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Drivers of Orphan Drug Development Ana Mingorance*
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Dracaena Consulting SL, Madrid 28036, Spain ABSTRACT: Previously neglected by the pharmaceutical industry, rare diseases and orphan drugs are rapidly becoming mainstream. Both market forces and technology enablers are responsible for this migration and combine to create multiple business approaches. This viewpoint discusses the drivers that attract different companies into this booming orphan drug space. KEYWORDS: Orphan drug, rare disease, pipeline, personalized medicine
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of orphan exclusivity granted in the different markets also ensures that the drug sponsor will enjoy a large period of reduced market competition. When combined, these factors make rare diseases an easier market than traditionally pursued large indications. The development of new technologies has also played a major role at driving the growth of orphan drugs in development. Advances in genomics as well as the more mainstream use of gene sequencing have made it possible to uncover that what we thought were common diseases are in fact a collection of separate (genetic) rare diseases.6 At the same time, other technologies such as gene therapy and antisense therapy have also enabled us to target these diseases in a way that would not have been possible some years ago.7 Combined, the progresses in technology have made it possible to both identify and treat rare genetic diseases, making them more tractable for drug development companies. Different Strategies for Pursuing Orphan Indications. The combination of market push (from large to rare) and technology pull (from symptomatic to disease-targeting) creates four different business propositions for a company to become interested in a rare disease (Figure 1). 1. Companies That Are Interested in Large Indications and Have a Therapy That Targets Symptoms. These are classical large pharmaceutical companies that are often interested in the broad markets and develop treatments− usually small molecules−able to treat an important symptom. While these companies are still developing the same type of treatments and are still interested in the same large markets, growing market competition and pricing uncertainties are increasingly pushing them into the orphan space, where they choose to develop a particular molecule for an orphan indication for strategic business reasons. 2. Companies That Are Interested in Rare Indications and Have a Therapy That Targets Symptoms. Some companies develop the same type of symptomatic treatments as
eveloping therapies for rare diseases used to be rare. Rare diseases affect by definition less than 200,000 people in the US (or less than 1 in 2,000 people in Europe) and therefore represent less attractive markets than more common diseases.1 Regulatory bodies in the major markets saw the need to approve incentives for drugs intending to treat rare diseases, known as orphan drugs. The first one was the US Food and Drug Administration (FDA) in 1983, followed by Japan in 1993 and the European Union in the year 2000. These incentives include 7 to 10 years of market exclusivity, depending on the market.1 Ever since these incentives were enacted, the number of orphan drugs approved and under development has soared,2 becoming some of the priciest drugs in the market.2,3 However, the decision to pursue an orphan indication is more complex than simply responding to regulatory incentives. Changes in the drug market, as well as advances in technologies, are also responsible for the increase in the number of products and companies targeting rare diseases. Main Drivers of Orphan Drug Strategy. Drug companies are driven toward orphan indications by a combination of reasons: a market push that takes them away from the large markets, and a technology pull that attracts them to rare diseases. In many of the large medical fields, such as diabetes or oncology, there is a marked move toward orphan indications.4 This phenomenon has been called “orphanization” and involves identifying disease subtypes and pursuing them as separate orphan indications. This move away from broad, common indications responds to a saturation in the market, which as a result of competing drug approvals experiences increasing pricing pressures and stricter reimbursement criteria.5 This has been called the “better than the Beatles” problem.5 Compared with these unfavorable market conditions, rare diseases include many indications where there is no drug already approved. They also generally have high clinical unmet need, making it easier to obtain a large market share and get reimbursement for high prices. The 7 to 10 years © XXXX American Chemical Society
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DOI: 10.1021/acsmedchemlett.8b00438 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
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of market pressure and technological advances, including improved diagnostics. Types of Orphan Opportunity. Based on the above forces, a rare disease becomes attractive for drug companies when it matches one of more of the main business propositions. A rare disease that has a common symptom shared with a broad disease will be attractive for companies concerned with saturation of the large market. For example, rare epilepsy syndromes represent an attractive target for companies with antiseizure drugs concerned with the competition in the broad epilepsy market. A company redeveloping an old molecule for a new indication will often also be looking at a rare disease due to the need of securing market exclusivity, even if their drug could treat the common symptom. Some companies developing molecules that target symptoms will also get interested in the orphan space if they cannot afford the expenses and lengthy trials associated with the large market. An example could be the multiple small companies going after monogenic forms of autism, even if their drug is not specific for any of those rare syndromes. Diseases that represent stepping-stone opportunities to larger markets are also attractive orphan drug indications. An example could be Gaucher’s disease for treatments that can potentially treat Parkinson’s disease, due to the shared biology between Gaucher’s with some forms of Parkinson’s. Some of these companies will ultimately develop their molecule for the larger indication, once it has been derisked in the more genetically homogeneous rare indication. Lastly, rare diseases, which count their patients in the thousands, might also benefit from increased attention by companies that are investing in technologies capable of addressing certain genetic defects. Examples could be gene therapy for ocular diseases or enzyme replacement therapies. They might also be medicinal chemistry approaches able to correct protein alterations, such as pharmacological chaperones or specific inhibitors of gain-of-function mutations. Companies developing these approaches will often select the most common rare disease that is likely to benefit from their therapeutic approach, in an effort to maximize the orphan market. Overall, a single rare disease might be a good match for one or more of these business reasons. As a result, some diseases, such as Duchenne muscular dystrophy and some forms of cancer, enjoy a disproportionate level of attention from the drug development industry in comparison with other rare diseases. Not All Orphan Drugs Look Like Orphan Drugs. The stereotypical orphan drug would be a therapy that specifically addresses a genetic problem that is responsible for a rare disease and that, therefore, has disease-modifying potential. Such properties would justify a high price that could compensate for the limited pool of patients. However, many orphan drugs do not look like these therapies and use instead conventional approaches targeting a common symptom, just like most of the traditional blockbuster drugs. The explanation for this phenomenon is pipeline maturity (Figure 2). Symptomatic drugs are often the first to move into a rare disease field and follow opportunistic, market-driven strategies. These initial symptomatic therapies are nonetheless extremely valuable for these fields, derisking the regulatory process and paving the way for more risky disease-targeting
Figure 1. Main drivers and strategies for pursuing orphan indications.
companies interested in large diseases but choose to focus on orphan indications as part of their business strategy. These are often smaller companies that would not have the financial means to go after large indications where clinical trials require thousands of participants. This is why smaller companies in general focus on smaller diseases, because these are the indications where they can afford to take a drug to the market or into pivotal trials. A second type of company in this category would be companies developing a repurposed molecule.8 Because of their weaker intellectual property position around these molecules, the market exclusivity offered by the orphan drug status becomes a central aspect of the drug development strategy. 3. Companies That Are Interested in Large Indications and Have a Therapy That Targets the Disease Biology. Some of the large drug companies, which often go after large markets and common diseases, adopt new technologies and strategies that enable them to target not only the symptoms but also the causes of a disease. This might involve medicinal chemistry approaches or gene- or protein-based therapeutics. Many rare diseases are monogenic examples of broader diseases. When a company targets the shared cause, the rare disease becomes a stepping-stone in the development program, allowing the company to derisk their drug in a clinical trial in the rare disease before launching a much more expensive clinical program in the broader disease that the company ultimately intents to treat. 4. Companies That Are Interested in Rare Indications and Have a Therapy That Targets the Disease Biology. Usually, companies that are focused around a technology platform are able to direct their therapies to specific genes or proteins, allowing them to target genetic diseases. Many genetic diseases are rare diseases. These companies might be working on fields such as gene therapy or personalized medicine and choose to focus on rare diseases because they offer a perfect match for these therapeutic approaches. These technology-driven companies are also more likely to develop a novel, innovative treatment specifically targeted to a disease versus opportunistic symptomatic treatments and might even develop potentially curative therapeutics. Overall, there are multiple reasons why a company−large or small−might choose to develop a therapy for a rare disease. Most of these reasons can be explained by the combined action B
DOI: 10.1021/acsmedchemlett.8b00438 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Viewpoint
(2) Meekings, K. N.; Williams, C. S.; Arrowsmith, J.E. Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discovery Today 2012, 17 (13−14), 660−4. (3) Check Hayden, E. Promising gene therapies pose million-dollar conundrum. Nature 2016, 534 (7607), 305−6. (4) Kumar Kakkar, A.; Dahiya, N. The evolving drug development landscape: from blockbusters to niche busters in the orphan drug space. Drug Dev. Res. 2014, 75 (4), 231−4. (5) Scannell, J. W.; Blanckley, A.; Boldon, H.; Warrington, B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug Discovery 2012, 11 (3), 191−200. (6) Mattick, J. S.; Dziadek, M. A.; Terrill, B. N.; Kaplan, W.; Spigelman, A. D.; Bowling, F. G.; Dinger, M.E. The impact of genomics on the future of medicine and health. Med. J. Aust. 2014, 201 (1), 17−20. (7) Personalized Medicine at FDA: 2017 Progress Report. http:// www.personalizedmedicinecoalition.org/Resources/Personalized_ Medicine_at_FDA_An_Annual_Research_Report (accessed 20 September 2018). (8) Austin, B. A.; Gadhia, A. D. New therapeutic uses for existing drugs. Adv. Exp. Med. Biol. 2017, 1031, 233−247. Figure 2. Stages of pipeline maturity.
therapeutics to be developed. In general, the drug pipeline around a rare disease goes through a maturation process where the first drugs to move in are often opportunistic symptomatic drugs, followed by second-generation therapeutics pursuing a superiority profile, and finally disease-targeting and potentially disease-modifying therapeutics. In some cases, in particular in diseases with very high mortality, there is little room for symptomatic treatments, and the first orphan treatment to be developed and approved might be already disease-modifying. Therefore, a particular rare disease field may be attractive to different companies, for different reasons, depending on the state of maturity of the drug pipeline for that disease. Conclusion. While traditionally neglected by the pharmaceutical industry, rare diseases and orphan drugs are rapidly becoming mainstream. A combination of market forces and technology enablers is responsible for this migration, creating multiple business approaches and supporting different business models. At a disease level, each rare disease represents a different business opportunity for different companies. Each rare disease also represents different business opportunities at different stages of pipeline development, with younger pipelines being richer in symptomatic treatments and more mature pipelines containing more advanced, disease-targeting therapies. As more companies move into the rare disease space, an increase in the number of disease-targeting treatments is expected.
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AUTHOR INFORMATION
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Ana Mingorance: 0000-0002-6213-6160 Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS. The author declares no competing financial interest.
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REFERENCES
(1) Franco, P. Orphan drugs: the regulatory environment. Drug Discovery Today 2013, 18 (3−4), 163−72. C
DOI: 10.1021/acsmedchemlett.8b00438 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
