The US Food and Drug Administration (FDA) granted Priority Review to the PKC412 (midostaurin) new drug application (NDA) for the treatment of acute myeloid leukemia (AML) in newly-diagnosed adults with an FMS-like tyrosine kinase-3 (FLT3) mutation, as well as for the treatment of advanced systemic mastocytosis (SM). The premarket approval application (PMA) for the PKC412 (midostaurin) FLT3 companion diagnostic, developed in collaboration with Invivoscribe Technologies, Inc. (IVS) has also been accepted for review by the FDA. Outside the US, the marketing authorization application for PKC412 (midostaurin) in these indications has already been accepted by the European Medicines Agency (EMA).
“FLT3-mutated AML and advanced SM are devastating and rare diseases, with significant unmet needs due to limited existing treatment options,” said Bruno Strigini, CEO, Novartis Oncology. “This regulatory designation signifies the importance of midostaurin as a potential therapy for these patients who haven’t had the benefit of targeted medicines.”
The NDA submission for PKC412 (midostaurin) includes data from the largest clinical trials conducted to date in each indication. In the Phase III RATIFY trial (CALGB 10603), which investigated PKC412 (midostaurin) plus standard chemotherapy versus placebo plus standard chemotherapy in adult patients less than 60 years of age with FLT3-mutated AML, those in the PKC412 (midostaurin) arm experienced a statistically significant improvement in overall survival (OS) with a 23% reduction in risk of death compared to the placebo arm (hazard ratio [HR] = 0.77, P = 0.0074). Based on these data, PKC412 (midostaurin) was also granted Breakthrough Therapy designation by the FDA earlier this year for newly-diagnosed FLT3-mutated AML.
In the RATIFY trial, no statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events (AEs) in the PKC412 (midostaurin) treatment group versus the placebo group. The most frequent all grade AEs were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae (small red skin spots) and pyrexia. A total of 36 deaths occurring within 30 days of the last dose of study drug were reported, with no difference in treatment-related deaths observedbetween groups.
Data from the Phase II single-arm study (CPKC412D2201) evaluating the efficacy of PKC412 (midostaurin) in patients with advanced SM were also published in the New England Journal of Medicine in June 2016. The study showed that treatment with PKC412 (midostaurin) resulted in an overall response rate of 60% (defined as complete or partial resolution of organ damage) with a median duration of response of 24.1 months (95% CI, 10.8-not estimated [NE]) and a median OS of 28.7 months (95% CI, 18.1-NE). The most frequent AEs were low-grade nausea, vomiting and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred mostly in patients with pre-existing cytopenias.
A Priority Review designation is granted by the FDA to therapies that may provide significant improvements in the treatment, diagnosis or prevention of serious conditions. According to the FDA, the goal is to take action on a Priority Review application within six months, compared to 10 months under the standard review process. Novartis has been granted a growing number of Priority Review designations by the FDA, underscoring the company’s ongoing commitment to developing innovative therapies for rare diseases or underserved cancer patients.