$PVCT: What Could A Relationship with Daiichi Sankyo Mean?

Daiichi Sankyo's interest in Provectus might range from something simple or narrow to something more robust.

You can read about Daiichi Sankyo's new 5-year business plan here.

$PVCT: J&J Visits The Blog

Folks from J&J Europe visited the blog, but didn't spend nearly as long as those from Daiichi Sankyo

J&J. Just sayin'.

$PVCT: Current SPA Guidance

Current management guidance on the receipt of the SPA appears to be Q2 2013.

In Dr. Andtbacka's Current Status of Injectable Therapy presentation at the HemOnc Today Melanoma and Cutaneous Malignancies Symposium in March, around the 17:43 mark of the video, a bullet point referencing mid-2013 enrollment in the pivotal MM Phase 3 trial appears. As referenced in his presentation, Dr. Andtbacka obtained his information from Eric.

In last week's Provectus PR about PV-10 combination therapy, Eric's second quote appears to be a so-called strong reference to his current confidence about a potential start date.

Mid-2013 might mean June or July. Allowing 30 days, give or take, post-SPA receipt to commence the trial, the receipt of the SPA could be announced in May or June.

$PVCT: Big Pharma Interest

This blog is one of the primary sources of information about Provectus. 

The blog can see, among several other things, where visitors come from (e.g., IP address, city, state/region, country, etc.) and how often they stay and read (page views, visits, visit lengths, etc.). Anytime you visit any destination on the world wide web, you are being tracked. Unless you use something like Tor to protect your privacy.

About 10 days ago I speculated about Daiichi Sankyo interest in PV-10. Why? Because...

First, folks from Daiichi Sankyo ("DS") in Japan visited multiple times and spent many, many hours on the blog. These visitors' IP address(es) originated from the pharmaceutical company's headquarters in Tokyo.

Then, folks from DS in the U.S. visited the blog. These visitors' IP address(es) originated from the pharmaceutical company's U.S. headquarters in Parsippany, New Jersey.

So, I began connecting dots available to connect; those above, and others. I think DS has been informal (formal, in this context, means one engages the target company) doing due diligence on Provectus. Why? For one thing, simple activities like scouring web-based sources of information and data is merely one way of doing due diligence on a target, without directly engaging the entity in which you're interested. If you spend a lot of time reading a blog about a biotechnology company not written by said company, you're either really bored or really interested. For another, historical information about Daiichi Sankyo does suggest they can and will do global licenses. DS is a global Big Pharma company, with additional regional interests in Japan and India (through Rambaxy Laboratories) and maybe elsewhere in Asia Pacific. For example, in February 2011, Daiichi Sankyo announced its acquisition of Plexxikon for $805 million up-front and near-term milestone payments associated with the approval of PLX4032 (vemurafenib, now Zelboraf) for up to an additional $130 million. The deal closed in April.

The next course action would be to ask various questions of Provectus management and gauge their responses, should of course they respond to questions about this topic.


At his presentation in New York in March, Craig noted Provectus was in the due diligence process of a pharmaceutical company for a global license. One presumes he did so because this Big Pharma had formally approached Provectus and were in formal due diligence with the company.

Is DS in formal due diligence with Provectus yet? If so, DS would make at least two Big Pharmas with a stated interest in the company.

If one assumes Pfizer has stated interest through Dr. Eagle's presence on Provectus' corporate advisory board, that would make three Big Pharmas. 

There's a fourth. It's IP address(es) comes from...

$PVCT: Post-AACR...

What now? AACR is finished. Two posters displayed: Moffitt and Provectus. Moffit's poster presentation displayed definitive data on PV-10's tumor-specific immunity (i.e., how PV-10 harnesses the immune system). Provectus' showed PV-10's orthogonality (i.e., how PV-10-based combination therapy can be efficacious for inaccessible tumor burden).

There are key questions to explore over the near-term. Among them:

• The FDA. Was the FDA convinced this local regional treatment can provide a systemic benefit to cancer patients? As the first intralesionally-injected compound that leads to the induction of tumor-specific immunity, does the FDA now understand the systemic benefit component of PV-10?

• Big Pharma. By providing not only anti-tumor immunity, but also inducing tumor-specific immunity, does Big Pharma now understand the systemic potential of PV-10?

My students competed well in London, but Wroclaw University of Economics are CFA Institute Research Challenge Global Final champions. "The CFA Institute Research Challenge is an annual global competition that provides university students with hands-on mentoring and intensive training in financial analysis and professional ethics. Students are tested on their analytic, valuation, report writing and presentation skills, and gain real-world experience as they assume the role of an equity research analyst. More than 3,500 students from over 755 universities in 55 countries participated in the 2012-2013 Research Challenge." To be that close will sting them (and me) for a while, but I think they'll harness this experience and success as they embark on their careers.

$PVCT: And Dr. Eric Wachter commented...

Eric's responsibility at Provectus comprises clinical development (e.g., trials, biostats, regulatory affairs, etc.), manufacturing and intellectual property (IP). In Provectus' PR about company research results at AACR, management inserted a quote attributable to Eric of "PV-10 is currently entering pivotal Phase 3 testing as a monotherapy for locoregional control of cutaneous metastatic melanoma." In the company's October 2012 ESMO PR, management wrote "The study duration is estimated to be approximately 30 months, with commencement expected in late 2012 or early 2013 following completion of review for SPA." The above describes Provectus' pursuit of the SPA since it first received guidance from the FDA to submit its Phase 3 protocol for review, either via standard review or a request for SPA in January 2012.

Eric and Provectus are pursuing paths to regulatory clarity with the FDA via the SPA and breakthrough therapy designation (whether that is fast track review, a more precise SPA or accelerated approval). I imagine Eric wants to make sure PV-10 is approved, which should include working hand-in-hand with the FDA to determine the best path for this.

The company has long said its primary customers are the FDA and Big Pharma. One would presume the FDA wanted to see Moffitt AACR data (presumably in the context of the fundamental local versus systemic paradigm shift). Now that they have, or when they do, the remaining clarity for shareholders is how and where the FDA directs Provectus to the eventual regulatory path.

$PVCT: London Calling (where else, @starbucks)

My students are doing what they need to do, effectively telling me they don't need me or need me around. I have more time on my hands then I thought...

Some thoughts on the AACR PRs:

• Per management's approach in the past, the audience for which the PRs were meant was the pharmaceutical industry, domestically and abroad (e.g., potential Chinese, Japanese, Indian and European partners).

• The PRs certainly weren't designed to inform retail investors. And, I doubt management is expending slightly more than perfunctory effort engaging life sciences fund money on this, other than revisiting the conversation post-AACR. I think the focus, rightly, is on getting regional and/or global license deals done.

• The PR for Moffitt's data (via Dr. Pilon-Thomas's quote) highlighted a key feature of PV-10's mechanism. For the tumor-specific immunity PV-10 generates, the drug's ablative process is critical for this in situ stimulation of the immune system, which I think is helpful for Big Pharma to better understand. Additionally, the PR reinforces the role T cells play in this response and PV-10's systemic capability, with Moffitt saying they would do more research into the processes that PV-10 induces, stimulates, creates, etc.

• The essence of the PR from Provectus' data was combination therapy (i.e., PV-10 plus something else, which in this case was anti-CTLA-4 antibody 9H10 (see below).

Provectus' work on combination therapy had several facets to it.

There does not appear to be disagreement that PV-10, as a monotherapy, utilized for locoregional control of cutaneous metastatic melanoma in Stage III patients is singularly dramatically effective. Adjusting for a treatment protocol that allows unlimited frequent injections of the drug for this stage of diseased patient, it's probably not unreasonable to believe efficacy could be near-100%.

Provectus extends this effectiveness by demonstrating themselves and through Moffitt's work that tumor-specific immunity is harnessed, and distant untreated metastases are suppressed  reduced or eliminated because of it. PV-10 successfully battles tumor heterogeneity of accessible injected lesions (tumors).

"...[A]dvanced melanoma patients, particularly those with stage IV disease, have substantial tumor burden in areas that are often non-accessible to injection with PV-10..." (Provectus' AACR PR) How does PV-10 deal with tumor heterogeneity in tumors into which it has not been injected or visceral metastases for these very late stage diseased patients?

Provectus hypothesized combining anti-CTLA-4 agents (like already approved Yervoy (ipilimumab) with PV-10. The thought was to leverage the incremental benefit of the additional systemic agent (i.e., ipi), while ensuring (demonstrating) there were no incremental safety issues or adverse event features resulting from the combination. "...Provectus aimed to ensure that any systemic treatment was potentially safe in combination with PV-10, and that efficacy signals from the combination therapy could be differentiated from those of PV-10 alone." (Provectus' AACR PR) 

The poster and PR showed that "..., as hypothesized, addition of the immunologic effects of an anti-CTLA-4 agent augments the benefits of PV-10." This allows two proofs to be made, in my view. First, the proof of orthogonality -- combination allows for benefit, but no added risk or no greater "un-safety." Second, allowing for the benefit of the combined therapy, in this case the anti-CTLA-4 antibody, to be utilized but at [apparently] lower doses and thus at lower toxicities.

Provectus' work suggests treatment options for very late stage patients can increase markedly by combining a host of other systemic therapies (in potentially less toxic doses) with PV-10 to more effectively defeat tumor burden in inaccessible regions of the body (where injection of PV-10 cannot be done) and visceral metastases (where tumor heterogeneity is more heterogeneous than what PV-10 previously conquered).

Furthermore, management's work suggests

• Yervoy could (would) be more effective and more safe for very late stage diseased patients when combined with PV-10 in doses lower than currently used, and
• PV-10 could potentially salvage Pfizer's tremelimumab, a close relative of Yervoy/ipilimumab, by turning the combination of PV-10 and treme into an alternative to Yervoy?

$PVCT: PV-10 Data Presented by Moffitt Cancer Center Researchers Examines Induction of Systemic Immune Response in Multiple Tumor Types

Provectus issued a PR to circulate Moffitt's AACR poster. The poster is here. It is worthwhile to focus on Moffitt's Dr. Pilon-Thomas' quote in the PR.

"The findings of this study confirmed not only that PV-10 induces tumor-specific immunity after a single treatment with IL-PV-10 in multiple tumor types, but that the ablative process is critical for this in situ stimulation of the immune system. The data also show that T cells play a critical role in this response."

$PVCT: Provectus Presents Data on PV-10 Combination Therapy at American Association of Cancer Research Annual Meeting

Provectus issued a PR to circulate its AACR poster. The poster is here. It is worthwhile to focus on Eric's quotes in the PR.

"Results of these studies demonstrate that immuno-chemoablation with PV-10 is highly effective when all tumors are accessible for injection, providing rapid reduction of tumor burden and tumor-specific immunity. PV-10's rapid tumor ablation and immunologic stimulation, combined with its distinctive adverse effects profile and pharmacology that minimizes the potential for drug interaction, represent a unique and powerful approach that could complement many systemic cancer therapies. This work shows that, as hypothesized, addition of the immunologic effects of an anti-CTLA-4 agent augments the benefits of PV-10. For visceral or other inaccessible disease, combination of PV-10 with CTLA-4 blockade offers important potential for synergy."

"PV-10 is currently entering pivotal Phase 3 testing as a monotherapy for locoregional control of cutaneous metastatic melanoma. These data on the potential benefits of combination therapy are encouraging, particularly for advanced melanoma patients with substantial tumor burden inaccessible to PV-10 injection. PV-10's ability to reduce tumor burden and elicit tumor-specific immunologic stimulation make it a logical potential complement to anti-CTLA-4 agents, such as ipilimumab. We believe these results warrant a Phase 1/2 dose escalation trial with 'ipi' to validate this effect and potentially advance the options available to patients."

A $PVCT Snippet

Management was focused on the reaction from the FDA and Big Pharma to Moffitt's poster at AACR, rather than the immediate attention (or lack thereof) of life sciences investors. Short interest for the period ending 3/28/13 fell 26%. I am traveling out of the country through the end of the week, and may blog sporadically until I return home.

@MelanomaReAlli CEO Wendy Selig Attended $PVCT's Presentation at BIO CEO 2013

Melanoma Research Alliance ("MRA") CEO Wendy K.D. Selig attended Peter's February presentation at BIO CEO 2013. Provectus was one of several sponsors of MRA's Fifth Annual Scientific Retreat in Washington, DC in February. I imagine the company participated in some fashion at the retreat.

$PVCT: @LIVESTRONGCEO Doug Ulman in Washington, DC

Southwest Airlines Flight 3600, on which Doug Ulman was when he tweeted the above, is an Austin (AUS) to Reagan National (DCA) flight. There's a good chance he is, among other potential commitments, with Peter and engaged in patient advocacy efforts at the conference and elsewhere in Washington.

Potential for 3 #FDA BTD $PVCT Applications

Earlier today, Pharmacyclics (NASDAQ:PCYC) announced it received a third Breakthrough Therapy Designation for ibrutinib from the FDA. It would seem each successive BTD is easier (or less hard) for PCYC to achieve than the prior one presumably because of the FDA gaining more and more comfort with the drug and more and more of an understanding of the drug's benefit with each submission.

Peter has said for some time Provectus enjoys a very collaborative relationship with the FDA. EOP2, the group within the FDA examining PV-10 for metastatic melanoma, also would examine PV-10 for HCC.

BTD Application #1 With Moffitt's data now in hand (i.e., poster and supporting materials), I think the company should have sufficient information to make a very strong case for BTD for melanoma.

BTD Application #2 Building upon the knowledge gained by the FDA from PV-10 & melanoma, once management has results of Provectus' contemplated expanded HCC Phase 1 trial in hand, I would think they should have sufficient information to make the case to the FDA for BTD for HCC.

BTD Application #3 Building upon the knowledge gained by the FDA from PV-10 & melanoma and PV-10 & HCC, and perhaps once management runs, say, a feasibility study for breast cancer, I would think they would make the case to the FDA for BTD for breast.

$PVCT Should Provide Moffitt Poster Once AACR ends

I would imagine because of AACR conference stipulations or regulations, Moffitt's poster will be made available when or after the conference ends (either Wednesday or Thursday). I have friends at the conference (smartphones anyone), but will wait until Provectus issues a proper poster copy to post and discuss.

$PVCT Files Prospectus (S-1) for February 2013 Fundraising

Management filed its prospectus (the document presented to prospective investors) today for the February 2013 fundraising.

$PVCT De-Registers Both $50MM Common Stock Shelf Filings (S3s)

Management de-registered (took down) both of the $50MM common shelf filings -- here and here -- they had registered in June 2010 and July 2011, respectively. The $100MM mixed securities shelf filing the company registered in July 2012 obviated the need for the other two shelfs.

@MoffittNews & $PVCT at #AACR: PV-10 Immunology Data Presented by Moffit Cancer Center Researchers at the American Association for Cancer Research Annual Meeting

Provectus issued a PR today about Moffitt's poster presentation.

Dr. Pilon-Thomas commented, “We believe our findings are meaningful because they confirm the induction of tumor-specific immunity after single treatment with IL-PV-10 in multiple tumor types. Our data show that T cells play a crucial roll in this response, and we are continuing our work to further elucidate the mechanisms that occur following PV-10 treatment.”

Dr. Amod Sarnaik observed, “The systemic response to intralesional PV-10 treatment observed in murine models was sufficiently compelling to warrant further clinical investigation. We look forward to additional insights from our current investigational study of the immune mechanism of PV-10 ablation in cutaneous melanoma patients.”

$PVCT: Daiichi Sankyo

It appears Daiichi Sankyo is interested in Provectus (based on some very specific information I unearthed that leads me to speculate this). It is not yet clear whether such interest is limited to Japan (and possibly India, through its ownership in Ranbaxy), or whether the Japanese global pharmaceutical company's interest extends to a global license of PV-10.

In February 2011, Daiichi Sankyo announced its acquisition of Plexxikon for $805 million up-front and near-term milestone payments associated with the approval of PLX4032 (vemurafenib, now Zelboraf) for up to an additional $130 million. The deal closed in April.

Other acquisitions include Zepharma (2006), the OTC drugs unit of Astellas Pharma, a majority stake in Indian generic drug maker Ranbaxy (2008) valued at ~$4.6 billion, and U3 Pharma (2008) for the company's anti-HER3 antibody. (See Wikipedia)

More Serious #Pharma Interest in $PVCT

At his presentation in New York in March, Craig noted Provectus was in the due diligence process of a pharmaceutical company for a global license. This is different from Pfizer's "interest" because, as far as we know, Dr. Eagle merely hangs out on Provectus' corporate advisory board. Of course, and as I written about copiously, Pfizer is in the pole position, and merely has to respond to some other competitor moving first by simply paying more. No guarantees of course, but that's the basic gist.

Management has not expressed elsewhere to which I can point other serious global pharmaceutical company interest.

I independently confirmed [what I think is] serious interest by another global player.

Provectus would not comment on the information (which did not originate from the pharma interested in PV-10) underlying my thought/belief/speculation. I want to dig further before naming the pharmaceutical company.

As Provectus approaches AACR week, things might be heating up.

$PVCT Pricing Power

Last week, when news surfaced about Biogen Idec setting the price for its new multiple sclerosis pill, a blog reader who informed me of this asked about Provectus' pricing perspective for PV-10. Tecfidera, Biogen's drug, is more commonly known as dimethyl fumarate. A good read about Tecfidera's pricing comes from Corante's David Lowe: "It [Tecfidera] joins the (not very long) list of industrial chemicals (the kind that can be purchased in railroad-car sizes) that are also approved pharmaceuticals for human use."

Management thinks it has significant pricing flexibility and thus tremendous pricing power for both PV-10 and PH-10 because of the compounds' manufacturing cost structures. Treatment cost, particularly in the context of evidence of PV-10's clinical superiority (as well as that of PH-10's), undoubtedly will be an important aspect of Provectus' discussions with prospective pharmaceutical partners, whether Big Pharma or pharma in China, India and elsewhere around the world.

Management understands and expects any pricing of PV-10 and PH-10, however, will be driven by Provectus' partners, up to (i.e., partners in regional license transactions, and the sale/license of the dermatology business) and including when the company is acquired by Big Pharma.

In other words, management will not set PV-10's price independent of partner guidance. More than likely, any PV-10 pricing will be determined after Provectus has been acquired, at least insofar as being publicly stated. Price points that management currently is considering solely are being used for business valuation purposes and done in consultation with prospective regional and global partners.

I have long been aware of and understood the cost structure underlying PV-10 (and PH-10); specifically, potential gross margins and costs of goods sold. Rose bengal's cost to manufacture and potential treatment prices, together with the drugs' efficacy and safety, make a very compelling value proposition.

Take melanoma, for example. The company surmises what each 5 ml vial of PV-10 a partner might price the vial at depending on the region of the world (e.g., U.S., European Union, Japan, Latin America, China, India, etc.). Management also can surmise the average number of vials per melanoma patient required. Such information, combined with the drug's superior clinical benefit, suggests PV-10's total value proposition (price + efficacy + safety) could very well fracture the competitive landscape of cancer treatment.