One of the biggest obstacles to advancing the development of therapies for pediatric rare diseases is that oftentimes we do not fully understand how a certain condition progresses in individuals over time. It is like driving someplace with a stalled navigation app and not knowing where to head beyond the next few turns.
Natural history research studies can point researchers in the right direction by providing a roadmap of the course a disease takes through different clinical stages. Knowing what to expect around the corner as a disease manifests allows researchers to establish valid end points for their studies. As they try various routes of investigation and collect data on the way, they can gauge new approaches’ effectiveness and help new drugs reach their final destination — U.S. Food and Drug Administration (FDA) approval.
David Lynch, MD, PhD, a pediatric neurologist at Children's Hospital of Philadelphia, director of CHOP’s Friedreich's Ataxia Program, and co-director of the Penn Medicine/CHOP Friedreich’s Ataxia Center of Excellence, is the principal investigator of a natural history study conducted by the Collaborative Clinical Research Network in Friedreich’s Ataxia, which is funded by the Friedreich's Ataxia Research Alliance (FARA). Dr. Lynch and his network colleagues have spent 15 years characterizing and understanding how individuals with Friedreich’s ataxia (FA) change during their lifetimes. Recent findings from the study provide new insights into comorbid medical conditions in FA.
A progressive neuromuscular disease, FA occurs in approximately one in 50,000 people in the U.S. The disease severely affects the flow of sensory information, leading to loss of reflexes, weakness, and poor balance and coordination. For most people with FA, movement problems (ataxia) first appear during childhood and worsen over time. It is caused by an autosomal recessive inherited genetic change (both parents must be carriers of the mutated gene) that silences the FXN gene, which provides instructions for making a protein called frataxin that is necessary for cells’ energy production. No FDA-approved treatments currently are available for FA.
“When we started the natural history study, we realized that to truly move forward with potential drug therapies for Friedreich’s ataxia, we needed to know more about the patient population,” Dr. Lynch said. “We knew a lot at that time about the molecular basis of the disease, but not enough about how we could introduce molecular interventions to patients and prove that they worked.”
The natural history study began with a group of 150 participants with FA gathered by seven medical centers in the U.S., and it has since grown to include a study population base of 850 patients across three continents and 12 sites. Researchers now have a variety of quantitative measures and data on how fast their disease process progresses and what constitutes reasonable improvement in their condition. This information is attractive to pharmaceutical companies interested in developing new drugs to treat FA, said Dr. Lynch, who also is a professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania.
“As a result, we have roughly 20 companies that are actively working on drug trials for Friedreich’s ataxia,” Dr. Lynch said. “It is because of this natural history data that we were able to get people interested in this research. They can understand the confounders of a clinical trial and what factors would make them more likely to be successful.”
For example, results from the natural history study published this year in the Journal of Child Neurology identified two diagnoses that were not traditionally associated with FA that are found at higher frequency in this disease. The prevalence of growth hormone deficiency was 28 times greater in the FA study cohort than the general population. And inflammatory bowel disease (IBD) was 3.5 times more common. As part of the study, the researchers also examined the medications used by patients to confirm the link with IBD.
This new information allows pharmaceutical companies to be more attuned to certain potential adverse events and possible drug interactions when they bring new therapies to market for FA, Dr. Lynch said. On the patient care side, the study findings allow physicians and patients to have a better idea of which medical problems that they observe are truly associated with FA and which are more likely to be coincidental. Other common features of FA that previously have been described medically include cardiac involvement, scoliosis, diabetes mellitus, urinary dysfunction, optic atrophy, and hearing loss.
Adding growth hormone deficiency and IBD to this list will generate new research opportunities within The Friedreich’s Ataxia Center of Excellence into the pathophysiology of FA and its molecular mechanisms. The Center, launched in 2014 with a $3.25 million gift from FARA in partnership with the Hamilton and Finneran families, focuses on expanding research on the cardiology of FA, pursuing new basic research avenues, facilitating drug discovery, and establishing a biomarker development program with the expertise of Ian Blair, PhD, vice chair of Penn’s department of Pharmacology and director of Penn’s Center for Cancer Pharmacology.
At the ninth annual Friedreich’s Ataxia Symposium held Oct. 17 in King of Prussia, Pa., Dr. Lynch provided patients and families with an update on the Center’s progress. Center researchers have begun to investigate mouse models to help identify the earliest changes that occur in the nervous system in FA. Also, they are completing final data analysis in a phase 3 clinical trial that is looking at a drug that increases frataxin levels. The FDA fast-tracked development of that drug, Actimmune® (interferon gamma-1b, Horizon Pharma Ireland), last year. A small pilot study completed at CHOP showed interferon gamma-1b may have positive effects in children with FA. And CHOP is the principal site for two other ongoing clinical trials, with several more planned for the coming year.
“We expect to have a new form of treatment for Friedreich’s Ataxia within the next several years,” Dr. Lynch said. “While that treatment may not be truly curative, once you start going down that path, the easier it is to make successes. The more you understand, the faster things can move.”