EMA designates allopurinol as first orphan drug for the treatment of Marfan syndrome

The European Medicines Agency (EMA) has designated allopurinol as the first orphan drug for the treatment of Marfan syndrome, a rare connective tissue disease which as no cure to date. This disease causes an aortic aneurysm (an abnormal dilatation of the aorta) and affects about 7 in 100,000 people in the European Union. Drugs known as orphan drugs are intended to treat such rare conditions that pharmaceutical companies need favourable conditions to market them.

The designation of this orphan drug — widely used until now for the treatment of gout — is a significant advance in research into new treatments for this serious minority disease that mainly affects the vascular component of the body. The designation does not establish the drug as safe or effective, it only indicates that the drug meets the European Commission's definition of orphan drug. Therefore, it is necessary to continue working on the corresponding clinical studies to obtain its authorization.

A research team from the University of Barcelona, the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and the Networking Biomedical Research Centre on Rare Diseases (CIBERER) has studied the possible application of this drug for the preventive and palliative treatment of the aortic aneurysm that is typical of Marfan syndrome. So far, researchers have conducted trials on animal models of the disease and international clinical trials in patients are expected to begin in the future.

This study has been carried out by the group led by Gustavo Egea, professor at the UB's Faculty of Medicine and Health Sciences and researcher at IDIBAPS, in close collaboration with Isaac Rodríguez-Rovira, postdoctoral researcher at the UB, and Victoria Campuzano, researcher at CIBERER.

About Marfan syndrome

Marfan syndrome is a genetic connective tissue disease that mainly affects the cardiovascular, skeletal and ocular systems. It is caused by mutations in the FBN1 gene, which encodes fibrillin-1, a protein essential for the structural integrity of many tissues in the body as it is part of the elastic fibres. The disease can manifest itself clinically in a variable manner between patients — more than 3,000 different mutations have been described — even within the same family with the same genetic variant.

This chronically debilitating disease leads to severe vascular disturbances, from abnormal dilatation of the aorta (aneurysm) to dissection and rupture. Other conditions, although not as fatal as aortic aneurysms, are respiratory (pneumothorax and sleep apnoea), ocular (blindness due to lens displacement) and musculoskeletal (muscle and joint flaccidity and elevated stature).

Repositioning medicines: new uses for medicines

Treatment with allopurinol, which acts as a potent antioxidant, has been shown to halt and prevent the progression and occurrence of aneurysm and aortic dissections. As an additional advantage to its pharmacological use, allopurinol is safe, inexpensive and well known in the clinical setting. Thus, the repositioning of this drug for cardiovascular treatment in Marfan syndrome (and probably also for other vascular diseases) makes it particularly attractive both because of its extensive clinical knowledge, its pharmacological safety and its low economic cost.

There is currently no approved curative treatment for the disease. Current pharmacological treatment is palliative and is based on the administration of beta-blockers and antihypertensives/angiotensin II receptor antagonists. However, its effectiveness is very limited, so new complementary treatments are needed to avoid, as far as possible, surgical intervention on the dilated aorta (preventive surgery) or on the already dissected aorta (emergency repair surgery), with the consequent risk inherent to this type of surgery.

The UB and the CIBERER: promoting orphan drugs

Allopurinol, used in clinical practice for the treatment of gout, is an inhibitor of the enzyme xanthine oxidoreductase, which generates uric acid and reactive oxygen species and is altered in the aorta of patients and in mouse models of Marfan syndrome.

Orphan drug designation by the European Medicines Agency (EMA) has a number of advantages, including exclusive marketing authorization for ten years during which time similar products cannot be marketed, access to free or reduced-cost scientific advice and support protocols, and exemption from designation fees. In addition, entities developing these medicines are eligible for specific grants from EU and member state programmes, which favours the development of treatments for pathologies with low private investment due to their low prevalence.

With this new designation, the CIBER has promoted 19 orphan drugs approved by the EMA, six of which have also been designated as such by the Food and Drug Administration (FDA). Eight of these drugs correspond to gene therapy and the other 11 are repositionings, i.e. drugs that are already used for other pathologies and are being evaluated for use in rare diseases.

In this context, the UB has also previously participated in the development of two orphan drugs promoted by the CIBER and approved by the EMA. Specifically, these are drugs for the treatment of cystinuria — the principal researcher was Professor Virginia Nunes (UB-IDIBELL), who passed away in 2024 — the megalencephalic leukoencephalopathy, with experts Raúl Estévez (UB-IDIBELL) and Assumpció Bosch (UAB) as principal researchers.