As reported earlier today by The Beacon ^[1], the U.S. Food & Drug Admin­is­tra­tion (FDA) this morning released key documents related to the agen­cy’s review of pano­bino­stat as a potential new treatment for multiple myeloma.

The documents consist of briefing reports, agendas, and other sup­port­ing material for the meeting of the FDA’s Oncologic Drugs Advisory Com­mit­tee (ODAC) this coming Thursday. The morning session of that meet­ing will be devoted to a review of pano­bino­stat ^[2] (Farydak), which is being developed by the Swiss pharmaceutical company Novartis (NYSE:NVS).

Among the documents released this morning, two in particular offer key data that could affect both how the ODAC votes in regard to pano­bino­stat on Thursday, and whether the FDA eventually approves pano­bino­stat.

The first is the FDA staff’s review and summary ^[3] of data from the key clinical trial, known as PANORAMA-1, providing data in support of pano­bino­stat’s new drug application.

The second is the question ^[4] the FDA staff has developed for the ODAC to consider and vote on during Thurs­day’s meeting. The question is accompanied by bullet points highlighting the FDA staff’s key take­aways from its analysis of the pano­bino­stat trial data.

Prior to today’s release of the meeting documents, the Beacon’s sense from discussions with myeloma specialists was that pano­bino­stat’s approval was likely to be supported by the ODAC, and that the FDA would eventually approve pano­bino­stat.

The data in the documents released today, however, suggest that ODAC’s support for pano­bino­stat – and FDA approval of the drug – may not be quite as certain as they were before.

In particular, the FDA staff note in their meeting documents that pano­bino­stat may not provide as much of a progression-free survival benefit as previously reported.

Up until today, pano­bino­stat’s progression-free survival benefit typically has been reported as being 3.9 months. The FDA staff point out, however, that an arguably more accurate estimate of the survival benefit is 2.2 months – and the benefit may even be less than two months.

In addition, the FDA staff note that pano­bino­stat appears to double the chance a patient may die during treatment due to causes not directly related to multiple myeloma. The staff also highlight evidence that pano­bino­stat may have heart-related toxicities.

These findings – particularly the lower estimate of pano­bino­stat’s survival benefit – suggest the rest of the drug’s path to approval may not be quite as easy as expected.

Why The Staff’s Findings May Be Important

In the past, myeloma experts have expressed a willingness to accept pano­bino­stat’s potential safety issues given the drug’s four-month progression-free survival benefit.

This support was bolstered by the fact that pano­bino­stat is from a completely different class of drugs than existing myeloma therapies. Panobinostat is what is known as a histone deacetylase (HDAC) inhibitor, and no HDAC inhibitor is currently approved – or regularly used – as a treatment for myeloma.

If, however, pano­bino­stat’s progression-free survival benefit is just two months, the benefit starts to enter territory where physicians – and the FDA – may not view the drug’s benefit as unequivocally worth its risks.

For example, another HDAC inhibitor, Zolinza ^[5] (vorinostat), was tested as a potential myeloma therapy in a major clinical trial and was found to have a 0.8 month progression-free survival benefit (see related Beacon ^[6] news). That survival benefit has been viewed by most myeloma experts as too small to justify using the drug regularly in the treatment of multiple myeloma.

Why The Staff’s Findings May Not Be Important

Despite the concerns just described, it is worth noting that nowhere in the documents prepared for this Thursday’s ODAC meeting does the FDA staff express outright concern about the FDA approving pano­bino­stat.

In comparison, when Kyprolis ^[7] (carfilzomib) was reviewed by the ODAC in 2012, the FDA staff said in its briefing report for the ODAC meeting that it was “very concerned” about “severe toxicities, including deaths” that have been observed in association with the use of Kyprolis (related Beacon ^[8] news). There are no such statements in the FDA staff reports about pano­bino­stat.

Moreover, despite the FDA staff’s concerns about Kyprolis’s safety expressed in its briefing for the 2012 ODAC meeting, the drug’s approval was strongly supported by the ODAC, and Kyprolis was approved by the FDA the following month.

Background

The Novartis 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 ^[9] (bortezomib) and dexamethasone ^[10] (Decadron) in multiple mye­lo­ma patients who have had one to three prior therapies.

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 ^[11] and the article in The Lancet Oncology [abstract ^[12]]). The published results mirror those presented at the American Society of Clin­i­cal Oncology (ASCO) annual meeting this past June (see related Beacon ^[13] news and the slides ^[14] from the ASCO presentation, courtesy of Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston).

Panobinostat’s Efficacy

A key concern raised by the FDA staff in its briefing report for Thursday’s ODAC meeting is the magnitude of pano­bino­stat’s survival benefit.

The staff note that, based on reports from trial investigators, pano­bino­stat has an estimated progression-free survival benefit of 3.9 months. Investigator reports indicate that patients treated with pano­bino­stat in the trial had a median progression-free survival of 12.0 months versus 8.1 months for the patients who were not treated with pano­bino­stat.

However, as the trial was being conducted, an audit determined that not all trial investigators were using the approved method for measuring patient M-spikes. Thus, an independent review committee (IRC) was appointed to review patient test results and develop new response and progression-free survival estimates.

The IRC’s estimate of pano­bino­stat’s progression-free survival benefit is 2.2 months – noticeably lower than the 3.9 months derived from investigator response estimates. The IRC calculated that patients treated with pano­bino­stat had a median progression-free survival of 9.9 months versus 7.7 months for the patients not treated with pano­bino­stat.

Additional sensitivity analyses, apparently carried out by the FDA staff, suggest that the progression-free survival benefit could be as low as 1.9 months.

The FDA also looked at the overall survival data from the PANORAMA-1 trial. Thus far, there is no statistically significant overall survival benefit to treatment with pano­bino­stat.

Panobinostat’s Safety

Previous summaries of the PANORAMA-1 trial results have noted that patients in the trial who were treated with pano­bino­stat were more likely to experience serious side effects, particularly low platelet counts, low white blood cell counts, and diarrhea.

The FDA staff report prepared for Thursday’s ODAC meeting also makes note of these results.

However, the FDA staff also noted that 64 percent of the pano­bino­stat-treated patients in the study experi­enced damage to their heart as evidenced by electrocardiogram (heart rhythm) changes. In comparison, heart rhythm changes were observed in only 42 percent of the patients who were not treated with pano­bino­stat.

The FDA staff also looked at how frequently patients in the PANORAMA-1 study died due to reasons not related to multiple myeloma while they were being treated. The staff found that this death rate was twice as high among pano­bino­stat-treated patients in the trial (7.0 percent) as in the patients not treated with pano­bino­stat (3.5 percent).

A list of all documents released today by the FDA in advance of Thursday’s ODAC meeting can be found at the FDA website ^[15].