FDA Grants Glasdegib Priority Review for Frontline AML

Mace Rothenberg, MD

The FDA has granted a priority review to a new drug application (NDA) for glasdegib for use in combination with chemotherapy for the frontline treatment of patients with acute myeloid leukemia (AML), according to Pfizer, the developer of the investigational oral smoothened (SMO) inhibitor.

The priority review is based on data from the phase II BRIGHT 1003 study, in which combining glasdegib with low-dose cytarabine (LDAC) reduced the risk of death by 49.9% versus LDAC alone in treatment-naïve patients with AML or high-risk myelodysplastic syndrome (MDS). The median overall survival (OS) was 8.8 months (95% CI, 5.0-11.7) versus 4.9 months (95% CI, 2.9-6.5), respectively (HR, 0.501; 95% CI, 0.334-0.752; P =.0003).

Under the priority designation, the FDA will review the NDA within 6 months from the acceptance of the filing, compared with the standard 10 months. The FDA is scheduled under the Prescription Drug User Fee Act to make its decision by December 2018.

“Patients with acute myeloid leukemia who are ineligible for intensive chemotherapy are in critical need of new treatment options to improve their overall survival,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a statement.

“In an investigational phase II study, glasdegib in combination with low-dose cytarabine showed a significant improvement in overall survival compared to patients who received low-dose cytarabine alone. Glasdegib is the first smoothened inhibitor to potentially offer such a benefit to patients with acute myeloid leukemia, and we are proud that our application was accepted by the FDA for priority review.”

Findings from BRIGHT were presented at the 2016 ASH Annual Meeting. The multicenter open-label trial included 132 treatment-naïve patients with AML or high-risk MDS who were not candidates for intensive chemotherapy. Overall, 88 patients were randomized to the glasdegib combination and 44 patients were assigned to LDAC alone. The primary endpoint was OS.

There were 55 patients with good/intermediate risk cytogenetics in the glasdegib arm, compared with 27 in the LDAC alone arm. Among these patients, the median OS was 12.2 months (95% CI, 7.5-14.9) versus 6.0 months (95% CI, 4.3-10), respectively (HR, 0.451; 95% CI, 0.262-0.776; P = .0016).

There were 33 patients with poor-risk cytogenetics in the glasdegib arm, compared with 17 in the control arm. Among these patients, the median OS was 4.4 months (95% CI, 3.1-7.4) versus 2.3 months (95% CI, 1.0-5.7), respectively (HR, 0.572; 95% CI, 0.310-1.057; P = .0353).

The most common (≥30%) adverse events (AEs) reported in the glasdegib arm were anemia (45% vs 42% with LDAC alone), febrile neutropenia (36% vs 27%), nausea (36% vs 12%), decreased appetite (32% vs 12%), fatigue (31% vs 20%), and thrombocytopenia (30% vs 27%). Serious AEs reported in ≥15% of patients in the glasdegib arm were febrile neutropenia (29% vs 20% in the control arm) and pneumonia (21% vs 17%).

The ongoing phase III BRIGHT AML 1019 trial (NCT03416179) is examining glasdegib combined with intensive or nonintensive chemotherapy in treatment-naïve patients with AML.

Cortes JE, et al. A phase II randomized study of low dose Ara-C with or without glasdegib (PF-04449913) in untreated patients with AML or High-Risk MDS. Presented at: 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 99.