Though a safety issue previously slowed development of the BCL-2 inhibitor venetoclax (ABT-199), the drug is now moving through the pipeline.
The US Food and Drug Administration (FDA) has granted venetoclax breakthrough therapy designation to treat patients with relapsed or refractory chronic lymphocytic leukemia (CLL), including those with 17p deletion.
The drug has proven active against CLL and other hematologic malignancies.
However, it is also known to induce tumor lysis syndrome (TLS). In fact, TLS-related deaths temporarily halted enrollment in trials of venetoclax. But researchers discovered ways to reduce the risk of TLS, and the trials continued.
Now, the FDA has granted the drug breakthrough designation, which is intended to expedite the development and review of drugs indicated for serious or life-threatening conditions.
The criteria for breakthrough designation include preliminary clinical evidence suggesting the drug may offer substantial improvement on at least one clinically significant endpoint compared to available therapy.
Venetoclax in CLL/SLL
Results presented at the 2014 EHA Congress suggested that venetoclax can be effective in patients with CLL/small lymphocytic lymphoma (SLL), and certain measures can reduce the risk of TLS.
Researchers reported that modifying the dosing schedule of venetoclax, administering TLS prophylaxis, and monitoring patients can decrease or eliminate the risk of TLS. And venetoclax can produce responses in patients with high-risk disease.
In a phase 1 trial, the researchers tested venetoclax monotherapy in 105 patients with high-risk CLL/SLL. Seventy-eight patients were evaluable for treatment response as of April 2014. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.
The response rate was 77% overall, 79% among patients with del (17p), 76% in patients who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23%, 26%, 22%, and 29%, respectively.
The median progression-free survival was about 18 months overall, but the median progression-free survival had not been reached for patients treated at or above 400 mg.
Seven patients developed TLS. One of these patients died, and 1 required dialysis. At the time of analysis, there were no cases of TLS among the 49 patients who received TLS prophylaxis and were given venetoclax according to the modified dosing schedule.
Common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.
Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).
Venetoclax is now being tested in phase 2 and 3 trials of CLL, as well as trials in other hematologic malignancies. Venetoclax is under development by AbbVie and Genentech/Roche.
