sachs disease | 5 | Hexosaminidase A |
| Growth disorders | ||
| Growth hormone deficiency | 10 | Growth hormone releasing hormone + other causes |
| Acromegaly | 5 | Pituitary gland tumour |
| Autoimmune diseases | ||
| Kawasaki syndrome | 1.4 | Unknown |
| Muckle–Wells syndrome | 0.1 | Cryopyrin |
| Sarcoidosis | 15 | Unknown |
| Stevens–Johnson syndrome | 0.5 | Severe adverse drug reaction |
| Scleroderma | 42 | Unknown |
| Blood disorders | ||
| Thalassaemia | 0.5 | Haemoglobin |
| Paroxysmal nocturnal haemoglobinuria | 0.8 | Haematopoietic stem cells |
| Myelofibrosis | 2.7 | Bone marrow stem cells, JAK2 |
| Cyclic thrombocytopenia | — | Growth factors, platelet autoantibodies |
| Eye disorders | ||
| Retinitis pigmentosa | 30 | Unknown |
| Chronic uveitis | 38 | Various primary diseases |
| Refractory glaucoma | — | Unknown |
| GI disorders | ||
| Paediatric ulcerative colitis | 2 | Unknown |
| Paediatric Crohn's disease | 2 | Innate immune system |
| Pouchitis | — | Unknown |
| Infectious diseases | ||
| Anthrax | — | Bacillus anthracis |
| Pulmonary infection in cystic fibrosis patients | — | Various infectious pathogens |
| Leishmaniasis | — | Protozoan parasites |
| Malaria | — | Plasmodium parasites |
| Chagas disease | — | Trypanosoma cruzi |
| Rare cancers | ||
| Acute myeloid leukaemia | 16 | Various genetic and environmental factors |
| Ewing's sarcoma | 0.1 | EWS protein |
| Renal cell carcinoma | 36 | Various lifestyle and genetic factors |
| Kaposi's sarcoma | 2.1 | Human herpes virus 8 |
| Movement disorders | ||
| Amyotrophic lateral sclerosis | 5 | Superoxide dismutase and various other genetic and environmental factors |
| Huntington's disease | 5 | Huntingtin |
| Freidreich's ataxia | 3 | Frataxin |
| Duchenne muscular dystrophy | 3.7 | Dystrophin |
| Neurological disorders | ||
| Narcolepsy | 26 | HLA complex |
| Post-herpetic neuralgia | — | Varicella zoster virus |
| Trigeminal neuralgia | 5 | Demyelination of ganglia axons |
| Lennox–Gastaut syndrome | 15 | Various genetic factors and inflammatory brain diseases |
| Charcot–Marie–Tooth disease | 24 | Myelin and axonal proteins |
| Cardiovascular diseases | ||
| Dilated cardiomyopathy | 40 | Myocardial damage by various pathogens and cytoskeletal genetic factors |
| Genetic disorders | ||
| Cystic fibrosis | 10 | Cystic fibrosis transmembrane conductance regulator |
| α1-Antitrypsin deficiency | 25 | α1-Antitrypsin |
| Sickle cell disease | 15 | β-Globin chain of haemoglobin |
| Cryopyrin-associated periodic syndrome | 0.1 | Cryopyrin |
| Hyperphenylalaninaemia | 0.4 | Phenylalanine hydroxylase |
| Epidermolysis bullosa | 2.5 | Collagen and laminin |
| Respiratory disorders | ||
| Acute respiratory distress syndrome | — | Various primary diseases and traumas |
| Idiopathic pulmonary fibrosis | 26 | Various viral infections and environmental factors |
| Pulmonary arterial hypertension | 20 | Glucose-6-phosphatase |
| Transplantation | ||
| Graft-versus-host disease | 2.8 | Graft immune cells |
| Ischemia-reperfusion injury | — | Various inflammatory mediators |
| Other | ||
| Primary focal segmental glomerulosclerosis | 0.3 | Viral and toxin agents, and renal haemodynamic changes |
| Acute radiation syndrome | — | Widespread cellular damage |
| Hepatic veno-occlusive disease | 11 | Unknown |
| Disease | Estimated prevalence per 100 000 | Causative link |
|---|---|---|
| Lysosomal storage disorders | ||
| Fabry disease | 1.8 | Alpha-galactosidase A |
| Pompe disease | 1 | Alpha-1,4-glucosidase |
| Hunter's syndrome | 1 | Iduronate-2-sulfatase deficiency |
| Gaucher disease | 1 | Glucocerebrosidase |
| Niemann-Pick disease | 2.5 | NPC |
| Tay–Sachs disease | 5 | Hexosaminidase A |
| Growth disorders | ||
| Growth hormone deficiency | 10 | Growth hormone releasing hormone + other causes |
| Acromegaly | 5 | Pituitary gland tumour |
| Autoimmune diseases | ||
| Kawasaki syndrome | 1.4 | Unknown |
| Muckle–Wells syndrome | 0.1 | Cryopyrin |
| Sarcoidosis | 15 | Unknown |
| Stevens–Johnson syndrome | 0.5 | Severe adverse drug reaction |
| Scleroderma | 42 | Unknown |
| Blood disorders | ||
| Thalassaemia | 0.5 | Haemoglobin |
| Paroxysmal nocturnal haemoglobinuria | 0.8 | Haematopoietic stem cells |
| Myelofibrosis | 2.7 | Bone marrow stem cells, JAK2 |
| Cyclic thrombocytopenia | — | Growth factors, platelet autoantibodies |
| Eye disorders | ||
| Retinitis pigmentosa | 30 | Unknown |
| Chronic uveitis | 38 | Various primary diseases |
| Refractory glaucoma | — | Unknown |
| GI disorders | ||
| Paediatric ulcerative colitis | 2 | Unknown |
| Paediatric Crohn's disease | 2 | Innate immune system |
| Pouchitis | — | Unknown |
| Infectious diseases | ||
| Anthrax | — | Bacillus anthracis |
| Pulmonary infection in cystic fibrosis patients | — | Various infectious pathogens |
| Leishmaniasis | — | Protozoan parasites |
| Malaria | — | Plasmodium parasites |
| Chagas disease | — | Trypanosoma cruzi |
| Rare cancers | ||
| Acute myeloid leukaemia | 16 | Various genetic and environmental factors |
| Ewing's sarcoma | 0.1 | EWS protein |
| Renal cell carcinoma | 36 | Various lifestyle and genetic factors |
| Kaposi's sarcoma | 2.1 | Human herpes virus 8 |
| Movement disorders | ||
| Amyotrophic lateral sclerosis | 5 | Superoxide dismutase and various other genetic and environmental factors |
| Huntington's disease | 5 | Huntingtin |
| Freidreich's ataxia | 3 | Frataxin |
| Duchenne muscular dystrophy | 3.7 | Dystrophin |
| Neurological disorders | ||
| Narcolepsy | 26 | HLA complex |
| Post-herpetic neuralgia | — | Varicella zoster virus |
| Trigeminal neuralgia | 5 | Demyelination of ganglia axons |
| Lennox–Gastaut syndrome | 15 | Various genetic factors and inflammatory brain diseases |
| Charcot–Marie–Tooth disease | 24 | Myelin and axonal proteins |
| Cardiovascular diseases | ||
| Dilated cardiomyopathy | 40 | Myocardial damage by various pathogens and cytoskeletal genetic factors |
| Genetic disorders | ||
| Cystic fibrosis | 10 | Cystic fibrosis transmembrane conductance regulator |
| α1-Antitrypsin deficiency | 25 | α1-Antitrypsin |
| Sickle cell disease | 15 | β-Globin chain of haemoglobin |
| Cryopyrin-associated periodic syndrome | 0.1 | Cryopyrin |
| Hyperphenylalaninaemia | 0.4 | Phenylalanine hydroxylase |
| Epidermolysis bullosa | 2.5 | Collagen and laminin |
| Respiratory disorders | ||
| Acute respiratory distress syndrome | — | Various primary diseases and traumas |
| Idiopathic pulmonary fibrosis | 26 | Various viral infections and environmental factors |
| Pulmonary arterial hypertension | 20 | Glucose-6-phosphatase |
| Transplantation | ||
| Graft-versus-host disease | 2.8 | Graft immune cells |
| Ischemia-reperfusion injury | — | Various inflammatory mediators |
| Other | ||
| Primary focal segmental glomerulosclerosis | 0.3 | Viral and toxin agents, and renal haemodynamic changes |
| Acute radiation syndrome | — | Widespread cellular damage |
| Hepatic veno-occlusive disease | 11 | Unknown |
One can see that some categories, for example lysosomal, genetic and respiratory disorders, are reasonably well served by the drugs displayed in Table 1.2, while in other categories such as gastrointestinal and movement disorders, these are much less well served.
It is also notable that while for many of the diseases listed in the table, a definite causative link has been elucidated, in many more cases there is no definitive molecular target for the disease. In some cases, even where a molecular target is implicated it is not always known in detail exactly how this creates the disease state. This does imply that there is a lack of basic research into many rare diseases.
In looking more closely at the range of rare diseases targeted by approved orphan drugs and how this picture has changed over the years, the chart in Figure 1.5 shows all the orphan drugs approved in the USA in the first 5 year period since the introduction of the Orphan Drug Act arranged by class.
FDA approvals in the first 5 years of the Orphan Drug Act. Data obtained from the US FDA OOPD website.18 The classification used follows a similar pattern to that used by the PhRMA resource.31
The largest proportion of drugs target blood disorders, with approximately half of all disease classes showing no drug approval. The chart in Figure 1.6 shows how this picture has changed when one now looks at approved drugs in the USA from the last 5 years.
FDA approvals in the last 5 years. The classification used follows a similar pattern to that used by the PhRMA resource.31
FDA approvals in the last 5 years. The classification used follows a similar pattern to that used by the PhRMA resource.31
The largest proportion of approved drugs now target cancers. Blood disorders still account for a significant number of orphan drugs, but neurological disorders are also now well represented. It is also notable that almost all rare disease classes are populated, although within each class of disease the proportion of all diseases that are targeted by an orphan drug remains small. This picture is similar to that of orphan drug approvals in the EU since 2000, as shown in Figure 1.7.
EU approvals since 2000. The classification used follows a similar pattern to that used by the PhRMA resource.31
EU approvals since 2000. The classification used follows a similar pattern to that used by the PhRMA resource.31
Looking ahead to what the next generation of orphan drugs may target, Figure 1.8 shows the orphan drugs that were in clinical development in 2011 according to the PhRMA resource.31 The trends in drug approvals from the last 5 years seen in both the EU and USA appears set to continue, but it is striking that a greater variety of disease classes are being evaluated clinically. This is probably driven, at least in part, by the recent advances in genetic screening and analysis technologies, and a significant increase in understanding of the genetic basis for some diseases. This is an encouraging sign that basic science advances of the last decade are fuelling the clinical advances of the next.
1.11 The Changing Face of Orphan Drug Developers
In the early years after the Orphan Drug Act was signed into law, there were relatively few industry drug developers focused on rare disease treatments. Companies such as Genzyme, Genentech, Shire Human Genetic Therapies, Amgen and Actelion were most closely associated with rare disease drug discovery.
In recent years, the companies involved in rare disease R&D have become much more diverse, as was highlighted in Table 1.1, and it is notable how many large pharma companies are now involved.43 This involvement has come in some cases from the creation of dedicated internal research and business units (including for example Pfizer and GSK), in some cases from acquisitions (for example the acquisition of Genzyme in 2011 by Sanofi, FoldRx by Pfizer in 2010 and the acquisition of Amira Pharma by BMS in 2011) and in some cases through licensing deals (for example the licensing of a selectin antagonist for vaso-occlusive crisis from GlycoMimetics by Pfizer in 2011, the licensing of non-US rights to Incyte's oral JAK inhibitor for myelofibrosis by Novartis and the licensing of an ERT from Angiochem for a lysosomal storage disorder by GSK) or technology-based collaborations (for example the Pfizer collaboration with Zacharon Pharmaceuticals to find rare disease treatments using small molecule drugs that target glycans and the GSK collaborations with Prosensa Therapeutics and ISIS Pharmaceuticals to seek rare disease therapies based on anti-sense technology).44
It is also notable that several smaller companies that have specialised exclusively in rare disease research have been hugely commercially successful. Alexion Pharmaceuticals is a small biotechnology company that markets but one product – Soliris for the treatment of paroxysmal nocturnal haemoglobinuria (PNH), which has been described as the most expensive drug in the world45 at $400 000 per treatment year in the USA, and sales projected to reach >$1 bn in 2012.46 The revenues generated by Soliris have enabled Alexion to acquire Enobia Pharma Inc., with a Phase 2 asset for hypophosphatasia and Taligen Therapeutics for access to their fusion protein technology to treat complement-mediated diseases. Biogen Idec is another company that has built an impressive portfolio of rare disease treatments for diseases that include multiple sclerosis and non-Hodgkin's lymphoma, and has embarked on a series of collaborations and acquisitions (Stromedix in 2012 for their idiopathic pulmonary fibrosis asset and Knopp Neurosciences for access to the Phase 2 asset dexpramipexole for amyotrophic lateral sclerosis).
Start-up biotechnology companies with a focus on rare diseases have attracted significant investor funding in recent years. These companies are often, but not always, established around a specific platform technology. Rare disease start-ups include Ultragenyx47 (developing an extended-release formulation of sialic acid for the treatment of hereditary inclusion body myopathy), Synageva48 (developing sebelipase, an ERT for the treatment of lysosomal acid lipase deficiency), Retrophin49 (developing an asset for the treatment of focal segmental glomerulosclerosis) and Sarepta38 (developing eteplirsen for the treatment of DMD).
The pricing debate will undoubtedly be reignited when the pricing of uniQure's gene therapy product Glybera is announced. The pricing of a one-time series of intramuscular injections of Glybera is likely to exceed that of all existing orphan drugs that are dosed chronically, and could exceed the $1 m per patient level.
1.12 The Next 30 Years of Orphan Drug Development
1.12.1 Value for Money
The analyses presented above indicate an encouraging era for rare disease research. More companies, including big pharma, are now involved in drug R&D than ever, and their attention is focused on more rare disease classes than ever. This increased level of investment is of course not a guarantee of successful drug products, but it certainly increases the chances of realising more new and innovative rare disease treatments. Much of this increased level of investment, and indeed the orphan drug model itself, has been predicated on the promise of premium pricing of drugs that are eventually brought to market, thereby guaranteeing a level of profit for the drug sponsor, and it is this aspect of orphan drug development that does seem set to evolve in the near to medium term. While the overall budget spend by healthcare systems around the world on orphan drugs is small compared to more mainstream products such as cardiovascular or anti-inflammatory treatments, and the rare diseases that those drugs treat are often serious and life-threatening, there does appear to be increasing scrutiny of orphan drug pricing.50 This can only intensify as more treatments come online and the cluster of rare disease treatments as a class starts to grow.
The key evidence for successful orphan drugs in the future will more than ever be safety and above all efficacy. This will be especially true in disease classes where multiple products exist, and one could envisage a system of ‘risk sharing’ in which a sponsor will be required to lower the cost of a drug treatment if it is shown to have less than expected efficacy.51 The corollary to this could be the advent of gene therapy, which in all likelihood will command ultra-premium prices but overall will provide greater value for money if the therapy offers a cure.
1.12.2 The Expanding Role of Government Translational Research Programmes with Industry Partnerships
Science will continue to advance in the coming decades on a number of fronts, and the cost of genetic diagnosis will continue to decrease. More accurate data of rare disease prevalence and genetic causal links will become available. Translational data sets to refine the targeting of small patient populations and measurement of meaningful clinical biomarkers to assess outcome measures as reliable indicators of drug efficacy will evolve. In the USA, the National Institutes of Health (NIH) provided more than $823 million for 1600 orphan product development activities in the fiscal year 2012. The special research emphasis on rare diseases at NIH has resulted in the allocation of $3.623 billion for 9400 research projects. Several research institutes and centres of the NIH have made available personnel and financial resources for translational research initiatives to respond to scientific opportunities and the need for interventions for the prevention, diagnosis or treatment of rare and common diseases. These resources bridge existing data gaps to complete the necessary studies to provide pre-clinical and clinical data required for regulatory purposes. Of particular interest are the translational research programmes offered by the National Center for Advancing Translational Sciences, the National Cancer Institute, The National Institute of Allergy and Infectious Diseases, The National Heart, Lung, and Blood Institute, and the National Institute of Neurological Disorders and Stroke. Although similar in many respects, there are differences in each of the translational research programmes, including the application and review processes. Some institutes make the traditional grants and contracts available for clinical trial planning and implementation. To avoid confusion with the different processes, it is advisable to identify those institutes with a research portfolio that includes a specific disease interest. These activities within the translational research programmes are expected to complement or supplement the existing biopharmaceutical industry efforts and not to replace the extensive activities related to rare disease research and orphan product development activities.
1.12.3 Expanding Role of Academic Centres and Industry to Identify and Develop Orphan Products for Rare Diseases
It is likely that with an increase in the role of big pharma in rare disease research and the opening of their large chemical files, drug repurposing will increase, to uncover new drugs for rare diseases, and potentially this could impact in the relatively near term (within the next 5 years). It will also be interesting to see if big pharma, and indeed smaller biotech companies, can be incentivised to work on rare diseases for which there is very little known and take the lead role in driving the basic science behind such diseases. Rare diseases can be staggering if you consider the need for sufficient resources to discover and develop products to diagnose, treat or prevent rare diseases experienced by approximately 6–8% of the population who have one of the more than 6000 rare diseases. Partnering and collaborating with the academic research community is an essential component of R&D efforts for the biopharmaceutical and medical device industries to develop a portfolio of potential interventions and diagnostics. The pharmaceutical industry, with its unique product R&D infrastructure and expertise, provides the academic research community with the capability of moving a discovery to the marketplace. Rare diseases do not respect geographical or national borders and offer numerous research and regulatory challenges requiring global efforts as we observe expansion of activities that include the academic research communities from around the world. Numerous academic and government technology transfer programmes are now available to industry. Many of these programmes are formal partnerships between the industry and the academic partners. Both initiatives can lead to products for rare diseases but require a keen understanding of these programmes and the responsible programme staff who provide the links to the existing resources. Collaborative public–private partnership efforts required for rare diseases use disease-specific steering committees often led by patient advocacy groups (PAGs) and their scientific or medical advisory board members, most of whom are research investigators and medical specialists from the academic research and medical care communities. It is equally important for the academic community to have a clear path to the biopharmaceutical and medical device industries by having knowledge of appropriate contacts and available programmes from the potential industry partners. Many of these arrangements require considerable time for resolution of legal considerations between two or more parties, involving intellectual property and the estimated value of this property, and the milestones associated with drug development.
1.12.4 Recognition and Acceptance of PAGs and Patients/Families as Research Partners
As mentioned earlier, there are now several successful models of PAGs directing partnerships to reach their organisational goals of providing treatments for their patients. Many of these organisations, such as the Cystic Fibrosis Foundation, Pulmonary Hypertension Association, the National Urea Cycle Diseases Foundation, the Parent Project for Duchenne Muscular Dystrophy, and the Progeria Research Foundation, continue to extend their traditional advocacy roles of emphasising rare diseases research and orphan products development and have led to the identification of potentially useful products for their diseases. This new coordinating role has relied upon guidance from the pharmaceutical, biotechnology and medical device industries and contract research organisations. Active relationships with PAGs has helped reduce some of the barriers to research of rare diseases and orphan products including gaining access to a sufficient number of patients to participate in clinical trials. Lack of access to a sufficient number of patients to open a clinical trial through numerous recruitment procedures at a particular research site requires a collaborative global effort including research investigators and PAGs around the world. The PAGs utilise their unique resources to develop patient registries, encourage patients and their families to participate in natural history studies, facilitate the development of acceptable informed consent documents, and encourage research investigators to develop and adhere to common research protocols. The leadership of the PAGs has been able to establish global communication and social media links. Many of these working relationships advancing to global research investigations are the result of sponsorship and attendance at patient or family and scientific conferences. Many members of the biopharmaceutical industry now include active staff liaison and outreach activities between the industry and the patient communities. These activities facilitate the transfer of valuable information about the disease and possible interventions to patients, families, physicians and other healthcare providers, and the public. The development of strong and knowledgeable leadership in the PAG community with their scientific and medical advisory boards is a key to the successful development of interventions for rare diseases. The leadership of many of the PAGs continues to be recognised as the knowledgeable voice of specific rare diseases to the scientific community, the pharmaceutical industry and the media.
1.12.5 Role and Value of Research Networks and Consortia for Rare Diseases Research and Orphan Products Development
For most rare diseases and conditions, local clinics and academic medical centres do not have access to a sufficient number of patients and clinical researchers to complete clinical trials in a timely fashion. The Rare Diseases Clinical Research Network (RDCRN) was created to respond to these needs and provide the infrastructure to conduct different types of studies with multiple investigators available at numerous research sites and ready access to a sufficient number of patients to initiate a clinical study and to complete the trial without unreasonable delays. The majority of studies in the RDCRN are longitudinal or natural history studies. Other types of study include pilot studies, and Phase I, II and III studies. Industry sponsorship of studies is encouraged. Individual consortia in the RDCRN support collaborative clinical research studies, provide training programmes for new clinical investigators, and enable the partnership role of PAGs in rare disease research programmes. The RDCRN utilises a Data Management and Coordinating Center (DMCC) as a facilitating centre to assist in the design of clinical protocols, data management and analyses from multiple diseases and multiple clinical research sites. The DMCC maintains a web-based patient contact registry as a recruitment and referral tool for all consortia to use.
The 17 consortia in the RDCRN are supported by the Office of Rare Diseases Research (ORDR) and eight research institutes at NIH. Each consortia is required to focus on a group of at least three related disorders and receives 5 years of support. The data from ongoing and completed RDCRN clinical studies are shared openly with the scientific community. ORDR-developed data is placed in the National Library of Medicine's dbGaP database. The RDCRN studies more than 200 diseases at 225 research sites around the world, with 86 active protocols and an additional 37 protocols in different stages of development. There have been more than 130 trainees in the second 5 year cycle of RDCRN, with approximately 175 trainees in both 5 year periods. More than 15 000 patients have enrolled in studies in the second 5 year period for a total of 22 000 people. A total of 119 studies have been activated since inception and 76 studies activated during the current grant period. There are 97 PAGs and collectively they have formed the Coalition of Patient Advocacy Groups (CPAG) to support the numerous activities of the individual RDCRN consortia. Several consortia have established international collaborations in 14 countries other than the USA, including Australia, Austria, Belgium, Canada, England, France, Germany, Iceland, India, Italy, the Netherlands, Scotland, Spain and Switzerland. The RDCRN Contact Registry, which enhances participation in clinical trials and disseminates information, has approximately 11 000 registrants from 90 countries for more than 200 rare diseases.
1.12.6 Collaborative Partnerships are Required for Advances
Most rare diseases affect multiple organ systems and each have their own clinical and research disciplines involved in research through the multidisciplinary research teams. With limited resources available, newer models have evolved that utilise the resources available from public–private partnerships. These models include major participatory efforts by the academic research community, federal research and regulatory agencies, private foundations, PAGs, and members of the pharmaceutical, biotechnology and medical device industries. The rare diseases community recognises and encourages the different multi-organisational approaches to drug discovery and development, especially if there is limited or no commercial interest in developing a product for rare diseases. These models also require resources and commitments be made from many private and public organisations to facilitate the development of products. A global approach is required to coordinate research efforts at multiple research sites working under a common protocol and utilising the skills and knowledge from multidisciplinary research teams. Coordinated and systematic efforts to research and product development require numerous highly motivated global partners utilising the strengths of the individual organisations towards a common goal of developing treatments or diagnostics for rare diseases.
