Awareness of $PVCT is clearly growing

Provectus' media/communications profile has resulted in this blog being more closely associated with the company, PV-10 and their digital brand. Google "Provectus Pharmaceuticals" and the blog shows up in the top 10 search results returned. Most searches with Provectus + [another word related to oncology or dermatology] may well result in a list that includes one or more blog posts. Thus, tracking unique visitors to the blog, I think, might be a decent proxy for tracking awareness of the company.

At the blog's first anniversary, readership statistics were:

After only 6 months following that date (November 16) -- that is, November 17, 2012 to May 16, 2013 -- readership statistics like unique visitors are nearly the same. Blog readership over the last 6 months has nearly matched readership over the blog's first 12 months.

The point I wish to make here is that while the share price has lagged, awareness of Provectus and PV-10 (measured through unique visitors to this blog) has steadily grown.

Just Put Some [of $PVCT's] PH-10 On It

From My Big Fat Greek Wedding. Toula Portokalos: [narrating] My dad believed in two things: That Greeks should educate non Greeks about being Greek and every ailment from psoriasis to poison ivy can be cured with Windex.

I am, of course, relentlessly bullish on rose bengal, and thus PV-10 and PH-10; in the case of PH-10 for inflammatory skin disorders, a topical agent with what appears to be a very high or, literally, no dosing limit.

Peter said "We are pursuing translational research with PH-10 comparable to that underway with PV-10 to clarify the regulatory and commercialization pathways of PH-10."

Translational research? As we saw with Moffitt's work (among others, including Provectus'), answers were provided to questions about PV-10, such as how does PV-10 do what it does, or what is PV-10's clinical relevance -- how and when do you use the drug. Very effective. Very safe. Regular, frequent use. Locoregional monotherapy. Systemtic benefit. Anti-tumor immunity. Tumor-specific immunity. Combination therapy for inaccessible tumors.

By doing this translational research work, Moffitt provides Provectus with a key piece of data, information and knowledge to convince the FDA of PV-10's benefit and explain the drug's clinical relevance to Big Pharma. Both drive value.

Derived from the same active ingredient, why would one think any differently of PH-10? Such translational work is being done at a world-renowned university in a laboratory whose head has a world-class reputation with the FDA. I connected the dots. This work may well be completed by now, or it may soon be completed.

An Inflection Point in $PVCT Data

We finally may have reached the long-awaited inflection point in Rose Bengal data (PV-10 & PH-10).

Management thinks 2013 marks a turning-point in how Provectus is regarded by the FDA, Big Pharma and medical community key opinion leaders (KOLs) vis a vis "the data:" MM Phase 1 & 2, Breast Phase 1, HCC/liver Phase 1, inflammatory skin disorder Phase 1/2, Moffitt murine model immunology, Provectus murine model combination therapy, and the compassionate use program.

That's not to say more data is not very desirable: MM Phase 3 (if necessary), breast Phase 2, pancreas Phase 1, skunk works success by Craig with another key indication, Moffitt human immunology, and Moffitt-like immunology (and also toxicity) investigational work into PH-10 by a world-renowned university whose laboratory head has a world-class reputation with the FDA.

$PVCT: $CELG's blockbuster dreams fade as apremilast PhIII fails to excite

FierceBiotech: Celgene's blockbuster dreams fade as apremilast PhIII fails to excite

Reading The WSJ and FierceBiotech articles makes me wonder if Celgene is talking to Provectus about PH-10.

$PVCT #Horse #Race (updated)

Last updated here.

Article: Effective Topical Agents and Emerging Perspectives in the Treatment of Psoriasis

A mention of Provectus and PH-10.

One of the authors (Andrea Chiricozzi) is from the Laboratory of Investigative Dermatology at The Rockefeller University.

Craig is a heretic. He does not believe psoriasis is an autoimmune disease, but an infection. He also believes other so-called autoimmune diseases are infections (or begin as one). For example, Crohn's disease is initiated by infection with mycobacterial pseudotuberculosis. Similarly, Craig believes psoriasis is caused by a gram positive bacterium on the skin that produces an exotoxin (e.g., a corynebacterium similar to corynebacterium diphtheriae), which causes cell proliferation. For psoriasis  we see disorganization of the outer skin layer and increased cellular proliferation in the germ layers. We also see small pus pockets beneath the stratum corneum. Full of polymorphonuclear leukocytes (PMNs), these cells go after bacteria. Craig thinks autoimmunity is more hypersensitivity to something. Those with it have a hypersensitive immune system that is overreacting to something that basically is normal flora, cleared or ignored by everyone else. Hence, he agrees with the immune discussion in this paper, for example, is correct. But, it's not the cause, just the result.

$PVCT: A Contrarian Indicator?

The post below was written last week by SG, a long-time poster on the Silicon Investor PVCT chat board.

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He first started contributing to the board in May 2006, noting his buys around that time (1st orange oval), perhaps in the $1.50-2.00 per share range. SG later wrote about his buys when the stock made an all-time high (intraday: $3.05, closing: $3.00) in September 2007 (2nd orange oval), perhaps in the $2.50-3.00 per share range.

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Last week, after holding Provectus shares for about 6.7 years, SG wrote he sold all but a 1,000 shares, perhaps in the $0.55-0.60 per share range (blue arrow), several cents above the stock's all-time closing low ($0.52). The intraday low was $0.43.

In reading his post, I was struck by its similarity to the magazine cover indicator, "which says that the cover story on the major business magazines, particularly BusinessWeek, Forbes and Fortune in the United States is often a contrary indicator."

Technical analysts often talk about a market washout -- a large share price plunge on above-average volume -- that clear the markets of bearish sentiment and help mark the/a major bottom.

It's quite possible Provectus' bottom, either in share price or market irrelevance or both, was quietly, perhaps a tad ignominiously, and most irrelevantly marked by the departure of SG, a retail investor who believed at one time but believed no more.

But no one really knows in the moment that a contrarian indicator (or any indicator for that matter) is indeed an indicator. With the benefit of hindsight, it always is.

Management has set several expectations for a busy calendar quarter (1Q13) that should have positive impacts on the share price. Let's see how the rest of this month and February shape up in that regard.

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I continue to perform due-diligence with KOLs relative to Provectus' value proposition, and will have more to share on that topic in due course.

$PVCT: Horse Race (updated)

Last updated here. For the moment, I returned the first group of horses to all being equally close to the finish line. In the second group, India, since my last update, has pulled ahead of Japan.

$PVCT: Horse Race (updated)

Last updated here. The horse race above is a snapshot in time. Horses surge ahead, they fall behind, they come out of nowhere. Sometimes, we don't know the outcome until they cross the wire. I adjusted some of the positions slightly to reflect more nuance and opinion.

$PVCT: Horse Race (updated)

Last updated here. The horse race above is a snapshot in time. Horses surge ahead, they fall behind and, sometimes, they come out of nowhere.

Sonodynamic Excitation of Rose Bengal for Eradication of Gram-Positive and Gram-Negative Bacteria

Read more here.

$PVCT: More Data Is Necessary Until It Isn't

On the one hand, Provectus has a $64MM market capitalization (as at Wednesday's closing price). On the other, Moffitt might say PV-10 is the nearest thing they have seen as a cure for cancer, or Pfizer might consider PV-10 the holy grail*. There's a lot of space between those two hands. Cures and grails obviously have not yet translated into a commensurate company valuation. And therein lies the answer, I think. You see it separately with PV-10 and PH-10.

PV-10: Big Pharma clearly recognizes a group of drug compounds have local and distant effects on lesions, substantiating the hypothesis injections of these drugs in local tumor lesions result in systemic effects. PV-10 works more easily and effectively. It took Moffitt time, effort and work to begin to wrap their heads around this "phenomena." In the process, they could confirm the first, second and last solution PV-10 may well be (e.g., a pre-surgery treatment).

PH-10: If the premise is that PH-10 has no toxicity, and that the "normal rules" of treatment do not apply, what then? Even though Provectus likely has sufficient directionally positive clinical data for a dermatology transaction, immunologic MOA characterization work, as I previously wrote about, would be helpful with the FDA in designing toxicity studies appropriate for an approved drug. This work should make dermatology companies more desirous of PH-10. The immunologic MOA characterization work came to the forefront when management was working on the remaining toxicity studies for the FDA. When they had difficulty finding any dose limiting toxicity (DLT) or maximum tolerable dose (MTD), they sought to better understand PH-10's unique lack of toxicity.

The answer? Big Pharma just might need more data than otherwise would have been necessary before pulling the trigger(s).

* "The holy grail for cancer would be to trigger the body’s own immune system to fight off the cancer, so that you somehow stimulate the antibodies in a way that that happens." Fareed Zakaria, Fareed Zakaria GPS

Possible $PVCT Publications In 2013

2012 produced the following investigator & researcher and sponsor abstracts/poster presentations and presentations:

• 2012 Society of Surgical Oncology Annual Meeting (Subject: Immunologic MOA Characterization, Author: Moffitt [several authors], Medium: Abstract/Poster presentation),
• HemOnc Today - Melanoma and Cutaneous Malignancies Conference (MM Phase 2 data, Dr. Merrick Ross, Presentation),
• 2nd European Post-Chicago Melanoma Meeting 2012, Interdisciplinary Global Conference on Developing New Treatments for Melanoma (Final MM Phase 2 Data, Dr. Sanjiv Agarwala, Presentation),
• European Society for Medical Oncology) 2012 Congress (Final MM Phase 2 Data, Dr. Sanjiv Agarwala et al., Poster Presentation), and
• Society for Immunotherapy of Cancer (SITC) 27th Annual Meeting (Immunologic MOA Characterization, Craig et al., Abstract/Poster Presentation).

Expectations for 2013 are:

• Subject: Final MM Phase 2 Data, Authors: Investigators (Agarwala, etc.) & Sponsor (Eric), Medium & Venue: Global Medical Journal
• Immunologic MOA Characterization, Moffitt [several authors], Journals and/or conferences
• HCC Phase 1 Data, Dr. Goldfarb-? & Eric, ?
• Psoriasis Phase 2c Data, Dr. Lebwohl-? & Eric, ?
• Compendium of the Use of Rose Bengal, Eric et al., ?
• PV-10 Compassionate Use Program, Site doctors-? & Eric et al., ?

$PVCT: January Effect

Before Big Pharma pays billions of dollars for Provectus, value-increasing steps obviously have to drive the company's market capitalization much higher from where it is now (such as to at least above $1 billion). The market cap could get there in January through some combination or permutation of:

• The SPA arrival;

• A regional geographic oncology deal (a "mini-oncology" deal) for China. Signed, but perhaps not closed;

• Visibility into Moffitt's forthcoming mouse and human immunologic MOA characterization work;

• A dermatology deal. Alternatively, we might learn more about the status of the license process: information about PH-10's immunologic MOA characterization, how this MOA work factors into questions about the lack of PH-10 toxicity, the end-of-Phase-2 meeting, and the Phase 3 trial design; and

• Another mini-oncology deal. Such a transaction might be another regional geographic deal, some form of equity investment in Provectus by Big Pharma or an "interesting" license-related/oriented transaction.

$PVCT: Horse Race (updated)

The geographies Provectus identified above probably represent the limit of the company's potential oncology end-game partners' disinterest. There likely is no appetite to geographically segment the licensure of PH-10.

$PVCT: If Not China, Then What?

In a prior post, I illustrated the then current snapshot of the horserace.

There may be a second geographic region in play (Australia?, India?*). My take on a comparison of license or deal headline numbers is below:

If the company wanted to hold onto oncology longer, a cost breakdown of the contemplated pivotal, key and other trials appears to be:

A China deal (or whatever possible combination of outlying geographic deals) that net a $25-50MM upfront payment goes a long way to providing the necessary funding for Provectus to make even more clinical trial progress.

Could dermatology nose out oncology at the finish line? Sure.

Recall the path Provectus traveled with PV-10 and oncology: clinical trials and regulatory discussions, followed by immunologic mechanism of action characterization work by a world-class institution. The early spadework to demonstrate efficacy, safety and multi-indication viability was followed and enhanced by Moffitt's past and future murine model results (not including, yet, human immunologic work). And while shareholders wished for Big/International Pharma to snap to attention (i.e., license PV-10) because of outstanding early-phase trial results, it now appears the immunology work already presented by Moffitt at SSO and Craig at SITC, followed by forthcoming work to be presented by Moffitt, is accelerating license interest and discussions of both regional and global natures.

Could PH-10 be following a similar path?

The "hang-up" with PV-10 appeared to have been with Big Pharma folks being unable to wrap their heads around how well PV-10 worked. They needed help to understand something they had never seen before. They appear to understand now, or at least are getting closer. As such, license interest and discussions are heating up.

It is not unreasonable to analogize PV-10's path to PH-10's, and thus potentially explain the delay in getting to a dermatology license or sale transaction. Perhaps immunologic mechanism of action characterization work is being done on PH-10 by a world-class institution to complete the understanding of prospective dermatology licensees before they fully commit to jumping into the pool. I think this immunology mechanism of action work is being at The Rockefeller University (the Laboratory for Investigative Dermatology?).

Once this PH-10 immunologic mechanism of action characterization work is completed and provided to prospective partners (I do not know when the work was started and when it and the subsequent analysis was or will be completed), and assuming this knowledge concludes their thinking, dermatology might well beat oncology to the finish line.

In this horse race, however, the more horses that cross the finish line -- Provectus licenses deals -- the better.

* I suspect PV-10's extremely low cost structure, and thus tremendous pricing flexibility, helps facilitate country discussions without fear or risk of patent loss (or too much of it).

$PVCT: 地理许可证

Provectus' share price has bounced above, below and around the 60-cent level following last month's terminated PVCTP "IPO." The SPA process has taken a toll on the stock in 2012. The market and life science investors' "certain" view the company will be forced to undergo substantial dilution to raise the necessary money for key and pivotal clinical trials (MM Phase 3, HCC expanded Phase 1 and Phase 2/3, pancreas Phase 1) weighs heavily on the share price too.

While management explored the opportunity to execute an "IPO," quarterly filings for Q2 and Q3 2012 indicated other avenues for seeking cash, such as from outlying geographic licenses (e.g., Australia, China, Japan,   MENA).

2Q12 10-Q Filing -- Click on the figure to enlarge it.

3Q12 10-Q Filing -- Click on the figure to enlarge it.

The horse race, which previously had a dermatology transaction and geographic-specific oncology deal in the lead (unless a company-friendly "IPO" could have been had to overtake them; in hindsight, it could not), now might see (for now at least) an outlying geography deal for oncology assume the lead. I am not sure if Provectus is in the homestretch in this regard, but we could shortly see if it is.

$PVCT.OB: The First Anniversary of This Blog

I wrote my first blog post on November 16, 2011. At the time of that post: "The share price is $0.88. 14,700 shares have traded." Today, it closed at approximately $0.53, down about 40%, and traded about 54,000 shares.

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In the past 12 months, Provectus' notable PRs included:

• October 29, 2012: Provectus Presents Nonclinical Data on Antitumor Immune Response to PV-10 Immuno-Chemoablation (very key),
• October 17, 2012: Provectus Pharmaceuticals Terminates Proposed Convertible Preferred Stock Offering (the failed IPO),
• October 2, 2012: Provectus Pharmaceuticals Presents Final Phase 2 Melanoma Data at ESMO 2012 (key),
• September 28, 2012: Provectus Pharmaceuticals' Patent Application Published for Combining Local and Systemic Therapies for Enhanced Treatment of Cancer (the joint Pfizer-Provectus patent app),
• September 27, 2012: Provectus Expands Protocol for Phase 1 Liver Cancer Study (important),
• June 26, 2012: Provectus Pharmaceuticals Presents Final Phase 2 on PV-10 At 2nd European Post-Chicago Melanoma Meeting 2012 on June 22, 2012 (visibility),
• May 30, 2012: Doug Ulman, National Cancer Survivorship Advocate, Joins Provectus Pharmaceuticals' Corporate Advisory Board (a great get),
• May 14, 2012: Provectus Pharmaceuticals Forms Independent Board to Meet Corporate Governance Requirements (an important corporate governance advance),
• April 10, 2012: Phase 2 Data on Provectus's PV-10 to Be Presented at the HemOnc Today - Melanoma and Cutaneous Malignancies Conference on April 13, 2012 (visibility),
• March 26, 2012: Intralesional PV-10 Treatment Leads to the Induction of Anti-Tumor Immunity  (very key),
• March 23, 2012: Mechanism of Action Data On PV-10 Demonstrates Therapy Induces Immunologic Response (very key),
• March 19, 2012: Provectus Announces Top Line Phase 2 Data For PH-10 in Its First Randomized Controlled Psoriasis Study (important), and
• January 18, 2012: Provectus Receives Guidance From FDA On Pathway to Approval for Phase 3 Trial of PV-10 For Metastatic Melanoma (important regulatory step).

As for the blog itself, readership has steadily grown.

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Thank you for visiting and reading!

$PVCT.OB: When Does PV-10 Fail?

"Put enough water onto the fire, and it goes out."

The compassionate use program, where doctors have significantly more flexibility than in the clinical trials to treat and re-treat patients revealed much to Provectus management about what the drug can truly accomplish when it enables the body's own immune system to cure cancer in a patient (and how to better design the pivotal MM Phase 3 trial). Put enough water onto the fire, and it goes out. Regularly treat the patient with enough PV-10 and, over time, the cancer goes away.

Constrained by treatment. As such, some trial failures of PV-10 are not actually failures. Some "failures" occur out of necessity because of the design of the trials. In both the dermatology and oncology studies, management was inhibited by the trial design per regulatory compliance. In the MM Phase 1 and 2 trials, principal investigators were only allowed to inject a few tumors. Nevertheless, you have to be impressed by how well the bystander effect worked given the trial constraints hamstringing the treatment approach. Injecting all accessible tumors with PV-10, of course, would be best. The impact of this is to (a) lower the tumor burden and, thus, the load the patient's immune system has to overcome, and (b) address tumor heterogeneity. Tumors are heterogeneous; that is, they are not all the same antigenically (i.e., what they present to the immune system). So, if the antigens the immune system needs to see are on in one tumor and not another, it is vital to inject PV-10 into as many tumors as possible.

Constrained by time of reporting. Some patients were fine at, say, week XXX; however, the trial design required observation at week X (XXX > X). Efficacy at week XXX, even if higher or better, goes unreported. The patient was listed as a failure.

Constrained by physician implementation. The trial design prevented tumors from being injected more than once: A doctor missed a tumor. There was no ability to retreat to correct the miss. The patient was listed as a failure.

Constrained by patient behavior. It is rumored a PV-10 trial patient flew from the U.S. to Australia in order to participate in the MM Phase 2 trial. His tumors were injected, and they went away. Apparently, it also is rumored that he broke his promise to stay and be observed, and returned home to the U.S. The patient was listed as a failure.

Our immune system can be overwhelmed. As with an infection, doctors use antibiotics to slow it down until the immune system itself can clear it away and cure the patient. If the host cannot help, there is no cure.

Provectus treats cancer like an infectious disease.

Thus, in the case of very late stage disease or very heavy tumor burden disease, more PV-10 is applied at the outset, the drug is applied again and again (i.e., re-treat or throw more water onto the fire), or PV-10 is combined with radiotherapy, chemotherapy or other immunotherapies to stimulate the immune system, reduce the burden and "hold the infection in place" and, eventually, allow the patient's immune system to takeover and finish the task of healing the body.

Failure? Perhaps not so much.

$PVCT.OB: Onychomycosis, Another Indication for PH-10?

Abstract: Onychomycosis, a fungal infection of the finger or toenails, is predominantly caused by Trichophyton rubrum. Treatment is difficult due to high recurrence rates and problems with treatment compliance. For these reasons, alternative therapies are needed. Here we describe the photoactivation of Rose Bengal (RB) using a green laser (λ = 532 nm) at fluences of 68, 133 and 228 J/cm2, and assess its fungicidal activity on T. rubrum spore suspensions. A 140 µM RB solution was able to induce a fungicidal effect on T. rubrum when photosensitized with the fluence of 228 J/cm2. RB photosensitization using a green laser provides a potential novel treatment for T. rubrum infections. (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)


About Onychomycosis: "Onychomycosis is a chronic persistent fungal infection of the nail bed resulting in thickening and discoloration of the nail, which sometimes can be accompanied by serious pain and disability. According to the Merck Manual, the worldwide incidence rate of onychomycosis is approximately 10%. As described by Iorizzo and Piraccini (2007), the incidence has been increasing due to diabetes, immunosuppression and an aging population. While occurring in approximately 2.6% of children younger than 18 years, it occurs in as much as 90% of the elderly population (eMedicine.medscape.com). As of 2008, Thomson Reuters Pharma had stated that the worldwide market was approximately $2.8 billion in size and is expected to grow to approximately $2.9 billion by 2014." [Source of paragraph above is in the link provided.]