June 13, 2013

$PVCT is Going for BTD. BTD is Tantamount to Approval.

In pursuit of accelerated approval

In April 2010, in response to Provectus' routine request for accelerated approval ("AA"), the Agency request proof of PV-10's systemic properties and benefit. Of note, Craig said "While we believe the Phase 3 with an SPA represents an industry standard path to approval, we believe the door may still be open for accelerated approval."

It would have seemed that, at the time, for a "mere" local-regional drug, showing PV-10 worked and worked well was insufficient to attain AA. Provectus learned it also had to show systemic benefit.

So, later in 2010, Provectus engaged Moffitt Cancer Center about conducting the necessary work to explain PV-10's mechanism of action ("MOA") and prove the compound's systemic benefit. MD Andersen Cancer Center also was considered as a potential partner for work.

By early 2011, Moffitt had begun conducting murine model work at its own expense, demonstrating [even back then] how excited the cancer center was to explore PV-10's MOA. Such work boded well for the eventual full-scale study work and publication of the data.

Into mid-2011, Moffitt was generating success from its work, such as demonstrating the so-called bystander effect in a very harsh lung metastases mouse model.

On January 17, 2012, Provectus issued a PR about the beginning of Moffitt's work, which was presented at the Society of Surgical Oncology Annual Meeting in March 2012.

Just recently, Moffitt presented more results of its work at AACR in April 2013: clear, unambiguous, unequivocal proof of PV-10's systemic properties and benefit. The FDA's request, it would seem, had been answered.

A parallel pursuit of a special protocol assessment

At the same April 2010 meeting with the FDA, the first end-of-Phase 2 ("EOP2") meeting, the journey towards a Phase 3 trial under a Special Protocol Assessment ("SPA") for metastatic melanoma began.

A second EOP2 meeting was held in March 2011.

A third meeting was held in November 2011.

On January 18, 2012, the FDA provided guidance to (told) Provectus no further end-of-Phase 2 meetings were required, and to submit the company's Phase 3 protocol for review, either via standard review or a request for Special Protocol Assessment ("SPA").

It seemed the first half of 2012 was spent finalizing the protocol for the trial, which was first noted in June 2012 (and discussed in more detail in October)

The second half of the year seemed to encompass, among other things, getting supportive programmatic elements into place, which was first noted in October 2012.

By March 2013, it appeared the Phase 3 trial was on track to commence enrollment by mid-2013.

In 2013 I have been left unsatisfied by management's explanation for the time taken in attaining the SPA. Their description of the process has been lacking, most recently in the annual CEO letter circulated in May 2013: "While preparation for submission of our SPA has taken longer than expected, it is crucial to remember that oncology presents a moving playing field."

By early June 2013, there seemed to be clear feedback the SPA had not yet been submitted.

The arrival of the breakthrough therapy designation

The Food and Drug Administration Safety and Innovation Act ("FDASIA") was signed into law in July 2012. Through FDASIA, the breakthrough therapy designation ("BTD") was offered.

Intended to expedite the development and review of drugs for serious or life-threatening conditions, the pharmaceutical industry now believes BTD is tantamount to approval.

Having been stalled in their circa 2010 and previous efforts to attain AA, opportunity in the form of BTD fell into management's lap.

By, I think, February 2013, management has begun to explore BTD as yet a third path to regulatory clarity, the first being AA and the second being the SPA.

As early as March 2013, management said they would submit a BTD application.

There was more than speculation earlier this year that the FDA asked Provectus to submit a BTD application. This "speculation" was confirmed in early June 2013.

Moffitt's upcoming peer-reviewed publication was thought to have been a fundamental component of the company's BTD application.

The criteria for breakthrough therapy designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. NCCN guidelines for patients with Stage III melanoma indicate the primary (main) treatment as systemic therapy, such as chemotherapy, which is dacarbazine (DTIC) or temozolomide (TMZ). Progression free survival ("PFS") for these drugs is about 2-3 months.

PFS for PV-10's Stage III patients in the company's Phase 2 trial, reported at ESMO in October 2012, was about 10 months, a substantial improvement over the available therapies of DTIC and TMZ. PFS is the primary endpoint of the contemplated MM Phase 3 trial for which the SPA is being sought.

A collaborative and supportive FDA

Provectus has described its relationship with the FDA as a collaborative and supportive one.

At the time, summer 2011, the new Division of Oncology Products 2 ("DOP2") took over review responsibility of PV-10 for melanoma after an extensive reorganization of the FDA. DOP2 personnel would review both the SPA and BTD submissions (and, I suppose, an AA request or submission).

It seems odd that DOP2 would evaluate three concurrent, parallel but different requests. It would seem there would or has to be some prioritization of these paths in the eyes of or by the FDA.

Moffitt, its already published work, work yet to be published and the results of ongoing work (e.g., the Phase 1 feasibility study, much more murine model work) seems to have dramatically changed for the positive the perception or view of PV-10 and Provectus in the eyes of the Agency.

There is preliminary clinical evidence that demonstrates PV-10 has substantial improvement on PFS over available therapy.

Is a collaborative and supportive FDA being proactive, guiding the company towards a BTD application submission (rather than an SPA one) that would translate into either a safety/truncated trial (less likely) or AA (more likely)? Better and best.

Better = a truncated trial. Best = AA. No need for good anymore.

I think the FDA is being proactive with Provectus and PV-10

PV-10 is a paradigm shift in the treatment of cancer. "In the eyes of Richard Pazdur, a breakthrough cancer drug should be "transformative." "It's really for transformative therapies that are a marked improvement, where there is no therapy, or a drug has a significant advance over what is out there," based on preliminary evidence, Dr. Pazdur said in an interview."

Management, it would seem, clearly is going for BTD.

BTD, according to the industry, is tantamount to approval.

For PV-10 and Provectus, the outcome is clear: approval.

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