"Why did it take four years...to arrive at this point?"

Eric's discussion on the May 23rd conference call of the history of the company's regulatory interactions with the FDA since the end of Provectus' metastatic melanoma Phase 2 trial about four years ago to arrive at this point is informative and useful. I edited the transcript to remove "so," "um" and "uh," and made a few other minor verbiage changes to make the material more readable. Bold emphasis of dates below is mine.

Why did it take four years from the end of phase two study to arrive at this point? 

I think it is good to start back in May of 2010 when the last patient completed the phase two study. Shortly before that point, we held our first type A meeting with the Agency. That was in April of that year when we had interim data from the first 40 patients in the study.  And what was interesting to me as the study progressed, we had interim analyses scheduled at N equals 20 patients, N equals 40 patients, and then a final analysis when the total of 80 intent to treat patients, or ITT population was enrolled. And by the time we got to N equals 40 patients, the numbers were looking better than what we had seen in phase one, which we expected based on a more aggressive treatment of the patients, despite the fact that we had, uh, a larger number of stage four patients in the patient population. I'll comment that as we finally matured the data to N equals 80 patients, the response metrics remained roughly the same over time. And at this time in April of 2010, the melanoma landscape was beginning to change very rapidly with ipilimumab and vemurafenib approvals approaching on the horizon. This meeting established that what we proposed at the time for phase three study in patients with a patient population and end point similar to studies underway at that time under special protocol assessment for two other investigational intralesional therapies for melanoma would not be appropriate going forward. 

The Agency told us that they did not like our proposed patient population nor our end points, and also cast tremendous amount of doubt on the relevance of the drug in melanoma, a disease that they noted was systemically malignant and would be difficult to treat with a local therapy. 

We matured the data from the phase two study further and held a second meeting finally in March of 2011 after completing our initial analysis of data from the full 80 patient data set from the phase two study. We went into the meeting with proposed end points and patient population modified based on guidance from the first meeting. That study design was proposed to evaluate response in patients with, uh, Stage IIIB to IVM1A disease. These are patients with cutaneous or nodal disease, uh, and where all disease would be accessible by intralesional injection. In addition, we tightened the definition of dermal response that we had proposed, uh, in that first meeting in light of the Agency's advice. At this meeting, the Agency made it clear that a time to event end point would be required and expressed concern about our proposed modifications to RECIST that we felt were relevant to treatment of local recurrence. 

We met with our advisors further and finally scheduled and held a third type B meeting in October of 2011. At that meeting, we proposed modified end points in the patient population, once again based on prior guidance. This study was proposed to evaluate response in patients with cutaneous or subcutaneous recurrent or metastatic melanoma. Okay. That's a lot to digest, the cutaneous or subcutaneous recurrent metastatic melanoma that had no active nodal or visceral disease. These were patients, for example, with a history of nodal disease that had undergone nodal resection and would be candidates because their nodal disease had been surgically removed. They had no active nodal disease, similarly a case for patients that might have had limited lung mets, for example, that had been successfully treated somehow surgically, radiation, or some other therapy. Progression free survival versus DTIC was proposed for our RCT. We proposed a time to event end point in a randomized controlled trial. The Agency at that point expressed continued concern about enrolling patients with any history of visceral disease based on the concern I mentioned earlier, that there was inadequate support for use of PV-10 intralesionally in patients with systemic disease, so local therapy for patients with systemic disease. They also expressed concern about our proposed effect size, which we were willing to address. At the conclusion of the meeting, we agreed to develop a revised RCT design in patients with no history of visceral disease and no active nodal disease, and to submit this for SPA. 

Now in light of our discussions in the second and third meetings with a lead medical reviewer concerning adequacy of support for potential distant effects of PV-10 ablation, which we had noticed in our so-called bystander effect in cutaneous lesions, untreated cutaneous lesions in phase one and in phase two testing, and in a limited number of patients with visceral mets at enrollment in the phase two study. Some of them showed regression of their untreated visceral mets over the study interval in a fashion similar to some other drugs that were being developed for melanoma at the time. 

We realized we needed to get the story straight on this systemic effect before we could have significant traction with regulators in the U.S. and presumably abroad.

We began a dialogue with researchers from Moffitt Cancer Center early in 2011. Between the the second and third meeting that by the end of that year evolved into formal non-clinical studies on the cellular basis underlying the bystander effect. And eventually, it matured into the translational medicine study that's began in early 2013 that we are expected to hear results on June 2nd [2014] at ASCO. Data from these projects were reported starting in March 2012 at the Society for Surgical Oncology annual meeting in 2013 at the Society for Immunotherapy with Cancer annual meeting, and at the 2013 and 2014 annual meetings in the American Association for Cancer Research. As I mentioned, additional clinical data from this effort is expected to be presented by the Moffitt team next week at ASCO. 

We believed at this time we started, and we continue to believe now, that this aspect of the PV[-10] story may be crucial to obtaining regulatory approval. 

During this period, we also convened several advisory boards comprised of investigators and key opinion leaders to work on design of the promised RCT. We met privately with a number of these experts and other similar experts to discuss the challenges of designing a RCT that could be balanced in terms of level of intervention between the PV-10 arm and the comparator arm appropriate for patients principally with Stage IIIB and IIIC disease, and it would not suffer unacceptably low accrual or high dropout from the comparator arm. As the melanoma landscape continued to evolve, this proved to be a difficult challenge. Over the same period, we worked on modernization of our PV-10 supply chain, uh, as evidenced by a recently issued U.S. patent September of 2013 covering methods for manufacturing Rose bengal to modern quality standards. I think absent this work, it is unlikely that early investigation drug product was used up to that time could have been qualified for phase three use, and certainly not for support of an NDA. As we announced when the patent issued last fall, a drug product appropriate for such phase three use has now been manufactured. 

Finally, by October of 2013, we had become sufficiently frustrated by the difficulties posed by design of a study based on the third type [B] meeting and the discussions leading up to that third type [B] meeting, and also encouraged with the emerging immunologic mechanism data, such that we requested an additional meeting with the Agency in the fall of 2013. That request was granted. And the type C meeting was held in December of that year. At that meeting, we provided an overview of PV-10 data in melanoma from both phase one and phase two melanoma studies from our expanded access protocol, which now has enrolled over 100 patients, uh, from our hepatic tumor study, from an investigator-initiated study of PV-10, followed by radiation therapy for treatment of melanoma, and from the afore-mentioned Moffitt study. This data included an exploratory subgroup analysis presented earlier that year at the European Cancer Conference and included response metrics for patients having all or substantially all other baseline disease treated with PV-10. 

We also presented a straw man outline for Breakthrough Therapy Designation request and asked for advice on such requests. To our surprise, in the meeting the Agency focused on the [ECC] 2013 subgroup analyses and clinical response evidenced in these patients via clinical photography. We had a lengthy discussion regarding patients with locally advanced cutaneous melanoma, the need for therapies for these patients, and the types of end points appropriate for demonstration of clinical benefit. Based on our positive impression and discussions from the meeting in the meeting minutes released a month later, we prepared and submitted our Breakthrough Designation application in March [2014]. 

I warned you there was a long road, a difficult, complicated story. And what it shows is that as our understanding of PV-10 has matured over time and as the melanoma landscape has evolved over time, our interaction with the Agency has improved over time in that we now are in a position that the Agency has helped us to define indications that they believe our drug shows potential value and have helped us to define types of end points that are vastly different than perhaps progression-free survival in the proposed phase three randomized control trial from the third type [B] meeting, which would have used DTIC as a comparator. It's impossible to run that study [under] the current climate. We wouldn't enroll patients with the appropriate, uh, extent of disease burden. Yes, I can understand the feeling that maybe we're the clever student in class that doesn't listen to the advice of the teacher. But I would prefer to think that we've been working with the Agency to understand what proved to be a very difficult challenge. We're taking a new class of agent. And there's superficial similarities to other investigational drugs currently under phase three investigation or recently under phase three investigation. But those similarities are superficial at best. The effect of the drug immediately via its primary ablation is very different than other drugs that have been developed. The secondary immunologic response that appears to occur in a large fraction of patients, as evidenced by the data coming out of Moffitt, is very different than what has been shown in the past. And understanding what patients might benefit in a clinical trial setting has been complicated. I think we have very good guidance now from the agency in terms of types of patients to look at types of end points to use. And I hope that we'll be able to convince all people that are watching this story that we're definitely listening to the teacher. 

And so, in the meeting in December [2013], the Agency said, to paraphrase, hey, we like this ablative effect that you're showing in these patients with disease confined to the skin. But can you show us that that also improves symptoms that we've heard are important in melanoma, pain, bleeding, infection, for example. That would be a winning combination.

The FDA Response

The Agency's letter to Provectus has the look and feel of two different sets of views.

Key for me to the FDA's response regarding the Agency's denial of the company's breakthrough therapy designation ("BTD") application include:

"We have reviewed your request and while we have determined that treatment of “locally advanced cutaneous melanoma” meets the criteria for a serious or life-threatening disease or condition, the preliminary clinical evidence you submitted does not indicate that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints." {Bold emphasis is mine} 

There seems to be clear recognition by the FDA of the applicability of local/intralesional agent PV-10 for the treatment of locally advanced cutaneous melanoma, which the Agency deemed a serious or life-threatening disease or condition. That is substantive recognition.

"The preliminary clinical data provided in your request for Breakthrough Therapy designation are indicative of drug activity in the treatment of local, satellite or in-transit recurrence of malignant melanoma; however, the preliminary clinical data do not demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints." {Bold emphasis is mine} 

The FDA also seems to have recognized the drug works, notably in malignant melanoma. Again, that is substantive recognition.

Yet, in both letter sentences above, and here's where the divergence of opinion appears to manifest itself, the FDA qualified their positive recognitions of PV-10 by noting preliminary clinical data submitted by Provectus in seeking BTD did not demonstrate substantial improvement over existing therapies in one or more clinically significant endpoints, which they identify below as pain, infection and significant bleeding.

"This determination is based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding) and our inability to determine the clinical significance of the reduction in the size in one to 10 target lesions in patients with locally advanced melanoma, who may have additional untreated cutaneous, subcutaneous, or visceral sites of disease." {Bold and bold underlined emphasis is mine} 

The FDA's choice of the word paucity is interesting and, I believe, nuanced: the presence of something only in small or insufficient quantities or amounts.

The Agency recognized the applicability of PV-10 to treat locally advanced cutaneous melanoma (which it also deemed a serious or life-threatening disease or condition). It recognized the drug worked. The FDA, however, said Provectus did not provide enough data -- from the 54 patient sub-group where all disease was followed and the 28 patient sub-group where all disease was treated -- regarding symptom control (e.g., pain, infection or significant bleeding) to warrant BTD. BTD's generalized two-fold criteria are (i) a serious condition and (ii) preliminary clinical evidence of substantial improvement over available therapy on a clinically significant endpoint(s). Robust complete response (which Eric believed was tantamount to symptom control) and some pain data from the aforementioned subgroups was not enough to establish the correlation between complete response and symptom control.

While the amount of data did not meet the FDA's threshold for BTD, the Agency agreed Provectus submitted appropriate data (albeit in small or insufficient quantities or amounts).

The company's metastatic melanoma Phase 2 trial data did not have as much information on pain, infection and significant bleeding as the FDA desired. This only was established at Provectus' December 16, 2013 meeting with the Agency:

"The Agency agreed with Provectus that treatment of cutaneous and subcutaneous tumors in patients with locally advanced cutaneous melanoma (i.e., recurrent, in-transit or satellite melanoma that has not yet spread from the skin to distant sites) could provide clinical benefit to such patients, particularly if the measured objective responses in patients' disease correlated to a demonstrated treatment effect on one or more symptoms of their disease (e.g., pain, infection or significant bleeding)."

Nothing we know today is any less positive than what we knew on Thursday. PV-10 works, and the Agency acknowledged it in writing. What we do know, however, is that BTD, at the moment, is not the appropriate program for the drug due to insufficient (not enough) data on pain, infection or significant bleeding.

What we need to know is what's next for PV-10's clinical development program to provide this data to the FDA. It would appear the FDA recognizes the company and drug can provide it.

Provectus was denied breakthrough therapy designation by the FDA

Provectus's breakthrough therapy designation application was turned down by the FDA. The company issued a press release entitled Provectus Biopharmaceuticals Inc. Reaffirms Its Commitment to Bringing PV-10 to Market Notwithstanding FDA Decision on Breakthrough Therapy Designation. The associated SEC 8-K filing is here. The included FDA letter response or notice is here.

More analysis and commentary to follow.

Updated (5/24/14): The Memorial Day long weekend here in the U.S. provides an opportunity to spread my writing, analysis and commentary over several days (stock markets are closed on Monday). I want to digest Friday's news, collect more information, and prepare for Tuesday and presumably the rest of next week's likely substantial volatility in the share price (the stock did not open for trading yesterday). Topics should include Provectus' conference call* (and the FDA response letter), management credibility, pathways to approval, risks, the state of my investment thesis, my estimation of worth, and others.

* "A digital replay will be available by telephone approximately two hours after the completion of the call until July 23, 2014, and may be accessed by dialing 877-660-6853 from the U.S. or 201-612-7415 for international callers, and using the Conference ID#13583661."

...endpoints considered “reasonably likely to predict clinical benefit...”

"...The Advancing Breakthrough Therapies for Patients Act was introduced and included as a component of the 2012 re-authorization of the Prescription Drug User Fee Act (Food and Drug Administration Safety and Innovation Act; FDASIA) to expedite development of new, potential “breakthrough” therapies." (quote link) More specifically, breakthrough therapy designation ("BTD") was introduced in July 2012.

About a year later, in April/June 2013, Reevaluating the Accelerated Approval Process for Oncology Drugs was authored by Wyndham Wilson (National Cancer Institute), David Schenkein (Agios Pharmaceuticals), Cheryl Jernigan (Susan G. Komen for the Cure), Janet Woodcock (CDER, FDA) and Richard Schilsky (American Society of Clinical Oncology) in Clinical Cancer Research.

The article's abstract was:

For a new therapy to qualify for the accelerated approval pathway, it must treat a serious disease for which there is “unmet medical need”—defined as providing a therapy where none exists or providing a therapy that may be potentially superior to existing therapy. The increasing number of available therapies, coupled with the lack of accepted endpoints considered “reasonably likely to predict clinical benefit” and the lack of clarity early in development about circumstances in which a new product will qualify for accelerated approval, is pushing developers to pursue accelerated approval in heavily pretreated patients to fulfill an unmet need. To optimize the accelerated approval pathway, we propose here a reevaluation of what constitutes “unmet medical need” and “available therapy” in oncology. We also discuss ways for new endpoints to become qualified for use in supporting accelerated approval, and propose a structured process for pursuing accelerated approval.

The authors observed "[s]ince the implementation of accelerated approval twenty years ago, the endpoints considered suitable for this pathway have changed little."

Further, "[m]any have called for the FDA to accept new endpoints for accelerated approval, such as novel imaging endpoints or biomarkers that can be measured earlier than ORR or PFS, or can be used in settings where conventional ORR and PFS cannot be readily or reproducibly assessed."

The article provides an example:

An example of a recently qualified endpoint is pathologic complete response (pCR) in locally advanced breast cancer. In May, 2012, the FDA announced its acceptance of pCR as an endpoint to support accelerated approval in certain breast cancer settings (e.g., neoadjuvant) and published a draft Guidance, Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval, to describe this endpoint and the basis for its qualification. In this Guidance, the FDA provided a formal regulatory definition of the proposed endpoint, pathologic complete response; explained the rationale for using this endpoint in the setting of neoadjuvant breast cancer therapy; summarized the evidence that supports the utility of pCR, and described the types of trials that would be appropriate for use of pCR to support accelerated approval. Importantly, the guidance noted that the analyses supporting use of pCR are currently limited to analyses of treatment response and stressed that future prospective studies are needed to fully understand the relationship of pCR to ultimate clinical benefit. Given the lack of alternative endpoints considered suitable for regulatory use in early-stage breast cancer, pCR is acceptable despite this uncertainty in situations with significant unmet medical need (e.g., high-grade, triple negative breast cancer). 

Breakthrough therapy is a designation, a gateway to a potentially faster process to approval or "yes" (or a quicker "no"). It is not a specific pathway. The steps, and thus the pathway, to approval unfolds following the granting of BTD. Management has communicated it believes the FDA considers the 28-patient subset of Provectus' metastatic melanoma Phase 2 trial in which all disease [of this subset of patients] was treated sufficient to merit application and consideration for BTD.

The target indication, of course, is locally advanced cutaneous melanoma (i.e., earlier stages of the disease), and not metastatic melanoma (late to very late stages of the disease).

Consider the article's theme of more novel endpoints to support accelerated approval.

It would seem part and parcel of evaluating and granting of BTD to establish the appropriate and necessary endpoints for and under which Provecus' data and application should and very likely would be considered, as those endpoints also would be, presumably, utilized in whatever steps follow BTD to establish an initial pathway to approval of PV-10.

Tumor-based endpoints.

From Provectus' January 24th press release Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes.

The Agency agreed with Provectus that treatment of cutaneous and subcutaneous tumors in patients with locally advanced cutaneous melanoma (i.e., recurrent, in-transit or satellite melanoma that has not yet spread from the skin to distant sites) could provide clinical benefit to such patients, particularly if the measured objective responses in patients' disease correlated to a demonstrated treatment effect on one or more symptoms of their disease (e.g., pain, infection or significant bleeding). 

The Agency agreed to work with Provectus to quantify symptom control in this patient population. 

In reference to discussions on the potential for breakthrough therapy designation, "FDA advised Provectus to provide objective response rates with adequate information to evaluate the symptomatic treatment effects (e.g. pain, infection, bleeding) in patients presenting with locally advanced cutaneous melanoma who received PV-10 to all lesions."

What's the novel endpoint, and could/will it be used to [accelerated] approval? We should learn more shortly, but I can't help but think the FDA and Provectus have already established the endpoint.

The company PV-10 keeps

There is a saying "you are the company you keep," or perhaps "you're only as good as the company you keep." PV-10's company? MPDL3280A (Roche),  Yervoy and nivolumab (Bristol Myers), MK-3475 (Merck), T-Vec (Amgen), Abraxane (Celgene), etc.

Over the next three months, April to June, PV-10 data will be presented and/or discussed in at least 6 presentations at five medical conferences. Never in Provectus' history has data been presented at so many venues in such a short period of time.

Click on the figure to enlarge it.

First, on April 6th, Moffitt Cancer Center presents a poster at the 2014 annual meeting of the American Academy of Cancer Research ("AACR") entitled Induction of anti-melanoma immunity after intralesional ablative therapy. The focus likely should be on the second step of PV-10's two-step mechanism of action ("MOA"), and perhaps further explanation of the drug's viability for multiple indications like breast cancer, on which I think Moffitt and Provectus may further collaborate.

Second, on April 11th, "PV-10 will be an integral part of..." the HemOnc Today - Melanoma and Cutaneous Malignancies Conference's Session 4: Local and Regional Therapy. The session will include Amgen's T-Vec, Vical's failed Allovectin-7, other intralesional therapies, and a debate about the role of systemic intralesional therapy.

Third, on May 7th, St. Luke's University Health Network's and Provectus principal investigator Dr. Sanjiv Agarwala will participate in a plenary session at the 10th European Association of Dermato-Oncology ("EADO") congress entitled New Drugs and new trials. Other drugs on the agenda include:

• Amgen's T-Vec,
• Bristol-Myer's Yervoy (ipilimumab, an anti-CTLA4 agent),
• Roche's MPDL3280A (an anti-PD-L1 agent),
• BMS' nivolumab (an anti-PD-1 agent),
• BMS' combination of Yervoy and nivolumab,
• Merck's MK-3475 (an anti-PD-1 agent), and
• OncoSec's ImmunoPulse.

Click on the figure to enlarge it.

Amgen, Bristol-Myers, Roche, Merck and...Provectus.

Fourth, on June 2nd, Dr. Agarwala will present a poster at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO") during the day's Poster Highlight Session (in addition to the regular poster presentation day and time) entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions. The focus likely should be on the 28-patient data subset of Provectus' metastatic melanoma Phase 2 trial that formed the basis of the company's breakthrough therapy designation ("BTD") application.

You know, the BTD submission stated or commented on publicly by management [at least] 11 times thus far --five press releases, three Provectus News items (to be fair, BTD submission was picked up by third parties),  two 8-Ks, one 10-K, and a partridge in a pear tree -- and on the website.

I'm obviously poking fun at management. For a company with a history of being somewhat opaque or obtuse in communications regarding clinical data, regulatory interaction, and other matters, it's not unreasonable for the casual observer to think Provectus currently is promotional in regards to their BTD submission. The change in stride certainly is notable. Once or twice, in an SEC filing, I get. But, more than ten times? The same casual observer might think it strange; however, long-time investors who have done their due diligence on Eric's historical interactions with the FDA along the company's regulatory approval journey understand, and I think the company has said as much in its PRs: the Agency appears to have (has) agreed tumor-based endpoints (i.e., complete response: "...if you inject PV-10 into melanoma tumors, the tumors go away...") and not survival-based endpoints (e.g., overall survival, progression free survival, etc.) are appropriate for approving this drug. If you assume this Agency embracing of PV-10 and hurdle-clearing of endpoints, and I cannot fault folks if they don't, one could understand management's confidence in securing BTD, and then (and only then) these many BTD submission mentions.

BTD, in some respects, marks the beginning of a potentially speedy pathway to approval. The decision tree might be one of the FDA either (a) requiring the company to conduct a bridging study in order to file a new drug application ("NDA") for PV-10 -- "...before...we have approval to sell PV-10..." -- or (b) permitting the study to be a post-marketing requirement/commitment -- "...after we have approval to sell PV-10..."

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Managing our investment in Provectus of course requires me to manage risk. Even as a presumably well-informed investor, it's still very hard for me to assume a BTD award is in the bag. Probable, yes. Certain, no. The FDA may say no, and the company (like others turned down before them) very likely would have been told by the Agency to obtain more clinical data. But, as I wrote in my post Provectus Submits Application to FDA for Breakthrough Therapy Designation, the FDA doesn't want nor does it encourage companies to submit BTD applications that are more likely to be turned down than accepted. One would imagine the boldness with which management speaks of BTD suggests they very strongly believe they'll attain it (because of interactions with the Agency that suggest so) on, before or well before May 23rd.

Fifth, also on June 2nd, Moffitt will present a poster at ASCO, also during the day's Poster Highlight Session (again, in addition to the regular poster presentation day and time) entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions. This presentation should elaborate on both the clinical (MOA step #1, ablation/destruction of injected lesions) and immune (MOA step #2, immune response/destruction of non-injected lesions) efficacy observed in patients enrolled in the cancer center's feasibility study, where Moffitt essentially experimented on them.

Sixth, on June 27th, Moffitt's Dr. Vernon Sondak will participate in a symposium session at the 4th European Post-Chicago Melanoma/Skin Cancer Meeting entitled New drugs and trials: An update on immunotherapy and chemotherapy. Other drugs on the agenda include:

• Bristol-Myer's Yervoy (ipilimumab),
• BMS' nivolumab,
• Merck's MK-3475,
• GlaxoSmithKline's failed MAGE-A3 (a cancer vaccine),
• Amgen's T-Vec,
• OncoSec's ImmunoPulse, and
• Celgene's Abraxane (chemotherapy nab-paclitaxel).

Click on the figure to enlarge it.

Bristol-Myers, Merck, GlaxoSmithKline, Amgen, Celgene and...Provectus.

This month and over the next two, we can expect a lot of pre-clinical and clinical PV-10 data, and potentially a positive BTD decision. More data and MOA elucidation is good (and I am very much looking forward to reading them). Regulatory clarity and steps (i.e., BTD and what comes with it) is better, and very, very necessary for this company.

But how now China? And/or other regional transactions? And/or the endgame?

If management believes it will get BTD for PV-10 for locally advanced melanoma, thinks they might have to conduct a bridging study prior to filing the NDA (i.e., in this case de facto approval) "at worst," has about $16 million of cash on the balance sheet (see the company's March 24th PR), and possibly estimates the cost of a bridging study at $5-$10 million or thereabouts (comparable or less if the trial is terminated early, and some patient number overlap is acceptable to the various geographical regulatory agencies), why consummate a deal with a Chinese partner or any partner for that matter until after a BTD decision and clarity is achieved as to the step(s) toward and after approval?

I'm particularly interested in Dr. Agarwala's ASCO presentation, which will focus on the 28-patient subset that formed the basis for Provectus' BTD application and in all likelihood its awarding. This data was first broken out at the 2013 European Cancer Congress in September: Exploratory Data Analyses of Intralesional PV-10 Clinical Phase 2 Study Results Presented at ECC 2013 Demonstrate Effective Locoregional Disease Control and Support Systemic Immunologic Activity in Refractory Metastatic Melanoma:

Click the table to enlarge it. Poster source is here.

If one were to not consider the non-evaluable subjects (NEV above), loco-regional control of the disease -- the value proposition underscoring approval of PV-10 for locally advanced melanoma: the drug forestalls or defeats the spread of the disease to a metastatic stage, or alternatively "...if you inject PV-10 into melanoma tumors, the tumors go away..." -- increases to 88%.

Craig would tell you the residual percentage, 12% w/o NEV (or 18% as presented at ECC 2013 for the full subset), is more than likely due to physicians not injecting the lesions properly and thus not getting the expected result. The results PV-10 and PH-10 generate appear to be startlingly consistent from properly injected lesion (volume of drug per unit volume of tumor, proper administration) to properly injected lesion.

88% loco-regional control, and you want to do a deal now? Wouldn't it make sense to wait or seriously contemplate waiting until after a decision (unless a counter party aggressively bids for a deal, which doesn't appear to be the case at the moment)? There is of course risk in doing so; however, if you're supremely confident based on clinical data and regulatory interaction heretofore, you wait. Wait for the bigger regional check as milestone payments turn into upfront payments based on what transpires regulatory-wise. Wait to submit a BTD application or two for your liver program (e.g., in combination with maintenance sorafenib, cancers metastatic to the liver). Wait until impatient Big Pharma with drugs and compounds that are not sufficiently efficacious or safe, and very expensive, see their respective Kodak moment coming and decide to deal. By Kodak moment, I specifically mean technology disruption that could end in a near-zero sum game in the case of PV-10. If you own it you survive, and flourish. If you don't...

As folks line up to associate themselves with Provectus, and/or deal with the company, Pfizer might lose first mover advantage. Provectus has three executives from two Top 15 ranked (by pharmaceutical sales) companies on its strategic advisory board. It may add executives from up to three more Top 15 firms.

Click on the figure to enlarge it. The table source is here.

There is much for the company to accomplish before thoughts of the end-game can and should percolate. And although I've written often on this blog that I think Pfizer will be the end-game acquirer, and a topic for another post, it's not a given the company with the biggest checkbook (and the nose under the tent for the longest time) wins. Vision, strategic rationale, ambitiousness and, ultimately, verve, together with a not inconsequential balance sheet should win the M&A day.

In Support of the Initial Label

Today's press release about Provectus' poster presentation at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO"), Provectus Biopharmaceuticals' PV-10 Data to Be Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, provided several items of useful information,

More detailed subset data to come. As the company has said in the past, it is relying on a 28-patient subset of its metastatic melanoma Phase 2 trial to seek breakthrough therapy designation ("BTD") and an initial pathway to approval. More information about the presentation should be forthcoming on May 14th when abstracts are released by ASCO; however, the title is informative: "Efficacy of intralesional Rose Bengal in patients receiving injection of all existing melanoma in phase II study PV-10-MM-02."

Data from the 28-patient subset of Phase 2 enrollees where all disease was treated was first highlighted at the 2013 European Cancer Congress in September (Exploratory Data Analyses of Intralesional PV-10 Clinical Phase 2 Study Results Presented at ECC 2013 Demonstrate Effective Locoregional Disease Control and Support Systemic Immunologic Activity in Refractory Metastatic Melanoma): "Results showed that for all subjects, BORR was 51% (26% CR, 25% PR) with the amount of tumor burden accessible to PV-10 injection prognostic for outcome. In the majority of subjects (68%) the lesions treated with PV-10, together with the up to two untreated bystander lesions, constituted all disease present, and these subjects achieved a BORR of 63%. In subjects where all disease was treated (35% of subjects) BORR further increased to 71% (with 50% achieving CR)." {Bold emphasis is mine}

Click the table to enlarge it. Poster source is here.

Following Provectus' December 16th meeting with the FDA, the company further discussed this 28-patient subset in its January 24th PR Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes.

First: "The meeting and official meeting minutes provided valuable guidance on a number of issues surrounding the approval path of PV-10:...In reference to discussions on the potential for breakthrough therapy designation, 'FDA advised Provectus to provide objective response rates with adequate information to evaluate the symptomatic treatment effects (e.g. pain, infection, bleeding) in patients presenting with locally advanced cutaneous melanoma who received PV-10 to all lesions.'" {Bold emphasis is mine}

Second: "The Phase 2 study of PV-10 showed:...In the subgroup of melanoma patients that received PV-10 injection into all known disease (28 of the 80 ITT patients), 50% achieved a complete response (71% ORR, CI 51-87%)."

Third, on a per-tumor basis for an expanded subset (all or ostensibly all disease treated): "In the subgroup of melanoma patients with locally advanced cutaneous melanoma that received PV-10 injection into all known disease or only had 1 or 2 designated bystander tumors untreated (54 of the 80 ITT patients), a complete response was achieved in 232 of 363 injected tumors (64% of lesions) with the vast majority of these tumors requiring only 1 or 2 injections." {Bold and underlined emphasis is mine}

Finally, fourth: "Dees continued, 'Measurement of tumor shrinkage via objective response criteria has been considered direct clinical benefit in drug approvals for other skin cancers and we believe a similar case can be made for PV-10 in locally advanced cutaneous melanoma. As advised by the Agency, we will submit data from the 28 patients in our Phase 2 study who had all existing disease treated in a formal BTD request this quarter, and should receive a decision within 60 days of receipt of that request.'" {Bold emphasis is mine}

The company continued to consistently communicate the narrative of PV-10 injected into all disease as the basis for its initial approval pathway in its March 24th PR Provectus Biopharmaceuticals Inc. Submits Application to FDA to Receive Breakthrough Therapy Designation for PV-10 for Treatment of Melanoma.

First: "Craig Dees, PhD, CEO of Provectus said, 'The decision to apply for BTD stems from our Type C meeting held with the FDA's Division of Oncology Products 2 in December 2013. At the meeting FDA expressed willingness to work with Provectus toward initial approval for the novel investigational oncology drug PV-10 in locally advanced cutaneous melanoma. This included a statement in the minutes that data in a cohort of patients that received PV-10 to all existing lesions should be submitted in a formal BTD application.'" {Bold emphasis is mine}

Second: "Dees continued, 'I want to make clear to our shareholders, the media and the market as a whole that BTD is not guaranteed and if the designation is conferred on PV-10 for melanoma, it does not bypass the need for a new drug application (NDA) and review, as both are required for commercialization of any drug. As I have stated previously, the Agency may yet recommend and it may be in the best interest of Provectus to undertake a small, short bridging study in patients where all tumor burden can be injected. This could occur either before or after we have approval to sell PV-10. Provectus has over $16 million in cash reserves and would not require additional capital or the resources of a partner to conduct such a study. If such a study is conducted, it also fits with needs for an international study supportive of licensure in Australia, Europe, China and India.'" {Bold emphasis is mine}

And third: "Dees concluded, 'We are confident that the studies done thus far illustrate the effectiveness and safety of PV-10: if you inject PV-10 into melanoma tumors, the tumors go away. For recurrent, aggressive skin cancers this unique mechanism confers tangible benefit to patients.'" {Bold emphasis is mine}

I imagine Provectus' ASCO poster (as well as their 2-5 slides that would be included in their poster highlight session) will provide more detailed per tumor data, and make clear the rationale the FDA appears to have embraced regarding treating all disease for locally advanced melanoma.

Poster Highlights Session selection. As noted in today's PR, the company's abstract was selected for this session, which should take place from 8 am to 12:45 pm CST on Monday, June 2nd. Dr. Agarwala (the probable discussant) likely will present a few slides during the session.

Breakthrough Therapy Designation. Selection to the poster highlight session must only have happened because the data underlying Provectus' abstract, the 28-patient "cohort," is being used to support BTD. While ASCO acceptance and highlighting certainly doesn't influence whether the company will secure the designation from the FDA, I think it is another measure of growing industry acceptance of the drug, the local nature of its use, and the initial indication for which it should (will) be applied. The "friendly reminder" in the PR that the company recently submitted a BTD application for melanoma may reflect management's supremely confident belief regarding successfully attaining the designation, Craig's "I want to make clear to our shareholders, the media and the market as a whole that BTD is not guaranteed..." notwithstanding.

Provectus Submits Application to FDA for Breakthrough Therapy Designation

The company issued press release Provectus Biopharmaceuticals Inc. Submits Application to FDA to Receive Breakthrough Therapy Designation for PV-10 for Treatment of Melanoma today, following their related 8-K filing Friday (about couriering the application to the Agency for receipt today). An 8-K filing associated with this press release also was filed.

Compelled by good SEC housekeeping practices to do so (see New SEC filing (March 21, 2014) under the blog's News tab), wholly confident they will attain breakthrough therapy designation ("BTD") (and thought a PR was a good idea) or some other rationale, the PR obviously establishes an event point for the market. 60 days or thereabouts from today (Friday, May 23rd) the company could announce in some form or fashion it received BTD from the FDA, or did not (consistency would require a PR too).

Adam Feuerstein asked on Twitter: "Other than $PVCT, how many drug cos. have spoken publicly about seeking BTD?" He notes Ariad Pharmaceuticals, which mentioned their rejection in an earnings call (2Q13):

Ariad: "One final note on 113. We filed for breakthrough therapy designation for 113 in ALK-positive non-small cell lung cancer. Which is a relatively short follow-up of many of the ALK-positive patients treated with 113 to date, and the small numbers, our request for breakthrough therapy designation was not granted by the FDA. We continue to move expeditiously in the development of 113 with a pivotal trial in ALK-positive lung cancer patients to begin as planned this quarter, and we believe this decision by the agency will have no impact on our ability to pursue our ambitious development plans and timeline. 113 has shown impressive response rates in patients with ALK-positive non-small cell lung cancer, including in brain metastasis in these patients, and we are pursuing this opportunity with great focus."

Analyst: "And then on the breakthrough therapy destination, that's something that's new for all of us who are all trying to learn the process here. I guess, is this something that you could, in the future, refile for with more data? And then when you cited the reasons that they denied that, do they specify that to you specifically? Or do you -- is that just an assumption that you have as to why they rejected that?"

Ariad: "...So our understanding, yes, we can refile if we wish. And if we deem it appropriate, there's no restriction on that. And yes, that commentary is directly from them. They have -- it's a pretty open and communicative process and response, and those were the cited reasons." {Bold and underlined emphasis is mine}

In the subsequent thread, other folks replied: @JacobEPVantage with MolMed S.p.A., an Italian biotechnology company in a February 2014 press release (they had previously and initially mentioned it in late-2013 one): "As far as the Breakthrough Therapy submission is concerned, the U.S. Food and Drug Administration (FDA) has not - at this time - granted the designation for the cell therapy TK as adjunctive treatment in hematopoietic stem cell transplantation (HSCT) for adult patients affected by high risk acute leukaemia. However, the FDA indicates that the Company can submit a new request once new clinical evidence becomes available." {Underlined emphasis is mine}

@bradloncar noted Advaxis, which mentioned BTD submission and rejection in [at least] its FY 2013 10-K: "On October 7, 2013, we submitted a request for breakthrough therapy designation (BTD) to the IND for ADXS-HPV in the treatment of invasive cervical cancer. The FDA denied the request in December 2013, but stated that a new request may be submitted if we obtain new clinical evidence that supports BTD." {Underlined emphasis is mine}

In Provectus' PR today Craig says: "The decision to apply for BTD stems from our Type C meeting held with the FDA's Division of Oncology Products 2 in December 2013. At the meeting FDA expressed willingness to work with Provectus toward initial approval for the novel investigational oncology drug PV-10 in locally advanced cutaneous melanoma. This included a statement in the minutes that data in a cohort of patients that received PV-10 to all existing lesions should be submitted in a formal BTD application."  {Bold and underlined emphasis is mine}

Recall the company's January 24th PR: "Measurement of tumor shrinkage via objective response criteria has been considered direct clinical benefit in drug approvals for other skin cancers and we believe a similar case can be made for PV-10 in locally advanced cutaneous melanoma. As advised by the Agency, we will submit data from the 28 patients in our Phase 2 study who had all existing disease treated in a formal BTD request this quarter, and should receive a decision within 60 days of receipt of that request." {Bold and underlined emphasis is mine}

One could observe the FDA indicated the 28-patient cohort who had all existing disease treated was sufficient clinical evidence to support BTD. But, as Craig said in today's PR: "I want to make clear to our shareholders, the media and the market as a whole that BTD is not guaranteed..." Still, the decision to publicly mention BTD submission irrespective of one's confidence level can be criticized. I too wonder why Provectus 8-Ked and PRed BTD submission. I had wanted management not to publicly disclose this.

The press release also addressed several notable items.

A small, short bridging study. While almost identical to Craig's comments in the January 24th press release Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes, there appears to be a key sentence in today's PR:

January 24th: "The Agency may yet recommend and it may be in the best interest of Provectus to undertake a small, short bridging study in patients where all tumor burden can be injected. This would allow more frequent dosing than was permitted in the Phase 2 study, presumably akin to the dosing schedule currently used to treat nearly 100 patients under our expanded access protocol, and allow symptomatic endpoints to be prospectively correlated with objective response criteria. Provectus has $18 million in cash reserves and would not require additional capital or the resources of a partner to conduct such a study. If such a study is conducted, it also fits with needs for an international study supportive of licensure in Australia, Europe, China and India."

Today: "As I have stated previously, the Agency may yet recommend and it may be in the best interest of Provectus to undertake a small, short bridging study in patients where all tumor burden can be injected. This could occur either before or after we have approval to sell PV-10. Provectus has over $16 million in cash reserves and would not require additional capital or the resources of a partner to conduct such a study. If such a study is conducted, it also fits with needs for an international study supportive of licensure in Australia, Europe, China and India." {Underlined emphasis is mine}

Today's PR appears to me to be much clearer than the January 24th one. Craig notes BTD is just that, a designation, and not itself a pathway to approval. By adding the underlined sentence above, it would seem to me the pathway to approval (i.e., approval established only after an NDA submission and review, and by the final process step of receipt of an action letter from the FDA) could be regular or accelerated approval ("AA"), where the bridging study is a post-marketing commitment ("PMC") or a post-marketing requirement ("PMR"), or the study is a "pre-marketing" study for approval. Some may debate whether a bridging study, technically or otherwise, still is a Phase 3 clinical trial.

If regular approval (outright or "OA") or AA, the process steps would include filing a new drug application (which Provectus may or may not PR), waiting 60 days after the aforementioned filing to conduct a preliminary review that would assess whether the NDA is "sufficiently complete to permit a substantive review" (the receipt of such notice the company would PR), and then working with the Agency for a time to complete the review, followed by Agency action. Presumably under the scenarios of OA or AA, the study would follow as a PMC by Provectus or a PMR of the FDA, respectively.

For Pharmacyclics' ibrutinib that received BTD and later received accelerated approval, the NDA filing was made June 28, 2013, the filing was accepted by the FDA on August 27, and approval was attained on November 13 (roughly four-and-a-half months from filing). The process of course can be longer.

If the bridging study is first required, the timeframe would be elongated presumably by the length of the study and subsequent data compilation, analysis and submission. With new tumor-based endpoints (primary as complete response, secondary as disease symptoms like pain, infection and/or significant bleeding) the per-patient time from enrollment to completion could be 2-3 months. The result of the first injection could take 1-2 weeks to assess if the tumor went away. Subsequent injections, if needed to make the tumor go away, would be administered every two weeks. Photographs likely would be taken during a one- to two-month period following injection to record confirmation of complete tumor destruction and disappearance. Multiple U.S. and international sites (e.g., Australia, Europe, China, India) might assist with rapid overall patient enrollment. The NDA review process then may (would) follow.

PV-10 makes tumors go away (a.k.a. a complete response). "We are confident that the studies done thus far illustrate the effectiveness and safety of PV-10: if you inject PV-10 into melanoma tumors, the tumors go away." {Bold and underlined emphasis is mine} Put enough water on the fire and it goes out.

Provectus' liver program. A cursory mention that deserves some follow-up. I'll address this item later.

M.D. Anderson added to the compassionate use program. The CUP on ClinicalTrial.gov only identifies 3 U.S. sites (Sharp Memorial, the University of Louisville, and St. Luke's Hospital). M.D. Anderson has been a CUP site on and off for quite a while. PV-10 supporter and key opinion leader Merrick Ross (a surgical oncologist) works here. See Journal Publication (February 11, 2014) under the blog's News tab. I believe there may be other unnamed sites.

"...one of...biotech's top prospects."

Note: I've edited and completely taken out of context a sentence from FierceBiotech's John Carroll's March 15 article Amgen's viral cancer vaccine T-Vec tackles melanoma tumors in PhIII. The full uncorrupted sentence is "While cancer vaccines have had a poor track record in the clinic in recent years, Amgen has tapped T-Vec as one of the big biotech's top prospects."

If:

• Dr. Roger M. Perlmutter, M.D., Ph.D., formerly of Amgen, now Merck's Executive Vice President and President of Merck Research Laboratories, convinces Amgen to buy BioVex in 2011 for $1 billion to gain access to T-Vec or talimogene laherparepvec, formerly OncoVEX, and
• T-Vec is one of B's top prospects in 2014, according to FierceBiotech, considering Amgen's acquisition of Onyx Pharmaceuticals in 2013 for $10 billion to gain access to Nexavar or sorafenib and Krypolis, and
• Perlmutter convinces Merck to combine anti-PD-1 agent MK-3475 or lambrolizumab with T-Vec for previously untreated advanced (metastatic) melanoma as well as drugs from Pfizer and Incyte, and
• Dr. Robert H.I. Andtbacka, M.D.,  who is a lead principal investigator on T-Vec's Phase 3 trial, routinely presents a table showing PV-10 very likely is significantly better than T-Vec for injected, non-injected and non-injected systemic lesions/tumors, and

Comparison of respective per-subject Phase 2 single-arm trials

• Amgen does analysis Responses of Injected and Uninjected Lesions to Intralesional Talimogene Laherparepvec (T-VEC) in the OPTiM Study and the Contribution of Surgery to Response similar to and six months after Provectus' analysis Locoregional Disease Control in Metastatic Melanoma: Exploratory Analyses From Phase 2 Testing of Intralesional Rose Bengal, and
• Amgen's Dr. Sean E. Harper, M.D., Executive Vice president, Research and Development, Perlmutter's replacement, says their analysis"...add[s] to the body of evidence supporting talimogene laherparepvec's local and distant effect, and its potential ability to stimulate a systemic anti-tumor immune response," and
• There's a good amount of data also to support PV-10's local and distant effect, and,
• Moffitt Cancer Center already noted PV-10 induces systemic immunity,

Then:

• PV-10 should be a top biotech prospect too, and
• PV-10 (value) > T-Vec (value).

Interestingly, 5-6 years after presumably final metastatic melanoma ("MM") Phase 2 trial results for T-Vec, Amgen/BioVex publishes a tumor analysis of this study. BioVex management designed their Phase 3 trial with survival-based endpoints, meeting them for the trial's interim analysis (Vical's Allovectin-7 failed to meet its overall survival endpoints). Provectus pursued survival-based endpoints and a special protocol assessment for a pivotal MM Phase 3 trial until they convinced the FDA tumor-based were more appropriate for locally advanced melanoma. It would strike me Provectus was ahead of the curve in focusing the Agency on the applicability of tumor-based endpoints for intralesional agents like PV-10 and their applicability to locally advanced melanoma. It would strike me Amgen (Dr. Andtbacka) is catching on through the completion of this variation of the Big Biotech's study analysis.

In Amgen's "tumor study," "Of the 295 patients treated with talimogene laherparepvec, almost 4,000 tumor lesions were tracked for this analysis. Half of these lesions were injected with talimogene laherparepvec at least once, while the rest were not injected, including visceral tumor lesions (tumors involving solid organs such as the lungs and liver). The results showed a 50 percent or greater reduction in tumor size in 64 percent of injected tumors. In addition, one-third of uninjected non-visceral tumors, and 15 percent of visceral tumors were also reduced by at least 50 percent. There were 35 melanoma-related surgeries performed during this trial of which 30 percent successfully removed all residual disease."

I cannot do a general comparison of the two because there is not sufficient publicly available PV-10 data, but I tried to construct what I could from the readily available information.

Click to enlarge the table

A couple of things jump out:

• While Amgen's poster may elucidate this, there is no mention (or breakdown) in the press release or SSO 2014 abstract about complete response.
• T-Vec's results are from a Phase 3 trial whose treatment protocol presumably is what would be used in the clinic, while PV-10's results are from a Phase 2 trial using a limited treatment protocol.

Notably, however, there is durability of response data for T-Vec: "This new analysis is built on a study that recently demonstrated a durable tumor response of at least 6 months in Phase III. And interim results from another study concluded that T-Vec patients had a median overall survival rate of 23.3 months compared to the 19-month average posted by patients treated only with GM-CSF" (Source: previously linked FierceBiotech article on Amgen and T-Vec). The other T-Vec study referred to above is BioVex's MM Phase 2 trial. Provectus management has not yet released durability data from its MM Phase 2 trial for PV-10, although previously released progression free survival data does provide somewhat of a facsimile.

Additionally, the Reuters article on the T-Vec work was revealing, given the Amgen's executive careful verbiage: "...its potential ability to  stimulate a systemic anti-tumor immune response." {Emphasis is mine}

Almost There

When the minutes arrive, what will they say/what will happen? As I wrote yesterday, in meetings such as the one Provectus publicized it had with the FDA on December 16th, the Agency and sponsor reach a consensus during the meeting. The sponsor subsequently waits until the FDA had codified the consensus reached (i.e., has memorialized and sent final meeting minutes) before the sponsor communicates the outcome to the public. There may be (and usually are) collaborative interactions between the Agency and sponsor prior to finalization of the minutes. I think Provectus is in the same situation. I also wrote I further believe the pathway may either be a one- or two-step process, both providing discernible timelines from the drug's approval and commercialization.

Management noted in Wednesday's 8-K filing they "...took the opportunity to provide input into the documentation of meeting minute notes." I believe this input refers to data and statistical analysis related to the topic of tumor destruction (and more broadly locoregional disease control) upon injection of PV-10 into patient lesions. Recall Provectus' European Cancer Congress ("ECC") 2013 poster presentation (poster here, press release here). While the trial was a typical or traditional patient study, Provectus also collected (categorized) data on a per lesion basis. One might almost think of the trial as a "lesion study," where although N was the number of patients or subjects, n was the number of lesions. I believe about or more than a 1,000 lesions were treated and/or observed, of which 491 were treated as target lesions. Among these 491 lesions, 53% achieved complete response ("CR"), 5% partial response ("PR") and 12% stable disease ("SD"). 70% locoregional disease control (CR+PR+SD).

Pieces of Craig's two quotes in the ECC 2013 press release are quite relevant (see my bold underlined emphasis below):

• "The researchers concluded that PV-10 has a unique immuno-chemoablative profile that offers significant potential due to several important attributes. First, its safety and efficacy compare favorably with existing and emerging therapies. Second, its safety profile makes it an attractive candidate as a combination strategy for treatment of advanced disease. And finally, it provides a powerful combination of rapid reduction of tumor burden with induction of tumor-specific immune response that can achieve rapid disease control in refractory patients with locally advanced melanoma."
• "Melanoma patients and their caregivers experience profound discouragement upon recurrence of the serious skin manifestations of this disease. The investigators on this study describe the effect of PV-10 as "rapid, durable response" but as the photographs have documented, many of the PV-10 treated tumors almost appear to have never been present. PV-10 was only injected intermittently, when tumors were present during the first 16 weeks of the study, in stark contrast to typical clinical studies where treatment is given until either resistance is engendered or patients experience unacceptable toxicity. We are gratified that response to PV-10 was demonstrated consistently across all study centers, with minimal intervention in patients refractory to multiple prior treatments. PV-10’s unique mechanism of action, alone or in combination with existing or emerging therapy, has the potential to shift the paradigm in oncology, where an intermittent intervention can dramatically reduce disease burden and may prod the immune system into preventing or arresting the formation of life threatening metastases."

Locoregional disease control via PV-10: The company appears to have successfully demonstrated to the FDA that the drug can provide rapid disease control and induce the immune system to delay, reverse or prevent progression of regional disease to distant metastatic disease. That is the key: Delay, reverse or prevent progression of regional disease to distant metastatic disease.

Eric, whose responsibilities at Provectus include biostatistics, may have worked with the FDA to provide or isolate data from the company's metastatic melanoma Phase 2 trial to support statistical significance or relevance of locoregional disease control at a lesion level (not merely at a patient level). p-values, for example, previously have been provided by the company for N (i.e., subjects) in past presentations. p-values, which I use for illustrative purposes (I don't know what specific statistical parameter(s) the Agency would require), for lesions have not. If the FDA recognized new endpoints (tumor- or symptom-based) were appropriate and necessary for PV-10, Eric, following the December 16th meeting, could have recasted already collected and locked data as such for the Agency to consider. If this work indeed was the "input" Provectus took the opportunity to provide, and if accepted by the FDA, then it's not unreasonable for an approval pathway potentially to follow.

Now consider the changes to the website presentation, which was updated today. It seems to me management is saying exactly that: an approval pathway, currently being collaboratively developed with the Agency, should follow.

Click to enlarge the figure.

BTD and/or AA. The approval pathway could be a one- or two-step process, both providing discernible timelines from the drug's approval and commercialization. One-step suggests either regular approval (what I term outright approval on the blog) or accelerated approval ("AA") with the post-marketing requirement ("PMR") of a confirmatory study employing what may be a new symptom-based endpoint appropriate to the local agent. Two-step could be, first, receiving breakthrough therapy designation, and second, after a little time has elapsed to permit further collaboration, receiving regular approval, or obtaining AA with the PMR above, or having to conduct a small bridging study (i.e., a study permitting international citizenry to be among the patient population, now utilizing the new endpoint) prior to then receiving regular approval. If management can achieve agreement with the FDA for regular approval or AA, the next step probably would be for Provectus to submit an NDA filing. The next Provectus PR should herald the approval pathway of the drug.

The FDA (What Does the FDA Say)

Ring-ding-ding-ding-dingeringeding!

Provectus Type C Meeting With FDA Oncology Division Held December 16, 2013

Chief Executive Officer Craig Dees, Ph.D., said, “This meeting with the FDA is a significant step forward in establishing a pathway to initial U.S. approval of PV-10 for the treatment of melanoma. There are different possible routes to approval of PV-10 such as a breakthrough therapy designation or accelerated approval, and each of these has different requirements and time lines. I appreciate that our shareholders are eager to receive as much information as possible, and while there is nothing more the Company can add until it has received the official meeting minutes, we wanted to provide this interim update. In addition, our discussions with several potential international licensing partners are not affected in any way.”

Bold and underlined emphasis is mine.

A material event to management, and thus to shareholders: Associated SEC filing here.

[Updated 12/18/13]: What wasn't said is as or more important as what was. Provectus' PR today included mentions of "breakthrough therapy designation" ("BTD") and "accelerated approval" ("AA"). There was, however, no mention of "a Phase 3 trial" or "a special protocol assessment" ("SPA"). While the company, it seemed to me, told the market PV-10 was "up for" either BTD (a categorization or "gold star" providing more and faster interaction with Agency personnel, and not a pathway onto itself) or AA, it also seemed to me management told the market there was no need for or consideration of a Phase 3 trial.

Waiting for Godot

In the play Waiting for Godot by Samuel Beckett, "...Vladimir and Estragon...wait endlessly and in vain for the arrival of someone named Godot." In his 1956 review of a version of the play Brooks Atkinson writes Waiting for Godot conveys "...the impression of some melancholy truths about the hopeless destiny of the human race." Considered an absurdist play, "...absurdist is a genre of literature...that focuses on the experiences of characters in a situation where they cannot find any inherent purpose in life, most often represented by ultimately meaningless actions and events."

The wait for Provectus from the outside perspective I have at times has seemed absurd. I don't doubt there is not an insignificant amount of reality in this absurdity, and absurdity in this reality. Waiting for what from whom? Regulatory clarity, of one sort or another, from the FDA. Yes, but there was more. This wait appears to be nearing a resolution.

The premise of why I'm long Provectus is a novel drug compound with a pristine safety profile, a treatment well tolerated by and easily administered to patients, a ready made product inexpensively produced at scale, and a vast addressable market of unmet need that should be fully and very profitably met over time.

Provectus’ discussions with the FDA may well be to, first, request some sort of accelerated path to approval (i.e., accelerated approval or outright approval) for Stage IIIb and IIIc patients with refractory, locally advanced disease, believing they have sufficiently demonstrated to the Agency PV-10’s clinical value proposition for this patient population.

According to the company's PR at ECC 2013, "[t]he international, multicenter, Phase 2 study examined the effect of up to 4 treatment cycles of intralesional (IL) PV-10 in 80 subjects with AJCC Stage IIIB-IV melanoma. All subjects had locally advanced disease refractory to a median of 6 previous interventions. Intralesional PV-10 tumor ablation provided, after a median of 2 treatment cycles, rapid locoregional disease control." Bold emphasis is mine.

Prior treatments trial patients received before receiving PV-10 in the study included:

Trial results, particularly for patients with all disease treated ("In subjects where all disease was treated (35% of subjects) BORR further increased to 71% (with 50% achieving CR).") included:

Click to enlarge the table.

Intermittently used in the metastatic melanoma ("MM") Phase 2 trial ("PV-10 was only injected intermittently, when tumors were present during the first 16 weeks of the study..."), PV-10 enabled loco-regional disease control (complete response + partial response + stable disease) more than 8 times out of 10 enabled for patients for whom all lesions were treated (i.e., all injectable disease). It would seem reasonable to conjecture:

• If the rumor of 75-80% of compassionate use program ("CUP") patients are cancer free (noting from the ECC 2013 press release that "[i]n addition to the 80 participants in the study, the researchers noted that over 90 additional melanoma patients have been treated with PV-10 under expanded access." -- the reason for noting this is...?) is true and,
• Understanding the CUP protocol for metastatic melanoma is to treat all untreated disease (i.e., all injectable disease) until it, the disease, goes away,...

...that patients could achieve near complete or complete loco-regional control if/when all of their lesions (i.e., all injectable disease) are treated.

I surmise (although I don't have full evidence to confirm it but I think I have sufficient evidence to suggest it, and I think management has sufficient evidence to assert it) that PV-10 can stop loco-regional MM in its tracks.

As Provectus wrote in its ECC 2013 press release: "...[I]ntralesional PV-10 provides a viable strategy to maintain long-term locoregional control of melanoma in patients whose cutaneous and subcutaneous melanoma has recurred." For this patient population -- "...patients who are refractory to all other therapies and who have injectable disease," -- PV-10 enables them to maintain loco-regional control of MM with minimal intervention and delay, reverse or prevent progression to life-threatening visceral disease.

Eric and his regulatory team, and thus Provectus, may be trying to accomplish a "regulatory two-step." Step #1: Ask the FDA for accelerated approval ("AA") or outright approval of PV-10 for MM Stage 3b-c patients who are refractory to all other therapies and who have injectable disease. I think this ask of the FDA by the company, finally, has been made.

Step #2: I don't understand precisely how Provectus is seeking breakthrough therapy designation ("BTD") in the context of a request for AA or outright approval. Is management seeking BTD for both the population set identified above and late stage patients? Or, is it seeking it only for Stage IV patients, where “sped up” discussions with dedicated senior Agency staff via this accelerated pathway could help design trials to show the immediate benefits of PV-10 in combination with approved MM drugs like ipilimumab (Yervoy) and vemurafenib (Zelboraf) for late stage or heavily diseased patients? Or, it is seeking BTD for both Stage IIIb-c patients and Stage IV patients, but asking for AA or outright approval for the Stage IIIb-c folks under the BTD umbrella, and discussing more trial work with the FDA to demonstrate the benefit of combining PV-10 with certain other drugs like ipi for late stage patients?

Ultimately, the mechanics of the ask(s) don't matter now, but rather the ask(s) itself (themselves) and outcome(s).

If Step #1 of the regulatory two-step is asking for AA or outright approval for patients who are refractory to all other therapies and who have injectable disease, Step #2 could be asking for BTD for Stage IV patients, with the path to approval of PV-10 for this additional population subsequently to be determined through further discussion with Agency staff and/or additional trial work.

Both in the ECC 2013 poster and press release, the company highlighted several things related to late stage patients:

• "Regression or stasis of untreated Visceral Disease observed in subjects with OR of Target Lesions; 44% 1-year survival in Stage IV(M1c) subjects,"
• "Second, its safety profile makes it an attractive candidate as a combination strategy for treatment of advanced disease," and
• "PV-10’s unique mechanism of action, alone or in combination with existing or emerging therapy, has the potential to shift the paradigm in oncology, where an intermittent intervention can dramatically reduce disease burden and may prod the immune system into preventing or arresting the formation of life threatening metastases."

I think the ask of BTD of the FDA by the company, finally, also has been made.

Although the first ask may appear to be a focused or "narrow" label -- patients who are refractory to all other therapies and who have injectable disease -- more broadly speaking it is far from narrow. The addressable market for loco-regional disease is very large because it represents nearly all incidences of melanoma. Localized melanoma, which is confirmed to the site of the disease, represents 84% of incidence (by stage distribution). Regional melanoma, where the disease has spread to regional lymph nodes, represents 9%. These statistics are from National Cancer Institute Stage Distribution and 5-year Relative Survival by Stage at Diagnosis for 2003-2009, All Races, Both Sexes data. Distant melanoma is 4%.

Of course, the first tool out of the oncologist's tool kit for early- and initially/originally-identified melanoma (local and, perhaps where resectable, regional) typically is excision or surgical resection, particularly when it is recurrent melanoma. Aggressive loco-regional therapy would be in order to reduce the risk of relapse, and the negative impact on prognosis and overall survival after loco-regional recurrence. For physicians, PV-10, as user friendly as it is, from safety and drug administration perspectives, and because of its ability to stop loco-regional disease in its tracks (if not cure it), might turn out to be the first tool out of their tool kit.

Best: Can management succeed in securing the first step of the regulatory two-step from the FDA? The outcome of "yes" is game-changing for the drug, the company and the stock. An outcome of BTD as a second step simply adds to the magnitude of the game-change. Better: An outcome of BTD, with a further discussion of the hows and whats, still is good. Good: An outcome of an SPA, which I have no doubt already has been agreed to with the FDA, is indeed is good but, given my diatribe above, would be disappointing yet essentially sufficient because it still is regulatory clarity.

A cursory Google search yields Michael Sinclair's attempt to explain the play: "The purpose of human life is an unanswerable question. It seems impossible to find an answer because we don't know where to begin looking or whom to ask. Existence, to us, seems to be something imposed upon us by an unknown force. There is no apparent meaning to it, and yet we suffer as a result of it. The world seems utterly chaotic. We therefore try to impose meaning on it through pattern and fabricated purposes to distract ourselves from the fact that our situation is hopelessly unfathomable. "Waiting for Godot" is a play that captures this feeling and view of the world, and characterizes it with archetypes that symbolize humanity and its behaviour when faced with this knowledge. According to the play, a human being's life is totally dependant on chance, and, by extension, time is meaningless; therefore, a human's life is also meaningless, and the realization of this drives humans to rely on nebulous, outside forces, which may be real or not, for order and direction."

Shareholders seem to have been waiting for the FDA to show up. Waiting for Godot conveys our lives are meaningless, and the realization of this drives us to rely on nebulous, outside forces, which may be real or not, for order and direction. At times, it's felt like Provectus' pursuit of regulatory clarity, opaque as it has seemed, incomprehensible as it has been communicated, has lacked meaning. For what and/or whom are we waiting? It might be that we've been waiting for management as a whole and Eric in particular, more than we've waited for the FDA. Godot, in the form of Eric, seems to have arrived, so to speak.

PV-10 exemplifies innovation over incrementalism, meaningful over marginal, productized technology over hypothetical, and changing the world over accepting the status quo, with not an insignificant amount of serendipity over contrivance. In sum, these form the quintessential essence of a paradigm shift in the treatment of cancer.

Some consider Google a paradigm shift in how individuals explore and utilize the Internet through its search engine, as Microsoft was a paradigm shift in the use of personal computers through its operating system. There were competing operating systems around the time of MS-DOS and Windows, as there were competing search engines. It would seem a paradigm shift is more so, now or at least recently in human history, because beyond the victorious technology/technological change there usually is a readily identifiable individual or corporate victor (or victors) who is (are) measurably monetarily successful.

Irrespective of how technology cycles, cycles of change and/or cycles in general have materially shortened literally in front of our eyes (say, over the last couple of decades when I have been old enough to pay attention), some of us think we're capable of seeing and identifying a shift in paradigm. I think, in reality, because human activity, ours that is, on a day-to-day basis seems to have sped up, it provides the rationale to support this contention that we are able to see change in so-called real-time. Maybe it's the case we are able to see paradigms shift because we can see more quickly this change or shift after an inflection point is reached instead of as it happens.

More to point, however, I also think we ascribe the certainty and greatness of the shift to a successful individual or company because they are monetarily or otherwise successful in that moment in time.

Provectus: Four transplants from Knoxville, ostensibly with no prior meaningful experience or track record of bringing a drug to market, or building a private or public company, trying to demonstrate their technology does shift the paradigm in the treatment of solid tumor cancer, eschewing to pursue and communicate development in a less than standard way.

It is this "less than standard way," whether conscious and premeditated, the inevitable result of shortcomings and experience, or some combination of both, that, together with the innovation and inexplicability until now of the mechanism of PV-10, has limited the embracing of the drug, and thus its creators, as a paradigm shift in the treatment of cancer.

I recently wrote to a biopharmaceutical industry individual, now a consultant (but with broad and extensive, operationally-focused, industry experience, particularly in drug development itself and, notably, with an approved oncology drug of significant fame) about his or her views on peer review publication (in light of Eric's completion of Provectus' final metastatic melanoma Phase 2 trial study report): "So anything reputable in oncology such as NEJM, JCO, Blood, Nature, Science, BMJ, The Lancet, Lancet Oncology, any AACR publication etc would indicate a high quality article with peer review. What one is ideally looking for is a body of work by top thought leaders in high impact journals demonstrating a solid track record of data...If doing due diligence on a drug or company I would be nervous if the company only ever published with, say, third tier thought leaders in second rate oncology journals. At some point, if the drug is good enough they have to step up to the plate and allow more in-depth scrutiny by peer review. Does it matter as an investor? It really depends on your level of risk. Personally, I like to see a solid track record across a number of key areas, including high impact journals." Bold emphasis is mine.

Coming from a predominantly (but not exclusively) non-"all things biological" background, I earnestly thought data publicly available, other found through diligence, and connected in a thoughtful (but obviously non-industry based way) would have been sufficient for others to draw what I had determined were obvious conclusions.

Thankfully, management finally will meet the peer review criticism this year with the publication of the final study report of the MM Phase 2 trial in a top tier journal (i.e., at the top of the above list). Ironically, if the expected regulatory clarity arrives before the article's publication, any bump in share price directly related to people buying into PV-10 and its clinical value proposition as a result of publication in a high impact journal may be an incremental one.

At the outset of this journey of mine, I hadn't fully appreciated the challenges faced by management to not only overcome the very high level of skepticism of a local agent having a systemic benefit, but to overcome the very high level of skepticism of itself.

I did not require the data to be published in a top tier journal. As the individual above appropriately concludes, "Does it matter as an investor? It really depends on your level of risk." I'm comfortable with the level of risk at the time and now of Provectus. Others, however, are not, as evidenced from the wallowing of the share price. Lack of publication of in a top tier publication is not the sole reason for where the share price is. There are other mitigating circumstances or explanations, like presence on a minor stock exchange, capital structure, manner of fund raising that ultimately lead to problems with capital structure, etc. The peer review publication issue, unfortunately, is endemic of management's "less than standard way." Don't doubt that less than standard has temporary and, potentially, permanent valuation implications.

Fighting the good fight of proving PV-10's systemic properties is one thing. It might constrain valuation in the interim. Fighting it with one hand tied behind your back, by being circumspect, by choosing to fundraise in certain manners (because of whatever certain reasons or circumstances), etc., has the potential to reduce valuation with the risk that some of the reduction never ever returns. I'm sure management understands by now if they didn't understand it at the outset, that $125 million raised at a $75 million [pre-money] valuation is not as good as the same amount raised at $250 million.

Should Craig ultimately be successful in having PV-10 and PH-10 approved for multiple oncology and dermatology indications, such as those as displayed in Alan Ross' Seeking Alpha article Provectus Pharmaceuticals Up 17% In A Month; Potential Still Huge last week, the team and he will find themselves (even after adjusting for the additional costs still required to gain approval for many of those indications to market, and which will incurred by Provectus' acquirer) very near to or at the bottom of Forbes' Matthew Herper's list of R&D Spending Per New Drug, which is exceedingly high praise for their possessing the unique combination of innovation and cost effective development. It's not quite a list of R&D spending per approved indication, but it gives you a sense of magnitude nevertheless, and Provectus' relative success.

Through it all, however, management has protected the economics, but "protecting the economics" can be hard to grasp. In my investment letter of September 22, I wrote: "Investors often misjudge risk in the context of return. That a so-called safe asset or security should provide a safe return does not mean the expected return is commensurate (high enough) for the risk incurred. Conversely, a so-called risky security that may have the potential to generate a robust return does not mean the associated potential risk is commensurate (too high) for the amount of return expected."

One measure of risk in biotechnology is the weighted average cost of capital ("WACC"), which is "...the rate that a company is expected to pay on average to all its security holders to finance its assets." Said another way, it's a measure of return you would expect to garner each year for every year you hold Provectus stock. Consider the table below:

Click to enlarge the table.

Let's assume a biotech WACC of 20%. There are several studies that have analyzed the WACC for the biotechnology, and been more specific as it relates to the size of the biotechnology company, and report a range of 8-20%. Let's assume Peter achieves something close to a Celgene-takeout-of-Abraxis payment, as he mentioned in one of his September interviews. Factor in the number of fully diluted shares outstanding. Establish a share price range at which you might sell your shares ($2-12 per share in the table above). Determine the number of years you've held the stock (1-8 years in the table above). Determine your cost basis ($1 per share in the table above). Calculate your annualized return (as shown). The table is a quick 'n dirty attempt to illustrate the protection of Provectus economics for a range of exit share prices and a range of holding periods.

I further wrote in my investment letter: "Provectus’ stock’s risk-reward profile is out of whack. The return opportunity is more than commensurate with its potential risk from here on out." Whether you're a longstanding shareholder, measured in a holding period closer to 8 years or thereabouts, a recent shareholder, and thus have a holding period of, say, one year or less, or someone in between, like me, depending of course on what value management sells Provectus for, your annualized return should be exceed the return required for the risk you took. In professional sports, generally speaking, the outcome only matters. Did you win or lose? An end-game in the range of most scenarios above is a win for shareholders and, thus, for management.