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A young patient suffering from the rare disease MPS1-HS blogged “My main reason for sharing comes from wishing when I was diagnosed that there had been someone like me out there, especially another young adult, blogging about their experiences.” The Incidence and Prevalence Database of Thomson Reuters enables new understanding of rare diseases, by describing the epidemiology of the most common rare disease in its database. This whitepaper endeavors to raise awareness for these conditions, by elaborating on the number of affected patients worldwide, the causes for these diseases, the aid obtained from patient advocacy organizations and rare disease-specific organizations, and the current market scenario regarding rare diseases.

How Many Are Affected?

Feb. 29, 2016 marked the 9th annual commemoration of the international Rare Disease Day. Currently, there are approximately 7,000 different types of rare diseases and disorders affecting about 350 million people worldwide. In the US, about 30 million people suffer from rare diseases (1 in 10 Americans or 10% of the U.S. population), and another 30 million people are living with rare diseases in Europe.

International definitions for rare diseases vary. In the US, a condition is considered “rare” when it affects fewer than 200,000 persons combined in a particular rare disease group. In the UK, a disease is considered rare if it affects fewer than 50,000 people. Some conditions initially classified as rare eventually outgrow this categorization (e.g., AIDS emerged in the United States as a rare disease, affecting fewer than 200,000 individuals, but spread to nearly 470,000 by 2007, with the number of HIV-infected individuals exceeding 1.1 million in 2009). Whereas effective but non-curative treatment can turn a rare disease into a common one, effective prevention can, conversely, turn a common condition into a rare disease, as is observed for many once-common childhood infections such as mumps and measles.

With this backdrop, the study of rare diseases—in particular, the prevalence (number of people affected at any one time), incidence (number of new cases in a given year), and pattern of the disease (e.g., age distribution) reported for a particular population—may be somewhat inexact over time.

The prevalence distribution of rare diseases is skewed. Of the roughly 7,000 rare diseases known to date, an estimated 350 rare diseases are responsible for affecting 80% of all rare disease patients. The rarity of such conditions is exemplified by studying the prevalence data on fibrodysplasia ossificans progressiva (FOP), a rare disease where the patients' muscles and tendons are replaced by bone. FOP affects about 3,300 people worldwide, or approximately 1 in 2 million people. Such statistics may be better grasped by the following example: if a large football stadium holds 100,000 fans, one would need to fill nearly 20 football stadiums to find 1 person who has FOP. At the present time, researchers are aware of approximately 700 people throughout the world who have FOP.

Approximately 50% of people affected by rare diseases are children, with 30% of children with rare disease not surviving their 5th birthday. Rare diseases are responsible for 35% of deaths in the first year of life. Osteogenesis imperfecta (OI), also known as brittle bone disease, affects males and females in equal numbers. Untreated individuals often suffer from hundreds of fractures, and have a severe short stature. In the US, OI type I is estimated to occur in 1 in 30,000 live births, whereas OI type II is estimated to occur in 1 in 60,000 live births. The overall prevalence of all types of OI is estimated at .5 per 10,000 individuals in the US, with approximately 20,000 to 50,000 individuals in the country suffering from this rare disease.

In Europe, Sweden has reported dominant mutations in collagen type I that are responsible for 90% of OI cases, while OI type III is the most severe type compatible with surviving the neonatal period. The country reports a point prevalence of OI at birth anticipated to be close to 10/100,000.

For further information on this and other rare diseases, see the Incidence & Prevalence Database, by Thomson Reuters.

What Causes Rare Diseases?

While patients and families struggle to grasp the meaning and impact of a rare disease diagnosis, epidemiological and molecular research point to a large number of these diseases caused by genetic defects. Up to 80% of rare diseases are genetic in origin, and thus are present throughout a person’s life even if symptoms do not immediately appear. The Orphan Drug Act, the Rare Diseases Act, and other policy initiatives have focused attention, resources, and incentives on the study of rare conditions and products to treat them.

However, understanding the genetic, infectious, or other cause of a disease does not necessarily mean that researchers understand the mechanism of the disease. The rare disease community knows little about von Hippel-Lindau (VHL) syndrome, even though mutations in the VHL gene have been identified as the cause and another gene has been implicated in disease variations. More common rare diseases such as cystic fibrosis and sickle cell disease have known causes and reasonably well-understood mechanisms but lack cures, satisfactory treatments, or preventive strategies.

Some rare conditions have multiple causes. Some forms of aplastic anemia, which is caused by damage to stem cells in the bone marrow and is diagnosed in about 500 to 1,000 people each year in the US, are inherited (e.g., Fanconi anemia). More often, though, the condition is acquired as a result of a toxic exposure (e.g., benzene, chloramphenicol), an infection (e.g., hepatitis, herpes virus), radiation or chemotherapy, or another disease (e.g., rheumatoid arthritis). This makes it difficult for the physician to determine the exact cause for a specific patient.

For certain rare diseases that have been named and characterized for decades, investigators still have not determined the cause. Whereas the disease was identified decades ago, no cause is reported for Gorham's disease, an extremely rare bone disorder that has been described under more than a dozen different names. The Vasculitis Research Consortium, which is part of the NIH-funded Rare Diseases Clinical Research Network, is investigating 6 forms of vasculitis (a group of rare conditions affecting blood vessels) for which the causes are not known.

What are Patient Advocacy Organizations?

“He looks like a perfectly normal child. You would never know that he is fighting daily for his life.”

- Mother of a patient suffering from juvenile dermatomyositis.

It takes the coming together of researchers, patients, caregivers and advocacy groups to raise disease awareness, especially when the disease is a rare one. By sharing individual case histories, patients, families, and caregivers form the basis for patient advocacy organizations that can advance drug development for rare indications into clinical development. Drug developers can benefit from access to such identified groups of patients, since it provides a pool of specific patients to register for clinical trials, for example. This is particularly important for rare diseases, where a lack of access to patients creates a significant hurdle in getting a new drug to market.

Western biopharma companies often have well-established relationships with patient groups in their focus area and provide significant levels of funding. In the US, the momentum to keep the research on rare diseases moving forward is crucial. The 21st Century Cures Act, passed by the US House of Representatives last year, spoke of integrating the patient's opinion when designing clinical trials for rare diseases. Companies such as Ionis Pharmaceuticals, Inc. have joined hands with the Amyloidosis Research Consortium, Cure SMA, and Myotonic Dystrophy Foundation to raise awareness of those living with rare diseases, as have other organizations worldwide.

How are Rare Disease-Specific Foundations helping?

If everyone with rare diseases lived in one country, it would be the world’s 3rd most populous country. Approximately 50% of rare diseases do not have a disease-specific foundation supporting or researching their cause. The Kakkis EveryLife Foundation has reported that up to 95% of rare diseases do not have a single FDA-approved drug treatment. In the 25 years since the Orphan Drug Act was passed (in 1983), only 326 new drugs were approved by the FDA and brought to market for all rare disease patients combined. According to the National Institutes of Health Office of Rare Disease Research, approximately 6% of the inquiries made to the Genetic and Rare Disease Information Center (GARD) are in reference to an undiagnosed disease.

It is a relatively recent phenomenon for pharmaceutical companies to strategically focus research and drug development in the field of rare diseases. Last year, up to half of the 45 FDA-approved new molecular entities targeted orphan indications. Organizations such as Global Genes, founded in 2008, are dedicated to helping families affected by rare disease and building a global network that promotes and supports the needs of the rare disease community. A growing pipeline of more than 460 orphan drugs is currently in development, which has boosted efforts in drug development and the understanding of rare diseases. Findacure, a UK-based charity, aims to build the rare disease community to drive research and develop treatments. In collaboration with Elsevier R&D Solutions, their mission will be to identify drug repurposing candidates for the rare disease congenital hyperinsulinism.

The Market Scenario

The recent boom in pharmaceutical mergers and acquisitions continues this year after the healthcare sector recorded its highest deal-making streak in history in 2015, with global transactions totaling $673 billion according to data from Thomson Reuters. This year, the pending takeover of Baxalta, Inc. by Shire plc. will create a world leader in rare diseases, with a focus on hematology, immunology, neuroscience, lysosomal storage disorders, gastrointestinal and endocrine disorders, hereditary angioedema, oncology and ophthalmology. Up to 60 programs are in the planning for clinical development, of which more than 50 have orphan drug status.

In the field of hemophilia alone, Baxalta is providing the recombinant Factor VIII product Advate (octocog alfa), recombinant human Factor VIII Recombinate, Obizur (susoctocog alfa/recombinant porcine factor VIII), and its long-acting PEGEGylated recombinant Factor VIII protein Adynovate, BAX-817, BAX-826, and BAX-888. In parallel, the US has launched Biogen’s long-acting product Eloctate (efmoroctocog alfa) in July 2014, and Roche’s experimental antibody ACE-910 is likely to arrive by late 2017 or 2018. According to Consensus data from Thomson Reuters Cortellis for CI, sales of Eloctate and ACE-910 are to reach $667.8 million and $852.7 million, respectively, in 2021 (versus $1.245 billion and $600.0 million for Advate and Adynovate, respectively).

The Incidence and Prevalence Database: New Emphasis on Rare Diseases

Figure 1: Hemophilia A: Countries/regions with the most published epidemiology data available in the IPD

The Incidence and Prevalence Database (IPD) is Thomson Reuters' tool for evaluating the world’s epidemiology data. The IPD covers over 4,500 diseases, procedures, symptoms and other health issues for incidence, prevalence, morbidity, mortality, comorbidity, treated or diagnosed rates, cost and much more. The IPD is now presenting epidemiological data on rare diseases in the form of Article Reviews and IPD Summaries. Within the Article Reviews, specific information on the incidence, prevalence, morbidity and mortality of rare conditions are reported. IPD Summaries present tables of worldwide and regional incidence and prevalence data for the top rare diseases.

The diseases currently studied involve lysosomal storage disorders (Gaucher disease, Hunter Syndrome [mucopolysaccharidosis II], Fabry disease [Anderson-Fabry disease]), prion diseases (Creutzfeldt-Jakob disease), Zika virus disease, primary immunodeficiency, gastrointestinal/endocrine disorders (short bowel syndrome, Graves' disease), ophthalmological disorders (dry eye disease, conjunctivitis, and retinopathy of prematurity), and hemophilia (Fig.1.). Several other rare diseases in the fields of hematology, oncology, central nervous system, and infectious diseases are in the pipeline for reporting at the IPD site.

For more insights from the team behind Thomson Reuters' Incidence & Prevalence Database, read "Zika Link to Birth Defects: Extraordinary Claims Require Extraordinary Evidence." Learn more about the Incidence & Prevalence Database.