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Summary

  • Provectus has been making a lot of news lately.
  • The company has up-listed to the NYSE-MKT and its lead cancer drug candidate was found to have a significant immunological effect in cancer by Moffitt Cancer Center researchers.
  • It has also seen high stock volatility, and the FDA rejected its application for Breakthrough Therapy Designation in melanoma.
  • In the FDA rejection, they acknowledged that the drug shrunk 1 to 10 tumors in patients that failed a median of 6 other therapies.
  • As a result, Provectus plans on another melanoma trial to satisfy FDA requirements and to continue its ongoing liver cancer trial.

INTRODUCTION

Provectus Biopharmaceuticals (NYSEMKT:PVCT) has been in the news much more than usual lately. The company has been the target of a number of negative articles in recent days, prompting increased stock price volatility just as it was being listed on the NYSE MKT. A few days later, Provectus Management learned that PV-10, their lead drug candidate, to treat melanoma, was denied Breakthrough Therapy Designation (BTD) by the FDA.

In this article I delve into how Provectus got to this point in its corporate history, the importance of the latest FDA decision, what that decision means for the company's future direction and whether recent events have changed the ultimate strategic goals of the company. To do this I have interviewed the Chief Operating Officer, who is also the Chief Financial Officer, and the Chief Technology Officer, who has oversight on the clinical research program and relations with the SEC. To supplement these interviews I have included a transcript of the relevant parts of the conference call that was held to allow shareholder and analyst questions about the FDA decision and the company's path forward.

INTERVIEW WITH PETER CULPEPPER, COO and CFO of PROVECTUS BIOPHARMACEUTICALS

1. When I mentioned the possibly of publishing the transcript of your Conference Call and discussing the FDA decision on PV-10 for melanoma, you thought it was a good idea and even agreed to do this interview. Why?

Answer: We want to show by our actions to the market, our stockholders, and patients that we are going to lead the effort to interact with the FDA in a confident manner to provide the necessary data to support PV-10 as a drug product candidate.

2. Can you briefly tell me why Provectus applied for Breakthrough Therapy status in melanoma for your PV-10 drug?

Answer: We did this because we believe it was what the FDA asked us to do, and we had sufficient data to be successful in that.

3. And why did you make the application public when most companies keep this a secret, just in case they are turned down?

Answer: We believed it was appropriate to be as transparent as possible and to minimize any insider information leaking.

4. Given Dr. Wachter's recap of the years of discussions with FDA and the citations by the FDA of the instances where they gave you specific guidance about collecting pain, bleeding and similar data, why didn't you provide it?

Answer: We believed the focus on these symptoms became more clear in our Type C meeting last December. We had already completed the Phase 2 study by then.

5. Given the request for pain, bleeding and similar data in the December meeting that was noted in the January Provectus press release, why did you think that PV-10 had a good chance of being approved for BTD, knowing that you did not purposely pick patients with these symptoms for the trial, which was run long before there was a BTD process?

Answer: We believed we had enough data complete response data of lesions, and that complete response is tantamount to symptomatic control.

6. Given long regulatory-related delays, the long-term differences of opinion between Provectus and the FDA, many people have concluded that an adversarial relationship is making regulatory progress more difficult. Is this assumption correct and, if it is not correct, what concrete evidence is there that the FDA wants to see PV-10 succeed and become available to help those suffering from cancer.

Answer: We believe no adversarial relationship exists. We are pleased that the FDA documented what they did (aside from the denial of course) in the Letter provided the afternoon of May 21st. We believe the Letter provides valuable insight in order for us to proceed forward.

7a. Will Provectus treat more melanoma patients, taking the clinical measures that FDA wants, in addition to the Tumor-Response data favored by Provectus, and submit another application for BTD?

Answer: This will be assessed by Dr. Eric Wachter and his team.

7b. And if so, do you have any idea of the time until re-submission?

Answer: This is being assessed now as well. Certainly the FDA appears supportive of this.

8a. If you are going to go for a Phase III trial instead, won't that need to use survival as an endpoint and take years the more successful PV-10 is?

Answer: No, we do not anticipate survival as the appropriate endpoint.

8b. Doesn't it seem counter-intuitive that greater success would mean that trials would take longer, keeping a successful drug from patients that desperately need it?

Answer: We have an unusual drug with unusual capabilities. We have actually been charting a new course which we believe is appropriate in our case.

9. Can you comment on the different way the FDA and much of the medical profession see local melanoma compared to systemic melanoma and why this causes problems for Provectus getting understanding of PV-10's dual capacity to kill tumors locally and have a systemic effect by stimulating the patient's immune system?

Answer: No one has done what we have done with local treatment of PV-10. People in the industry understand now that PV-10 is appropriate for local treatment for certain patients and in combination for other patients.

10. Have you gotten feedback on the FDA letter from the medical community and/or other pharmaceutical companies (like those represented on your Strategic Advisory Board) and can you share them with us?

Answer: Yes we have, and it is not appropriate to share at this time, other than to say the retail mindset of BTD and consequences of being denied is very much different than that of life science professionals.

11a. Are you planning on applying for BTD status using the data from your ongoing liver cancer trials?

Answer: We believe this makes sense although we will continue to assess the best way to move PV-10 forward to treat liver cancer.

11b. And if so, have you checked with the FDA so that you are 100% certain that what you are measuring and how you are measuring the effects of treatment is the kind of data the FDA requires in relation to a BTD application.

Answer: This is an important area that we are very much assessing to ensure if we apply for BTD for PV-10 for liver cancer that we will be successful.

12. Can you share any general impression on how the liver data are coming in, compared to the initial patients, all of whom were helped by PV-10 treatment?

Answer: This will be communicated when we have appropriate amounts of data in acceptable formats, like peer-reviewed publications.

13. Assuming the liver trial data is positive and Provectus wants to apply for BTD, and given the FDA record in deciding within 60 days, when would it be reasonable for people to expect the BTD decision.

Answer: This will be communicated when we have enough data to further advance PV-10 to treat liver cancer in Phase 2 and beyond.

14. Will liver cancer or melanoma be the next regulatory event or step for Provectus?

Answer: Both are front and center for us.

15a. It seems like we have not heard anything about PH-10 for skin disorders for years. Has this been abandoned?

Answer: No, it was mentioned in the press release last Friday.

15b. If not, why is it taking so long and when are we likely to hear about proof of mode of action and the next regulatory step?

Answer: We are working on this program and will communicate when we can this year.

16. Why did you hire a Washington lobbying firm?

Answer: We want to maximize visibility we have in D.C. with key constituents. They are public policy focused and have valuable insights into FDA interaction.

17. Why doesn't PV-10 get more coverage in the popular press, given that it seems to eliminate cancer tumors and is so different than the typical cancer drug under development.

Answer: We need more data and to be in Phase 3 or some similar level of progress, like BTD, or have a partner.

18a. Provectus has announced the hiring of a Chinese Investment Bank. Did you take this step because you are close to signing a deal?

Answer: It was prudent to help ensure we cover all bases in getting a deal done.

18b. Has the recent FDA decision affected getting the deal done or is it too soon to know.

Answer: I don't believe it matters for India and China. What matters is protocol for them to use for both melanoma and liver.

19a. Are there other licensing or Joint Venture deals in negotiations?

Answer: We will communicate on this when appropriate.

19b. If so can you give us some color on them?

Answer: It's logical to say this is wise to wait until at least a Memorandum of Understanding is signed by Provectus and potential partner(s).

20. Do you now have enough cash, without deals, to fund both melanoma and liver trials through the next FDA step or application?

Answer: Yes.

21. If there are up-front payments in a deal, do you have goals for this money?

Answer: Yes. Up-front cash payments from licensing deals will be used to enable enhanced valuation, prior to final sale of company.

22. What can you do and what will Provectus do to speed up the research and regulatory progress, compared to how you operated before. For example, can and will you have more trial centers and faster patient recruitment?

Answer: This is being assessed by Eric and his management team.

23. Is Provectus' goal still to sell the company to a major pharmaceutical company that has the resources to speed the development and approval of PV-10 for all solid-tumor cancers?

Answer: Yes. No change to this.

24. If so, what is the minimum kind of deal that would be acceptable and why?

Answer: We have not changed our view that PV-10 and PH-10 are unprecedented in their value potential.

25. If potential acquirers are not prepared to meet the minimum, can Provectus fully commercialize PV-10 on its own, despite the long delays that are too typical in the industry and that Provectus has already experienced?

Answer: Yes, although this would necessitate a different corporate structure than we have now, and we don't believe this will be the end of the day scenario.

26a. If you commercialize PV-10 without being acquired or a Joint Venture, how long is your patent protection?

Answer: To 2031.

26b. How do you stop people or companies from making bootleg PV-10 from industrial grade Rose Bengal, in the USA or elsewhere?

Answer: This is complex area. The commercial grade therapeutic drug product specifications are very strict. Industrial grade Rose Bengal does not meet those specifications.

INTERVIEW WITH ERIC WACHTER, PH.D., CTO of PROVECTUS BIOPHARMACEUTICALS

1. The FDA says it does not view tumor shrinkage, even in multiple tumors, indicative of clinical benefit and that is what they want. Can you tell us your views on this and how you view "tumor response" as an indication of successful treatment?

Answer: We agree that "tumor shrinkage" has never been proven to provide clinical benefit to melanoma patients. The BTD application was based on "tumor elimination" (i.e., complete response). Objective response ("tumor shrinkage") is an at least 30% reduction in tumor size, whereas complete response, as the name implies, is a 100% reduction. We believe complete response is tantamount to eliminating the physical or psychological symptoms of melanoma of the skin, but the denial of the request and the wording of the denial letter show this message was not successfully communicated.

The patients that we presented in our request had no visceral sites of disease. About half of them had one or two intentionally untreated cutaneous lesions (i.e., bystanders) that were monitored over the study interval. Thus, complete response of study lesions represented complete elimination of melanoma in these patients.

2. Given that Clovis got BTD for lung cancer with "Observable Response" tumor-response data, is proving efficacy with tumor-response only a problem with Melanoma?

Answer: Melanoma has proven to be especially challenging from a regulatory perspective with regard to tumor-response data. This is compounded by the fact that PV-10 is a locally- administered dual-mode drug (direct ablation and induced immune response) that makes for a uniquely complex story. As noted in the CC we have been working for at least the last several years to fill in gaps in the story and arrive at an indication (locally advanced cutaneous melanoma) that can provide an appropriate path toward approval.

3. Has tumor-response been explicitly approved as the primary endpoint in the Liver cancer research? Are there other endpoints like liver function, jaundice and digestive problems specified by FDA as clinical symptoms that must show improvement and are you measuring all of the ones required in the unmodified way expected by the FDA?

Answer: We anticipate that Overall Survival will be the approval endpoint for Hepatocellular carcinoma. We are also investigating other hepatic tumor indications that may be approvable based on functional or symptomatic endpoints.

4a. Given that Provectus has no clinical data on melanoma in the relevant population (that starts out with pain, bleeding etc.) for the endpoints required by the FDA, don't you have to start over with a new melanoma patient #1 and do enough patients to convince the FDA?

Answer: This is not true. The phase 2 study did not require patients to have these symptoms, and while data on bleeding and infection were not rigorously collected, pain data was collected from all patients throughout the study and a substantial minority of patients reported pain at baseline. However, when data are analyzed from a substantial minority of a sub-group of patients statistical power is compromised making conclusive demonstration impossible. We showed that these patients tended to show a clinically meaningful decrease in pain that coincided with tumor ablation. The Agency also expressed concerns with the tools we used to assess pain, and these will be addressed in any further studies.

4b. Will that be for BTD or straight to NDA?

Answer: It is not possible to speculate at this point whether prospective pain data would be used for a follow-up BTD application or for NDA.

5. Given that Liver cancer efficacy measures that have been FDA approved have been collected in more than 6 patients, isn't Liver cancer now your lead drug candidate in the sense of being closest to a BTD application?

Answer: The Company is aware of the potential of the liver work, however, since many-fold greater number of melanoma patients have received PV-10 our understanding of the drug activity in these patients is greater and for the foreseeable future both programs will continue to be actively pursued.

TRANSCRIPT OF THE PROVECTUS BIOPHARMACEUTICALS CONFERENCE CALL OF MAY 23, 20014

On May 23, 2014 Provectus held a conference call run by COO/CFO Peter Culpepper and featuring Eric Wachter, Ph.D. the Provectus Chief Technology Officer. The following is a transcript of that call, complied by Mr. John Daciuk. The focus of the call was to discuss and allow questions about the denied FDA application for Breakthrough Therapy Designation. I am told that an official transcript will be transcribed and posted on the Provectus website. Provectus has a disclaimer related to this audio of the Conference Call, as follows: "No claims with respect to PV-10 are intended regarding safety or efficacy in the context of the forward looking statements contained in the comments made on this webcast." I also remind readers that a representative of Provectus made a comprehensive legal disclaimer at the start of the Conference Call. If you are interested, you can access the audio of the call on the company website.

Peter Culpepper, CFO/COO: "We're here to discuss the press release and news from the FDA and obviously, let me begin by saying we are all very disappointed that the FDA has declined to grant us breakthrough therapy designation for PV-10. But we strongly emphasize, and this is the point of the call, this is not over and we are proceeding and we are reaffirming our commitment for shareholders, stockholders, and patients who are even right now using PV-10. So there are people that are relying on what we are doing, we have active studies in place, we have individuals literally being treated with our drug. It is very important for patients, it is very important for us and the company, we have an obligation, and especially not for the patients, but on this call, the shareholders and the constituents who are very invested in our success, which I'm very confident we will achieve.

I would like to hand it over now to Dr. Wachter."

Dr. Wachter, CTO: "Thanks Pete, and I'd like to say good afternoon as well. This is Eric Wachter, as Pete has mentioned, and I am the Chief Technology Officer of Provectus. I'd like to start my comments today by noting that breakthrough therapy designation is just one path of putting PV-10 on the market. And as Pete indicated, that is our ultimate goal. But the agency has refused to grant BTD applications in nearly two thirds of the cases since it adopted this as a method of moving drugs along more quickly, in 2012. Failure to receive BTD does not mean the end of the road for a drug and we need to stress that. The FDA has not said PV-10 is a dead end. In fact it's reinforced the relevance of it, potentially, for patients. When we announced our application for BTD in March of 2014, we stated in the press release that BTD is not guaranteed and if the designation is conferred on PV-10, that would not bypass the need for a new drug application, or NDA, and review of that NDA as both are required for commercialization of a drug. Historically, BTD has conferred an advantage of time to market, but it still takes an average of ten months from receiving designation to commencement of sales of the product.

We also noted that 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 may be injected. This could occur either before or after we have approval to sell PV-10. At the time of that statement, Provectus had over $16 million in cash reserves and it would not be necessary to raise additional capital or reserves to conduct such a study. Currently, we have $19 million in cash. In other words, we have the money to move ahead. If you had a chance to read the FDA letter, which we filed as an 8k - as an exhibit in the 8k - you'll see that the agency acknowledges that PV-10 data is, "indicative of drug activity in the treatment of local, satellite or in-transit recurrence of malignant melanoma." In other words, they are saying that it has positive effect. I'll refer you to our May 15 press release for details and data from Moffitt and Saint Luke's, for example, that demonstrate drug activity in melanoma. Where we came up short is that the data submitted, "do not demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints."

The FDA clearly says that Provectus may submit a new request, "if you obtain new clinical evidence that PV-10 demonstrates a substantial improvement over existing therapies on one or more clinically significant endpoints in the treatment of locally advanced cutaneous melanoma."

Among the endpoints the agency mentioned were infection, bleeding, and pain. While these weren't requirements for enrollments in the study, in terms of pain, we were able to identify a subset of patients with pre-treatment pain and to provide some analysis for this. There may be other endpoints that are appropriate as well in the existing data set. However, clearly as we are moving forward we are going to need to enroll some more patients in a new study. That's made very clear in the letter. How many, how long, are obvious questions that we cannot answer immediately after receiving this news. We fully plan to have a research plan developed quickly and are committed to having it ready, at very least in out line form, for the ASCO conference on June 2. However, as of right now, our advisors and regulatory experts have yet to work with us to discuss the news and find possible next moves."

Peter Culpepper: "Thank you Eric. Mike, those are our prepared comments. Would you like to take it from here?"

Question and answer session:

"Our first question comes from the Maxim group"

Questioner: "This is Dan Bollestra [?], I called rather late, I didn't receive an email. So, what exactly was not appropriate in the data set that was sent to the FDA that they denied breakthrough designation and what are they looking for?

Eric Wachter: "That's a good question, Dan, how you doing? So in the application we submitted a subgroup analysis of 28 patients with all existing melanoma lesions injected and an additional 26 patients who had only one or two injected bystander lesions. So a total of 54 patients. We were able to show that the best overall response rate in the 28 patients where we treated all the disease, was exceptionally high. 71% with a 95% competence interval which went from 51-81%. And most notably a 50% complete response rate, which is a confidence interval of 31 to 69%. We showed among the total of those 54 patients, patients who had all of their disease monitored in the study, complete response was achieved in 232 of 363 injected lesions. So that was 64% complete response rate. The complete response was achieved quite quickly in the majority of those lesions: 121 after a single injection of PV-10, 84 requiring 2 injections, 22 requiring 3 injections and only 5 of those requiring 4 injections. We felt that data provided a logical justification for the application in that it seemed clear to us that complete response in all lesions implied resolution of any melanoma related symptoms present at baseline. We had lengthy discussion with the Agency in our December 2013 meeting on the outcome of these patients, discussed the objective response parameters and the agency asked us for additional evidence showing those responses correlated with symptomatic improvement in the patients. That is, improvement in pain of the lesions, bleeding of the lesions, infection of the lesions and so on.

Unfortunately, the phase 2 study did not require patients to have base line symptoms of these types, outside the existence of biopsy proven melanoma for enrollment. And we did not design the study to collect the type of detailed information on symptoms that might be ideal for showing that correlation. Available symptom assessment instruments were used, such as the EORTC QLQC30, that's a lot of letters and numbers, but it's a quality of life questionnaire that has been validated for cancer. But unfortunately, that and other similar validated instruments are primarily used for symptoms related to systemic disease and the effects of systemic therapies, not proven to be particularly valuable in addressing and quantifying the kinds of local and regional symptoms that effect the patents in this 54 patient subgroup. So we followed up on that meeting with the agency by conferring with our bio statistician who analyzed the infected response data, calculated the confidence intervals for us and we also poured through visual analogue pain data, which I mentioned the visual analogue scale in the letter. And we had used a visual analogue scale designed, implemented uniformly throughout the study to assess pain pre-treatment and at various time points subsequent PV10 treatment.

Because of the lack of requirement for patients to have pain symptoms prior to enrollment, only a small fraction of the patents had clinically significant pain at baseline. So we analyzed those patients and presented them that analysis of those data in the context of the objective response data. We found there was a strong relationship between the two types of data but there was simply not enough of the symptomology data to show a statistical function. I have to conclude that is the basis for the rejection of the application.

I'd say that it was our assumption going into the application that improvement in symptoms, that we made the patents lesions go away that was tantamount to making the symptoms go away. We don't seem to have been successful in convincing the agency that."

Questioner: "So, am I able to assume that moving forward that we will design the study that will meet the endpoints of the systematic data and an you comment on that design at this time?"

Dr. Wachter: "I can't comment on it at great detail. We have obviously spent some amount of effort discussing with our advisors what sort of measurements we might make to capture symptomatic improvement. And we also went to an FDA workshop two weeks ago in Washington that was principally related to the design and use of tools to measure patient reported outcomes. So these are things like pain where you can't measure it by objective means, you have to ask the patients in some standardized fashion to describe what they're experiencing. The lesson that I derived from that meeting was that those are very attractive endpoints but they are also very difficult to validate and to execute and I have some reservation about basing a significant effort on substantial pivotal study that would require measurement of a patient reported outcome as a primary or important secondary endpoint. That being said, certainly the second lesson from that workshop was that the most directed patient recorded outcome are the best and the most robust. And an example was given was for pain, for example, as being a relatively robust endpoint. We have experience with pain assessment from the phase 2 study. We learned a little bit about the properties of pain and the patients who did report pain at baseline and so it is conceivable that we could design a study that would draw that correlation. As we mentioned in the press release to close the loops, as it were, between objective response and symptomatic response. We reference, of course the January 24th press release."

Questioner: "Was there any FDA guidance on how to assist you in meeting these endpoints?"

Dr. Wachter: "The agency doesn't typically go into that sort of detail with sponsors. And I would say we got a very useful guidance from the agency in that regard, but not the sort of detail that you might expect from that question. "

Questioner: "Understood. Well I appreciate the time and the responses and I hope you guys have a wonderful Memorial Day weekend. I appreciate your time and assistance in responding to my questions."

Peter Culpepper: "Thank you, Dan."

Questioner: "Just out of curiosity, I had seen posted somewhere that you all had received this letter as early as the 16th. Can you confirm or deny when you actually received it, and if it was at that point in time, why are we only hearing about it now?"

Dr. Wachter: "Ok, this is Eric Wachter and I will jump in on that topic. So the typical pattern of communication with the agency these days, at least with our portion of the agency that we interact with for the IND is through formal written communication that is submitted in paper copy and informal courtesy copies that are typically submitted either from the agency to us or from us to the agency by email. Occasionally the agency will send communication via fax, but I can't think of a case in the last several years where that has been the case. And certainly in the case of our oncology IND, since it's been in the hands of the DOP2 office, the Department of Oncology Products 2 office, that communication has typically been by email, followed by official copy by USPS or FEDEX, courier or other similar courier system.

So in the weeks leading up to today, which by my calculus, is day 60 from the date of receipt of the application by the agency, we had, and by we, I mean I, had been closely watching my email inbox, my spam inbox and our physical mailbox for a response by the agency. About a month ago, we had received a request for clarification of several items in the application, which we had been told prior to submission of the application was typically the case, during the review process. That request was received via email with a formal copy by paper mail, days afterwards, in fact after we had submitted our response to the request. So obviously it was a very tense last week or so for some of us as we waited patiently for a response by the agency. And so Wednesday afternoon, which I guess is the 21st, I was becoming very curious as to why we hadn't heard anything from the agency in terms of response and so I sent an email to my regulatory project manager. And within five minutes she responded and said that she had, one was sorry and two, had not had a chance to send us the electronic courtesy copy of the response until that email that she sent to me in response, on the 21st. This is the afternoon of the 21st. And that included the letter that has been filed as the attachment to the 8k today, the decision on the application. It was signed by Dr. Keegan, the head of DOP on the 16th, but as I just outlined for you, we had not received it until the 21st and we have as of today taken possession of the formal paper copy, or the official paper copy that bears a postmark of the 20th and I have to speculate that it landed in the mailbox yesterday, when we were out of town."

Questioner: "Ok, so that fictitious date that is flying around is just that?"

Dr. Wachter: "No the 16th is the date that the letter was signed, but you either believe me or you don't, that I received it the afternoon of the 21st."

Questioner: "Good afternoon gentlemen, thank you for taking my question. Very disappointed, but that's the way it goes. I have two questions, a question and then a followup question. The first question is, is this going to require, going forward, is this going to require a secondary? And the followup question is, how is this going to affect our listing on the NYSE?

Dr. Wachter: "Pete will definitely answer these questions."

Pete Culpepper: "Ok, thank you Albert. So we do not plan, as we indicated in the press release, to do a secondary. We have adequate capital for the work Eric believes is necessary to provide the data that he will further discuss, as we mentioned, at ASCO, June 2. So we believe we have adequate capital to do what we believe needs to be done in order to move forward with PV-10, that's number one. As far as the NYSE, we are in direct touch with the NYSE and we'll work with them to ensure we do whatever we need to do to continue to be in the position we're at, as listing company.

Questioner: "Are you guys open to a reverse split?"

Peter Culpepper: "No, Albert. We have said that we do not want to do a reverse split. We have many dedicated and long term shareholders. We do not have also, in the bylaws, the authorization to do a reverse split. We'd have to put it out there to the shareholders as a proposal before we even did it and we have not, according to our understanding of the shareholder base, come to the conclusion that was what the shareholders want."

Questioner: "Just one more, how do we deal with this Adam Feuerstein, this character?"

Peter Culpepper: "The reason we'll be successful, Albert, is because we do have a drug that works, as Eric indicated, very well. The Rose Bengal, the active ingredient, of course, has been pre approved by the FDA, as we know on this call, has been a previously approved agent in two previously known applications. It's a well known compound, we're the only ones using it therapeutically. We have very rare opportunity, to take a very effective, a very well tolerated agent, it's just unusual because it's not delivered intravenously, it's delivered of course locally, intra-lesionally and this where the importance, we should emphasize, the importance of the data at ASCO, June 2, should be, or comes to our attention is critical to help the oncology community better understand the way PV-10 is working in a unique fashion. So that's how we're going to deal with people."

Questioner: "We're saving lives here, we're saving lives. And this nonsense - I say it's a political ploy with the FDA and so on. We have it in black and white, what more do they want? It's ridiculous."

Peter Culpepper: "What it really comes down to Albert, it's data in a certain fashion for the agency to understand, to support the approval of the drug. The data has to be in such a way that the regulators can assimilate. And this is what we will ensure we will continue to work on, because we know it's saving lives, we know the patients that we had treated successfully, that have no evident disease, years after. This is absolutely critical that we succeed and we have no question in our minds that we will continue and that we will be successful, simply because the drug works.

Dr. Wachter: "Peter I want to make a quick redirect or comment on that topic as well. We drafted anticipate questions in advance of the call today and I'm going to read from one that's captioned, "Aren't you mad as hell at the FDA?" That seems like something that you just asked, in one way or another. Obviously we would have preferred a positive response to the application. And I stated before that we felt at the time of submission, and we still feel at this time, that eliminating patients tumors is tantamount to symptomatic improvement in patients disease. With that being said, within the denial letter, there are some very positive statements. For example, it's very significant that the agency has clearly stated that the data presented that PV-10 is active in melanoma. And, furthermore, that they recognize that the condition that is the lead indication, locally advanced cutaneous melanoma, meets the criteria for a serious or life threatening diseases or condition. These are dramatic changes in position from the agency versus where we stood two years ago, when we had a third type B meeting with the agency.

Nonetheless, at the end of the day, we must work within the existing regulatory framework, for the benefit of patients, and the agencies letter provides valuable insights into what will be needed to demonstrate clinical benefit. I think Mr. Feuerstein is serving, in a certain capacity, as a straw man for doubt about the potential utility of PV-10, based on an incomplete understanding of the primary ablative and secondary immunological action, what we've been working on for the past two years, since our last end of phase 2 meeting, has been to fill in the gaps in that story. We are very excited about going to ASCO next week, where that will become manifest in clinical data from patients by the team at Moffitt, independent research on their part, sponsored study that they proposed to us, showing systemic immunologic effects in patients. We believe this is a first for a small molecule ablative agent and it's certainly an important step forward in casting aside doubts about the potential value of the drug in melanoma patients.

That being said, the agency clearly notes from the phase 2 data, absent any of that secondary immunologic effect, that ablation of tumors with PV-10 in patients with cutaneous disease, had some value."

Peter Culpepper: "And for clarification, Eric is referring to the June 2 ASCO conference."

Questioner: "Hi Pete and Eric. Eric, after listening to your comments, it sounds to me when the FDA, in I believe in a quote that was attributed to them in the January 24th release was that the FDA agrees with Provectus that the destruction of the primary tumor is clinically beneficial and relevant and that's why you guys were so excited with the 64% complete response rate, but then what you had to do was go back to a trial from three years ago, and basically, go back at this trial that wasn't run for bleeding and pain and all the things that they wanted to see in order to say this is how you get your breakthrough designation. Am I, I don't want to put the words for you, but is the reason that you were so excited about the opportunity for breakthrough because you had such a great response rate, 64% complete response in all the burden that was hit. Is it, that's where it went wrong that we went back to a trial and they were asking you stuff that was inefficient because that was not what the trial was really meant for?"

Dr. Wachter: "Yes. To make a very short answer. The longer version of my answer is definitely. Definitely we were very encouraged by the meeting with the agency, that being said, I described myself recently as being a professional worrier. Maybe that's good for someone who is responsible for clinical development in a small company. I was worried about being able to conclusively demonstrate correlation between this high level of objective response, and I'll use that loosely, what I mean by that is objectively observable response, evidenced by complete responses in patients so that all of their disease is gone after PV-10 injection in 50% of those patients, versus what I knew was very thin data conceding the types of symptoms that the agency was suggesting should be shown improvement in.

So we did our best with that study and looked at, as I mentioned earlier, pain data, and were able to draw some supporting evidence to show that there is definitely a trend in pain data that matches the objectively observed response of tumors. The quality of life EORTC QLQC30 instrument, this questionnaire that is principally designed for patients with late stage systemic disease, maybe that are taking toxic chemo therapy. I had great concerns that this was not going to be valuable because we had already shown in the 80 patient study that there were no clear trends evident other than the patients didn't get worse and that proved to be correct; there was nothing that we could extract from that particular instrument. So it was a measured risk submitting the application. But again, as I mentioned earlier, our logic seemed clear that if we were making the patients tumors disappear in 50% of the patients, that was a very large effect size and that was tantamount to making any symptoms they were suffering from the tumor burden, disappear".

Questioner: "And Peter, we heard on the press release from the 24th that there could be a small bridging study that may be required. What would be the size of the bridging study? What would be the timeframe and number of patients and costs to Provectus?"

Peter Culpepper: "Good questions Joe. I think it's fair to say from what Eric has said and what we said in the press release that we would have more specifics as our objective June 2 at ASCO to address that, other than to say we have adequate capitals for that study."

Question: "Eric, can you comment on the release from Moffitt where they talk about the 8 patients and 6 being refractory to all other therapies and that 66% had a complete response. Is that your understanding that when they say complete response, they couldn't find melanoma in the patients that had the complete response?"

Dr. Wachter: "That will require just a small amount of explanation. So, they reported pCR, which is a pathological complete response in injections. That is a pathology confirmed response, so it is a more comprehensive assessment than clinical response, which is looking at the patient and visually or palpably determining if the lesion is gone. They are actually taking tissue specimens from the injecting lesion and sending them to the pathologist and the histopathologist is looking at them both for physical and immunohisti-chemical indicators that there is remaining melanoma. Now the study that is ongoing at Moffit is small mechanism of action, study where the patients they reported in AACR had one lesion injected and an additional lesion left uninfected. Both of those lesions were biopsied a week before PV-10 injection into the lesion that was designated for injection. Then 7-14 days after that, both of those lesions were excised for assessment of those pCR point. So patients may have had a large number of lesions but only two of those lesions were considered for the purpose of that mechanism study.

The interesting aspect of the study, as it was originally authored, is based on interaction that we had with the investigator and his team, the objective was to look at immune cell infiltrates into the injected lesion and the bystander lesion at the 7-14 time frame and it turned out to be a problem for the study initially, when they analyzed the samples of the first several subjects and noticed that there was no melanoma tissues left in those specimens. Hence there was nothing left to probe for immune cell infiltrates. That led to a lot of patients in the study to provide a more comprehensive assessment of immune cell activity in peripheral blood, which is part of the data that was reported at AACR and our understanding of the report and larger data set at ASCO on June 2".

Question about partnerships

Peter Culpepper: "For potential partners in India and China, in particular, there is an interest in exclusive use of PV-10 in those geographic areas. We are talking about PV-10 for various solid tumors, primary liver cancer, cellular carcinoma is a very prominent area of interest, in of course in China, but also in India. But we do have data to support use of PV-10. We are, when we work with potential partners, PV-10 for melanoma and a study that Eric will be designing and further communicating at ASCO, on June 2, that kind of study design, and once we have the protocol, that of course is going to be of interest to partners in India and China. But yes, there are other aspects to what we are discussing. We are going to keep moving forward because we know PV-10 has value."

Question: Is PV-10 something like a student who knows the answer but the teacher wants it a certain way and they think they know better.

Dr. Wachter: "I will redirecting this question to the following question: Why did it take 4 years after the phase 2 study to get to this point?

"I think it's good to start back in may of 2010, when the last patient completed the Phase 2 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 of the study. What was interesting to me as the study progressed was that interim study data released at n=20 patients, n=40 patients, and the final analysis when the total 80 patient ITT patients were enrolled. By the time we got to n=40 patients the numbers were looking better than what we had seen in phase 1, which we expected based on more aggressive treatment of the patients, despite the fact that we had a larger number of stage 4 patients in the patient population. And I'll comment that as we finally matured the data to n=80 patients, the response metrics remained roughly the same over time.

But at this time in April 2010, the melanoma landscape was beginning to change very rapidly with the ipilimumab and [another - can't make it out] approvals approaching on the horizon. This meeting established that what we proposed in time for a phase 3 study in patients, with a patient population and endpoints similar to studies going on at that time under SPA for two other investigation studies for intralesional studies of melanoma, would not be appropriate going forward. So the agency told us they did not like our proposed patient population nor our endpoints and also cast a tremendous amount of drug in melanoma, a disease that they noted was systemically malignant and would be difficult to treat with a local therapy. So we matured the data from the phase 2 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 2 study.

We went into the meeting with proposed endpoints and data population based modified and based on guidance from the first meeting. That study design was proposed to evaluate response in patients with stage 3b-4 m1A disease. These are patients with cutaneous or nodal disease where all disease would be accessible from intralesional injection. In addition we tightened the definition of durable response that we had proposed in the first meeting, in light of the agencies advice. At this meeting, the agency made it clear that a timed even endpoint would be required and expressed a concern about our proposed modifications to RECIST that we thought were relevant for treatment of local recurrence.

So we met with our advisers further and finally scheduled and held a third type B meeting in October 2011. At that meeting we proposed modified endpoints, 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 that had no active nodal or visceral disease. So these were patients with a history of nodal disease who had undergone nodal resection and would be candidates because their nodal disease had been surgically removed, so they had no nodal disease, similarly the case for patients who may have had limited lung mets who have been successfully treated, for example, with radiation or some other therapy. Progression free survival versus [unclear at 49:55] was proposed for RCT so we proposed a timed event endpoint and a randomized control trial.

The agency at that time expressed continued concern of enrolling patients with any history of visceral disease based on the concern I mentioned earlier because there was inadequate support of PV-10 intralesionally in patients with systemic disease, so local therapy for patients with systemic disease. They also expressed concern about our proposed size, which we were willing to address. At the conclusion of the meeting we agreed to develop a revised RCT for 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 discussions with the lead medical reviewer concerning adequacy of support for potential distant effects of PV-10 ablation, which we had noticed in our bystander effect for untreated cutaneous lesions in Phase I and Phase II testing and a limited number of patients with visceral mets at enrollment in the Phase II study, some of them showed regression of their untreated visual mets over the study interval in a fashion similar to other drugs that were being developed for melanoma at the time. We realized we needed to get the story straight with this systemic effect before we could have significant traction with regulators in the US and presumably abroad.

So we began a dialogue with from Moffitt cancer center early in 2011 between the second and third meeting, that by the end of the year turned into formal non clinical studies on the cellular level that studied the bystander effect. Eventually it matured into the translation medicine study that began in early 2013 that we are expecting to hear results on June 2 at ASCO.

Data from these projects were reported starting March 2012 at the Society of Surgical Oncology annual meeting, in 2013 at the Society for Immunotherapy Cancer meeting. And at the 2013 and 2014 AACR. And as I said. it is expected to be presented next week at ASCO.

We started and we continue to believe now that this aspect of the PV-10 story may be crucial for PV-10 to gain approval from regulatory agencies.

During this time, we also convened several advisory boards comprised of investigators and opinion leaders to work on the promised RTC and met privately with a number of these experts and other similar experts to discuss the challenge of designing an RTC that is could balanced in terms of level of intervention between the PV10 arm and the control arm, appropriate for patients with stage 3b and 3c disease, and that would not suffer unacceptably low accrual or high drop out from the comparator arm.

As the melanoma landscape continued to evolve, this proved to be a difficult challenge. At the same period we worked on modernization of our PV-10 supply chain, as evidenced by recently issued US patent September of 2013 covering methods for manufacturing Rose Bengal to modern quality standards. I think absence of this work, it is unlikely that early investigation drug product that was used to that time could have been used for phase 3 use and certainly not for support of an NDA. As we announced when the patent issued last fall, drug product appropriate for such phase 3 use has now been manufactured.

So finally by October of 2013 we had become sufficiently frustrated by the difficulties posed by design of the study based on the third Type C meeting and discussion leading up to that third type C meeting and also encouraged by the emerging immunological data, essentially 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 1 and phase 2 data and from our expanded access protocol, which now has enrolled over 100 patients, from our hepatic tumor study, from an investigator initiated study of PV-10 followed by radiation therapy in treatment of melanoma, and from the aforementioned 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 of their baseline disease injected with PV-10. We also presented a straw man outline for a breakthrough therapy request and asked for advice on such a request.

To our surprise, in the meeting, the agency focused on the ECCO 2013 subgroup analysis and the clinical response evidenced in these patients via clinicatography [?]. We had a lengthy discussion regarding patients with local advanced cutaneous melanoma regarding the need for therapies for these patients and the types of endpoints appropriate for demonstration of clinical benefit. Based on our positive impression of the meeting minutes released a month later, we prepared and submitted our Breakthrough Designation application in March.

So, I warned you that it was a long road, a difficult and complicated story. What it showed is that as our understanding of PV10 has matured over time and as the melanoma landscape has evolved over time, our interaction with the agency has improved over time, in that now we are in a position that the agency has helped us to define an indication that our drug shows potential value and have helped us to define types of endpoints that are vastly different than, perhaps, progression free survival in the proposed phase 3 randomized control trial from the third type 3 meeting which would have used BTIC as a comparator. It's impossible to run that study in the current climate and enroll patients with the appropriate extent of the disease burden.

So I can understand the impression that we are the 'clever student that doesn't listen to the advice of the teacher', but I prefer to think that we are working with the agency to understand what proves to be a very difficult challenge. We are taking a new class of agent. There is superficial similarity to other investigation drugs currently under phase 3 investigation or previously in phase 3 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 immunological response appears to occur in a large fraction of patients, as evidenced by the data coming out from Moffitt, is much different than what has been shown in the past. And understanding what patients might benefit in, say, clinical trial setting has been complicated. I think we have very good guidance now, in terms of types of patients to look at, types of endpoints to use, and I hope that we will be able to condense: For all people listening to this story, we are definitely 'listening to the teacher' [what the person asking the questions mentioned].

In the meeting in December the agency said, to paraphrase, 'We like this ablative effect that you're showing in patients with disease confined to the skin. But can you show us that also improves symptoms that we heard are important in melanoma: pain, bleeding, infection, for example. And that would be a winning combination." We did our best with the data we had in existence. And that clearly was not enough."

Question: I just wonder if you need more advocacy groups behind you.

Dr. Wachter: "That's a great question. We have very aggressively increased our involvement with key opinion leaders in the medical oncology community over the past year. Now that we have an immunologic story that shows that there is potentially a systemic benefit, for this crazy - and it sounds crazy - this drug that you inject into a tumor in your skin may make the tumor in your lung go away. We now have an immunologic basis to say, that's quite possible. And that attracted the attention of that community which is less than responsive to us. The surgical oncology community has been very keen on PV-10 from the beginning because it's something that fits with this locally advanced cutaneous melanoma, very closely with the types of patients they see every day and what they see routinely doing with those patients."

Source: Provectus Forges Ahead After FDA Setback