FDA approval has arrived for Novartis AG's Rydapt (midostaurin), a breakthrough-designated treatment for adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML). The oral, multitargeted kinase inhibitor, approved for use in combination with chemotherapy and a companion diagnostic developed by Invivoscribe Technologies Inc. to detect the FLT3 mutation, is the first targeted therapy to treat patients with AML.

AML is a fast-growing cancer that forms in the bone marrow, leading to an increased number of immature white blood cells in the bloodstream. It's primarily treated with chemotherapy, though in some cases radiotherapy, immunotherapy or stem cell transplantation are used. About 19,930 people were expected to be diagnosed with AML in 2016 and 10,430 were projected to die of the disease, according to the National Cancer Institute. FLT3 is mutated in about a third of AML patients.

A Cortellis consensus forecast suggests the medicine could bring Novartis $56 million in revenue this year, growing to $145 million in 2018. But analysts suggest that challenges could come from two next-generation FLT3 inhibitors in development, Astellas Pharma Inc.'s gilteritinib and Daiichi Sankyo Co. Ltd.'s quizartinib, both of which are in phase III.

During a recent conference call organized by Suntrust Robinson Humphrey to discuss the evolving AML landscape, Roland Walter, a doctor and associate member of the clinical research division at the Fred Hutchinson Cancer Center, said of midostaurin that "it's sort of an incremental improvement," and observed that AML "currently goes from incremental improvement to incremental improvement," according to a transcript of the call. "It's not going to be a game-changing new development, but it will provide some benefit to patients, and I think the drug, unless it's relatively expensive, will probably be used," he said.

Rydapt is a kinase inhibitor that works by blocking several enzymes that promote cell growth. The approval was primarily based on positive results from the phase III trial Ratify, which randomized 717 newly diagnosed AML patients, under the age of 60, to receive either Rydapt and chemotherapy or placebo and chemo. Patients in the study who received Rydapt plus standard induction and consolidation chemotherapy and as a monotherapy up to one year for maintenance experienced a 23 percent reduction in the risk of death vs. standard chemotherapy and placebo. The median overall survival for patients in the Rydapt treatment group was 74.7 months vs. 26 months for patients in the placebo group.

Julie Masow, a spokeswoman for Novartis, told BioWorld Today that Rydapt will be available to May 1. The price is both indication- and dose-dependent. The U.S. wholesale acquisition cost (WAC) for the AML indication is $7,495 for a 14-day package and $14,990 for a 28-day package — though what patients actually pay will, of course, vary based on their insurance, the duration of treatment and other factors.

During the Ratify trial, the median duration of therapy for AML patients was 1.4 months, which would be a total WAC of $22,485. Some patients in the trial were on treatment longer and received up to 12 cycles of single-agent continuation Rydapt.

Novartis has also submitted marketing authorization applications to the EMA for midostaurin in newly diagnosed FLT3 mutation-positive AML and aggressive systemic mastocytosis (ASM). Both were accepted by the EMA for review in November 2016.

Common side effects of Rydapt in patients with AML include low levels of white blood cells with fever, nausea, inflammation of the mucous membranes, vomiting, headache, spots on the skin due to bleeding, musculoskeletal pain, nosebleeds, device-related infection, high blood sugar, and upper respiratory tract infection. In August 2016, Novartis started a phase I trial of the candidate in patients with CD123-expressing hematological malignancies, including AML.

In June 2016, Novartis announced a collaboration and licensing agreement with Xencor Inc. for the development of bispecific antibodies for treating cancer. As part of the deal, valued at up to $2.4 billion, the companies are co-developing XmAb-14045, a humanized anti-CD123 x anti-CD3 bispecific antibody.

The only current molecular targeted therapy approved for AML is Mylotarg (gemtuzumab ozogamicin), but the drug was withdrawn from the U.S. market in 2010 due to safety concerns. It was not approved in Europe and its use in Japan is limited to elderly, relapsed patients. (See BioWorld Today, June 29, 2016.)

A RARE INDICATION, TOO

The Friday approval also extends to the treatment of adults with certain types of rare blood disorders, including the ultra-rare condition ASM, systemic mastocytosis with associated hematological neoplasm and mast cell leukemia. The FDA granted the Rydapt application priority review and fast track status for the mastocytosis indication.

The recommended dose of Rydapt for ASM is 100 mg twice daily, for a WAC of $32,121 for 30 days. The median duration of treatment for ASM patients observed in clinical trials was 11.4 months, which would suggest a WAC of $359,755.

Masow said that, in ASM, Rydapt "is priced well in line with other ultra-rare disease therapies, and Novartis has initiated an innovative indication-based rebate offer to payers" related to its use for the indication, which will require a patient cost-savings provision, to further reduce the net cost.