FDA Approves Farydak (Panobinostat) For The Treatment Of Relapsed Multiple Myeloma
The U.S. Food and Drug Administration (FDA) has approved panobinostat, which will be marketed under the brand name Farydak, for the treatment of relapsed and refractory multiple myeloma.
Specifically, Farydak has been approved for use in combination with Velcade (bortezomib) and dexamethasone (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 (lenalidomide), thalidomide, and Pomalyst (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 (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, 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 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 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 (vorinostat), Istodax (romidepsin), ricolinostat (ACY-1215), quisinostat, and CUDC-907.
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 and the article in The Lancet Oncology [abstract]). The published results mirror those presented at the American Society of Clinical Oncology (ASCO) annual meeting in June last year (see related Beacon news and the slides 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.
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Another tool in the shed!! Thanks Beacon.
Good to have another option but looks like some potentially nasty side effects
i was excited until I read the possible side effect.
Since the mild triplet CyBorD put me into atrial fibrillation, I won't be tempted to try Farydak with its acknowledged cardiotoxicity.
Given the frequent side effects and limited additional benefit with this HDAC inhibitor, it is a surprise that the US FDA has approved this medication for refractory myeloma. Certainly the monoclonal antibodies have more promise in this setting. However, the more options and therapeutic categories are available, when used skillfully, the better. Thank you for this unexpected report.
Quoting from the Lancet abstract:
"Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3–4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%])."
Yep, those numbers don't look too enticing!
Thanks for the breaking news, MB Staff!
Dear Beacon Staff,
Thanks for the important news and clear explanation of the approval rationale.
Hi folks. Lots of concern here about the drug's safety. When ODAC voted against panobinistat approval, I questioned the wisdom of that rejection, especially given that Kyprolis had been approved with not dissimilar safety concerns. I really worry about treatment drugs that can cause deaths, but I've mostly come to grips with that. At least in terms of recognizing that some level of such risk needs to be accepted, as long as we are aware of these dangers in making treatment decisions. In our myeloma world where recurrence and becoming refractory are the norm, absent the Holy Grail of a cure, I think we need as many options as can be developed.
I am grateful for those true heroes in the lab fighting for us and each step of progress we make. I'm optimistic about the next wave of immunotherapies and T-cell treatments on the horizon as well. I was looking at a slideshare from Dana Farber recently on lymphoma (my sister's cancer) and was stunned to see how slow the progress has been over the last 30 years or so. Maybe a couple of drugs per decade. And, here we are looking at what could be 5 in 5 years in myeloma research. Just a kind of "wow" moment ...
Hi Lou,
Great seeing you post. I hope you are doing well. I miss your columns.
Mark
There is not a single one of the novel agents that doesn't have some serious side effects. I found it interesting that in the Lancet abtract, cited by Steve, that 42% of those in the placebo group reported serious side effects. Even with thrombocytopenia 31% of the placebo group reported that effect.
The big question, perhaps not yet resolved, in improving myeloma therapeutic outcome is related to the cause of myeloma. What is driving the development of this type of cancer and what types of drugs can be used to shut down the cause? That is a general question, but a specific one is what is driving my type of cancer? Let's get individualized and personalize therapy for myeloma! It is now possible to use tumor specimens to get this information through bioinformatics inquiry. Has anyone ever had their myeloma analyzed to see what is driving it and what might be used to overcome this driver and knock out the source of new tumor cells?
Lonnie,
I don't think they have nailed down a cause. Chemical or biologic agents are suspected to trigger an immune response that then goes off the tracks. Why some people's immune system/bone marrow is triggered to produce excess paraproteins is still not understood. Some patients have distinctive chromosome markers but many do not. Then the disease has a tendency to morph and a chromosome marker may later turn up that didn't exist at the time of diagnosis. The disease, even though varied, does share common characteristics. That is why certain classes of drugs appear to work on almost all patients. For some that is an extended period of time, but not so for others. Patients with certain specific chromosome markers tend to relapse faster and have poorer overall outcomes. Why they have those markers and others do not is still a mystery.
Very frustrating.
Ron
I am in month 11.5 of a Kyprolis / Farydak trial. Three weeks on, one week off. Blood numbers somewhat low, but no one's worried. The usual fatigue. Maybe one day and half of diarrhea in the three-week treatment period. Elevated blood pressure, but meds are controlling that. Numbers in urine still very low and stable. Overall, it's been an easy, quiet treatment ... feel too good to have cancer!
Don't be hasty to discount this regimen. You know the mantra, "we all respond differently!" Be encouraged!
- Dave, 8 years and counting ...