FDA's Panobinostat Approval Ushers in New Class of Drug to Treat Multiple Myeloma

The FDA’s approval of panobinostat (Farydak) for multiple myeloma, the first histone deacetylase (HDAC) inhibitor to be approved in this space, provides a new option and new hope for patients with this disease, Walter M. Capone, President and Chief Executive Officer of the Multiple Myeloma Research Foundation, said.

“The promise of the HDAC class of drugs, that targets malignant cells in a completely different manner, is an important advance in helping patients whose myeloma is progressing despite prior treatments and can contribute to our mission of attaining cures for all patients,” he said in a statement.

The agent is approved for patients with advanced myeloma and treatment resistant multiple myeloma in combination with bortezomib (Velcade) and dexamethasone for patients who have received at least two prior standard therapies, including bortezomib and an immunomodulatory (IMiD) agent.

“Farydak has a new mechanism of action that distinguishes it from prior drugs approved to treat multiple myeloma, making it a potentially attractive candidate agent for the treatment of multiple myeloma,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a press release. “Farydak’s approval is particularly important because it has been shown to slow the progression of multiple myeloma.”

“The MMRF commends the diligence of Drs. Pazdur, [Christopher] Farrell and the Division of Hematology Products at FDA, as well as the myeloma community, working with Novartis in approving the HDAC inhibitor, an entirely new and important class of treatments for multiple myeloma,” Capone said. “In particular, their enlightened efforts to specify the profile of patients most likely to benefit from Farydak, will enable patients and their doctors to access a vital new option for the most challenging relapsed disease.”

In November, however, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 5-2 against the accelerated approval the agent in this setting, asserting that the benefits of the panobinostat combination did not outweigh the risks.

Panobinostat was approved with a Boxed Warning regarding severe diarrhea and severe and fatal cardiac events, arrhythmias and electrocardiogram (ECG) changes. As a result of these side effects, the drug has also been approved along with a Risk Evaluation and Mitigation Strategy (REMS).

The prespecified analysis from the PANORAMA-1 trial, which the approval was based on, looked specifically at 193 patients from the phase III study that were treated with bortezomib and an IMiD. In this population, the median progression-free survival (PFS) with the panobinostat combination was 10.6 months versus 5.8 months with placebo (HR = 0.52; 95% CI, 0.36-0.76). Additionally, the tumor shrinkage rate with panobinostat was 59% versus 41% with bortezomib and dexamethasone alone.

By investigator assessment, the overall response rate (ORR) was 61% with panobinostat versus 55% in the placebo arm. The median duration of response with panobinostat was 13.1 months versus 10.9 months with placebo.

The ORR after independent review was 64% with panobinostat and 54% with placebo. The complete response rate was 12% versus 7% and the duration of response was 11.8 months versus 9.7 months, for panobinostat and placebo, respectively.

Serious adverse events (AEs) were more common with panobinostat versus placebo. The most common for panobinostat and placebo, respectively, were thrombocytopenia (7.3% vs 2.2%), diarrhea (11.1% vs 2.4%), fatigue (6.7% vs 1.6%), pneumonia (18.1% vs 14.2%), and sepsis (6% vs 3%).

A higher number of patients discontinued treatment in the panobinostat arm compared with placebo as a result of adverse events or consent withdrawal (34% vs 17%). However, 40% of patients in the placebo arm stopped therapy as a result of progression compared with 21% in the panobinostat arm.

Despite this, study investigator Paul Richardson, MD, said, “Farydak represents an exciting agent with a new mechanism of action that is part of a promising class of drugs in this setting.”

Richardson, the Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, added that “Farydak has been shown to improve progression-free survival in relapsed multiple myeloma patients who have received at least two prior regimens, including bortezomib and an IMiD, which is an area of particular unmet medical need."

Clinical trials continue to investigate the safety and efficacy of panobinostat across a variety of settings. A phase I/II study is exploring the combination of lenalidomide, bortezomib, and dexamethasone plus panobinostat as a treatment for transplant-eligible newly diagnosed patients with multiple myeloma. Additionally, panobinostat is being explored in combination with other proteasome inhibitors, namely carfilzomib.