FDA Issues CRL for Dasatinib/Startase in Patients with Chronic Myelogenous Leukemia

The U.S. Food and Drug Administration has issued a complete response letter (CRL) to a New Drug Application (NDA) seeking approval ofdasatinib (Dasatinib), a next-generation formulation of a protein kinase inhibitor for the treatment of patients with chronic myelogenous leukemia (CML). The FDA's decision was based on observations of good manufacturing practices at the company's contract manufacturing facilities. Although there were no observations specific to the dasatinib manufacturing line, the FDA is suspending approval of new products at this site while corrective actions are implemented.

According to the manufacturer, a remediation program has been initiated and a meeting with the U.S. Food and Drug Administration is planned for December 2025 to resolve outstanding issues. The NDA for dasatinib seeks approval of a formulation designed to maintain efficacy at lower doses, reduce pharmacokinetic variability, and mitigate drug interactions commonly associated with acid inhibitors.

What is the mechanism of action of dasatinib?

It is well known that dasatinib has pH-dependent solubility and an increase in gastric pH will significantly reduce plasma drug concentration. Combining dasatinib with a proton pump inhibitor reduced systemic exposure by more than 40%, prompting the U.S. Food and Drug Administration to issue a warning guidance. Dasatinib is designed to increase the solubility of the active compound at slightly acidic and neutral pH levels, reducing its dependence on gastric acid absorption. This property enables stable pharmacokinetics even when administered with proton pump inhibitors such as omeprazole.

What clinical and regulatory activity has dasatinib received to date?

Evidence from a retrospective registry presented at the 2022 ASH Annual Meeting showed that CML patients (n=302) who received a combination of TKIs and proton pump inhibitors had a 5-year overall survival rate of 79%, which was lower than the 94% rate for patients who received TKIs alone (n=374; HR, 3.5; 95% CI, 2.1-5.3; P<0.0001). These results highlight the detrimental effects of reduced TKI absorption following coadministration of proton pump inhibitors.

Dasatinib was previously administeredDesignated as an orphan drug by the U.S. Food and Drug Administration in 2022 for the treatment of patients with chronic myelogenous leukemia, reflecting the FDA's recognition of its therapeutic relevance in this patient population. On February 13, 2024, the U.S. Food and Drug Administration accepted the resubmitted new drug application for dasatinib to treat patients with chronic myeloid leukemia.

Dasatinib's original NDA was submitted in 2021 under the 505(b)(2) regulatory pathway, which is used to approve modified or improved versions of drugs. The U.S. Food and Drug Administration conducted a full review of the application in early 2022. However, in July 2023, the FDA issued a CRL to the manufacturer requesting more information on optimal dosing parameters and details related to third-party manufacturing facilities.

The CRL applies to all six proposed dose strengths of dasatinib (15mg, 36mg, 50mg, 57mg, 70mg and 100mg) but does not cite any deficiencies in product stability or clinical data supporting its efficacy and safety. Instead, the FDA requested further clarification to ensure consistency in dosing and manufacturing processes. After receiving the CRL, Xspray Pharma worked to comply with the FDA's requirements and resubmitted an NDA containing the required information.

Reference materials:https://www.onclive.com/view/fda-issues-crl-for-dasatinib-in-chronic-myeloid-leukemia