PKC412 (midostaurin) significantly improved overall survival of adult patients eligible to receive standard induction and consolidation chemotherapy

•AML has the lowest survival rate of all adult leukemias[1] and the treatment strategy with chemotherapy has remained unchanged for more than 25 years[2],[3]

•Currently there are no approved targeted AML treatments; global regulatory submissions for PKC412 (midostaurin) are on track to begin in H1 2016

Basel, February 19, 2016 - Novartis announced today that the United States Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to PKC412 (midostaurin). PKC412 (midostaurin) is an investigational treatment for adults with newly-diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy.

The Breakthrough Therapy designation for PKC412 (midostaurin) is primarily based upon the positive results from the Phase III RATIFY (CALGB 10603) clinical trial. This study was conducted in partnership with the Alliance for Clinical Trials in Oncology and presented during a plenary session at the 57th American Society of Hematology (ASH) Annual Meeting[4].

Patients who received PKC412 (midostaurin) and standard induction and consolidation chemotherapy experienced a significant improvement in overall survival (OS) (hazard ratio = 0.77, P = 0.0074) compared to those who received standard induction and consolidation chemotherapy alone[4]. The median OS for patients in the PKC412 (midostaurin) treatment group was 74.7 months (95% confidence interval [CI]: 31.7, not attained), versus 25.6 months (95% CI: 18.6, 42.9) for patients in the placebo group[4]. No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events in the PKC412 (midostaurin) treatment group versus the placebo group[4]. A total of 37 deaths were reported, with no difference in treatment-related deaths observed between groups[4].

"For more than 25 years, medical developments have been limited for AML patients and the chemotherapy treatment strategy has essentially remained unchanged," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "We look forward to working closely with the FDA to bring PKC412 (midostaurin), the first potential AML targeted therapy, to patients as quickly as possible."

According to the FDA, Breakthrough Therapy designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint. The designation includes all of the Fast Track program features, as well as more intensive FDA guidance on an efficient drug development program[5].

This designation adds to the growing number granted to Novartis by the FDA, illustrating the company's continued commitment to developing innovative therapies for diseases with a significant unmet medical need.

In the US, about 20,000 people were diagnosed with AML in 2015, the majority of whom were adults[6]. According to the latest research, approximately one-third of AML patients also harbor a FLT3 gene mutation[7], which is associated with worse outcomes and shorter survival than in those without the mutation[8]. PKC412 (midostaurin) is the first drug targeting FLT3 to demonstrate an overall survival benefit in AML[4].

Since PKC412 (midostaurin) is investigational at this time and is expected to be submitted for FDA approval, Novartis opened a Global Individual Patient Program (compassionate use program) and a US Expanded Treatment Protocol (ETP) to enable PKC412 (midostaurin) access. Patients 18 years of age and older with newly-diagnosed FLT3-mutated AML and able to receive standard induction and consolidation therapy will be considered.

In order to help identify patients who may have a FLT3 mutation and potentially benefit from treatment with PKC412 (midostaurin), Novartis is collaborating with Invivoscribe Technologies, Inc. who is leading regulatory submissions for a companion diagnostic.

About acute myeloid leukemia (AML) and the FLT3 mutation
AML is an aggressive cancer of the blood and bone marrow[9]. It prevents white blood cells from maturing, causing an accumulation of "blasts" which do not allow room for the normal blood cells[9]. AML is the most common acute leukemia in adults, but also has the lowest survival rate[1]. AML accounts for approximately 25% of all adult leukemias worldwide, with the highest incidence rates occurring in the United States, Europe and Australia[1].

Mutations in specific genes are found in many cases of AML, and biomarker testing is considered standard of care for newly-diagnosed patients to help determine the best possible treatment option[7]. FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase, a type of cell-surface receptor, which plays a role in the proliferation, or increase, in the number of certain blood cells[10].

About PKC412 (midostaurin)
PKC412 (midostaurin) is an investigational, oral, multi-targeted kinase inhibitor in development for the treatment of patients with AML with a FLT3 mutation. The safety and efficacy profile has not been fully established. There is no guarantee that PKC412 (midostaurin) will become commercially available.

PKC412 (midostaurin) is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "Breakthrough Therapy," "on track," "investigational
... etc etc.

Novartis is on Twitter. Sign up to follow @Novartis at http://twitter.com/novartis(link is external).

References
[1] Deschler B, Lübbert M. Acute myeloid leukemia: epidemiology and etiology. Cancer. 2006;107(9):2009-2107.
[2] NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) Version 1. 2015 Acute Myeloid Leukemia. http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf(link is external). Accessed October 2015.
[3] Lin TL, Levy MY. Acute myeloid leukemia: focus on novel therapeutic strategies. Clinical Medicine Insights: Oncology. 2012;6:205-217.
[4] Stone RM, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Presented at the 57th Annual Meeting of the American Society of Hematology.
[5] US Food and Drug Administration. Frequently Asked Questions: Breakthrough Therapies. http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm341027.htm(link is external). Accessed February 2016.
[6] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. Ca Cancer J Clin. 2015;65(1):5-29.
[7] Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology Am Soc Hematol Educ Program. 2013;2013:220-6.
[8] Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19(8):1345-1349.
[9] National Institute of Health (NIH) National Cancer Institute (NCI). Adult Acute Myeloid Leukemia Treatment (PDQ®) http://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq(link is external). Accessed February 2016.
[10] Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100(5):1532-42.

# # #