Omacetaxine mepesuccinate has been approved for treating adults with chronic myeloid leukemia that has progressed after treatment with at least two tyrosine kinase inhibitors, the Food and Drug Administration announced on Oct. 26.
The new agent will be marketed as Synribo by Teva Pharmaceuticals, an Israel-based company with a U.S. presence in Frazer, Pa.
It is the second drug approved this fall for patients who are not being helped by standard treatments for chronic myeloid leukemia (CML). On Sept. 4, the FDA approved bosutinib (Bosulif) to treat patients with chronic, accelerated or blast phase Philadelphia chromosome positive CML who are resistant to or who cannot tolerate other therapies
Synribo is the latest name for omacetaxine, a synthetic formulation of homoharringtonine, a drug used in China, where it was first extracted from an evergreen tree (Cephalotaxus). It had been studied for acute and chronic myeloid leukemias before imatinib (Gleevec) emerged as a standard therapy in CML, but interest flagged after imatinib was approved.
More recently, another manufacturer sought approval of omacetaxine under the brand name Omapro for CML patients after failure of prior therapy with imatinib in patients with the Bcr-Abl T3151 mutation, which is highly resistant to current treatments.
In 2010, however, the FDA’s Oncologic Drugs Advisory Committee agreed with the FDA that a validated test for the T3151 mutation was needed before the drug could be indicated for patients with the mutation. The FDA statement announcing approval of omacetaxine makes no mention of T3151.
Omacetaxine was designated as an orphan drug and was approved under the FDA’s accelerated approval program, "which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate end point that is reasonably likely to predict a clinical benefit to patients," the statement said.
Dr. Jorge Cortes discussed omacetaxine at the 2009 meeting of the American Society of Hematology
The approved indication is in patients with chronic or accelerated phase CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval is based on response rate, according to the drug’s prescribing information, which states that "there are no trials verifying an improvement in disease-related symptoms or increased survival" with omacetaxine.
A protein synthesis inhibitor omacetaxine is administered at a dose of 1.25 mg/m2 subcutaneously twice daily for 14 days over a 28-day-cycle for the induction phase, after which it is administered twice daily for 7 consecutive days over a 28-day cycle, for a maintenance phase.
Approval was based on the combined results of two studies of patients with CML who had received at least two approved TKIs and had documented evidence of resistance or intolerance to dasatinib (Sprycel) and/or nilotinib (Tasigna) at a minimum, according to the statement. Teva said many of the patients had also been treated with imatinib and other treatments, including hydroxyurea, interferon, and cytarabine.
Among 76 patients with chronic phase CML, 14 (18.4%) achieved a major cytogenic response, the primary efficacy end point, in a mean of 3.5 months; the median duration of the response was 12.5 months.
Among the 35 patients with accelerated phase CML, 5 (14.3%) achieved a major hematologic response (a complete hematologic response or no evidence of leukemia, lasting for a median of 4.7 months. The mean time to the onset of the response in the 5 patients was 2.3 months, according to the prescribing information. None of the patients had a major cytogenic response.
In studies, the most common grade 1-4 adverse reactions (affecting 20% or more of treated patients) included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, weakness and fatigue, injection site reactions, pyrexia, infection, and lymphopenia, according to the FDA.
Thrombocytopenia, anemia, neutropenia, febrile neutropenia, asthenia/fatigue, pyrexia and diarrhea, were the most common grade 3/4 adverse reactions, affecting 5% or more of treated patients.
"Today’s approval provides a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML," said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research.
The FDA cited the National Institutes of Health estimate that about 5,430 people will be diagnosed with CML this year.
The drug’s prescribing information is available here.