Steven Benner of Astellas Discusses New Gilteritinib Designation

Mathew Shanley

Earlier this month, Tokyo-based Astellas Pharmaceuticals received Fast Track designation from the U.S. Food and Drug Administration (FDA) for gilteritinib, an investigational compound intended to treat adult patients with FLT3 mutation-positive relapsed/refractory acute myeloid leukemia.

Rare Disease Report spoke with Steven Benner, MD, Astellas’ Senior Vice President and Global Therapeutic Area Head of Oncology Development about the new designation, what the development program for the drug entails, and the exact functionality and target for the potential therapy.

Rare Disease Report: Why should those affected by AML by excited about gilteritinib, and what are the primary targets of the drug?

Benner: Gilteritinib is a compound we’re very excited about. It was actually discovered internally at Astellas by our colleagues in Japan. We’ve developed, primarily the FLT3 inhibitor. FLT3 is a very common mutation – 40% of all patients with AML will have this mutation. When it’s present, it’s a driver mutation, so patients who have this mutation have a greater likelihood of having relapse, and when they relapse, the survival is worse than in patients without the mutation. It’s both a target and a driver of outcomes.

Our agent is very potent for hitting both kinds of FLT3 mutations. It also hit AXL, which may be important for chemotherapy resistance. We did an initial Phase 1/2 study in patients with AML because we knew that the target population would be AML and we’re really struck that we saw activity of the whole range. When we went up to the therapeutic doses – above 80 mg – then we saw an overall response rate improvement. We also saw what we thought was a reasonable toxicity profile; this is an oral agent that was given to patients with relapse or refractory AML, so patients who typically receive salvage chemotherapy and, unfortunately, tend to have a poor prognosis. Based on that study, which was fairly recently published in Lancet Oncology, we started the ongoing ADMIRAL study, which is a Phase 3 study for relapsed/refractory AML – the same patient population, essentially. This study randomizes between salvage chemotherapy or our agent therapy, gilteritinib, alone. In that study, we’ve still been accruing patients and we hope to have top-line results in 2018. We think that this study will serve as the basis for our initial (FDA) approval of gilteritinib.

RDR: Can you describe the development program in place for gilteritinib?

Benner: As for the development program, we’re doing a broad program. We have a whole series of additional Phase 3 studies to support future indications. One of those is with the BMT CTN from our transplant clinical trials network to look at patients who have a FLT3 mutation in their AML and have already undergone a stem cell transplant. We have another phase 3 that’s being run in patients who have undergone induction chemotherapy. We have another phase 3 trial for patients who are unable to receive high-dosages of chemotherapy. Lastly, we have an earlier phase 1 study looking at combination (of gilteritinib) with induction chemotherapy.
Our intent is to get an initial approval for gilteritinib for the relapsed/refractory patient population, but then to build on that with these ongoing phase 3 studies to be able to bring the drug to patients with a FLT3 mutation, regardless of where they are in the treatment spectrum.

RDR: Is the FLT3 mutation the only target?

Benner: FLT3 is a tyrosine kinase, and there are two kinds of FLT3 mutations. The most common is an internal tandem duplication (ITD); that occurs in about 25% of patients. The other is a tyrosine kinase domain (TKD) mutation that occurs in about 5% and gilteritinib is active against both of those forms of mutations. That’s important because you might see one arise, especially the TKD as a form of resistance to earlier therapies.

The other target is AXL. Tyrosine kinase inhibitors typically hit a variety of tyrosine kinsases, and ours is very potent for FLT3 which is the most important target, but it does also hit AXL, which could be important because AXL has been implicated in resistance to treatment.

RDR: What does the Fast Track designation mean for Astellas and patients with AML?

Benner: We were very pleased that the FDA granted Astellas fast-track status. What that will enable us to do is have more frequent interactions with the FDA. It may help us enable a priority review, which would be important for patients, as it may allow us to get the drug approved quickly.

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