Panobinostat had an important appointment this morning with a group of on­col­o­gists.

The appointment did not go so well.

The Oncologic Drugs Advisory Committee (ODAC) of the U.S. Food and Drug Administration (FDA) conducted a four-hour review of panobinostat (Farydak) earlier today.

At the end of the meeting, members of the committee were asked to vote whether they felt the benefits of panobinostat as a potential treatment for relapsed myeloma outweighed its risks.

Five committee members voted "no." Only two members voted "yes."

The advisory committee's vote is a serious setback for panobinostat's chances of being approved by the FDA in the near future. The agency is not obligated to follow the advice of its advisory committees, but it gen­er­al­ly does.

Novartis (NYSE:NVS), the pharmaceutical company that has been developing panobinostat, completed an application to the FDA in March of this year to have the drug approved as a new treatment for relapsed myeloma (see related Beacon news).

Given when the new drug application was filed with the FDA, a decision on the application is expected by the end of this month.  Although the agency could choose to delay its decision, it most likely will take one of two actions.

First, it still has the option of approving panobinostat, despite today's ODAC vote.

Second, the agency could issue Novartis what is known as a "complete response letter." This document would explain to Novartis why the FDA currently is unwilling to approve panobinostat, and what steps could be taken to allow the agency to once again consider the drug for approval.

Details Of Today's Meeting

The discussion at today's ODAC meeting focused on results from the Phase 3 PANORAMA1 clinical trial, which are the primary basis for panobinostat's application for FDA approval.

The PANORAMA1 trial included relapsed myeloma patients who were randomly assigned to receive one of two treatment regimens. One group of patients received panobinostat in combination with Velcade (bor­tez­o­mib) and dexa­metha­sone (Decadron). The other group received a placebo (sugar pill) combined with Velcade and dexamethasone.

As today's meeting progressed, it became clear that key FDA staffers as well as several ODAC members have concerns about multiple aspects of the trial's results. The questions raised during the meeting were not solely about how effective the drug is, nor were they solely about how safe the drug is. The concerns were broad and, in many ways, interrelated.

For example, there was initial discussion about which of several measures of progression-free survival should be used to assess panobinostat's survival benefit. As representatives from Novartis sought to ad­dress that issue, however, additional questions were raised as to the general reliability of survival esti­mates from the trial.

That question was linked to the impact of patients dropping out of the trial ("censoring") — which ties in directly with concerns about panobinostat's safety. If patients treated with panobinostat were more likely to drop out of the trial due to the drug's side effects, and if this happened particularly when patients were not experiencing a benefit from treatment, many key trial results could be biased.

Discussions about the impact of patients dropping out of the trial took place repeatedly during the meeting.

Of course, there also were numerous exchanges during the meeting directly about panobinostat's safety.  A frequent focus of these discussions was the fact that more patients in the panobinostat arm of the trial died while on treatment than in the placebo arm of the trial.

The FDA staff also introduced into the discussion a metric – "time to treatment failure" – often used for ther­a­pies that have significant side effects. It captures as "treatment failure" not just disease progression, but also the need to switch treatment due to side effects. The staff noted that it found no difference in the time to treatment failure between the patients treated with panobinostat and those who were not treated with the drug.

Prior to its final discussion of the data reviewed during the meeting, members of the ODAC heard from myeloma patients, caregivers, and representatives of myeloma advocacy groups. Many of these pre­sen­ta­tions emphasized how it would be valuable to have a new treatment for multiple myeloma, particularly one from a class of drugs different from existing myeloma therapies. This is a point that representatives from Novartis and several myeloma specialists also had made earlier in the meeting.

Panobinostat is a histone deacetylase (HDAC) inhibitor, and no HDAC inhibitor is currently approved as a treatment for myeloma.

Nevertheless, as the committee wrapped up its review prior to voting, it became clear that many ODAC members still had concerns about panobinostat's efficacy and safety.  Once the committee finally voted, many committee members said that it was a difficult vote for them.  Many also said that they hope that, at some point, a way is found for panobinostat to be available to myeloma patients who are particular­ly likely to benefit from it without having to take on too many safety risks.

For a complete account of today's ODAC review of panobinostat, see the Beacon's liveblog of the com­mit­tee meeting.  The Beacon's review of the briefing documents prepared for the meeting also offers insights into many of the concerns raised during the meeting.