The U.S. Food and Drug Administration (FDA) has approved panobinostat, which will be marketed under the brand name Farydak ^[1], for the treatment of relapsed and refractory multiple myeloma.

Specifically, Farydak has been approved for use in combination with Velcade ^[2] (bortezomib) and dexamethasone ^[3] (Decadron) in patients with multiple myeloma who have received at least two prior standard therapies.

The two prior therapies must include Velcade and at least one treatment from the immunomodulatory class of drugs, which includes Revlimid ^[4] (lenalidomide), thalidomide ^[5], and Pomalyst ^[6] (pomalidomide, Imnovid).

The FDA approval of Farydak is the agency's third go-ahead for a new myeloma therapy in less than three years. Prior to Farydak, the agency approved Pomalyst in early 2013 and Kyprolis ^[7] (carfilzomib) in the summer of 2012.

Farydak will be marketed by the Swiss pharmaceutical company Novartis (NYSE:NVS), which has been developing the drug.

The FDA's decision was announced earlier this afternoon by the agency in a press release ^[8], which also noted that the drug's approved prescribing information will contain a so-called black box warning.  Such warnings are intended to highlight important safety issues associated with a drug.

In the case of Farydak, the black box warning alerts "patients and health care professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias and electrocardiogram (ECG) changes have occurred in patients receiving Farydak," according to the FDA press release.

Farydak, which at times has been known by the code name LBH589, continues to be under review for potential regulatory approval in Europe. A decision on the drug's Euro­pean marketing application can be expected by this summer, given typical timetables for European regu­la­tory review of drug approval applications.

An Eventful Road To Approval

The FDA’s decision to approve Farydak is likely to come as a surprise to many people. The drug was re­viewed during an FDA advisory committee meeting in early November last year, but failed to gain the support of the committee, which voted 5 to 2 against recommending the drug for FDA approval (see related Beacon ^[9] news).

The FDA typically makes approval decisions that reflect the recommendations of its advisory committees. Thus, there was widespread pessimism about Farydak’s chances for FDA approval following the early November advisory committee vote.

Some of that pessimism dissipated, however, when the FDA announced late in November that it was giving itself an extra three months to reach a decision on Farydak’s approval application. Had it not taken that step, the agency would have had to announce its decision by the end of November (see related Beacon ^[10] news).

There are many reasons why the FDA can decide to delay an approval decision. However, in this case, one reasonable interpretation was that the agency was unwilling to make a quick decision based on its advisory committee’s recommendation.

There also was speculation at the time that one option the FDA might be considering was an approval of Farydak that was more restrictive than what Novartis requested in its approval application.

This, in fact, is what has happened.

Novartis originally requested Farydak approval for use in myeloma patients who have had one previous therapy. The FDA approval announced today is more restrictive. It specifies that Farydak is to be used in patients with at least two prior therapies, and there are additional requirements as to what those previous therapies must be.

The FDA decision to approve Farydak caps a long, arduous effort by Novartis to develop the drug as a new cancer therapy. After initially testing Farydak in a wide range of different cancers, Novartis decided in 2009 to ask the FDA to approve the drug as a new treatment for Hodgkin’s lymphoma. That new drug application, however, was turned down by the federal regulator after less than 60 days of review.

Following the FDA rejection of Farydak’s lymphoma new drug application, Novartis shifted gears and focused development of the drug on its potential use as a myeloma therapy. The company initiated a number of different trials testing Farydak in multiple myeloma, including the trial that eventually served as the basis for the regulatory submission that led to today’s approval announcement.

Novartis has not yet indicated when Farydak will be available in U.S. pharmacies, or what the drug’s cost will be.

Farydak And Its Key Clinical Trial Data

Farydak is an orally administered drug that belongs to a class of drugs called histone deacetylase (HDAC) inhibitors. These drugs work by increasing the production of proteins that slow cell division and cause cell death.

Other HDAC inhibitors have been, or are currently being, investigated as potential myeloma therapies, in­clud­ing Zolinza ^[11] (vorinostat), Istodax ^[12] (romidepsin), ricolinostat ^[13] (ACY-1215 ^[14]), quisinostat ^[15], and CUDC-907 ^[16].

The FDA’s approval of Farydak is based on data from the Phase 3 clinical trial known as PANORAMA-1. The trial tested Farydak in combination with Velcade and dexamethasone in relapsed/refractory multiple mye­lo­ma patients who have failed at least one prior treatment.

Patients in the trial were randomly assigned to one of two treatment regimens: Farydak, Velcade, and dexa­meth­a­sone; or a placebo (sugar pill) combined with Velcade and dexamethasone.

The published results of the trial show that adding Farydak to treatment with Velcade and dexamethasone improved pro­gression-free survival in trial participants by almost 4 months (from 8.1 months to 12 months).  There also was a trend to improved overall survival.

In its press release today, however, the FDA described the progression-free survival of Farydak somewhat differently than in the previously published results, saying:

Study results showed participants receiving the Farydak combination saw a delay in their disease progression (progression-free survival) for about 10.6 months, compared to 5.8 months in participants treated with bortezomib and dexamethasone alone.

Participants in the PANORAMA-1 trial who were treated with Farydak also experienced frequent side effects. These included low blood cell counts, which often occur in patients being treated with anti-myeloma thera­pies, as well as significant gastrointestinal side effects.  

The frequency and seriousness of these side effects are likely a key reason for the black-box safety warning the FDA has included in the drug's officially approved prescribing information.

Results of the PANORAMA-1 trial were published four months ago (see related Novartis press release ^[17] and the article in The Lancet Oncology [abstract ^[18]]). The published results mirror those presented at the American Society of Clin­i­cal Oncology (ASCO) annual meeting in June last year (see related Beacon ^[19] news and the slides ^[20] from the ASCO presentation, courtesy of Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston).

The Beacon will be updating this article throughout the rest of the day and tomorrow as additional in­for­ma­tion related to the FDA approval of Farydak becomes available.