Most people are familiar with the leading causes of morbidity and mortality in the United States—heart disease, cancer, and diabetes. However, did you know that an estimated 350 million people worldwide suffer from rare diseases? In this blog post, I’ll be discussing what constitutes a rare disease, how developing orphan drugs to treat rare diseases presents unique challenges, and how a team at Certara worked to solve a “PK Mystery” to develop a novel medication for an ultra-rare disease.
What constitutes a “rare disease?”
A disease is considered to be rare when it affects fewer than 1 in 2000 people. Although each rare disease does not affect a large number of patients, there are estimated to be over 7000 rare diseases. And since there are no treatments for 95% of rare diseases, they collectively cause suffering for many people. Some of the rare diseases that my scientist colleagues have worked to develop treatments for include: short-bowel syndrome, smallpox, anthrax, and atypical hemolytic uremic syndrome.
Orphan drug development for rare diseases presents unique challenges
Due to the small market size, there are limited drug discovery initiatives by pharmaceutical companies when therapeutic targets are known. For this reason, the FDA’s Office of Orphan Products Development provides incentives for pharmaceutical companies to develop treatments for rare diseases. These incentives are working; a 2013 report estimated that there are more than 450 orphan drugs in development for rare diseases. Orphan drug developers must tackle distinct challenges facing drug approvals in rare disease indications including: heterogeneity in disease progress and treatment outcomes, few patients to run new studies, uncertain appropriate duration of treatment, and sparse existing data available.
Pediatric drug development for an orphan drug with unusual PK
A team of Certara scientists recently helped a sponsor to develop an orphan drug for a cluster of ultra-rare diseases resulting from genetic mutations in an essential metabolic pathway. Without treatment, these patients can suffer brain damage, coma, and even death. While a treatment had been developed for this devastating disease, it was administered in an undesirable manner. Thus, the sponsor was seeking to develop a new formulation that would reduce these administration issues.
The sponsor had identified a promising new formulation whose development was stymied when it failed to prove bioequivalent to the previously approved treatment. While the two drugs failed to show bioequivalence in terms of plasma levels of key metabolites, urinary metabolite excretion was almost identical between formulations.To attain regulatory approval, the sponsor had to determine the mechanism for the drug’s unusual pharmacokinetics (PK) and develop a sound rationale for pediatric and adult dosing.
This condition is an “ultra orphan” disorder affecting fewer than 1000 patients in the US. Thus, it is extremely difficult to get enough patients for inclusion in clinical trials. To understand the benefit-risk profile of the new formulation, Certara scientists had to leverage every bit of the sparse available data. Since non-compartmental analysis (NCA) did not fully describe the dose-exposure relationship of the new formulation, mechanistic, physiologically-relevant modeling techniques were applied to describe the blood and urine levels of key metabolites. It turned out that the drug’s unusual PK was due to extensive first-pass metabolism.
The next challenge was to determine pediatric and adult dosing recommendations. Since the literature suggested that body surface area might provide a more useful basis than body weight for scaling, exposure modeling was based on body surface area. Dose simulations using this model reproduced observed drug exposure levels and helped determine dosing for patients from two years of age through adulthood. The results from this model were included in the sponsor’s fast-track New Drug Application (NDA). After reviewing the NDA, the FDA approved the novel drug formulation for use in both children and adults.
Learn how Certara helped a sponsor gain approval for their drug
My colleagues recently wrote up this project as a case study, “A PK Mystery Solved” for Applied Clinical Trials. I hope that you’ll read it and let me know what you think!
Are you working on an orphan drug for a rare disease? What are some of the challenges that you are facing? Let us know in the comments!