Silver Spring, MD (Press Release) – On February 23, 2015, the U.S. Food and Drug Admin­istra­tion (FDA) granted accelerated approval to panobinostat (FARYDAK capsules, Novartis Pharma­ceu­ticals) in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone for the treat­ment of patients with multiple myeloma who have received at least two prior regi­mens, in­­clud­ing bor­tez­o­mib and an immuno­modu­la­tory agent. As a con­di­tion of this accelerated approval, FDA requires the sponsor to conduct a trial to verify and describe the clin­i­cal benefit of panobinostat for patients with multiple myeloma.

Panobinostat is a histone deacetylase inhibitor.

The approval was based on the results of pro­gres­sion-free survival (PFS) in a subgroup of patients from a ran­dom­ized, inter­na­tional, two-arm, placebo-controlled trial eval­u­ating panobinostat (or placebo) in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone. In this pre-specified subgroup of 193 patients who had received prior treat­ment with bor­tez­o­mib and an immuno­modu­la­tory agent, the median age was 60 years (range 28-79).

The pri­mary efficacy end­point was PFS determined by investigators. The median PFS values were 10.6 and 5.8 months in the panobinostat-containing arm (panobinostat-bortezomib-dexamethasone) and control (placebo-bortezomib-dexamethasone), re­spec­tive­ly [HR 0.52 (95% CI: 0.36, 0.76)]. Overall response rates were 58.5% (95% CI:47.9, 68.6) in the panobinostat arm and 41.4% (95% CI:31.6, 51.8) in the placebo arm.

Safety was eval­u­ated in 758 patients with re­lapsed multiple myeloma who were treated with panobinostat-bortezomib-dexamethasone or placebo-bortezomib-dexamethasone. The most common adverse reac­tions (>20%) on the panobinostat-containing arm were diarrhea, fatigue, nausea, periph­eral edema, de­creased appetite, pyrexia, and vomiting. Serious adverse reac­tions in­cluded pneu­monia, diarrhea, thrombo­cytopenia, fatigue, and sepsis. There was an in­­creased incidence in deaths not due to progressive disease (7% vs. 3.2%) on the panobinostat-containing arm.

The most common hema­to­logic ab­nor­mal­i­ties in­cluded thrombo­cytopenia and neu­tro­penia; the most common chemistry ab­nor­mal­i­ties were hypophosphatemia and hypokalemia. ECG changes, in­­clud­ing new T-wave changes and ST-segment depressions, occurred in 64% of patients in the panobinostat-containing arm and 42% in the control arm. Arrhythmias occurred more frequently in patients receiving panobinostat compared to the control arm (12% vs. 5%).

Panobinostat is approved with a BOXED WARNING alerting patients and health care providers of severe and fatal cardiac toxicities and severe diarrhea. Hemorrhage and hepato­tox­ic­ity are other important safety concerns with panobinostat and are in­cluded in the WARNINGS and PRECAUTIONS section of the label.

Recommended Treatment Regimen for Panobinostat

Treatment Phase 1: Cycles 1-8, 3 week cycles (Total time 24 weeks):

• Panobinostat 20 mg orally once daily 3 times a week for 2 weeks per 3 week cycle
• Bortezomib 1.3mg/m2 intravenously twice weekly for 2 weeks per 3 week cycle
• Dexamethasone 20 mg orally per day of bortezomib and the day after each dose

Treatment Phase 2: Cycles 9-16, 3 week cycles (Total time 24 addi­tional weeks):

Patients achieving clin­i­cal benefit (defined as a response category of ‘No Change’, PR, MR, nCR, or CR) without unresolved severe or medically sig­nif­i­cant toxicity may be con­sidered for another 8 cycles of ther­apy at modified dosing.

• Panobinostat 20 mg orally once daily 3 times a week for 2 weeks per 3 week cycle
• Bortezomib 1.3mg/m2 intravenously once weekly for 2 weeks per 3 week cycle
• Dexamethasone 20 mg orally per day of bortezomib and the day after each dose

Full pre­scrib­ing in­­for­ma­tion is avail­able at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205353s000lbl.pdf

Healthcare professionals should report all serious adverse events sus­pected to be asso­ci­ated with the use of any medicine and device to FDA's MedWatch Reporting System by com­plet­ing an online form at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Source: Food and Drug Admin­istra­tion.