The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for Farydak (panobinostat, previously known as LBH589) capsules, in combination with bortezomib and dexamethasone, for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent (IMiD). If approved in the EU, panobinostat will be first in its class of anticancer agents available to these patients.

Multiple myeloma is a cancer of the plasma cells, a type of white blood cell present in the bone marrow, and affects approximately 84,000 people in Europe. Panobinostat is the first histone deacetylase (HDAC) inhibitor to show efficacy in multiple myeloma. As an HDAC inhibitor, its epigenetic activity may help restore cell function in patients with multiple myeloma.

"Panobinostat is the first and only HDAC inhibitor recommended by the CHMP for the treatment of patients living with multiple myeloma who have progressed after standard-of-care therapy with bortezomib and an IMiD," said Alessandro Riva, MD, Global Head of Oncology Development and Medical Affairs, Novartis Oncology. "We are pleased with the positive CHMP opinion on panobinostat for previously treated patients because it brings us one step closer to providing a new treatment option for patients in need in Europe."

The CHMP recommendation is based on efficacy and safety data in a subgroup analysis of 147 patients who had received at least two prior regimens, including bortezomib and an IMiD, during the phase III, randomized, double-blind, placebo-controlled, multicenter global registration trial, called PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA), evaluating panobinostat in combination with bortezomib and dexamethasone against bortezomib and dexamethasone alone in patients with relapsed and/or relapsed and refractory multiple myeloma. The trial found that the median progression-free survival (PFS) benefit increased in panobinostat patients who had received prior treatment with both bortezomib and an IMiD (12.5 months; n=73), as compared to the placebo arm (4.7 months; n=74) (hazard ratio=0.47 [95% confidence interval (CI): 0.31, 0.72]).

The most common non hematological adverse reactions included diarrhea, fatigue, nausea and vomiting. Treatment-emergent hematological toxicities included thrombocytopenia, anemia, neutropenia and lymphopenia. QTc prolongation of >480 and <500 msec was recorded in 1.3% of patients and change from baseline of >60 msec was observed in 0.8% of patients. No patients had an absolute QTc prolongation of >500 msec. Cardiac events (most frequently atrial fibrillation, tachycardia, palpitation and sinus tachycardia) were reported in 17.6% of the panobinostat-treated patients versus 9.8% of placebo-treated patients and syncope events were reported in 6.0% versus 2.4%. Discontinuation due to adverse events (AEs), regardless of causality, was observed in 36.2% of patients. The most common AEs leading to treatment discontinuation were diarrhea (4.5%), asthenia and fatigue (2.9% each) and pneumonia (1.3%). On treatment deaths not due to the study indication (multiple myeloma) were reported in 6.8% of panobinostat-treated patients versus 3.2% of placebo-treated patients.

In the EU, the European Commission generally follows the recommendation of the CHMP and delivers its final decision within three months of the CHMP recommendation. The decision will be applicable to all 28 EU member states plus Iceland, Norway and Liechtenstein. Additional regulatory submissions for panobinostat are being reviewed by health authorities worldwide. Panobinostat in combination with bortezomib and dexamethasone was approved in the US in February 2015 and Chile in May 2015 under brand name Farydak for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an IMiD. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) is a phase III randomized, double-blind, placebo-controlled, multicenter global registration trial to evaluate panobinostat in combination with bortezomib and dexamethasone against bortezomib and dexamethasone alone in patients with relapsed or relapsed and refractory multiple myeloma who failed on at least one prior treatment. The study of 768 patients took place in 215 clinical trial sites worldwide making it the largest global registration trial for multiple myeloma to date. The primary endpoint of the trial was PFS. Data for overall survival, the key secondary endpoint of the trial, are not yet mature. Other secondary endpoints include overall response rate, duration of response and safety.

Panobinostat is approved as Farydak in the US and Chile 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 IMiD. Farydak, an HDAC inhibitor, has an impact on epigenetics and may help restore cell function in patients with multiple myeloma.

Additional regulatory submissions for Farydak are being reviewed by health authorities worldwide. The safety and efficacy profile of panobinostat has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that panobinostat will become commercially available for additional indications anywhere else in the world.