"Intralesional rose bengal as an ablative immunotherapy for hepatic tumors"

Abstracts from the 26th Annual Conference of APASL (February 15th to 19th) are available here, including that of Provectus (shown below).

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Click to enlarge. Left-hand side text, and top right image.

Clash of Clans

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Every drug or drug compound, and drug category or class has a clan.

Clan members comprise all manner of biopharmaceutical industry constituency or stakeholder; from physicians, clinicians and medical researchers to global regulatory agency staff to Big Pharma/Biotech executives and employees to pharma and biotech investors and traders to media, journalists and commentators to medical conferences to...

Whether one's "schtick" are immune checkpoint inhibitors, targeted therapies, radiation or radiotherapy, intralesional therapies, etc., we've all got our clan or tribe.

I believe, by virtue of this blog and talking our book, that our clan(s) is(are):

• First, PV-10, and Rose Bengal, which fall into the category of small [chemical] molecules that rely on their physical (and not biological) chemistry properties, and

• Second, intralesional (IL) or intratumoral (IL) therapies (aka local, loco-regional or local-regional, and regional therapies), because route of delivery matters.

But there is good reason for the biopharmaceutical industry ecosystem to be skeptical of the class of IL therapies. First, until very recently (October 2015 for talimogene laherparepvec or T-Vec), there had been no history of clinical success and, thus, regulatory approval. Second, what promising, approved therapy there has been (T-Vec) has turned out to be a marginal product with an uncompelling clinical value proposition. Before Amgen's T-Vec was approved in 2015 as Imlygic for advanced melanoma, failure preceded it more than two year before in the form of Vical's IL agent velimogene aliplasmid (Allovectin-7) in August 2013 for the same indication. Before Vical, there was the failure of IL agent bacillus Calmette-Guérin (BCG) in 1978, also for advanced melanoma. Taken together, IL therapies would have a modest-to-no history of regulatory validation for nearly 40 years.

Now consider HemOnc Today's July 10, 2016 article entitled "Intralesional agents show promise in melanoma but may serve ‘narrow clientele.’" After reading it, I am struck by what seems to be physician clan members -- of the IL therapy clan -- endeavoring to frame the potentially notable clinical benefits and patient outcomes IL cancer therapies could generate or yield if only there was a better IL therapy to be their flagbearer. T-Vec was the first guy through the wall, opening the regulatory and commercial doors for IL therapies. The article made me think these clan members were waiting for PV-10 to bust through the door, breaking its frame in the process.

• HemOnc Today's article's page links

• Page 1,
• Page 2,
• Page 3,
• Page 4,
• Page 5, and
• Page 6

• Quoted physicians

• Sanjiv S. Agarwala, MD (medical oncologist, aka Dr. Rose Bengal) —a T-Vec and PV-10 clinical trial investigator from St. Luke's University Health Network in Bethlehem, Pennsylvania,

• Robert H.I. Andtbacka, MD (surgical oncologist) — a T-Vec and PV-10 clinical trial investigator from Huntsman Cancer Institute in Salt Lake City, Utah,

• Dale Han, MD (surgical oncologist) — no affiliations were disclosed, and from Yale School of Medicine in New Haven, Connecticut,

• Vernon K. Sondak, MD (surgical oncologist) — a consultant to Amgen and Provectus from Moffitt Cancer Center in Tampa, Florida, and

• Jeffrey S. Weber, MD, PhD (medical oncologist) — an advisor to Amgen and a PV-10 clinical researcher from NYU Langone Medical Center.

Article paragraphs and quotes of interest to me:

• "HemOnc Today spoke with medical and surgical melanoma specialists about the future of intralesional agents for melanoma, whether oncolytic agents likely will be used as single agents or in combination with immunotherapies, and the lingering questions surrounding T-VEC’s efficacy based on the OPTiM trial."

• "“If you look specifically at patients with stage IIIB or stage IIIC disease on the OPTiM trial, their response rate was 52%,” Robert H.I. Andtbacka, MD, CM, FACS, FRCSC, associate professor of surgery at Huntsman Cancer Institute at University of Utah, as well as a HemOnc Today Editorial Board member, told HemOnc Today. “None of the other immunotherapies and checkpoint inhibitors have come close to having that response rate in that patient population.” 

Andtbacka, who served as an investigator on the OPTiM trial, said the positive outcome and FDA approval signal the utility of intralesional agents in the rapidly expanding melanoma landscape."

• "The relatively mild toxicity profile of T-VEC may make it more appealing to some patients than immunotherapies, which can produce virulent adverse events, Sondak added.

“Adverse events can be quite modest when you are just injecting a [lesion], rather than trying to treat the entire patient,” Sondak said. “If we can get the immune system to pay attention to the melanoma and do something good because of it, then you are looking at a low-toxicity means of producing an important, clinically relevant immune response.”" 

• "Although most oncologists agree T-VEC has a role in the melanoma treatment armamentarium, the design of the OPTiM trial has prompted a number of clinicians to question how large that role should be.

The primary reason for concern is the use of GM-CSF as the control. 

“T-VEC was approved on the basis of a clinical trial design that will certainly never be replicated,” Sondak said. “The control arm was basically a placebo, with no basis in why one would choose to use that particular regimen. I don’t know if that design would be approved today by the FDA.” 

OPTiM researchers enrolled patients between May 2009 and July 2011. The majority of new melanoma therapeutic options were approved after that period, leaving some oncologists to wonder how the results might differ if the trial were conducted now."

• "“There are many patients who have tumors that do not have tumor-infiltrating lymphocytes, and checkpoint inhibitors cannot work unless those lymphocytes are there,” Andtbacka said. “Using an oncolytic therapy can actually change the tumor microenvironment, and essentially make a ‘cold’ tumor become a ‘hot’ tumor. When we do that, it appears that we can make a nonresponder into a responder.”"

• "“The preliminary data for T-VEC combinations look promising,” Han said. “The whole idea of treating systemic melanoma has really blossomed into the idea of combination therapy. Combining T-VEC with other effective systemic treatments was the natural next step to see if we could further improve outcomes.”"

• "“The beauty of combinations is that you can take a patient who has an in situ tumor reachable by a needle and inject it with something that makes the tumor more immunogenic,” Agarwala said. “If you throw in a confirmed immunotherapy that works well, you have the potential for synergy.”

Because melanoma has been shown to respond to combinations, the use of these regimens should be considered when possible, Agarwala added. 

“I like to say, ‘Make the tumor your friend, and make it your ally,’” he said. “If you can’t remove the tumor — if you’ve tried everything and it keeps coming back — instead of just trying to remove it again or giving systemic therapy, why not add an intralesional agent that gets into the microenvironment and releases antigens? That is a concept that highly appeals to me.”"

• "The labor involved in preparing a T-VEC injection may drive cost-related considerations.

“The biggest cost factor with an intralesional therapy, aside from the drug, is time,” Agarwala said. “It’s not just a nurse hanging a bag. You have to have a doctor or a provider actually do a procedure, and that procedure is billable. It taxes the provider’s time. I am not sure if anyone has studied the total cost yet, but the short answer is that it’s an issue.” 

Weber agreed. 

“An injection like this can take up a room for 20 minutes and might be viewed as a hassle by a doctor with a busy practice,” Weber said. “If a nurse practitioner is doing the injection, that’s time she or he is not seeing other patients. I do not think it is unreasonable to say that some busy oncologists view it as more work than it is worth.”"

• "T-VEC is the first intralesional agent to be approved as monotherapy for the treatment of advanced melanoma. However, it is far from the only oncolytic agent under investigation.

“These agents are safe and produce good response rates,” Agarwala said. “Some of the ongoing trials of new oncolytic agents can address the concerns left over from the OPTiM trial.” 

Agarwala serves as an investigator on a phase 3 study investigating PV-10 (Provectus Biopharmaceuticals), an injectable form of rose bengal disodium that received FDA orphan drug designation for melanoma and hepatocellular carcinoma."

• "“The current PV-10 randomized trial only includes patients who have failed immunotherapy or are not candidates,” Agarwala said. “In that sense, it is much more of a real-world trial [than OPTiM]. The control arm of the trial is chemotherapy, which is reasonable, because if you have tried everything else, it is a fair comparator.”"

• "“These agents may have theoretical or practical advantages compared with T-VEC,” Sondak said. “They are all worthy of investigation, without question, and some could be real advances. There is value to having T-VEC available, but it will also be important for these other agents to have their chance to show what they can do.”"

For the first time that I can recall, an article discussing by therapies addressed treatment administration by non-physician providers (e.g., nurse practitioners, physician's assistants, nurses). See page 6 of the article here.

The article's author should have discussed this topic with Dr. Agarwala's NPs, PAs and/or RNs, and solicited their opinions of PV-10.

It's 2016: Intralesional therapy [for oncology] is "here to stay"

(H/t a regular hatter for the article heads-up and link)

Melanoma, intralesional (IL) agent for oncology, and PV-10 key opinion leader Dr. Sanjiv Agarwala, MD of St. Luke’s Cancer Center (and a HemOnc Today editorial board member) made his presentation Current Trials with Oncolytic Agents at the HemOnc Today Melanoma and Cutaneous Malignancies conference on Friday in New York.

In a March 19th article by Alexandra Todak entitled Intralesional therapy ‘here to stay’ for melanoma, Agarwala said the following.

About Provectus' pivotal Phase 3 trial entitled PV-10 vs Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma:

“If we’re going to show monotherapy with PV-10 works, you have to design a randomized trial. It is not easy to design a randomized trial for a monotherapy intralesional agent, when you have all of these drugs available. This trial is designed in a very specific way, and it will be very interesting to see the results of this trial compared to the talimogene laherparepvec [Imlygic, Amgen] trial, because that trial was designed in a different era.”

About the role of IL agents in a physician's toolkit:

“There is no getting away from the fact that even monotherapy with intralesional agents for the right patient population produces good clinical results. The question is, in what setting are you going to use it? For us, in the medical oncology world, whether we will pick this first or not is a bit of a question.”

About the utility of IL agents for later-stage (i.e., advanced or metastatic) melanoma patients:

“We’ve been able to now make an intralesional therapy applicable to not only patients with M1a disease, but also to patients with M1b and M1c disease. So, patients with multiple metastatic sites might be able to benefit.”

About the combination of IL agents with other cancer therapeutics and therapies like immune checkpoint inhibitors; Provectus' Phase 1b/2 program in this regard is entitled PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma:

“Combinations will be the future. Why not find a way to combine modalities that have different mechanisms of action and have, very importantly, nonoverlapping toxicities?” 

And:

“We have to realize intralesional therapy is not going anywhere, it is here to stay. It is a new paradigm for potential combinations, and perhaps in the future the ultimate melanoma regimen is going to be with an intralesional therapy with a systemic, checkpoint inhibitor. Monotherapy also is applicable to specific patients.”

Trendwatching

[In no particular (including chronological) order:]

September 2, 2015 / The undifferentiation of immune checkpoint inhibitors? Incyte Corporation (Nasdaq: INCY), a nearly $21 billion biopharmaceutical company as of a 9/4/15 share price close, announced a global license and collaboration agreement with China's Jiangsu Hengrui Medicine to develop and commercialize the latter's investigational anti-PD-1 agent (SHR-1210). Under the agreement, Incyte would have exclusive worldwide rights to SHR-1210 except for mainland China, Hong Kong, Macau and Taiwan.

Possible or potential item takeaway: For the deal structured and money paid by Incyte, it didn't want or couldn't get from Jiangsu Hengrui Medicine China and SARs.

According to the Incyte press release "SHR-1210 is expected to enter proof-of-concept studies for the treatment of patients with advanced solid tumors in the coming months." {Italicized emphasis is mine}

As backdrop, as FierceBiotech's John Carroll writes, "[a] little more than a year ago Incyte swiftly lined up combination deals that matched its IDO1 inhibitor, epacadostat (INCB24360), with PD-1 and PD-L1 drugs from Bristol-Myers Squibb ($BMY), Merck ($MRK), Roche ($RHHBY) and AstraZeneca ($AZN). INCB24360 is an immunotherapy designed to amp up an immune system attack on cancer, while the checkpoint programs are designed to dismantle cancer cells' cloaking mechanism that prevents an assault from happening." The idea of the combination therapy approach above is/was the use of an immune system amper upper — Incyte's IDO1 inhibitor epacadostat (INCB24360) — to help/assist/partner with the back-end — immune checkpoint inhibitors or co-inhibitory blockade agents like anti-PD-1 and anti-PD-L1 agents from the above mentioned companies.

Last year, for example, Roche partnered up with NewLink and its IDO inhibitor (NLG919). Later, in 2015, Roche partnered with India's Curadev Pharma and its IDO inhibitor.

According to Chen and Mellman's 2010's Oncology Meets Immunology: The Cancer-Immunity Cycle, IDO inhibitors do not appear to be front-ends or immune system accelerators or amper uppers or stimulatory factors or agonists or co-stims but rather back-ends or inhibitors or antagonists.

Click to enlarge. Image source (Figure 2)

Possible or potential item takeaway: Incyte brought an immune checkpoint inhibitor in-house because...

• Combination therapies [of some sort] will become standard of care for advanced-stage cancer (eschewing [making obsolete] monotherapeutic use of immune checkpoint inhibitors)?

• It is better to own both parts of the pairing for various clinical and/or business reasons?

• If it is better to own both parts, differentiation of co-inhibitory blockade is more business (or marketing) than clinical?

• Win or lose, Bristol-Myers PD-1-related lawsuit against Merck is irrelevant (or its outcome de minimis)? "Every" biopharmaceutical company, including Chinese companies for their own domestic (as well as for international collaboration purposes), has or will have an immune checkpoint inhibitor?

September 1 / A new class of immunotherapy.

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If/when PV-10 stands on the cusp of approval (in T-Vec's case, while not certain, probable approval would occur by or before the drug's October 27, 2015 PDUFA date), it would be a new class of immunotherapy. And St. Luke’s University Health Network's Dr. Sanjiv Agarwala would be PV-10's Dr. Howard Kaufman, MD. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part I (July 13, 2015) on the blog's Current News page.

Possible or potential item takeaway: What is PV-10? An ablative immunotherapy? An autologous vaccine? An oncolytic immunotherapy? PV-10 has no specific target, receptor or pathway; however, this item cannot be properly discussed at the current time because knowledge and discussion presumably definitively relies on the presentation/publications of the results of Moffitt Cancer Center's mechanism(s) of action study due later this year. See August 29, 2015 blog post PV-10 has much better gas mileage.

September 1, 3 and 4, 2015 / Tinkering with Mother Nature. The official blog of AACR posted a 9/1 entry by Dr. Srivani Ravoori, PhD entitled Advances in Immunotherapy: Fine-tuning CAR T Cells. On 9/3 FierceBiotech's Carroll wrote an article entitled Novartis team tracks remissions of 4-plus years in a pioneering CAR-T study. In The Pipeline's Dr. Derek Lowe, PhD blogged CAR-T Follow Up on 9/4.

Ravoori wrote about scientists from the University of Pennsylvania and The University of Texas MD Anderson Cancer Center tinkering with the target-binding end of CAR T cells to make them safe for patients with solid tumors:

"CAR T cells designed to target CD19 in B-cell cancers are not selective. They cannot distinguish cancerous B cells that have high levels of CD19 from normal B cells that have physiological (lower) levels of the same protein. But this does not severely impede treating B-cell malignancies because a patient’s immune system can function even when normal B cells are depleted. This form of immunotherapy, however, is not readily adaptable to solid tumors because targetable proteins present on the cancer cells of solid tumors, such as ErbB2 and EGFR, are also present on normal cells that form the vital organs of the body. While losing normal B cells when treated with CD19 CAR T-cell therapy poses manageable side effects in a patient, loss of normal cells that are part of vital organs when treating solid tumors with CAR T-cell therapy can damage these vital organs, which has serious consequences. In fact, in a case report, CAR T cells designed to target ErbB2 present in metastatic colon cancer cells also attacked cells in the patient’s lungs that had low levels of ErbB2, resulting in severe toxicity and death. So, it became evident that if CAR T-cell therapy were to work for solid tumors, engineering T cells that can selectively target cancer cells and spare normal cells is inevitable." {Underlined emphasis is mine}

But, according to Ravoori:

Enter scientists from the University of Pennsylvania and The University of Texas MD Anderson Cancer Center, two teams that used different approaches to answer the same question: Will lowering the affinity of CAR T cells to the target protein make them selective to cancer cells that have high levels of the protein and spare normal cells that have low levels of the same protein? Based on the data the two teams published independently in the AACR’s journal Cancer Research, it appears the answer is “Yes.”

Carroll wrote:

Five years after the University of Pennsylvania began recruiting a small group of 14 patients with hard-to-treat chronic lymphocytic leukemia, researchers are still tracking three of them who are still alive with no signs of their cancer returning after being treated with a first-generation CAR-T therapy...Out of the 14, four experienced complete remissions, meaning their cancer was no longer detectable. One of those four later died of other causes. Four patients had partial responses, with two of them dying after 10 months and 27 months of therapy. One of the partial-response patients died from a pulmonary embolism, and the other was switched to a different therapy after 13 months and died after three years.

But, according to Carroll:

All of the patients who responded to the therapy experienced a potentially life-threatening case of cytokine release syndrome, sometimes called a cytokine storm, with the drug triggering high fevers and in several cases difficulty with breathing and low blood pressure. Doctors responded with the antibody drug tocilizumab and steroids, and all of the patients survived...In a small study like this, investigators can learn as much from failure as they can from success. Testing the 6 patients who did not respond, the scientists said that their customized T cell populations did not expand as aggressively as in the patients who were first flattened by a cytokine storm in their first response to the solo treatment. 

Finally, Lower wrote (about the Novartis study):

"So there’s definitely something major here, and definitely room to improve it. That’s what Novartis, and Juno, and Kite (and who knows who else) are frantically working to do right now. The biggest prizes are to extend this idea to more tumor classes, and to make it scalable to larger numbers of patients. The second one is a big challenge, and the first is even bigger. People have been antigen-hunting for quite a while now, looking for something that’s fit to turn the immune system on in other types of tumors, and it’s slow going. But you have to be sure, because if the immune system can strip a couple of pounds of aberrant white blood cells out of your system, so vigorously that it nearly overloads your kidneys, then it can do the same with lots of other tissues, too, some of which you might prefer to keep. Ripping out a couple of pounds of motor neurons or Kupffer cells would be suboptimal, to say the least."

Possible or potential item takeaway: Safety, specificity, durability? Questions UPenn/Novartis and MD Anderson are a long, long way from fully answering.

September 4, 2015 / A Rumsfeldian Perspective. Lowe, in his 9/4 blog post, wrote "People have been antigen-hunting for quite a while now, looking for something that’s fit to turn the immune system on in other types of tumors, and it’s slow going."

US Secretary of Defense Donald Rumsfeld was once quoted as saying"...because as we know, there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns – the ones we don't know we don't know."

As Provectus' Chairman and CEO Dr. Craig Dees, PhD has discussed with me almost from the beginning of my due diligence and share ownership (paraphrasing in Rumsfeldian), there antigens we know, antigens we don't know, and antigens we don't know we don't know.

And this knowledge or lack of knowledge (crucially relevant in the treatment of cancer because antigens equal targets) is but one aspect of Dees, President Dr. Tim Scott, PhD and CTO Dr. Eric Wachter's belief that killing cancer tumors in the correct way held the key to successful medical treatment because a proper approach could enable the immune system to stimulate cancer-killing cells throughout the body.

Properly destroying cancer tumors means killing only tumors and doing so completely, quickly and, very importantly, safely (that is, leaving healthy tissue unharmed). They believe this approach is the only effective way of sustainably stimulating a person’s natural anti-cancer defenses. Instead of bathing the entire body or even parts of it with radiation, or filling the bloodstream with oral or intravenous chemotherapies or present-day immunotherapies, Dees et al. firmly hold the position that stimulating the immune system is best achieved through treating tumor tissue by injecting into it a drug capable of destroying the entire tumor as quickly as possible without damaging surrounding healthy cells. Completely also means everything from visible tumor tissue to occult or hidden cells in and immediately around the injection site. Quickly means having the drug processed through and excreted from the body in short order. Antigens generated from the tumor destruction caused by drug injection then can be presented to the body’s cells responsible for selecting the best and most relevant antigens in order to encourage cancer-killing cells to replicate themselves throughout the body. Importantly, tumor antigens have to be viewed in context; physical tumor destruction techniques such as heating or freezing tissue destroyed fragile antigens and disrupted their relevant contextual structures. Disruption of cell membranes and removal of lipids, proteins, and complex carbohydrates destroy the antigens’ context, which is to what immune system cells respond. Thermal destruction denatures potential antigens, changing their chemical structure so that they were no longer representative of the tumor cell. In order to work rapid destruction of tumors has to preserve both antigenic structure and biological context. (Paragraph source, with slight edits by me for verb tense: MicroCap Review, pp. 6-8, September 2015)

Possible or potential item takeaway: For Craig et al. to have PV-10, and themselves, more fully recognized, all constituents of the biopharmaceutical ecosystem are going to have to embrace the above.

"PV-10 delivers greatest effects when all lesions are injected"

The title of an article published this week by medical writer Janet Fricker, who has written several times about PV-10, provided a cogent description of the drug's value proposition for its patient population afflicted with melanoma, and, eventually, I believe, for all solid tumor cancers: PV-10 delivers greatest effects when all lesions are injected, which discussed Provectus' completed Phase 2 trial data presented at ESMO 2014.

Because PV-10 is very safe, the more you give, the more you get. No dose limiting toxicity.

The article frames what might be expected from the upcoming pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma, in large part because of the trial's design whereby all lesions will be injected:

"The latest analysis reported at ESMO reveals that the subgroup of 28 patients who had all their lesions injected achieved a progression free survival of 9.8 months compared to 6.0 months for the seven patients who had a median of five untreated lesions. “The progression free survival of 9.8 months compares favourably with historical progression free survivals of less than 2.5 months for DTIC/TMZ,” commented Sanjiv Agarwala, the first author from St. Luke’s Hospital and Health Network, Bethlehem, Pennsylvania." {Underlined emphasis is mine}

The more lesions into which PV-10 is injected ("the more you give"), the more antigens are created and released, the more antigens then are presented, the more the immune system then is primed and activated, the more T-cells then are trafficked to tumors, the more T-cells then infiltrate tumors, the more cancer cells then are recognized by T-cells, and the more cancer cells finally are killed ("the more you get").

No dose limiting toxicity. PV-10 can deliver its greatest effect because it can be injected into all lesions until they (and occult cancer cells) go away.

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Provectus made a Form D filing on October 15th related to a possible financing of up to $15 million through Network 1 Financial Securities. I previously wrote about this two weeks ago. See Fundraising (October 3, 2014) and Fundraising -- Updated (October 4, 2014) on the blog's News page. The filing noted: "Sales in the offering will be staged incrementally at the sole discretion of the Company."

It has been said the company could require additional cash to meet requested or demanded requirements of the New York Stock Exchange and/or Provectus' accounting firm BDO. Be that as it may, Provectus concurrently is trying to close a regional license transaction with Chinese pharmaceutical distributor Sinopharm and garner sufficient payment at the signing of a definitive agreement in order to obviate the need to raise money via Network 1.

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A deal structure that potentially may provide insight into Provectus' discussions with Sinopharm is Celsion's 2013 license deal, ultimately not consummated, with Zhejiang Hisun Pharmaceutical Company ("Hisun) for China. This deal was constructed as:

• $25 million at signing of a definitive agreement (Celsion previously received $10 million from two payments, which then were credited against the signing amount),
• $55 million in upfront milestone and regulatory milestone payments over 18 months,
• $45 million in sales target milestone payments, and 
• Escalating double-digit sales royalties over ten years.

Because no further or amended Form D filing has been made as of this writing (to disclose Provectus took in money from the above mentioned offering), I assume Peter is able to "hold off" the NYSE and/or BDO for a period of time until he can ascertain what cash he would receive from Sinopharm upon signing of a definitive agreement (should such a license transaction be completed).

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St. Luke's Cancer Center's Dr. Sanjiv Agarwala, M.D. is presenting at 5:30 pm local time (5:30 am EST) on October 18th (today) at the 2014 Beijing International Melanoma Congress. See 2014 Beijing International Melanoma Congress (October 7, 2014) on the blog's News page. An interview with Peter conducted by BioMedReports, which discussed the Provectus-Sinopharm memorandum of understanding, was published on October 16th. I very much dislike Provectus raising this topic beyond the initial press release of August 18th (much like they repetitively mentioned their breakthrough therapy application earlier this year). Nevertheless, the interview, likely conducted this week, and proximate to Dr. Agarwala's presentation, at which I imagine Provectus principals and/or advisors should be in attendance, contained some noteworthy items, among them:

"We will be able to assign the license agreement and will control the supply chain unless we agree to do otherwise." Being able to assign the license to an end-game acquirer is an important Provectus-Sinopharm contract item. Under what circumstances would Provectus agree to relinquishing supply chain control? I would think Provectus would consider this only in the context of Big Pharma discussions about a transaction for the company, and only in conjunction with a global partner that has an existing (e.g., Pfizer's 2012 national retail strategic cooperation framework agreement) or planned partnership with Sinopharm.

"Also, PV-10 as an anti-tumor agent that is injected is very appealing to the China and India patient population and their caregivers."

Peter also replied, in answer to the question of what is the object PVCT has in doing business in Asia: "For our signature drug, PV-10 to treat liver cancer, most of the liver patients are in Asia versus the US or Western Europe." I think it's obvious the Chinese, in this case Sinopharm, are more interested in seeing or confirming the final and/or filed liver protocol for a Provectus Phase 2 liver trial than they would be in a filed protocol for the Phase 3 melanoma trial.

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Returning to the Celsion deal structure, it seems to me the nature of the discussions and negotiations between Provectus and Sinopharm probably now revolve around how much of near-term money is available (from Sinopharm) to be paid (to Provectus) at (i) signing of a definitive agreement and (ii) upon checking of whatever box(es) to be deemed an upfront payment. This matters for both substantive and cosmetic reasons. For example, more money sooner is better than the same money later...duh. More money sooner makes a bigger splash. All of this assumes the other compoents of the deal structure are sufficiently good.

Ultimately, Provectus shareholders want management to close a good deal that is well structured, and not contrived. Management has not reached for nor agreed to [very likely informal] deal offers in the past that poorly valued their innovation. I do not expect them to start settling now.

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On October 15th the company issued another press release about Moffitt's presentation at the annual meeting of SITC in early-November, and filed an associated 8-K. Of note was the comment Moffitt's poster will be available and presented at two sessions, during the regular poster viewing one and at an evening Presidential reception. In addition, Craig's obligatory quote contained a couple of potentially notable words and phrases, which I hope ultimately are indeed notable.

“Dr. Pilon-Thomas and her team at Moffitt have been doing very interesting work assessing the potential combinations of PV-10 with immune checkpoint inhibitors for melanoma. Their work may be an important step forward as part of our corporate strategy for addressing unmet need in late stage melanoma patients and in other uses of PV-10.” {Underlined emphasis is mine}

I suppose “very interesting” means unprecedented and unique in scientific parlance? Does “other uses” means other indications (like breast cancer, which was included in Moffitt's AACR 2013 poster: Intralesional Injection with PV-10 Induces a Systemic Anti-tumor Immune Response in Murine Models of Breast Cancer and Melanoma)?

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Finally, in a press release and associated 8-K filing on October 16th Provectus confirmed Dr. Agarwala's presentation of PV-10 clinical data and value proposition (as a monotherapy and in combination) as part of a satellite session sponsored by Amgen and titled “Oncolytic immunotherapy – engaging the immune system to target melanoma” on November 15th at the 11th International Congress of the Society for Melanoma Research in Zurich, Switzerland. See Melanoma Congress 2014 (October 15, 2014) on the blog's News page.

Dr. Agarwala's continues his three-month world tour of Spain (September 28th), Russia (October 12th), China (October 18th) and, now, Switzerland (November 15th). Medical oncologist Agarwala may see the potential opportunity to enhance his position as a global key opinion leader with the success of PV-10 as a monotherapy for earlier stages of disease.

Medical oncologist and Moffitt Cancer Center's Dr. Jeffrey Weber probably sees the potential opportunity to further enhance his position as a global key opinion leader responsible for translating investigational compounds into approved drugs with the success of PV-10 in combination with immune checkpoint blockade (inhibitors) for late stage disease. That, however, is for a later discussion and debate once we learn more about Moffitt's presentation and data at SITC 2014 on November 8th.

“We should see a difference very quickly between PV-10 and chemotherapy responses”

Medical writer Walter Alexander, who has written several articles and stories about Rose Bengal, PV-10 and Provectus (such as here, here and here), penned another article, Cutaneous, Locoregional Melanomas Show High, Rapid Responses to Injection With Rose-Bengal Solution: Presented at ESMO Congress (October 2, 2014). I found the following noteworthy and repeating.

Intralesional injections of PV-10 accumulate rapidly in tumour lysosomes, causing lysosomal rupture within 30 to 60 minutes and subsequent tumour-cell rupture, noted lead investigator Sanjiv Agarwala, MD, St. Luke’s University Hospital & Health Network, Bethlehem, Pennsylvania, speaking here at a poster session on September 28. Research has shown subsequent tumour-specific T-cell responses to occur within 7 days, he added. {Underlined emphasis is mine. 

 I added the illustration below from Provectus' ESMO 2014 poster for effect.

Click to enlarge.

In the All Lesions Treated group, 121 complete responses were observed after 1 injection, 84 complete responses after 2 injections, 22 complete responses after 3 injections, and 5 complete responses after 4 injections. 

I added the illustration below from Provectus' ESMO 2014 poster for effect. Note the drug's 74% complete response, and that PV-10 was last allowed at week 16. In Amgen's talimogene laherparepvec's ("T-Vec's") pre-specified retrospective analysis of tumor-level responses from its pivotal Phase 3 trial, T-Vec achieved 47% complete response (almost 4000 lesions were included in the analysis).

Click to enlarge.

Progression-free survival in the All Lesions Treated group was 9.8 months. In the uninjected Bystander Lesion group from the original trial, progression-free survival was 8.9 months.

I added the illustration below from Provectus' ESMO 2014 poster for effect. Note PFS calculations are consistent with RECIST 1.1.}

Click to enlarge.

“We should see a difference very quickly between PV-10 and chemotherapy responses,” Dr. Agarwala added.

From my news item How much is enough, and when? (September 16, 2014): In the upcoming Phase 3 trial Provectus will measure PFS as the trial's primary endpoint, utilize RECIST 1.1 to measure it, and inject patients every two weeks until CR or PD is achieved (i.e., the duration of the treatment interval will be until one of the two outcomes is achieved). It then could be reasonable to project a PV-10 arm PFS of 12 months for a 12-month observance period, 9 months for a 9-month period, 6 months for a 6-month period or 3 months for 3-month period -- where, at best, the PFS and its confidence interval are the same line, or, at worst, the CI is a narrow band around the PV-10 PFS figure, which itself would be a horizontal line at 1.0 or 100%. Thus, patients with all of their disease treated by PV-10 would never progress, while patients in the control arm (those treated with DTIC or TMZ) would suffer progression as historically demonstrated through prior use and over many previous clinical trials.

Click to enlarge.

Approximately 1 third of patients with melanoma are diagnosed with predominantly locoregional disease.

From my news item PV-10 is tantamount to surgery? (September 5, 2014): The silent masses who make up the bulk of patients with melanoma (and the much larger addressable market), however, remain without effective options:

Click to enlarge.
SEER Stat Fact Sheets: Melanoma of the Skin, National Cancer Institute

Provectus' ESMO 2014 poster (Updated)

A blog post about Provectus' abstract at the 2014 European Society for Medical Oncology Subgroup efficacy in patients receiving intralesional rose bengal to all existing melanoma in phase II study PV-10-MM-02, may be found here. The poster was presented yesterday in Madrid, Spain. The company's press release on it and the associated 8-K filing are here and here, respectively. The focus of the ESMO poster, as with the ASCO poster, was the subgroup All Melanoma Followed of the metastatic melanoma Phase 2 trial highlighted in yellow below, and the two sub-subgroups Bystanders Untreated and All Lesions Treated. The abstract initially stated:

"The high rate of symptom control in refractory patients, manifest in CR of injected lesions after minimal intervention, was the basis for a breakthrough therapy designation application to the US FDA based on the 28 patient “all treated” subgroup..."

The poster notes Provectus is working with ERT to address the measurement and reporting of patient reported outcomes ("PROs"), a secondary endpoint of the upcoming pivotal Phase 3 trial.

The abstract also stated:

"...and implications of the Agency’s ruling on this application will be presented."

These implications appear to be the enablement of the Phase 3's study design through, per the poster:

• "Facilitating dialog with regulatory authorities on patient population and endpoints
• Suggesting a substantial PFS advantage for PV-10 over historical data on comparator
• Enabling optimization of PV-10 dose schedule"

Changes in the Phase 3 trial design in the ESMO poster compared to the ASCO one include:

• An estimated sample size of 219 (compared to 210),
• Four week treatment cycles (PV-10 or DTIC/TMZ) during initial 12 week treatment phase (compared to three week), and
• [From a poster perspective] the reordering of secondary endpoints placing patient reported outcomes ("PROs") above overall survival ["OS"] (compared to OS above PROs)

The poster also teased the upcoming Moffitt murine model work to be presented on a poster at SITC in November (sub-titled in the ESMO poster's conclusion PV-10 with Immune Checkpoint Blockade for Widely Metastatic Disease):

• "Emerging immunology data supports T-cell mediated tumor-specific response secondary to PV-10 ablation
• Data to be presented in November on IL PV-10 in combination with immune checkpoint blockade in melanoma models may indicate clinical studies are warranted
• Design of a Phase 1b/2 combination study is underway"

Contrast the ESMO 2014 poster conclusion below...

Click to enlarge.

...with the ASCO 2014 poster "Path Forward" section below.

Click to enlarge.

Updated 9/30/14: There are several aspects of the poster/press release that warrant further discussion, and they appear cleanly identified by the PR's four quotes.

PR quote #1: Commenting on the poster, Dr. Agarwala said, "Although the primary ablative effect of PV-10 can lead to rapid regression of injected lesions, durability of response may signal the effects of an immunologic process secondary to ablation. In addition to offering the potential to relieve symptoms of cutaneous melanoma, a robust, tumor-specific immunologic response could have the potential of changing the course of the disease." {Underlined emphasis is mine.}

Dr. Agarwala, from St. Luke's University Hospital/St. Luke's University Health Network of Bethlehem, Pennsylvania, addresses two points. First, he notes the durability or length of PV-10's response on lesions following injection (noting the last allowed injection was at week 16). Durability and durable benefit should materially contribute to long-term survival and benefit. The associated poster portion is below.

Click to enlarge

Second, Agarwala addresses both components of PV-10's two-step mechanism of action, (a) rapid ablation and (b) immunomodulation. The associated poster portion is below.

Click to enlarge.

In each case, his comments contextualize cutaneous melanoma -- the most common type of melanoma -- and PV-10's role in defeating or containing it. Defeat would come through complete response. The FDA, however, wanted, at the time of breakthrough therapy designation ["BTD"] application, and wants, via the upcoming pivotal Phase 3 trial, the association (correlation) between complete response and symptom control more fully elucidated. Containment comes through demonstrating that if you truly effectively treat disease in Stage III (or, of course, earlier or much earlier), it forestalls or prevents it from progressing to Stage IV. See blog post Treating Cancer, and news item How much is enough, and when? (September 16, 2014).

Quote #2: Eric Wachter, PhD and Chief Technology Officer of Provectus, said, "We are very pleased to share the patient-level PFS data at ESMO that defined our design parameters for the upcoming phase 3 trial. These study results demonstrate the potential of an intralesional approach to delay progression while alleviating symptoms of locally advanced melanoma." {Underlined emphasis is mine.}

The underlined sentence above asserts the clinical value proposition of PV-10 as appropriate for the treatment of local disease, the vast majority of the melanoma market and comprised of the silent masses for which surgery, chemotherapy, etc. are their only options.

Quote #3: Wachter continued, "We are looking forward to initiation of the phase 3 trial and have assembled an experienced multi-disciplinary team to help us execute this important study. For example, we are thrilled to collaborate with ERT, Inc., experts in quantifying patient reported outcomes for pivotal oncology trials, and expect this collaboration to help place Provectus at the forefront in the study of cutaneous symptoms of locally advanced melanoma." {Underlined emphasis is mine.}

It seems to me the secondary endpoint of PROs is quite important for this patient population indicating cutaneous symptoms of locally advanced melanoma, and is addressed by Agarwala and Eric. Interestingly, and I suppose not the least bit ironically, there does not appear to be medical literature that tabulates and documents that if you stop melanoma at Stage III (when, generally speaking, if you effectively and comprehensively treat the patient you can save him or her) it won't progress to Stage IV. Potential innovational cancer drug treatment progress like PV-10 still seems to boil down to having to show that effective local treatment (where the treatment does not have to be systemic) can be a good thing. It would seem only Provectus is doing this approach of studying cutaneous symptoms in relation to ablation, and ultimately having the goal of showing when disease (melanoma) is ablated in Stage III it is forestalled from getting to Stage IV.

Quote #4: Wachter concluded, "[i] The data presented at ESMO were fundamental in allowing us be in a position to commence pivotal testing of PV-10 in locally advanced melanoma patients. [ii] Furthermore, understanding the bystander effect is critical to rational combination of PV-10 with systemic drugs in patients with significant disease inaccessible to intralesional injection, and [iii] we look forward to seeing additional data on this important topic in coming months." {Parenthetical numbering is mine.}

i. I presume this sentence refers to implications in the abstract where Provectus wrote (see underlined emphasis below): "The high rate of symptom control in refractory patients, manifest in CR of injected lesions after minimal intervention, was the basis for a breakthrough therapy designation application to the US FDA based on the 28 patient “all treated” subgroup, and implications of the Agency’s ruling on this application will be presented." The FDA's BTD denial letter referenced a determination "...based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding)..." According to the portion of the ESMO poster below (this portion also was part of the company's ASCO 2014 poster), only 13 patients in the All Melanoma Followed (N=54) provided trackable data related to symptomatic status. How many of the subset of this group, All Lesions Treated, the basis for the BTD application, provided trackable symptomatic information? In hindsight, the answer was not enough. Eric understood it to be a "measured risk" (a phrase from the company's May 23rd conference call) to submit for BTD without enough symptomatic data; however, as he said on the same call, "...our logic seemed clearer that if we were making the patients' tumors disappear in 50 percent of the patients that was a very large effect size, and that was tantamount to making any symptoms that they might have been suffering from the tumor burden disappear."

Click to enlarge.

ii. The bystander effect represents PV-10's immunologic activity, locally in terms of (a) locoregional blistering, which Provectus believed "...may be indicative of nascent local immunologic response" (ECCO 2013) and, I believe, (b) pathologic complete response (ASCO 2014), where presumably even occult cells are destroyed, and systemically. Understanding this immunologic activity, in terms of the steps of the cancer immunity cycle that PV-10 promotes, and seeing more data will be key to the interest of Big Pharma wishing to combine their immune checkpoint inhibitors with PV-10. As the global development team leader of an immune checkpoint inhibitor said to me: "I'm not familiar with hard data on PV-10 having strong immunologic properties...However, if [it] does generate significant anti-cancer immune responses that are inhibited by [their immune checkpoint inhibitor], then such a combo could make sense."

iii. Teasing Moffitt Cancer Center's presentation at SITC 2014, and possible related data publication(s) prior to this conference.

#ESMO14: Subgroup efficacy in patients receiving intralesional rose bengal to all existing melanoma in phase II study PV-10-MM-02

The abstract of Provectus and its principal investigators from the company's metastatic melanoma Phase 2 trial was posted today on the 2014 European Society for Medical Oncology's conference website. The ESMO 2014 conference runs from September 26th to 30th in Madrid, Spain, and Provectus' poster is slated for the 28th. The poster is an extension of/related to the company's 2014 American Society of Clinical Oncology annual meeting poster Efficacy of intralesional rose bengal in patients receiving injection in all existing melanoma in phase II study PV-10-MM-02, where the sub-group of "All Melanoma Followed" (n=54 [out of 80]) was highlighted, together with the "Bystanders Treated" (n=26) and "All Lesions Treated" (n=28) sub-sub-groups. Both posters ultimately derive, in my view, from Provectus' 2013 European Cancer Congress poster Locoregional Disease Control in Metastatic Melanoma: Exploratory Analyses From Phase 2 Testing of Intralesional Rose Bengal.

The ESMO 2014's abstract's conclusion reads:

Recurrent locoregional melanoma can be a source of persistent morbidity, including disfigurement frequently accompanied with pain, ulceration, bleeding and infection. The high rate of symptom control in refractory patients, manifest in CR of injected lesions after minimal intervention, was the basis for a breakthrough therapy designation application to the US FDA based on the 28 patient “all treated” subgroup, and implications of the Agency’s ruling on this application will be presented. Although the primary ablative effect is responsible for CR in injected tumors, durability of response and bystander response implicate an immunologic mechanism of action secondary to ablation. {Underlined emphasis is mine}

More information may or will of course be forthcoming on the conference poster, such as:

• Potentially, further details on the upcoming pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma,

• Curiously, the implications of the FDA ruling on Provectus' breakthrough therapy application, and

• Specifically, more data on the All Disease Treated sub-sub-group, such as durability of response.

"Intralesional Rose Bengal in patients receiving injection of all existing melanoma"

In the video below, Dr. Agarwala discusses PV-10, and Provectus and Moffitt's ASCO 2014 posters.

I think Dr. Agarwala raises a key point. Many Phase 2 patients in Provectus' PV-10 trial were elderly, and received multiple prior therapies and treatment for melanoma that did not work (a "fairly refractory group of patients"). See below; the median number of prior treatments was 6.

Click to enlarge

Despite treating patients who appear to have run out of answers and solutions to treat their melanoma before finally receiving PV-10, and presumably having weakened or compromised immune systems, PV-10 nevertheless generated an objective response rate ("ORR") of 51% and achieved a complete response ("CR") of 26% in injected lesions, as well as a 54% ORR in non-injected lesions and a 23% CR in them. Or, about half of the patients in the trial had their tumors shrink (had a response), and a quarter of patients had their tumors shrink completely (go away). Additionally, more than half of the patients had non-injected tumors shrink (had a response), and about a quarter had their non-injected tumors shrink completely (go away).

"Of the 13 consented patients [in Moffitt's feasibility study], 5 had no previous treatment, 6 received ILI or ipilimumab [sold as Yervoy], and 2 received PD-1 blocking antibody; 6 received two or more prior systemic therapy." ILI refers to isolated limb infusion. Other systemic therapies included vemurafenib (sold as Zelboraf), temozolomide or "TMZ" (an orally administered systemic chemotherapy), and carbotaxol (another systemic chemotherapy).

It would seem Provectus' pivotal Phase 3 trial may prove PV-10 has the potential to be better (much better) than what's available today and on the horizon for patients, both in terms of "new melanoma drugs" (e.g., anti-CTLA-4, BRAF and anti-PD-1 agents) and standards of care (i.e., systemic chemotherapy). In particular, the trial would take patients that have progressed on systemic immunotherapies (i.e., anti-CTLA-4 and anti-PD-1 agents), have not responded to them, or cannot receive them.

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.

$PVCT Going For The Deep Ball

My post entitled Counting Down elicited several inquiries from blog readers exclusively focused on whether or not Provectus had submitted a breakthrough therapy designation application ("BTD") to the FDA. The collection of opinions I sought over the last few days varied from "no" to "yes." Dot 1: I lean towards "yes."

On Friday, I was trying to verify a rumor that Peter was in China. He previously had been in Europe (Amsterdam) attending ECCO 2013, followed up by various investor and shareholder meetings (from what I gathered listening to several people). Dot 2: Follow-up suggested it was not likely he in China, but was he somewhere with the Chinese (i.e., Eddingpharm and/or Hisun-Pfizer)?

Speaking of ECCO 2013, on Friday, two more articles emerged from the conference about Provectus' poster presentation: FirstWord Pharma's Intralesional PV-10 Shows High Response Rate in Advanced Melanoma, Evidence of Systemic Effects and ecancer News' PV-10 in Metastatic Melanoma: blistering predicts good outcomes. The latter was written by the same author who penned Wednesday's PharmiWeb.com's Metastatic Melanoma: blistering in PV-10 treatment predicts good outcome. Like with the first article, there were some interesting content and quotes, by Dr Agarwala and, this time, Eric.

"“The principle is that this agent has a local chemoablative effect, one where we believe it enters into lysosomes causing local necrosis, and sometimes blistering of the lesion -- and then, in some patients, a systemic effect that we believe is immunologically mediated,” Dr. Agarwala explained. Further evidence of systemic effects, he noted, comes from a 54% complete plus partial response rate in uninjected “bystander” lesions." FirstWord article. Bold emphasis mine.

"Dr. Agarwala proposed 3 possible scenarios for PV-10 use -- for if and when it receives approval. First, it might be used in patients who are refractory to all other therapies and who have injectable disease. Second, it might be used in patients who have injectable lesions but who are not eligible for systemic therapy (e.g., the elderly or those with comorbidities). Third, it might be used in combination with other therapies (e.g., ipilimumab or nivolumab or both). “Of course, all of these need to be tested in clinical trials,” he said. A further option for PV-10 use, Dr. Agarwala added, would be in an attempt to turn unresectable lesions into resectable ones. “Beyond this, many of my surgical colleagues are interested in the idea of using PV-10 to stimulate the immune system before surgery to potentially lower the odds of recurrence,” he commented." FirstWord article. Bold emphasis mine.

"“Now we have the mechanistic explanation for our bystander effect, that we’re inducing a highly-specific T cell mediated response,” said Wachter. Data on the immunological mechanism of action, he added, suggested that PV-10 might be particularly relevant for patients with inhomogeneous clonal populations." ecancer article. Bold emphasis mine. As clarification, according to Eric, "inhomogeneous" and "heterogeneous" have equivalent meanings in this context.

You may recall my posts on tumor heterogeneity, such as $PVCT: #Tumor Heterogeneity. I’ve previously written that to understand PV-10 is to understand the relationship between chemoablation and immune-mediated signaling. It's what Craig means when he says the immune system responds in direct proportion to the degree of insult. Think of PV-10 chemoablation as the proxy for the degree of insult, which is rapid, complete and durable in the case of PV-10. But when Craig describes his approach in this way, what is he really getting at? How did he approach tackling or solving tumor heterogeneity?

Tumor heterogeneity is a critical problem. In any given cell there are, say, 15,000 unique mRNAs at any given second. A few seconds later, illustratively, 15,000 new ones. There are, for example, at least 15,000 to 20,000 unique proteins on a membrane surface at any one time. These change continuously. Does picking one of them to form the basis of a cancer treatment make sense? Does targeting a specific antigen as a holistic solution make sense? Heterogeneity is so wide, trying to target a specific antigen might be tough if not hopeless task. A needle in a haystack? Maybe a needle in an entire whole galaxy. Treating as many tumors as you can with PV-10 intratumorally achieves two significant positive outcomes. First, you lower the patient's overall tumor burden so as to allow the immune system to work better. Second, you allow more of the heterogeneous antigens (from the injected heterogeneous tumor) to be seen by the immune system. The more tumors treated by PV-10 the better.

Consider a 2012 article by Zhang and Austin, Physics of Cancer: The Impact of Heterogeneity (Annual Review of Condensed Matter Physics): "It is a common mistake to view cancer as a single disease with a single possible cure which we have just not found yet. In reality cancer takes on many forms that share a common symptom: uncontrolled cell growth and successful invasion of cancer colonies to remote regions of the body. The key reason why we may never be able to defeat cancer may lie in the extreme heterogeneity of the population of the cells in a tumor: there is no one magic bullet." This link, if you click on it, automatically will download a copy of the article.

Friday's statements dovetail with Wednesday's article's final sentence: "Provectus Pharmaceuticals believe they now have sufficient data to seek regulatory approval for PV-10." I've written about this before, and it seems even more clear. Management is seeking approval for the use of PV-10 in patients (metastatic melanoma Stage IIIb and IIIc) who are refractory to all other therapies and who have injectable disease because the data showed results: "...[f]or all subjects, BORR was 51% (26% complete response, 25% partial response) with the amount of tumour burden accessible to PV-10 injection prognostic for outcome." Furthermore, Provectus demonstrated clinical response predicted outcome in another way: "“If blistering occurs you can reassure patients that they’re likely to achieve a good response. It provides further evidence for an immunological basis for the mechanism of action.”" Dot 3: Management is seeking approval of PV-10 for this "narrow" label or claim, something that has become more obvious, at least to me, only over the last few months.

But how does Dot 3 relate to BTD? It's here where and about this I am fuzzy. Is Provectus seeking outright approval of PV-10, for the narrow claim above, under the BTD umbrella or separate from and in addition it? Did management simply move beyond the SPA, obfuscating its non-pursuit pursuit, to focus on what they've been trying to do since 2010, which is/was to convince the FDA to approve PV-10 for the narrow label of patients who are refractory to all other therapies and who have injectable disease.

I don't think just asking or focusing on whether the company submitted the/a BTD application alone or in a vacuum is productive or fulfilling. What else would be necessary to gain approval? Completing certain key elements of a new drug application ("NDA") filing? It's a topic I've queried management about for several months.

If Peter continues to speak with the Chinese (and the Indians), what then would be the ramifications on regional deal valuations and payment components of outright approval of PV-10? Again, it gets a little fuzzy here for me. Provectus is seeking outright approval of PV-10 for patients who are refractory to all other therapies and who have injectable metastatic melanoma, the company's lead indication. Yet, the lead indication for discussions with the Chinese and Indians is liver cancer ("HCC," or hepatocellular carcinoma). What then are the ramifications of an approval for melanoma, and/or BTD for it, on discussions related to HCC?

You'll recall Peter's slip of the pen, so to speak. In my post entitled And Now For Something Completely Different: $PVCT I wrote: Peter's TWST transcript revision is interesting. It was changed from "So our goals are to be in a Phase III trial in melanoma or submitting for FDA approval, and to be in Phase II in liver cancer, potentially with breakthrough therapy designation, because we have also filed the application for breakthrough therapy designation in both the melanoma and liver indications" to "So our goals are to be in a Phase III trial in melanoma or submitting for  FDA approval, and to be in Phase II in liver cancer, potentially with breakthrough therapy designation, which means an application for breakthrough therapy designation in both the melanoma and liver indications." Dot 4: How can regional license discussions advance on the basis of the sparse liver information made available by Provectus thus far?

I'm not saying the company has submitted BTD applications for melanoma and liver cancer. Still, what happened to progress towards the expanded Phase 1 HCC trial comparing sorafenib and sorafenib plus PV-10? Haven't one or a couple of patients (?) or more (?) been enrolled and treated? Haven't more sites (?) been added to the existing ones in San Diego (Sharp Memorial Hospital) and Florida (The Southeastern Center for Digestive Disorders & Pancreatic Cancer)?

In my investment letter posted on Seeking Alhpa, I wrote in regards to if I am wrong what would that scenario look like, management could be unable to monetize Provectus at a valuation commensurate with their innovation. In his TWST interview, Peter said management believes they "…could potentially do something along the lines of a Celgene-Abraxis type transaction, where Celgene acquired Abraxis for $2.9 billion upfront…" Bridging the valuation gap between Friday's $113 million market capitalization and a multi-billion payout will require definitive regulatory clarity, sizable commercial validation, and a copious amount of stock market exuberance. Dot 5: What exactly are the terms of a China deal (and/or of an Indian one, which I think mirrors the Chinese deal, or vice versa) in light of a focus on liver as the lead indication rather than melanoma?

I presume management is striving to protect the economics, particularly for HCC, which is the third leading cause of deaths related to cancer in the world. I had heard, albeit not verified by any stretch, that regional value components were in the range of $10 million upfront and $40-50 million upon some indeterminate regulatory clarity. That seems light to me, which makes me wonder just exactly what is management negotiating (and seeking) and how much money gets unlocked when regulatory clarity arrives.

A Hail Mary pass, "a very long forward pass in American football, made in desperation with only a small chance of success," by definition, is a deep ball (in U.S. football parlance). A deep ball is not a Hail Mary pass. A deep ball is a pass attempt over 20 yards in distance, and can be a key aspect part of a successful offensive strategy. With good to great X and Z wide receivers, defenses can't necessarily stack the box to stop the run, or overly focus on the slot receivers or tight ends running routes in the middle of the field. Of course, you have to have a good running game to which you commit, and capable slot receivers/tight ends. But well schemed offenses thoughtfully employing deep balls catch defenses napping and often lead to touchdowns when well executed.