Credit: Esther Dyson
The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).
AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.
Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.
The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.
AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.
Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.
Phase 1 trial results
Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).
The trial included 35 patients with a median age of 68 years (range, 48-81).
Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.
The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.
The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).
Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.
Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.
The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.
Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.
This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.
