Elinor Bouvy-Berends, chairperson of the Dutch FOP-Foundation, spoke to SE about the extremely rare disease FOP and the global struggle of finding a cure.
Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare disease in which muscle and connective tissue, including tendons and ligaments, are gradually replaced by bone. Frederick Kaplan, the founder of FOP Research at the University of Pennsylvania Perelman School of Medicine used to refer to FOP as “the Mount Everest of genetic skeletal disorders”. SciTech Europa spoke to the chairperson (Elinor Bouvy-Berends) of the only FOP foundation in the Netherlands: the Dutch FOP foundation.
What is the work and role of Dutch FOP-foundation?
The Dutch Fibrodysplasia Ossificans Progressiva (FOP) Foundation is a patient association of and for people with the ultra-rare disease FOP. The Dutch FOP Foundation was founded in 2004, with the primary objective of supporting people with FOP and those directly involved. Advocacy, information and peer support are major spearheads of this organisation run exclusively by volunteers.
Additionally, the foundation facilitates activities to promote research in the Netherlands and abroad. FOP is an ultra-rare disease; only one in two million people get this extremely debilitating condition. Muscles, tendons and ligaments change into bone. As a result, movement is no longer possible, and joints become locked. One is, as it were, caught in one’s own armor, a second skeleton. The disease has a progressive course. The genetic cause of the disorder is well known, but a large part of the disease process is not yet known, and good therapeutic options are still not available.
Furthermore, scientific research mainly takes place in the US, UK, Japan, Italy, France and the Netherlands. The researchers have regular contact with each other and with the FOP patients. As a result, in recent years drugs have been discovered that could potentially lead to treatment of FOP. People with FOP want to lead an independent life, but know that when their body loses mobility, they become increasingly dependent on others. By the time of adulthood, most people with FOP end up in a wheelchair, almost half of them can no longer open their mouth properly around the age of eighteen and often no longer move their arms or elbow properly.
Yet, no effective treatment has been discovered. The rapid advances in clinical drug trials are followed with great interest; two clinical studies are currently underway. There is intensive communication with international FOP organisations and patient associations. The foundation considers it her mission to provide detailed information to the relatively small patient population in the Netherlands about recent developments in medical research and clinical trials.
Since the foundation was founded in 2004, how far has FOP research and awareness come?
Since the foundation was founded in 2004, major steps have been made in revealing the pathophysiology of this extremely rare disease. One of the major breakthroughs has been the discovery of the causative gene mutation in 2006 by the laboratory of the UPenn geneticist Dr Eileen Shore et al. In addition to this, it has also been discovered that malformed big toes are always present at birth. Unfortunately this important early sign of FOP before the onset of extra bone is often missed, leading to a delay of the diagnosis and deterioration of the condition of the patient by maltreatment.
Due to this discovery, research moved ahead quickly as the pathways were revealed on how this mutation eventually leads to bone formation in these patients. As a result, pharmaceutical companies became involved as the discovery of the pathways gave therapeutic options to stop bone formation. At the moment of writing, two pharmaceutical companies (Regeneron Pharmaceuticals inc. and Clementia Pharmaceuticals) are executing a clinical trial in FOP-patients to test their drug.
On top of this, multiple other pharmaceutical companies are currently testing their drugs in the lab or designing a clinical trial themselves. We of course hope that one of these drugs will eventually prevent bone to form at an early age, preventing patients from becoming wheelchair bound due to excessive bone formation throughout the body. We have had this hope for the past 15 years of, but at that time there was only little knowledge on the disease and only a few researchers were interested. This has, luckily, changed remarkably throughout the years and we are more closer to a treatment for FOP than we ever have been before. However, of course, we need to wait for the results to know whether the current drugs being tested are effective in stopping excessive bone formation.
What would you say is the importance of foundations such as Dutch FOP-foundation?
The Dutch FOP-foundation aims to address every aspect that may impact the Dutch FOP community. Access to excellent medical care, and the well-being of people with FOP, take top priority. The focus is also on social issues: housing, education and work. The Dutch FOP-foundation aims to be a reliable source of information about the disease and its impact; for people with FOP, living independently cannot be taken for granted.
Since 2015, the Amsterdam VUmc is recognised as the only Expert Centre for FOP in the Netherlands. This centre is part of the European Reference Network on Bone Disorders (ERN BOND). At the centre, people with FOP receive the best possible care and treatment. Every year, outpatient FOP check-ups take place at the VUmc. This involves checking all important organ functions and extensive blood tests are performed. Patients also receive a lung function test and heart tests. This care has come about in collaboration with the Dutch FOP patients foundation.
Among other things, an [18F] sodium fluoride PET / CT is made with special attention to the activity of the disease. With this method, the activity of incipient bone formation can be detected at a very early stage of a flare-up. This method can also be applied to precisely measure the course of active bone formation, whether or not under the influence of new medication. This imaging technique is, for this disease, only used in few places. Patients from both home and abroad come to VUmc for this special form of diagnostics. At present , the FOP Expert Center is recognised as one of the most prominent Academic FOP research centers in the world. In addition to this, multiple clinical drug trials are being conducted in Amsterdam.
What are the main challenges in terms of FOP research?
The main challenge for research on FOP is mainly the lack of bodily material, as invasive procedures (biopsies, surgeries, traumatic blood draw etc.) may worsen the disease. The lack of these materials challenge the researchers to gain knowledge about the pathophysiology from other sources. One of these sources is a mouse model with the human mutation, to mimic the disease from human FOP patients into these FOP-mice. It should be noted that, even though mouse models are for FOP a good way to study the disease, a check with human material is always needed to see whether the processes in the FOP mice are identical to the processes in the FOP-patient. Another challenge for the researchers, and in particular the pharmaceutical companies, is the rarity of the disease. To test a drug, participants with FOP are needed to test the drug in a phase II and phase III trial. But as the disease is extremely rare with about 900 known patients world-wide, it will be a challenge for those companies to find enough patients to have their drugs tested on.
What is next for Dutch FOP-foundation?
The Dutch FOP- foundation Netherlands faces a number of challenges. Firstly, running a small patient organisation with only volunteers has its own challenges. Continually, more work needs to be done with fewer people in a world where it is increasingly difficult to find volunteers. The Dutch government has recently granted an extra subsidy for Back-office tasks to professionalise the management of patient organisations.
Patient involvement throughout the medicines research and development process is high on the agenda. The international training for patient representatives into equal discussion partners in drug development developed by EUPATI does not seem easily accessible for the small patient group in the Netherlands. Still, patients contribution in preparing the research agenda is of utmost importance. The foundation has a responsibility to contribute from the patient’s perspective to the development of care standards and guidelines. Developing information for, or promoting awareness with, specific target groups such as doctors, healthcare providers, institutions, schools or training courses with regard to this extremely rare condition requires great efforts from this small patient organisation.
New guidelines for engagement with biopharmaceutical companies have recently been published by IFOPA (International FOP Association); the involvement of patient organisations in the biopharmaceutical industry needs to be reviewed. When searching for patients to participate in a clinical drug trial, pharmaceutical companies may not adhere to the code of conduct and contact individual patients. The Dutch FOP-foundation rejects these individual contacts but is open to co-operation with pharmaceutical companies within the framework of the IFOPA guidelines. Most importantly however, finding a cure for FOP is a global struggle; that is the real challenge for the Dutch FOP foundation.