August 25, 2013

I Wait. You Wait. He/She Waits. They Wait.

wait·ing [wey-ting]

For management...

When will Provectus principals complete the management of the regulatory approval process for PV-10's lead indication of metastatic melanoma ("MM")? After all, that's what they, the markets and shareholders have been and currently are waiting for.

I'm not particularly certain if or when breakthrough therapy designation ("BTD") application was submitted to the FDA. If it was, it recently was sent in. If it wasn't, it should be transmitted very soon.

It appears the quest for BTD comprised the following:
  • The application itself, and the criteria for the award of such therein,
  • The MM Phase 2 final clinical study report,
  • Moffitt Cancer Center's publication of the work summarized by its AACR 2013 poster presentation,
  • The MM Phase 3 SPA protocol, and
  • The programmatic elements of this trial.
Protocol & Program: I believe the Agency and Provectus already agreed to the Phase 3 protocol and program, which I believe the company first conveyed in its October 2, 2012 press release entitled Provectus Pharmaceuticals Presents Final Phase 2 Melanoma Data at ESMO 2012. I don't think there has been any "issue" with the SPA, but rather a change of perspective of where it fits into the regulatory approval process, if at all (that is, a change in focus from the SPA as the primary path to approval to, now, BTD and whatever comes with the new designation).

Moffitt Cancer Center: Its contribution to the effort (i.e., the BTD application) is complete:
As an aside, views of Moffitt's PLoS paper appear to have increased at least 20-25% in the days following its PR.

I believe the paper was transmitted to the FDA around the time it was published (July). Aside from the powerful statements in the PR, I believe it also conveyed a sufficiency of prior efforts to date to demonstrate proof and elucidate the benefits of PV-10's systemic properties. As a result, I do not think completion of Moffitt's Phase 1 feasibility study is necessary in order to submit the BTD application. Moffitt expects to publish a paper on this human study early next year.

Provectus: What remains, then, is the completion of the final clinical study report. The process to arrive there has been a very lengthy one:
I imagine the finalization of the study report has marked the end of the company's analysis of the MM Phase 2 trial dataset. ECCO 2013, while not necessarily linked to the completion of the report, provides the venue for the company to discuss heretofore unpublished clinical results, such as the durability of PV-10's immune response.

The time taken to finalize the study emanates from continued efforts by Eric to mine the data, which appears to have led to a representation of better efficacy results and more knowledge about what transpired and was seen.

Data mining has both pros and cons.

A positive can be, for example, a better or more correct assessment of the adjudication of whether an injected lesion was a CR, PR, PD or SD, which was the iteration on display at ESMO 2012 (vis a vis Melanoma 2010). A con can be sub-dividing the data into certain categories (whatever the miner wants them to be) and attempting in order to attempt make a clinical case or proposition based on such subsets, or one of them, that conflicts with the initial conclusion or proposition of the overall dataset.

If the company is true to form, based on how the data process, analysis, representation and presentation has progressed thus far, I would expect Provectus to issue a PR at ECCO 2013 highlighting results that only further establish PV-10's clinical value proposition, particularly with respect to the key target population of MM Stage IIIb and IIIc patients, which I think is the label being sought under BTD.

As for when or whether the final clinical report was submitted to the FDA, I suspect only the Shadow knows (and Eric, too). I'd imagine before the end of August, at least at this writing, is not unreasonable.

For the FDA...

When and what will the decision be?

I suppose the Agency has be asked first, which of course boils down to, first, the timing of Provectus' BTD request and, second, what the FDA decides comes with BTD, if the designation is so awarded.

Although I may well be wrong, there may not be a particular order to things, such as submitting the final clinical study report for the MM P2 trial to the Agency before submitting the BTD application. It does make sense, I suppose, that a decision cannot be made until all of the components are all "done:" the application, the final study report, Moffitt's publication, the SPA protocol, and the Phase 3 trial's programmatic elements.

Assuming the final clinical study report is in, I think the focus is on when the Agency will weigh in on BTD for PV-10 and MM. The so-called decision clock is a 60-day one. Human nature would suggest evaluators would take most if not all of the available time, although it's possible a decision might arrive faster than that.

But what comes with BTD?

Management consistently has communicated they have asked the FDA for the accelerated approval ("AA") of PV-10 since 2010. Is Provectus asking for the same thing now? As I have previously written, it's not unreasonable to think the collaboration between the Agency and Provectus's regulatory affairs team centers around what comes with BTD:
  • AA (which means skipping a Phase 3 trial altogether, but likely completing some sort of post-marketing study),
  • A truncated or modified Phase 3 trial (i.e., shorter, in some form or fashion, such as a smaller number of patients, or a single-arm study), or
  • A quicker response on the SPA-designed/agreed upon Phase 3 trial, or outright approval of PV-10.
These outcomes have been the essence of the blog's polls, which, when you take out the timing factor, overwhelmingly voice shareholder belief the likely outcome is AA after BTD is attained.

I think management thinks the initial outcome, overwhelmingly too, is BTD. I think they think AA is the most likely outcome thereafter; that is, what follows or comes with BTD. It's hard not to believe a further trial of some sort would be a disappointment, ultimately further delaying, although not by much in the grand scheme of things, the distribution of the drug, which certainly has proven its clinical value proposition, to physicians and their patients.

For Moffitt Cancer Center...

What's next?

More indications. More combinations. More superlatives about PV-10. I keep going back to Moffitt's PR from last week.

Clinical value proposition (as I think of and articulate it): Oncology compound PV-10 is very safe, very efficacious locally and systemically, and very specific in its action. The drug robustly stimulates the immune system both locally and systemically, drug creates systemic anti-tumor immunity, is both a targeted therapy and an immunotherapy, works on multiple cancers, and has the potential to be used as a pre-neoadjuvant, a neoadjuvant, a monotherapy, an adjuvant and a combination therapy.

Moffitt's PR unequivocally hammers home the point [bold emphasis for portions from the PR]:
  • Safe: "The researchers said the dye solution...may be safer than existing immunological agents."
  • Locally efficacious: "In the initial study, researchers injected a single dose of PV-10 into mice with melanoma. The result was a significant reduction in the skin cancer lesions..."
  • Systemically efficacious: "In the initial study, researchers injected a single dose of PV-10 into mice with melanoma. The result was...a sizable reduction in melanoma tumors that had spread to the lungs."
  • Local immune response: "Early clinical trials show PV-10 can boost immune response in melanoma tumors..."
  • Systemic immune response"Early clinical trials show PV-10 can boost immune response in...the blood stream."
  • Multiple indication viability: "The result was a significant reduction in the skin cancer lesions, as well as a sizable reduction in melanoma tumors that had spread to the lungs."
While management consistently has communicated the contemplated MM Phase 3 protocol would provide the opportunity for accessible patient lesions to be injected as often as necessary (the effectiveness of which has long been established in compassionate use program) -- since, for example, an initial injection may be administered incorrectly and thus are ineffective, or more volume of compound is necessary for the volume of tumor targeted -- it was very compelling to read Moffitt's conclusion only one treatment (one shot) was necessary.

One shot, one kill. That's revolutionary.

For China...

When will a deal be consummated?

It might seem China momentum has slowed or ground to a halt relative to the activity earlier this year. It also might seem that prospective Chinese partners, with whom Peter has met on several occasions, back in China, in Washington, DC at AACR 2013, and in New York (as well as, of course, over the telephone), since his first trip to the country in November 2012 (he made a subsequent trip in February 2013, and should travel to there again in September), are the primary reason for the apparent slow walk. Provectus has employed multiple agents or intermediaries in China to facilitate introductions to government and commercial leaders with the hopes of securing a license deal.

The absence of a deal by now (although, put into context, only 10 months or so have elapsed since Peter's first visit and direct engagement of interested parties) might suggest disinterest, delay or desire for more information on the part of prospective Chinese licensees. It's not unreasonable for the short-list of companies that have interest to license PV-10 to want to wait for regulatory clarity. After all, that's what Big Pharma also are waiting for.

Knowing Provectus management, however, it also suggests, at least to me, that company principals also are waiting. I believe if management wanted to do a deal, any deal, one could be had right now. Let's say $10MM upfront, several tens of millions of dollars in milestone payments (I think between $50 and $100 million) and a sizable double digit percent royalty payment. Whatever the details of a potential deal, I believe the Chinese would do a deal now if they could (i.e., if management would agree to sign).

But, I think management wants to wait for regulatory clarity to reveal itself before signing this or thinking of signing this deal. Why? Because, while I don't think regulatory clarity necessarily changes the terms of a Chinese deal (in fact, I think the company has moved beyond terms to what happens if/when a deal is signed, such as an in-country trial, choice of trial site, manufacturing considerations given China's proclivity to respect other folks' intellectual property, etc.), clarity may well change how other players, specifically global ones, behave and act.

It appears Hisun-Pfizer Pharmaceutical is the leading prospective Chinese partner, an introduction that was facilitated by Pfizer. Perhaps clarity might encourage Pfizer to go direct to China, rather than permit a pathway via Hisun-Pfizer. While striking a deal with Hisun-Pfizer should be a lucrative opportunity for Provectus, and thus shareholders, it is possible clarity allows for a more valuable geographic relationship through Pfizer itself.

Management can only know that, and more, after clarity is attained, when all of the players are given the opportunity to act and/or react based on more information.

For India...

When will a deal be consummated?

Peter's first trip to India was in June, following which he remarked how sophisticated and nuanced Indian pharmaceutical company executives and researchers were in their knowledge of Rose Bengal and PV-10. Indian companies have been aggressive in their business expansion efforts, whether through M&A or licensing. Recall, for example, Sun Pharmaceuticals's late but larger and unsuccessful bid for Bausch & Lomb, which eventually was acquired by Valeant Pharmaceuticals in May. As with China, I believe there are companies interested in and willing to do (i.e., sign) a deal now.

A potential risk, it would appear, and I am unsure how this would or will play out in discussions, is the issue of pharmaceutical companies struggling to obtain and enforce patent rights under India’s patent system. Provectus' pricing flexibility with PV-10 is immense, with gross margins in excess of 99%. India's goal, it seems, with their behavior towards Western pharmaceutical companies, aside from providing domestic players with opportunity and advantage, ostensibly is to bring down the cost of drugs for the local population, which simply cannot afford them (2012 per capita GDP in US dollars was $1,500 for India versus $50,000 for the U.S.).

I would assume in doing a deal in India and China and elsewhere would (will) require some level of pricing harmonization, or at least keeping this in mind, so all geographic parties, countries as well as regional and global licensees, are happy.

For Japan...

When will a deal be consummated?

Peter's first trip to Japan was in May. I think the Japanese continue to do their due diligence, although I think this includes both PV-10 and PH-10, whereas interest in China and India appears to be primarily focused on PV-10.

Peter may travel to Japan, too, when he travels to China (potentially with Eric) in September. I do not believe there are Japanese pharmaceutical companies that are desirous of signing deals now; however, Japan remains a key value driver should management elect to consummate a transaction there.

One of the challenges for Peter is that while Chinese companies wish a license geography that includes China, Taiwan, Hong Kong and Macau, Japanese companies routinely ask for both Japan and Chinese territories or areas.

For PH-10...

When will management reveal more information about progress to date?

Think about PV-10's "one shot one kill" (as well as its systemic benefits and immune response). Amazing.

PH-10's unique lack of toxicity also should be considered revolutionary, much as Moffitt framed PV-10. Think about the ability to continually apply the PH-10 gel so as to moderate, improve or over time cure an inflammatory skin disorder with fear or concern of toxicity and side effects.

I'm sure there is much to say and even more to learn about PH-10 and the second therapeutic area of anti-infection.

Compassionate use program...

When will more information about progress be to date be revealed?

The compassionate use program ("CUP") has been for quite a while and is becoming a great asset for Provectus and opportunity for patients seeking relief.

For metastatic melanoma, patients who went from the MM Phase 2 trial “expanded access” continued to receive as much PV-10 as they needed. The CUP or expanded access study on the website is separate.

The CUP program has treated multiple indications, where the indication-oriented protocols to treat afflicted patients has been allowed by the FDA; that is, different protocols for different patients.

I presume Provectus collects information on how physicians use and deliver PV-10 for different indications to both inform the company for eventual protocols for eventual trials and understand best or new practices for down the road. It is this broad spectrum of result from PV-10 treatment that continues to exceed even the loftiest of expectations.

It strikes me the CUP is, very loosely speaking, de facto approval of PV-10 by the FDA. I understand the limitations set on the program despite what I have to think are routine requests by hospitals and clinics to be CUP sites or physicians desiring to to compassionately use PV-10. I imagine, at this point in time (and until the drug is approved), despite the demand and need for the drug, that management is careful to work with only those folks the company is close to or via Provectus investigators and/or medical folks with whom they have direct experience with in prior studies. It makes me wonder how much of an influence the program has had on the FDA's decision-making.

"They" say great things comes to those who wait.
In this instance, I think, believe and hope so, too.

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