Rare diseases pose a major challenge to healthcare systems due to the difficulties in diagnosing and treating them. Rare diseases are usually defined as those that affect fewer than 5 per 10 000 people in a given population. Their diagnosis is difficult and can take years, and rare diseases are often severe, chronic and life-threatening. It is estimated that between 2 and 3 million people suffer from rare diseases in Poland. The small number of patients suffering from these conditions compared to the number of patients suffering from more common diseases makes drug development costly and unprofitable for the pharmaceutical industry. High production costs and a limited market effectively discourage pharmaceutical companies from investing in the development of so-called orphan drugs. If a drug is already produced, it is often the only one available to treat a particular rare disease, and so is extremely expensive, which significantly limits availability to patients, putting their health and lives at risk.
To promote the development and availability of drugs for rare diseases, systems to support research and registration of these products have been introduced in various countries. The first regulations appeared in the US in 1983 with the passing of the Orphan Drug Act, which introduced a number of benefits for pharmaceutical companies, such as tax credits, research grants and extended periods of market exclusivity. Similar regulations have been introduced in Japan, Australia and the European Union.
In the European Union in 2000, Regulation 141/2000 of 16 December 1999 was enacted, which created a legal framework to support the production of orphan drug products. Under this regulation, the Committee for Orphan Medicinal Products (COMP) was established at the European Medicines Agency (EMA), which evaluates applications to grant orphan drug status to a medicinal product and participates in international cooperation related to the topic of orphan drugs and works with patient advocacy groups to ensure adequate background for the development and availability of these drugs. Despite these regulations, the problem of the high cost of rare disease medications and their limited availability remains a challenge, requiring further action on a financial and legal level to provide patients with the necessary therapies.
The latest reform of the pharmaceutical law of the EU, which was adopted in 2024 by the European Parliament, guarantees support for innovation and the development of drugs that address previously unmet needs, and also provides for greater security of supply, availability and affordability of high-quality medicinal products. The EU pharmaceutical reform also covers medicines for the treatment of rare diseases. The proposed changes include a system of benefits for orphan drug producers, including adjustments to periods of market exclusivity. The criteria for granting orphan drug status are also modified and the procedure for obtaining orphan designation will be simplified, with competence transferred from the European Commission to the EMA. The new legislation introduces a seven-year validity of the designation, with the possibility of extension depending on the research progress. The cost of developing and marketing a medicinal product for the diagnosis, prevention or treatment of a rare disease is simply higher than the expected return on sale of that product, so the pharmaceutical industry, without additional incentives in the form of research funding and facilitated registration of medicinal products for rare diseases, has been reluctant to develop such products. The above reform aims to counteract this.
The Council of Ministers of the Republic of Poland, in response to the reform of the EU pharmaceutical law, in June 2024, adopted the 'Plan for Rare Diseases for the period 2024-2025,' to improve the quality of medical care for patients with rare diseases. The plan envisages the establishment of new Centres of Expertise for Rare Diseases, increased access to modern diagnostic methods using genomic technologies, modern medical equipment and drugs, medical devices and foodstuffs for special nutritional use used in rare diseases. The plan also includes measures for the development of the Polish Register of Rare Diseases and the Rare Disease Patient Card, as well as the maintenance of the 'Rare Diseases' Information Platform. All of the measures are to be implemented by the end of 2025, with almost PLN 100 million earmarked for this purpose.
At the moment, there are already some centres of expertise for rare diseases in Poland and they are located in several cities across the country, with the largest number, 20, in Warsaw. These national centres of expertise are also part of the European network. The number of these centres is to be increased, but this will depend on the number of patients with a given rare disease. In ultra rare diseases, according to the Ministry of Health website, there can only be one centre per country.
In Poland, only in the case of a few rare diseases do the implemented screening programmes allow rapid detection. This is the case, for example, with phenylketonuria - a simple non-invasive test is performed on every newborn in Poland.
The total number of patients in Poland who suffer from a rare disease, according to statistical data, is over 3.5 million people, which, to illustrate, is as if the entire population of a city as large as two Warsaw cities was ill (the population of Warsaw at the moment is over one million eight hundred thousand people). And there is a whole lot of people who have not been correctly diagnosed and, because there is no data in the system, increase the final number of those affected.
Meanwhile, general awareness of rare diseases is not satisfactory. Many circles only learned about the stiff person syndrome (SPS) after the condition was brought to public attention by the famous singer Celine Dion. Another serious disease, namely amyotrophic lateral sclerosis (SLA/ALS), is associated by most people with the 'Ice Bucket Challenge', a bucket of ice-cold water poured over the head as part of a social media campaign that took over the internet a few years ago. Yet it is one of a number of progressive and fatal diseases that affect some 352 000 people worldwide and for which there are currently no effective medications. For more than a decade, Biogen has been conducting research into the disease. This year, the company received European Commission authorisation to market the drug Tofersen, which is a synthetic modified antisense oligonucleotide (ASO) that lowers SOD1 protein levels. It is the first drug dedicated to the version of ALS with a mutation of the SOD1 gene, which occurs in approximately 2% of patients. This is an exceptionally severe form of the disease, as when diagnosed with the above mutation, a patient's life expectancy can be very short, with some patients not living to a year after diagnosis. The drug has the orphan drug status. The European Academy of Neurology has confirmed new guidelines for the treatment of ALS, which state that Tofersen should be used as a first-line drug in ALS patients with the mutation in the SOD1 gene. This is a huge advance in the treatment of SLA.
Despite the efforts of both the European Union and national regulators to improve the diagnostics and availability of drugs for patients affected by rare diseases, the situation remains serious. The lack of registered drugs for rare diseases remains an issue. This is because trials of drugs for rare diseases are more difficult and in order to meet the requirements of clinical trials, a defined number of patients are required in each trial. If standards are not harmonised across the EU, there may not be a sufficient group of patients in a given country to conduct a trial, which then hinders the progress of commercially available therapies.
Therefore, the Plan for Rare Diseases also provides for measures to promote greater research activity and international academic cooperation of national centres for rare disease patients, including:
- to foster scientific research and clinical trials aimed at finding innovative solutions for rare diseases by competitions dedicated to this area and periodically organised by state institutions such as the Medical Research Agency, the National Centre for Research and Development and the National Science Centre;
- to support efforts for the participation of national Centres of Expertise for Rare Diseases (CERD) and Polish members of the European Reference Networks (ERNs) in international projects, including, inter alia, to establish a 'Mirror Group' to the existing structure of the European Joint Programme on Rare Diseases.
The issue of rare diseases and the pressure to find new and, above all, effective drugs is a very topical subject. According to a compilation on the website of the non-profit organisation Global Genes, rare diseases affect more people than cancer and AIDS combined, so despite the established nomenclature, they are no longer rare, because 1 in 10 people is affected by a rare disease, globally as many as 400 million people suffer from rare diseases, of which 1 in 2 patients is a child, there is no FDA-approved treatment for 95% of rare diseases and, in addition, the average time for a patient to receive a proper diagnosis is 6 years or more.
This is an alarming state of affairs that calls for more proactive action towards the diagnosis and treatment of rare diseases, and from an economic point of view such actions simply have to prove profitable for companies. The new reform seems to address the unmet needs of both pharmaceutical and medical biotechnology companies as well as patients. Particularly that the reform also aims to ensure equal access to medications across the European Union.
For a pharmaceutical or medical biotechnology company to be able to convert its achievements in identifying or producing a rare disease drug into a tangible income, it must, as outlined above, have market exclusivity for its product. In such a situation, it is a good solution to obtain patent protection for the invention as a complement to the exclusivity provided by the regulations on orphan drug products. And the example of what the US company KV Pharmaceuticals experienced with the orphan drug Makena may illustrate some of the limitations of orphan drug protection. In this case, the protection granted to orphan products was effectively circumvented by pharmacies which manufactured the formulations of the product themselves and thus did not need to seek FDA approval for their version of the drug, and bypassed the FDA's guaranteed market exclusivity for the orphan drug. Such market conduct may further discourage companies from seeking and producing orphan drugs. An effective patent strategy can effectively reduce the risk or block such actions altogether.
In accordance with the pharmaceutical law, the exclusivity for a drug is only for the specific health indication contained in the drug specification. However, once a drug is authorised for sale, doctors may prescribe the drug for a purpose other than the indication for disorders other than the specific conditions for which the drug was approved. Exclusivity for an orphan drug does not extend to other uses of the drug, whereas a valid patent that remains in force may already provide the patent holder with such exclusivity. In this way, patent protection helps to avoid competitive risks associated with off-label use. It is possible to seek patent protection for a medicinal substance as such, for various therapeutic uses, without being limited to the indication associated with the relevant orphan drug, as well as for various methods of manufacturing the medicinal substance. This is subject to the condition that the criteria of novelty, non-obviousness and industrial application are met, in accordance with patent law. However, an effective patent strategy must be well thought out so that there is not too much disclosure at the various stages of a drug's development, so that your own patent applications, once published, do not constitute documents that threaten the novelty criterion for subsequent patent applications. The patent claims that will provide the broadest protection are those that relate to a medicinal substance or a new medicinal composition, but the discovery of new compounds or compositions occurs at a very early stage of a drug's development, before its therapeutic activity has been confirmed in clinical trials, which can take many years. How, then, should these fundamentally contradictory indications, i.e. the approximately 10-year time from the discovery to the market introduction of an orphan drug, be reconciled with a patent, where the decisive aspect is to file an application as soon as possible so that another competing company working on a similar solution cannot overtake us? Given these circumstances, by the time an orphan drug is launched on the market, the life of the patent will already be short. In order to maximise exclusivity, additional applications covering advances made during the development process of a new drug are recommended. Such a subsequent patent may relate to a dosage form, formulation, mode of administration, combination therapy, etc. Previous filings by the same entity can be a real obstacle to further patenting. Any subsequent application should therefore be strategically planned, preferably in consultation with a professional attorney such as a patent attorney.
Thus, with appropriate regulation and a good patenting strategy, efforts in this direction can pay off measurably. Given the often elusive nature of rare diseases, novel diagnostic tools or methods can be revolutionary. One aspect that is worth patenting is the development of devices or methods to identify biomarkers specific to a rare disease, another category could be innovations in imaging techniques to obtain clearer images analysing changes in affected organs.
Examples of patent applications relating to the use of specific substances include European patent application EP3858358 A1 by METRIOPHARM AG relating to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione for the treatment of rare chronic lung diseases. The invention specifically relates to the use of the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione. Or Chinese patent CN111526720B granted to SANGAMO THERAPEUTICS INC. relating to methods and compositions for the treatment of rare diseases, with international application PCT/US2018/057312 and European application EP3716767A4 claiming priority to the said patent. The invention relates to the modulation of genes involved in rare diseases, including in the diagnosis and treatment of rare diseases such as Angelman syndrome, facioscapulohumeral muscular dystrophy (FHMD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and spinal muscular atrophy (SMA).
When discussing innovation in the diagnosis and treatment of rare diseases, we cannot ignore the role of artificial intelligence (AI). With the intensive development of AI, more and more attention is being paid to its use in medicine, particularly in the diagnosis of various types of conditions. Among the recently published inventions, of note is international application no. WO2024049873A1 to THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, which relates to the diagnosis of rare diseases by using data from electronic medical records and a machine learning technique to estimate the presence of a rare disease, in a given patient, and/or to recommend referring the patient for further diagnosis. As more than 80% of rare diseases are genetic in origin and start in foetal life, it is important to identify genomic mutations and changes in gene expression that cause disease early in life. In order to make the diagnosis process more efficient, international application no. WO2022169684A1 to ROSEBUD BIOSCIENCES INC proposes a method to identify gene mutations that cause diseases using high-throughput genomic assays, phenotypic measurements and artificial intelligence in human induced pluripotent stem cell (hiPSC) disease models. The method makes it possible to identify DNA mutations and gene expression changes that cause diseases in early childhood.
Thus, the best way to ensure a sufficient return on investment in orphan drug development is to combine the benefits of regulatory exclusivity with patent protection. Profitability is one thing, but in all of this we also really need to find the main reason for engaging in drug discovery for rare diseases, which is the other people in need. This is because the approach to treating rare diseases will not improve quickly without this particular motivation.
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