FDA Approves Panobinostat for Relapsed Multiple Myeloma

Roxanne Nelson

Disclosures

February 23, 2015

The US Food and Drug Administration (FDA) today granted accelerated approval to panobinostat (Farydak, Novartis) for the treatment of certain patients with relapsed multiple myeloma.

Late last year, panobinostat was voted down at an FDA Oncologic Drugs Advisory Committee meeting that had considered its use in relapsed multiple myeloma. The agency said that after that meeting the company submitted additional information supporting the agent's use for a slightly different indication, and it was this that was approved.

The approval is for use of the panobinostat in patients with relapsed multiple myeloma who have received at least two prior standard therapies, including bortezomib (Velcade, Millennium) and an immunomodulatory agent. This is an area of unmet medical need, the company noted.

Panobinostat is approved for use in combination with bortezomib and dexamethasone.

The drug is a first in a new class of agents that act as inhibitors of histone deacetylases.

"Panobinostat has a new mechanism of action that distinguishes it from prior drugs approved to treat multiple myeloma, making it a potentially attractive candidate agent," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, in a statement.

This FDA approval is based on efficacy and safety data in a prespecified subgroup analysis of 193 patients who had received prior treatment with both bortezomib and an immunomodulatory agent. This subgroup of patients participated in the phase 3, randomized, double-blind, placebo-controlled, multicenter global registration trial, known as PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA).

The findings showed that, in this subgroup, the median progression-free survival in patients treated with panobinostat was higher than that in the placebo arm (10.6 months, n = 94 vs 5.8 months, n = 99; hazard ratio = 0.52).

Concern Over Side-Effects

At the FDA Oncologic Drugs Advisory Committee meeting in November 2014, experts on the panel had voted against recommending approval of the drug for use in relapsed multiple myeloma because, on the basis of the data reviewed, the drug's benefits did not outweigh its risks for patients with relapsed multiple myeloma. As previously reported by Medscape Medical News, the majority of the members of the Oncologic Drugs Advisory Committee felt that the risks for harm or death outweighed the potential benefit in the panobinostat/bortezomib/dexamethasone combination.

According to Sagar Lonial, MD, professor and vice chair of clinical affairs, department of hematology and medical oncology, Emory University School of Medicine, Atlanta, Georgia, one of the challenges in that study was the adverse events, including nausea, vomiting, diarrhea, and fatigue. "A lot of that was thought to be associated with the use of intravenous bortezomib rather than subcutaneous and a bit of a learning curve with panobinostat for a number of investigators," he told Medscape Medical News in an interview.

The most common adverse reactions (incidence ≥ 20%) observed in clinical trials were diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting, with the most common nonhematologic laboratory abnormalities (incidence ≥ 40%) being hypophosphatemia, hypokalemia, hyponatremia, and increased creatinine.

Common hematologic laboratory abnormalities (incidence ≥ 60%) include thrombocytopenia, lymphopenia, leukopenia, neutropenia, and anemia. The agent can also cause fatal and serious toxicities including severe diarrhea and cardiac toxicities. Serious adverse events occurred in 60% of patients treated with panobinostat, bortezomib, and dexamethasone compared to 42% of patients in the control arm.

Panobinostat carries a boxed warning alerting patients and healthcare professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias, and electrocardiogram changes have occurred in patients receiving the drug. Due to these risks, the drug has been approved with a Risk Evaluation and Mitigation Strategy consisting of a communication plan to inform healthcare professionals of these risks and how to minimize them.

The approval is part of the FDA's accelerated approval program, and, according to the manufacturer, regulatory applications are under way in the EU, Japan, and worldwide.

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