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The Food and Drug Administration has given both Orphan Drug and Rare Pediatric Disease Designations to entrectinib for the treatment of neuroblastoma. The drug, made by Ignyta and until recently named RXDX-101, is described as a potent, novel, orally available, selective tyrosine kinase inhibitor of the Trk family of tyrosine kinase receptors (TrkA, TrkB, and TrkC), ROS1 and ALK proteins.

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Entrectinib is designed as a targeted therapeutic candidate to treat patients with cancers that harbor activating alterations to TrkA, TrkB, TrkC, ROS1, or ALK. The drug has demonstrated in vivo antitumor activity against various TrkA, ROS1, or ALK-driven mouse xenograft models of different human cancers, as well as oral bioavailability and has been shown in animal studies to efficiently cross the blood brain barrier.


Entrectinib is currently in two Phase I/II clinical trials: STARTRK-1 and ALKA-372-001. Interim results from the ALKA-372-001 study were presented in September at the ESMO Annual Meeting, which showed no dose-limiting toxicities and only one Grade 3 or higher possibly drug-related adverse event (fatigue, which subsided with a dose reduction). Eight patients in the trial remained on active treatment across the three dosing schedules, with four patients having received nine to 21 cycles.


One patient with ROS1-positive non-small cell lung cancer (NSCLC) had a complete response; partial responses were seen in five patients with colorectal cancer, NSCLC, and neuroblastoma and in patients with each of TrkA, ROS1 and ALK alterations; and prolonged stable disease occurred in two patients (one with ALK-positive NSCLC and one with ROS1-positive pancreatic cancer).


The company notes that in addition to neuroblastoma, applications with the FDA for orphan drug designations have been filed for several other indications in adult patients.


The Orphan Drug designation-to encourage development of drugs in the diagnosis, prevention, or treatment of a medical condition affecting fewer than 200,000 people in the U.S.-grants a product market exclusivity for a seven-year period if the sponsor complies with certain FDA specifications, as well as tax credits and prescription drug user fee waivers.


Under the FDA's Pediatric Disease Priority Review Voucher program, upon the approval of a qualifying new drug application (NDA) or biologics license application (BLA) for the treatment of a rare pediatric disease, the sponsor is eligible to obtain priority review for a subsequent NDA or BLA. The FDA defines a "rare pediatric disease" as a disease that affects fewer than 200,000 individuals in the U.S. primarily aged from birth to 18 years.