The U.S. Food and Drug Administration (FDA) is giving itself an extra two to three months to decide whether to approve panobinostat as a new treatment for mul­ti­ple myeloma.

The FDA had been expected to reach a decision on the panobinostat new drug application by last Tuesday.  Now, however, a decision is unlikely to occur until the end of November or sometime in December.

The Swiss pharmaceutical company Novartis (NYSE:NVS) filed an ap­pli­ca­tion with the FDA in March to have panobinostat, in combination with Velcade (bortezomib) and dexamethasone (Decadron), approved as a new treatment for relapsed multiple myeloma.

Based on the timing of the application and the fact it was granted a six-month “priority review” – instead of a 10-month “standard review” – the FDA was expected to make a decision about panobinostat by the end of last month (see related Beacon news).

Earlier today, however, the FDA effectively announced that it has delayed its decision. The agency filed a notice to be published in the Federal Register saying that it will convene a meeting of its Oncologic Drugs Advisory Committee (ODAC) on November 6 to review panobinostat’s application and vote whether to recommend that panobinostat be approved by the FDA.

Important Update: In response to this article, a Novartis representative has clarified to The Beacon that there has not been any change in the FDA review timetable for panobinostat. For full details of this development, see the related Beacon news article published October 9, 2014.

The ODAC is one of a number of FDA advisory committees, which are comprised mainly of physicians. Up until today's change in the FDA's plans, the agency had not scheduled an ODAC meeting to review pano­bino­stat.

The FDA is not obligated to follow the recommendations of its advisory committees, but it typically does.

Given that ODAC's review of panobinostat will take place in early November, an FDA decision about the drug can be expected by mid December.

At that time, the FDA will decide either to approve panobinostat as a new treatment for multiple myeloma, or to issue Novartis a “complete response letter,” which will explain why the FDA is not currently prepared to approve the drug.

If panobinostat is approved, it currently is expected to be marketed under the brand name "Farydak."

Today's news does not have any immediate impact on plans for panobinostat outside the U.S.  Novartis re­ported recently that it has filed an application to have the drug approved in Europe, and additional regu­la­tory filings are underway elsewhere in the world.

When contacted last week to comment on the apparent delay in the FDA's panobinostat decision, a Novartis spokeswoman said that the company was "not able to provide further information other than what has already been provided (and which is in the public domain)." She also indicated the company might provide further information about the matter in its October 28 quarterly earnings report.

Significance Of The FDA’s New Review Schedule

Today’s news raises the obvious question: Does the delay in panobinostat’s review mean the drug’s chances of being approved by the FDA have changed?

The answer to that question depends on the reason for the schedule change, which is something only the FDA knows, and the agency does not comment publicly on such matters.

Of the many potential reasons for why the FDA changed its plans, there are two that deserve particular attention.

One possibility is that, during its review of panobinostat, the FDA uncovered previously undisclosed issues with the drug that require greater scrutiny, and which could reduce the chances of panobinostat eventually being approved as a new myeloma therapy.

In discussions and email exchanges with a number of myeloma experts over the course of the last week, however, The Beacon has received no indication that this has happened.

Instead, the experts with whom The Beacon has consulted believe it entirely possible that the change in the FDA’s plans is due to reasons that imply no fundamental change in panobinostat’s chances for approval.

This second potential explanation is more complex than the first.  It relies on details of FDA procedures and aspects of the trial data that have been submitted to support panobinostat’s application.

The crux of the explanation, however, is that the FDA could very well have extended its review of panobinostat for reasons that have nothing to do with previously undisclosed “dark secrets.”

The Potential Second Explanation In Detail

The FDA must make a decision about whether or not to grant a drug priority review – rather than a standard review – during the first two months after it receives a new drug application.

There are aspects of the data submitted in support of panobinostat’s application, however, which initially may have led the FDA to believe the drug should be reviewed in a short period of time, and without input from an advisory committee.

For example, panobinostat’s application for approval is based on data from a large Phase 3 trial.  In addi­tion, the trial results clearly show that panobinostat provides a clinically meaningful progression-free sur­viv­al benefit in relapsed myeloma patients.  (The trial and its results are discussed in more detail below.)

It would not be until the FDA conducted more in-depth analyses of the data in panobinostat’s application, however, that the agency would be likely to find trial results which – although well known to myeloma special­ists – might lead the FDA to believe additional time and feedback are warranted for its review.

In the key panobinostat trial carried out to support the drug’s FDA approval application, for example, patients treated with panobinostat were more likely to experience serious side effects than those who were not treated with the drug.

These side effects have been reported in the past and are not news to myeloma specialists.   They also are not the sort of safety issues that would call undue attention to themselves during the FDA’s initial review of the panobinostat application.

Thus, the FDA may very well have changed its review schedule for panobinostat not because of any new, “dark secrets,” but because of the way it reviews drug applications and the nature of panobinostat’s trial data.

More About Panobinostat And Its Application For Approval

Panobinostat 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.

Application Based On Data From PANORAMA-1 Clinical Trial

The application requesting FDA approval of panobinostat is based on data from the Phase 3 clinical trial known as PANORAMA-1. The trial tested panobinostat 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: panobinostat, Velcade, and dexa­meth­a­sone; or a placebo (sugar pill) combined with Velcade and dexamethasone.

Results of that trial were published last month (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 this past June (see related Beacon news and the slides from the ASCO presentation, courtesy of Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston).

Efficacy Results From The Trial

The PANORAMA-1 trial found that 61 percent of patients receiving panobinostat, Velcade, and dexa­meth­a­sone responded to the treatment, compared to 55 percent of patients who received a placebo plus Velcade, and dexamethasone.

The patients in the panobinostat arm of the trial also experienced longer progression-free survival than the pa­tients in the placebo arm (12 months versus 8.1 months, respectively).  In addition, overall survival was longer in the panobinostat-treated patients versus those who received the placebo (34 months versus 30 months), but this difference is not yet statistically significant.

Side Effects Reported During The Trial

As mentioned earlier, the PANORAMA-1 trial results also showed that patients treated with panobinostat experienced a noticeably higher rate of severe side effects than patients in the placebo arm of the trial. Many of the side effects were related to low blood cell counts, which often can be addressed by dose adjustments or the use of drugs such as Neupogen (filgrastim).

However, there was also a higher rate of severe diarrhea among patients who received panobinostat (25 per­cent versus 8 percent in the placebo arm), and almost twice as many patients in the panobinostat arm of the trial dis­con­tinued treatment due to side effects compared to those in the placebo arm of the trial (36 per­cent versus 20 per­cent respectively).

Update (Oct 9, 8:00 a.m.) - Formal notice of the ODAC meeting where panobinostat will be reviewed has been published on the Federal Register website.