General Information

Farydak (panobinostat) is a histone deacetylase inhibitor.

Farydak is specifically indicated for use in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. This indication is approved under accelerated approval based on progression free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Farydak is supplied as a capsule for oral administration. The recommended dose is 20 mg, taken orally once every other day for three doses per week (on Days 1, 3, 5, 8, 10, and 12) of Weeks 1 and 2 of each 21-day cycle for 8 cycles.

Clinical Results

FDA Approval

The FDA approval of Farydak was based on a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed multiple myeloma who had received 1 to 3 prior lines of therapy. A total of 768 subjects received bortezomib (1.3 mg/m2 injected intravenously) with dexamethasone (20 mg) in addition to Farydak 20 mg (or placebo), taken orally every other day, for 3 doses per week in Weeks 1 and 2 of each 21-day cycle. Treatment was administered for a maximum of 16 cycles (48 weeks). The primary endpoint was progression-free survival (PFS), using modified European Bone Marrow Transplant Group (EBMT) criteria, as assessed by the investigators. In the overall trial population, the median PFS was 12 months in the Farydak, bortezomib, dexamethasone arm and 8.1 months in the placebo, bortezomib, dexamethasone arm. At the time of interim analysis, overall survival was not statistically different between arms. The approval of Farydak was based upon the efficacy and safety in a prespecified subgroup analysis of 193 patients who had received prior treatment with both bortezomib and an immunomodulatory agent and a median of 2 prior therapies as the benefit:risk appeared to be greater in this more heavily pretreated population than in the overall trial population. Of these 193 patients, 76% of them had received ≥2 prior lines of therapy. The median PFS was 10.6 months in the Farydak, bortezomib, and dexamethasone arm and 5.8 months in the placebo, bortezomib, and dexamethasone arm.

Side Effects

Adverse effects associated with the use of Farydak may include, but are not limited to, the following:

diarrhea

fatigue

nausea

peripheral edema

decreased appetite

pyrexia

vomiting

Fardak comes with a black box labeled warning. Severe diarrhea occurred in 25% of Farydak treated patients. Monitor for symptoms, institute anti-diarrheal treatment, interrupt Farydak and then reduce dose or discontinue Farydak. Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred in patients receiving Farydak. Arrhythmias may be exacerbated by electrolyte abnormalities. Obtain ECG and electrolytes at baseline and periodically during treatment as clinically indicated.

Mechanism of Action

Farydak (panobinostat) is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. In vitro, panobinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Increased levels of acetylated histones were observed in xenografts from mice that were treated with panobinostat. Panobinostat shows more cytotoxicity towards tumor cells compared to normal cells.