On April 28, 2017, Novartis received FDA approval of Rydapt (midostaurin), the first FLT3 tyrosine kinase inhibitor (TKI) indicated for the treatment of newly diagnosed patients with FLT3-mutated (FLT3+) acute myeloid leukemia (AML) based on the Phase III RATIFY (CALGB 10603) clinical trial. With Rydapt’s approval, a specific and effective treatment option is available for FLT3+ AML patients for whom the treatment of care has been the standard 7+3 (seven days of cytarabine and three days of daunorubicin) chemotherapy induction and consolidation with cytarabine and/or hematopoietic stem cell transplantation (HSCT).

Mutations in FLT3 are associated with poor prognosis and are among the most commonly observed genetic alterations in AML, occurring in about 30 percent of the patients. Despite resulting in high remission rates, relapse is inevitable in most FLT3+ AML patients who receive the 7+3 regimen and there is a high unmet need for therapies that will result in more durable responses and long-term clinical benefit.

The first-to-market advantage will allow Rydapt to be rapidly integrated into the treatment paradigm of FLT3+ AML. However, GlobalData anticipates that a number of factors will challenge the prospective growth of Rydapt’s market share in the FLT3+ AML segment. To this end, Rydapt is likely to be adopted initially only in a small subset of patients with FLT3+ AML. In the RATIFY trial, the results of which were used for the FDA filing, Rydapt was evaluated against placebo in combination with 7+3 specifically in young (ages 60 years and younger) patients with FLT3+ AML. Despite the documented overall survival (OS) benefit in young patients (74.7 vs. 26.0 months for Rydapt vs placebo, P = 0.007), AML is far more common in the elderly, with a median age at diagnosis of 67 years.

In other studies that evaluated Rydapt in young and elderly patients in combination with azacitidine (median age 65 years, range 21–85 years) or 7+3 (median age 54 years, range 18–70), the combination regimens resulted in significant safety signals; hematological grade 3–4 adverse events such as neutropenia and thrombocytopenia were seen in more than 90 percent of the patients who received Rydapt + azacitidine, and dose reductions of Rydapt occurred in up to 71 percent of patients who received it in combination with 7+3. Therefore, without definitive efficacy and safety data, physicians may be reluctant to use Rydapt in older patients with FLT3+ AML, prompting Novartis to conduct additional clinical studies to boost physician adoption of the drug in the elderly.     

Despite the first-to-market advantage in newly diagnosed young patients with FLT3+ AML, Rydapt is not expected to become the preferred treatment option in later treatment lines. This is mainly due to the fact that as a monotherapy Rydapt was not effective at inducing complete or partial remissions in patients with relapsed/refractory FLT3+ AML. This is in contrast with rival FLT3 inhibitors such as Daiichi Sankyo’s quizartinib, Astellas’ gilteritinib, and Arog’s crenolanib, all of which –as single agents–resulted in remission rates of 40–50 percent in relapsed/refractory FLT3+ AML. In addition, agents like crenolanib and gilteritinib demonstrated remission rates ranging from 30–40 percent in patients who progressed on prior TKIs, making them more desirable treatment options in the relapsed/refractory treatment setting.    

In the face of impending competition from the three more effective FLT3 TKIs, which are positioned in numerous treatment lines irrespective of age or prior TKI treatment, Novartis is already thinking outside of the FLT3+ AML. In an earlier Phase IB trial, Rydapt remarkably demonstrated comparable remission rates in both FLT3+ (n=13) and wild-type (WT, n=27) AML patients in combination with 7+3 (92 percent [12/13] vs 74 percent [20/27], respectively).

Considered to be the least specific TKI for FLT3 among the four contenders, Rydapt’s weak affinity for FLT3 may play to its advantage in AML, allowing it to be used in WT patients as well, whereas the more specific FLT3 TKIs would be restricted to the FLT3+ AML patients only.

To this end, Novartis has already listed Rydapt’s label expansion to WT AML under planned filings as early as 2021. A prospective approval in WT AML would free Rydapt of competition from rival FLT3 TKIs and significantly boost the drug’s revenues as a result of the expansion of its target population by more than two-fold over the existing patient population.