Novartis Pharmaceuticals recently received FDA approval for panobinostat, a blood cancer drug that targets multiple myeloma.
This was a surprising ruling, as it was a turnaround from last year’s Oncologic Drugs Advisory Committee’s 5-2 vote against approval which noted the severity of side effects and the submission of incomplete data. The FDA added three months to the review time for the drug, which then received approval after review of additional information.
According to an article in FierceBiotech, “Novartis came back with data on 193 multiple myeloma sufferers who had failed on Velcade and an immunomodulatory agent. In that group, patients who got panobinostat in addition to the other drugs posted progression-free survival of 10.6 months compared to 5.8 months for those taking Takeda’s drug and dexamethasone alone. And 59% of patients in the panobinostat arm saw their cancer shrink or disappear during treatment, beating the other group’s 41 percent.” (Damian Garde, FierceBiotech, February 23, 2015)
LRG’s Research Team member, Dr. Sebastian Bauer, has been conducting a Phase I study of panobinostat and imatinib in GIST patients.
Data published by Bauer and LRG research team member Maria Debiec-Rychter in 2009 showed that panobinostat plus imatinib was therapeutically active against imatinib resistant human GIST tumor biopsies grafted into mice and in GIST cell lines.
Panobinostat is an HDAC inhibitor, which is a new class of drugs that show anti-cancer activity in three ways:
- Inducing apoptosis
- Arresting the cell cycle
- Destabilizing certain cancer-causing proteins such as bcr-abl (and possibly KIT). This may occur because HDAC inhibitors cause hsp90 to become inactive, possibly resulting in the destruction of the KIT protein.
Another way that HDAC inhibitors might accomplish their effects is by “turning on” some tumor suppressor genes that have been silenced.
HDAC inhibitors are in various stages of development. LBH589 (panobinostat) in combination with Glivec is in a phase I trial for GIST in Germany.
- Istodax (romidepsin)- FDA approved for cutaneous T cell lymphoma (CTCL)
- Zolinza (vorinostat) – FDA-approved for cutaneous T-cell lymphoma (CTCL)
- LBH589 – In phase II trials for solid tumors and a phase I trial in combination Glivec
In summary, a number of different strategies are being tried to overcome Gleevec resistance. Different classes of drugs use different strategies to accomplish this. Some classes of drugs use multiple strategies. Understanding the classes and strategies may help patients evaluate their treatment options.