Biotechnology, crucial in addressing the global challenge posed by rare diseases

The World Health Organization (WHO) estimates that there are over 7,000 rare or uncommon diseases defined, affecting up to seven percent of the world's population. These are characterized by low prevalence in the population: affecting fewer than five out of every 10,000 people. The Spanish Federation of Rare Diseases (Feder) estimates that around three million people in Spain live with rare diseases or are in search of a diagnosis.

The lack of information and research on rare diseases is one of the main barriers faced by those affected. Feder indicates that only 20% of the over 6,313 rare diseases identified in Europe are currently under investigation. The problem is compounded by the different pathways to achieve a diagnosis. In this regard, neonatal screenings are highlighted, whose application varies both at the European level (currently covering a minimum of seven pathologies) and at the state level (some autonomous communities exceed 40).

In addition to these screenings, other diagnostic methods such as genetic testing are used. Recently, the Ministry of Health has presented its new Catalog of Genetic Tests, which represents an important step in terms of early access to diagnosis, along with the recent announcement of the recognition of the genetics specialty.
Despite these advances, rare diseases continue to be largely neglected. 43% of people with a rare disease do not have access to treatment, and if they do, it is often inadequate. Feder reports that over 30% of individuals living with rare diseases have experienced delays in diagnosis, resulting in a worsening of their condition. Additionally, 29% receive no support or treatment, and up to 18% may not have received appropriate treatment for their condition.

Biotechnology radically transforms the approach to rare diseases

Faced with this alarming scenario, biotechnology is providing solutions in areas with unresolved clinical needs such as diagnosis and treatment. Genetic engineering, especially in the field of pharmacology, is achieving significant breakthroughs against rare diseases such as Fabry, Pompe, or Gaucher diseases. In recent years, advanced therapies have been providing answers to some rare diseases, such as tissue therapy and butterfly skin disease. In this regard, it is worth noting that only six percent of rare diseases have available medications, and access to them is unequal. Therefore, ensuring access and equity, reducing access times, and incentivizing the development and research of new treatments are fundamental. A challenge in which biotechnology emerges as a key player and lays the groundwork for the future of medicine. In the last few decades, biotechnology has revolutionized the discovery of new drugs, with over 300 biotechnological medicines approved for around 250 indications, and thousands of molecules in various stages of research worldwide, aiming to find new therapeutic active principles or discover new applications for existing ones.

"The good news is that there is more awareness and more research compared to a few years ago, but unfortunately, for most diseases, there are still no treatments or advanced development projects. There is still much to be done," says Marc Martinell, CEO of Minoryx Therapeutics, a biotechnology company focused on finding new treatments for severe rare diseases with a focus on pediatric diseases.

Currently, in the European Union, efforts are underway to obtain marketing approval for leriglitazone (Nezglyal) for the treatment of X-linked adrenoleukodystrophy (X-ALD). "In the United States, we are conducting a phase 3 trial in agreement with the Food and Drug Administration (FDA). For a large part of the population with this disease, leriglitazone could be the first drug to reach the market," he argues.

"We prioritize diseases with a pediatric component. The cerebral form of X-ALD (cALD) affects both children and adults and is lethal within three or four years," he points out. Minoryx emphasizes the urgent need to better understand rare diseases in order to develop treatments, reduce diagnosis times, and maintain long-term efforts and investments "to successfully bring drugs to approval," Martinell concludes.

Research, the cornerstone in the fight against rare diseases

Feder emphasizes that Spain "has always been a pioneer in rare diseases, being one of the first countries to promote its own Strategy or leading the proposal of the UN Resolution. However, significant differences are found with other European countries in key aspects such as investment in research, different neonatal screening tests for early diagnosis access, or access to orphan drugs."

The International Consortium of Rare Diseases Research (IRDiRC) outlines the main research challenges that rare diseases must face. Broadly speaking, they highlight promoting the development of new therapies for rare diseases in Spain (the international goal is to have 1,000 new therapies globally by 2027), and supporting the development of diagnostics (the goal for 2027 is to diagnose anyone affected by a rare disease in less than a year).

Research is fundamental to achieving progress against rare diseases. In the case of our country, most of the funding allocated to rare diseases is focused and centralized, operationally, through the Biomedical Research Networking Center for Rare Diseases (CIBERER). This comprises a human team of over 700 professionals and integrates 56 research groups, 20 linked clinical groups, belonging to institutions of diverse nature.

"The research on low-prevalence diseases has experienced significant growth in recent years, although, of course, there are currently many unmet needs, given the intrinsic characteristics of this group of pathologies, such as: a high number of diseases, geographic dispersion, less interest from the pharmaceutical industry, lack of specialized training, scarcity of resources, etc.," explains Beatriz Gómez González, Manager of Scientific Activity at CIBERER.

"The challenges in Spain, of course, align with the objectives of IRDiRC, which include achieving higher and earlier diagnosis rates, accelerating drug development at reduced costs, improving patient care, and empowering all stakeholders," states Beatriz Gómez, who emphasizes that "the low prevalence of diseases makes it difficult to initiate clinical trials, as well as to attract funding from the private sector for the development of the latest stages of clinical trials and commercialization."

CIBERER highlights the crucial role that biobanks play in researching rare diseases. They point out that the availability of biological samples for rare diseases is very limited. "Biobanks allow for the storage of samples for national and international research, which allows for more robust and conclusive research results," which is why in 2010 they launched the CIBERER Biobank, a public and nonprofit biobank that centralizes the reception of samples, both pediatric and adult, of high biological value for research in rare diseases.

The groups at CIBERER directly or indirectly investigate over 2,000 rare diseases or groups of rare diseases, from different approaches, whether molecular, diagnostic, or therapeutic. Among the achievements, for example, in the diagnostic field, it can be highlighted that researchers at the center have described over 120 new genes associated with rare diseases in the last decade. Additionally, in the field of new therapies, the center has contributed to the designation of 28 orphan drugs in Europe or the United States and has directly sponsored 15 of these drugs.

Orphan Drugs: A Challenge in the Fight Against Rare Diseases

Orphan drugs are those specifically developed to diagnose, prevent, or treat rare diseases. Due to their low prevalence, they often are not economically attractive for pharmaceutical companies to develop and market treatments under normal market conditions.

The designation of "orphan" refers to the lack of interest from pharmaceutical companies in developing and marketing treatments for conditions that are uncommon, as the return on investment is uncertain or unlikely. The importance of orphan drugs lies in the fact that they provide necessary treatment options for patients who might otherwise have no hope of treatment due to the rarity of their condition. These drugs contribute to improving the quality of life and, in some cases, prolonging the survival of patients with rare diseases.

Asphalion, a consultancy for International Scientific and Regulatory Affairs, has expert teams dedicated to analyzing the context of each therapeutic product intended for the treatment of rare diseases. They provide advice on the available options to obtain Orphan Drug Designation (ODD) and manage the entire process until obtaining such designation.

"The orphan drug designation is a special status granted by the FDA or the European Medicines Agency (EMA) to drugs or substances intended for the diagnosis, prevention, or treatment of rare diseases. The designation as an orphan drug is voluntarily and free of charge since pharmaceutical companies can benefit from benefits and incentives provided for in the regulation to develop treatments for these rare diseases, without which the marketing of such drugs would likely not generate enough revenue to justify the necessary investment," explain from Asphalion, emphasizing that "the orphan designation does not establish that the drug is effective or safe, but it does indicate that the drug meets the orphan definition established in the regulation."

The current issues facing orphan drugs in Europe and Spain are multifaceted and complex. In Europe, Asphalion identifies obstacles such as high costs and market access since "marketing authorization does not guarantee access to patients, as each EU country has its own reimbursement system and health technology assessment (HTA), which can result in delays." They add other issues such as lack of clinical evidence (clinical trials of these drugs often have a small number of participants), inequality in access, and the sustainability of healthcare systems, which "are under pressure to fund expensive orphan treatments, raising questions about sustainability and equity in resource allocation."

In the specific case of Spain, they mention that the financing process for an orphan drug is long and complex, the challenge posed by health technology assessments for these drugs given the scarcity of data, limited budgets, and lack of knowledge and specialization in rare diseases.

"In response to these challenges, initiatives are being carried out at the EU and national levels to improve access to orphan drugs, including collaboration in HTA evaluations, initiatives to improve pricing and reimbursement systems, and efforts to promote research and development in the field of rare diseases," argue from Asphalion.

"Obtaining ODD simplifies the drug development process for rare diseases, which is already very complex. By providing support in this regard, our goal is to maximize the chances of products being approved and, therefore, becoming therapeutic options for unmet medical needs," they conclude.