Cristian Ionita, M.D.
There are more than 7,000 known rare diseases and disorders that collectively affect nearly 30 million people in the United States alone. While there have been many important advances in research in recent years, the vast majority of rare diseases still have no treatments available. The lack of treatments in this category may be impart due to the unique challenges that researchers often face in developing new drugs to treat rare diseases.
A primary challenge in developing new therapies for rare diseases is the small number of patients that have the disease. Researchers must work aggressively to identify patients to participate in clinical trials and once identified, it may be difficult for the patients to participate due to the limited number of trial sites. Traveling to the trial sites for appointments and laboratory tests is often difficult for patients and their families. Because the population is small, there is often limited data available about the disease, natural course and impact of symptoms on patient health and quality of life. In many cases, there has been very limited (if any) prior clinical research that can be used to support clinical trial design and planning. Development programs must often identify new pathways in research and endpoints or biomarkers that have not been used previously in order to advance promising therapies through clinical research. Many of these challenges can be compounded by the fact that many rare diseases are degenerative and can progress rapidly. About 50% of patients with rare diseases are children, which also presents special challenges in planning and executing a clinical trial.
There are many examples of the challenges both researchers and regulators can face in targeting new therapies for rare diseases. One examples is Duchenne muscular dystrophy (DMD), the most common type of muscular dystrophy. It is a rare neuromuscular disease caused by a lack of functional dystrophin protein that results in progressive muscle weakness. The disease almost always affects boys, and symptoms usually begin early in childhood. Patients typically have a hard time standing up, walking and climbing stairs and eventually are unable to care for themselves. They can lose the ability to walk in their early teens and have a shorter lifespan due to life-threatening lung and heart complications. But the symptoms and severity of disease can vary, which can make it difficult to establish appropriate criteria to demonstrate clinical benefit in research. Setting up and executing an appropriate clinical research program and then analyzing the results requires entirely new levels of innovation and flexibility.
To support and guide clinical research related to DMD, the European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) have recommended the 6-minute walk test (6MWT) as a standard to measure gross motor function in ambulatory DMD patients in clinical trials. Although the 6MWT is widely used to assess changes in motor function in research, there are some limitations in its use in research in DMD.
The 6MWT will only show changes at the time the test is given. Insights related to shorter or longer-term benefit of treatment will be limited. As a result, in cases where the benefit of treatment may be cumulative, data related to 6MWT may not offer a precise assessment of efficacy. In addition, it only measures lower limb strength as it requires people to be ambulatory to participate in the 6MWT. Upper limb strength, lung function and cardiac integrity are important in maintaining QOL and extending life.
The example of DMD also presents some insights showing how clinical research and regulatory review in rare diseases can be improved in the years ahead. In recognition of the challenges in developing therapies for rare diseases, the FDA introduced the Safety and Improvement Act (FDASIA) of 2012 and the 21st Century Cures Act of 2016, both of which include provisions that can lead to new levels of flexibility in the regulatory review process for rare diseases. These efforts also highlight the essential need to review perspectives from patients and caregivers in the review process to help address limitations in understanding the patient experience that may be the result of limited or no available relevant clinical data.
Another challenge in designing clinical trials in rare diseases is understanding the relationship between trial endpoints/drug efficacy and patient health and quality of life. This is where input from patients and care partners can play a vital role. In some cases, clinical trial endpoints may not always correlate with benefits that are meaningful to patients. In rare diseases, the patient voice can provide insights beyond what is available in clinical data. For example, a patient with DMD may consider being able to use the restroom without assistance or being able continue to feed themselves as the most important factor in assessing the results of treatment. This again can highlight the essential need to review the totality of clinical data related to a therapy for a rare disease, even in cases where a trial misses a primary endpoint, and to also consider perspectives from patients in regulatory review.
In the treatment of DMD an investigational drug called ataluren is scheduled to be reviewed by the FDA in September 2017. It is designed to enable the production of a functional protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the creation of an essential protein. Approximately 13% of DMD patients produce no dystrophin due to nonsense mutations in the dystrophin gene. Translarna facilitates production of normal dystrophin despite the presence of a nonsense mutation. Although Translarna failed to achieve its primary endpoint in clinical trials, the totality of data showed that Translarna can deliver meaningful clinical benefits. There are no treatments that target the underlying cause of nonsense mutation Duchenne. These data were supported by perspectives from clinicians, patients and families about the benefits of treatment with Translarna.
Research related to DMD and many other rare diseases reinforce the need for innovative approaches in clinical research that can often require new levels of flexibility in the regulatory review process. Without this flexibility, it is possible that many promising therapies might be delayed for years or might not be approved, leaving patients without treatment options that can deliver significant clinical benefits.