Rare Diseases: The Next Frontier for Pharmaceutical Innovation
Orphan diseases represent a significant burden for the patients. An orphan disease is defined by its very small number of patients, which complicates considerably their everyday life. There are more than seven thousand different rare diseases, affecting more than three hundred million individuals in total (1). The challenges and problems of rare diseases include: a difficulty of diagnosis, a lack of preventive and curative medication, high medical costs and more generally high cost of illness, and reduced quality of life. To overcome these difficulties, many pharmaceutical and biotech companies are seeking not only to develop drugs for these diseases, but also to repurpose already existing drugs to treat and prevent orphan diseases.
In recent years, a large number of drugs have been approved for the European market for treating orphan diseases. These interventions can be divided into two categories: Drugs with orphan drug designation (ODD), and drugs that do not have this designation but are used/designated for rare diseases (2).
The rare diseases market is booming, brimming with opportunities with a total worth of nearly $250 billion in 2024, and this market is increasing rapidly. Indeed, we've seen a compound annual growth rate (CAGR) of around 11.3% since 2017 (3). According to estimates, this rate will remain from 11.3 to 12 for the next few years (4), giving rise to a global market size of around $460 billion in 2032. In other words, we will see an increase in market value of around 142% from 2024 to 2032, which is more than double in less than 10 years (5). This strong market growth would be due to a number of different factors, including the increased prevalence of rare diseases thanks to improved diagnostics, greater visibility of orphan diseases, and considerable advances in genetic and precision medicine (6). This improvement in genetic analysis has enabled diagnoses to become more accurate, as over 80% of rare diseases are linked to genetic problems. Most rare diseases are therefore apparent from birth (7). In addition, government regulations such as the Orphan Drug Act (8) is a real factor in the expansion of this market. The Orphan Drug Act was passed in the US in 1983 to encourage the development of drugs for orphan diseases, with financial incentives such as tax credits for clinical research, market exclusivity for up to seven years, and orphan drug designation (9). As a result of this legislation, the US has developed the highest amount of drugs for orphan diseases. As a matter of fact, the US has acquired over half of the global rare disease market share in 2023, the exact number around 54% (5).
On a global scale, we see that rare diseases are at the heart of research in the northern hemisphere, more specifically in the developed countries, in contrast to the underdeveloped countries. This inequality and disparity in research, funding and access to care is a real problem for third world countries (10). Therefore it can be inferred that developed countries dominate rare diseases space. In this article (11), we analyzed the major players in this market, the orphan drugs currently under development and those present on the European market. The sources present in this article are the pipelines of the pharmaceutical and biotech companies, the list of orphan drugs authorized on the European market, as well as the financial statements of the companies mentioned. The drug developmental pipelines of AbbVie, Amgen, Astrazeneca, BMS, Roche, Novartis, Janssen, Sanofi Genzyme, Pfizer, Alexion, Takeda, Biogen, Vertex, Bayer, Ipsen, Apellis, Affinia Therapeutics, Alchemab Therapeutics, Beam Therapeutics, BioMarin Pharmaceutical, Bluebird Bio, Evox Therapeutics, Fulcrum Therapeutics, Horizon Therapeutics, Imara Inc, iOnctura, Ionis Pharmaceuticals, LogicBio Therapeutics, Orchard Therapeutics, Pharnext, PTC Therapeutics, Rockets Pharmaceuticals, Sarepta Therapeutics, Sio Gene Therapeutics, Spero Therapeutics, SpliceBio, Travere Therapeutics, Ultragenyx Pharmaceuticals, Denali Therapeutics and Sumitomo Pharma were analyzed.
This meta-analysis study reveals that the most widespread types of therapy are targeted therapy, accounting for 65.99% of therapy space. Enzyme replacement therapy is the second most common therapy (10.03%), followed by gene therapy (6.74%), combination therapy (4.39%) and antisense RNA therapy (3.45%). Targeted therapy involves targeting specific protein targets in order to either activate or inhibit them. Indeed, the symptoms of orphan diseases are often caused by an overproduction or underproduction of a certain type of protein, thus posing a genetic problem. Enzyme replacement therapy is used when an individual's body lacks or does not produce enough of a specific enzyme. This defective enzyme is then injected, and it is either a human or genetically modified enzyme. Gene therapy acts on the patients’ genes, to introduce, delete or modify the same. Finally, antisense RNA therapy prevents genetic mutations and corrects genetic defects using specific RNA molecules that bind to other defective or mutant RNAs (12).
The predominant mechanisms of action (MoA) are BTK inhibitor, with over 10 drugs in development, CFTR activators (n=8), transthyretin (TTR) inhibitors (n=7), recombinant human coagulation factor VIII (n=6) and finally DNA alkylating agent (n=5). These pharmaceutical and biotech companies base their research primarily on the following diseases: Systemic lupus erythematosus, Multiple myeloma, IgA nephropathy, Duchenne muscular dystrophy, Amyotrophic lateral sclerosis and Spinal muscular atrophy. These diseases lack drugs on the market and have a high unmet need. Focusing research on these diseases offers companies significant market potential. In addition, orphan drug designation and/or these unmet medical needs for patients justify a higher drug price, which will help to cover the costs of the drug's research and clinical trials. On the other hand, clinical trials for orphan drugs require a smaller number of volunteers, making them apparently less complex and time-consuming from developmental time point; similarly, approvals are accelerated. The development of orphan drugs offers a genuine opportunity for market exclusivity (13). It is also important to emphasize that these types of therapies and mechanisms of action truly reflect revolutionary emerging innovations. This renewal and scientific progress attracts new investors, which is financially beneficial (14).
It can be noted that companies have various collaborations for some of their drugs in development. The pharmaceutical companies with the highest number of collaborations are Roche with 15 partners, Takeda with over 10 partnerships, AbbVie (n=8), Biogen (n>5), and Affinia Therapeutics (n=5). These collaborations demonstrate an economic strategy to reduce drug research and development costs, reduce risks, and increase the number of products in development. In addition to being perceived as influential and market leaders in this emerging market, these partnerships offer a multitude of opportunities for the companies such as access to new, more innovative technologies, and a consequent guaranteed place in the market. After analyzing the revenue generated by 210 orphan drugs (105 with orphan drug designation and 105 without this designation but intended for rare diseases, all in Europe), we arrive at a total revenue, on an international scale, in 2023, of $180 billion. This very high revenue demonstrates the strong potential of this market, and that the field of rare diseases offers a multitude of opportunities for pharmaceutical companies. Janssen, with 8.6% market share, Roche (7.7%), AbbVie (6.9%), Celgene (6.8%), BMS (5.5%), Novartis (5.2%), Merck (4.6%), Vertex Pharmaceuticals (4.4%), Amgen (3.5%), Pfizer (3.5%), Alexion (3.3%), CSL Behring (2.6%), Astrazeneca (2.5%), Takeda (1.7%), Biogen (1.6%), Genzyme (1.6%), BioMarin (1.1%), Novo Nordisk (0.8%) and Bayer (0.7%) are the top 20 pharmaceuticals in terms of market shares. This concentration of market share by these dominant companies emphasizes on the fact that they have the capabilities, resources and technologies to treat orphan diseases, which holds promise for the years ahead.
The orphan diseases with the highest market shares are Multiple myeloma with 10.93% market share, followed by Cystic fibrosis (8.05%), Polyarticular juvenile idiopathic arthritis (5.44%), Renal cell carcinoma (3.81%), Haemophilia A (3.6%), Chronic lymphocytic leukemia (2.76%), Spinal muscular atrophy (2.64%), Pulmonary arterial hypertension (2.59%), Idiopathic pulmonary fibrosis (2.269%), and Mantle cell lymphoma (relapsed/refractory) (2.267%).
These orphan diseases having the highest market shares, predict priority areas for future investment. Indeed, investing in these specific orphan diseases guarantees investors a significant return on investment, a strategic way to benefit from profits in the rare disease market. The 10 orphan drugs generating the most revenue in 2023, in millions of dollars and on an international scale, are AbbVie’s HUMIRA generating $14,404 millions of dollars, Janssen's DARZALEX (9,774), Vertex Pharmaceuticals' KAFTRIO (8,945), Celgene's REVLIMID (6,097), HEMLIBRA from Roche (4,634), BRONCHITOL from Pharmaxis (4,295), KEYTRUDA from Merck (4,023), OFEV from Boehringer Ingelheim (3,800), ORENCIA from BMS (3,601), IMNOVID from Celgene (3,441).
In conclusion, the rare disease market is a dynamic market which is growing constantly and significantly, enriched with opportunities and responding to critical medical needs. Emerging scientific and technological advances, greatly improved diagnostics and considerable progress in genetic and precision medicine, are all factors favoring research, developing orphan drugs, attracting investors, and above all helping patients to reduce their high unmet medical needs. It is a market with a high degree of promising projections for the coming years.
References:
1. Health, T. L. G. The landscape for rare diseases in 2024. Lancet Glob. Health 12, e341 (2024).
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11. Cacoub, E., Lefebvre, N. B., Milunov, D., Sarkar, M. & Saha, S. Quantifying hope: An EU perspective of rare disease therapeutic space and market dynamics. Preprint at https://doi.org/10.1101/2024.07.21.24310776 (2024).
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Written by
Emmanuelle Cacoub
