On May 17, the U.S. Food and Drug Administration granted an expanded approval to Vertex’s Kalydeco (ivacaflor), tripling the number of mutations in the cystic fibrosis (CF)-associated gene CFTR that the drug can treat, from 10 to 33. The agency’s action was unusual in that, for the first time ever, they based their decision on laboratory data in conjunction with evidence from earlier human trials, particularly a study focused on patients with one of the newly approved mutations.
No clinical trials were specifically run in support of the expanded approvals. Instead, Vertex had used an in vitro cell-based model to reasonably predict clinical response to Kalydeco. When additional mutations responded to the drug in the laboratory test, researchers were able to extrapolate the expected benefit from the clinical response seen in trials focused on other CFTR mutations.
In the FDA’s statement commenting on the approval, Janet Woodcock, M.D., Director of the Center for Drug Evaluation and Research, noted that many rare CF mutations have such small patient populations that clinical trials for each are not feasible. This challenge prompted the Agency to adopt an alternate approach based on precision medicine that led to the identification of certain CFTR gene mutations likely to respond to Kalydeco.
But this was not the only unusual FDA action in recent weeks. On May 5, the agency approved Mitsubishi Tababe’s Radicava (edaravone) for the treatment of ALS. The first new drug to gain U.S. approval for that indication in 15 years, Radicava partially slows progression of the disease, which in the majority of cases proves fatal two to five years after diagnosis. Phase 3 data from a six month, placebo-controlled study in Japan showed that Radicava slowed the rate of physical function decline in treated patients by 33%. What is unique about this FDA action is that the Agency had reached out to Mitsubishi Tanabe to request the company file for U.S. approval after the drug was approved in Japan and South Korea in 2015. The company submitted its application in June 2016, and U.S. approval was granted based on the existing Japanese clinical trial data.
And there have been other noteworthy “out of the box” approvals in recent months. We recently wrote about Merck’s Keytruda approval for patients with cancers exhibiting a specific biomarker rather than originating from a particular tissue type. We’ve also pointed to Marathon’s Emflaza, which received its U.S. approval as a treatment for Duchenne’s muscular dystrophy (DMD) based on clinical data from a 1995 study, as well as the approval for Sarepta’s DMD treatment, Exondys 51 (eteplirsen), which was approved to great controversy after a 16-patient, open-label trial with no placebo control and much lobbying on the drug’s behalf.
Are these non-canonical approvals the bellwether for major changes at the FDA? It remains to be seen, but they do show growing understanding by the Agency that rare diseases with small patient populations need flexibility. And they also point to, once again, the growing importance of biomarkers as a tool to guide both the clinical use of drugs, as well as patient selection for trials.