September 18, 2014

Treating Cancer

In my September 22, 2013 investment letter entitled Why I'm Long Provectus Biopharmaceuticals, which you can find and/or read in its entirety on the blog's page of the same name (see the right sidebar entitled Pages) I wrote:
PV-10, a novel oncology compound being developed by Knoxville, Tennessee-based Provectus Biopharmaceuticals, Inc. (“Provectus” or the “Company”) (NYSE MKT: PVCT), exemplifies innovation over incrementalism, meaningful over marginal, productized technology over hypothetical, and changing the world over accepting the status quo, with not an insignificant amount of serendipity over contrivance. In sum, these form the quintessential essence of a paradigm shift in the treatment of cancer. 
It seems to me traditional modalities of cancer treatment look like this:
Surgery is the first line of defense when early stage cancer first strikes, while therapies and treatments and repetitions and combinations of them are fall back positions as cancer progresses and recurs towards its later stages.

I contend PV-10 is a paradigm shift in the treatment of cancer because it should play key roles in both ends of the disease spectrum illustrated above:
  • For earlier stages of cancer (shift #1a), the far greater majority or supermajority of those afflicted (the "silent masses"), the drug may effectively defeat or control local-regional disease to deny, prevent or forestall its metastatic and visceral spread, and present itself as a viable and far better alternative to surgery.
  • For later stages (shift #1b), the current focus of most of the biopharmaceutical industry, PV-10 may, as the tip of the treatment spear, in combination with other therapies, bring the immune system back into an immune surveillance (immunosurveillance) state to conquer heavy tumor burden and visceral disease.
See the blog's PVCT page.

Shift #1a. I think the upcoming pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma helps further make the case 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. I believe this because Provectus' metastatic melanoma Phase 2 trial data appeared to highlight that PV-10 injection lasted, as illustrated by progression-free survival (the time between initial treatment and tumor progression) approximately for the duration of the treatment interval of the drug. If the treatment interval was longer, PFS would be longer as well, until at some point complete response were achieved.

The FDA denied the company breakthrough therapy designation determined on the basis of the paucity of data, which I take simply to mean not enough of the data previously presented -- specifically, the sub-group of patients in the Phase 2 trial who had all of their disease treated (28 patients), which is the patient population of the Phase 3 trial.

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). This protocol, which is what oncologists presumably would use when treating patients, thus would see patients with all of their disease treated by PV-10 potentially never progress.

Shift #1b. This aspect of my presumed assumption of PV-10 as a paradigm shift in the treatment of cancer has yet to unfold. I was struck by an early-September article published by Moffitt staffers who include a key PV-10 researcher (Dr. Shari Pilon-Thomas) entitled Immunotherapy Combined With Chemotherapy for Pancreatic Cancer: A Game Changer?
Of note, the immune system’s involvement in cancer development and progression has sparked much interest in recent years. The model of the cancer-immunity cycle suggests an interplay of immune-suppression and immune-stimulation. In normal individuals, a state of immunosurveillance is in place. However, within the tumor microenvironment, inhibitory signals and immunosuppressive cells are present and tip the scale in favor of immune suppression.
The authors go on to write:
Chen and Mellman have delineated the cancer-immunity cycle, which depicts the immune system’s role in controlling tumor growth in normal individuals. Understanding this cycle provides insight into how tumors can evade it...The idea of the cancer-immunity cycle proposes that, for a cancer immune response to be generated, the net balance between immune stimulation versus immune suppression must be tipped in favor of the former. Studies in various cancers have suggested that tumors evade the immunogenic process mostly by factors that promote immunosuppression.
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See the blog's PV-10, and the Cancer Immunity Cycle page.

As researchers better understand how to treat late stage cancer, specifically and directly fighting tolerance and recurrence, I believe Moffitt has further their understanding of the cancer immunity cycle as it relates to the potential role(s) PV-10 does and could play. We may learn more about this in early-November at the 2014 annual meeting of the Society for the Immunotherapy of Cancer.
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September 17, 2014

#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.

September 9, 2014

Bristol-Myers vs. The Field (ex-Provectus)

Last week Bristol-Myers filed a lawsuit against Merck over [anti-]PD-1 agent pembrolizumab (trade name Keytruda), which was approved last week by the FDA for late-stage or metastatic melanoma.
Specifically, Bristol-Myers claims that Merck is violating the patent on its Opdivo mediation for tackling melanoma, which was recently approved in Japan and became the first so-called PD-1 inhibitor to win regulatory backing anywhere. A PD-1 inhibitor blocks a protein that acts as a brake on certain immune system cells and prevents them from attacking healthy tissue. (Bristol-Myers Sues Merck Over a Patent on its new Cancer Drug, The Wall Street Journal, September 8, 2014)
Merck disclosed PD-1 antibody patent oppositions and litigation, at the time in Europe, in its 10-Q filing for the period ending June 30, 2014 (see page 22):
As previously disclosed, Ono Pharmaceutical Co. (“Ono”) has a European patent (EP 1 537 878) (“’878”) that broadly claims the use of an anti-PD-1 antibody, such as the Company’s immunotherapy, pembrolizumab (MK-3475), for the treatment of cancer. Ono has previously licensed its commercial rights to an anti-PD-1 antibody to Bristol-Myers Squibb (“BMS”) in certain markets. The Company believes that the ‘878 patent is invalid and filed an opposition in the European Patent Office (the “EPO”) seeking its revocation. In June 2014, the Opposition Division of the EPO found the claims in the ‘878 patent are valid. The Company expects to receive the Opposition Division’s written opinion in the third quarter of 2014, after which it will begin the appeal process. {Underlined emphasis is mine}
As FiercePharma's Tracy Staton writes: "The lawsuit asks for damages, but more importantly, asks the court to declare that Merck infringes that PD-1 patent. Such a decision would bolster Bristol-Myers and Ono's argument that they are owed royalties on sales of rival PD-1 drugs."

As I wrote in my Why Keytruda's approval is a good thing for PV-10 (September 8, 2014) news item under the blog's News tab:
KOLs see PD-1s as treating the bulk of late stage cancer. Key opinion leaders ("KOLs") see PD-1s, which fall under the category of checkpoint protein inhibitors that also include CTLA-4 and PD-L-1 agents, as an improvement over CTLA-4 agents like approved ipilimumab (trade name Yervoy) and tremelimumab. KOLs will use PD-1s to treat as many indications as they can scientifically support. Abstracts of Merck oncology-sponsored pembrolizumab studies being presented at ESMO 2014 in late-September, for example, include bladder and gastric cancer, advanced melanoma, non-small cell lung cancer ("NSCLC"), and head and neck cancer.
Bristol-Myers and Merck's PD-1s are projected to play key roles in the supposed several tens of billions of dollars equity research analysts estimate will be derived from the immuno-oncology addressable market.

But KOLs believe the more dominant use of PD-1s will come from combining them with other drugs to treat late-stage cancer, rather than strictly using them as monotherapies. I summarized 14 previously announced and/or conducted combination studies below, and first in my Combinations (July 24, 2014) news items under the blog's News tab.
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Bristol-Myers, however, has its bases covered with a combination therapy patent that covers PD-1s and other therapeutic compounds and compound categories. Again, Merck challenged it, noting such in the above mentioned quarterly filing:
On April 30, 2014, the Company, and three other companies, opposed another European patent (EP 2 161 336) (“’336”) owned by BMS and Ono that it believes is invalid. The ‘336 patent, if valid, broadly claims anti-PD-1 antibodies that could include pembrolizumab. {Underlined emphasis is mine.}
Bristol-Myers and Ono Pharmaceutical's '878 patent covers PD-1s as monotherapies.

Bristol-Myers and Ono's '336 patent covers PD-1s in combination with other agents, and appears to include a number of companies' products including Amgen's oncolytic virus and intralesional agent talimogene laherparepvec ("T-Vec"). T-Vec had been combined with Bristol-Myer's approved [anti-]CTLA-4 agent ipilimumab (trade name Yervoy), the results of which were presented at ASCO 2014. Amgen and Merck plan to combine T-Vec with Keytruda in a trial slated to start later this year.

A Big Pharma (BMS) with a market capitalization of about $85 billion (per Yahoo! Finance as of yesterday's close) battling one (MRK) with a market cap of about $176 billion. Afterall, in 2013, Citi analyst Andrew Baum estimated potential annual immuno-oncology-related sales to be $35 billion by 2023 (cough). Titans battling...

It does not appear PV-10 is covered by Bristol-Myers and Ono Pharmaceutical's '336 combination therapy patent. PD-1s in combination with PV-10 apparently are, however, covered by Provectus' combination therapy patent application (20120263677 ["'677"]) that it jointly filed with Pfizer (through an expansion, or continuation in part, of Claim #1) in 2012. Pfizer and Provectus would share CTLA-4-related combination therapy sales revenue via the '667 patent application if/when issued, but the former has no claim in the patent app on economics derived from PD-1-related combination therapy sales.

Whether the '878 monotherapy patent ultimately prevails -- that is, whether Merck is violating the patent for tackling cancer (see paragraph 047) -- is Merck's problem, and the Big Pharma eventually may elect to direct royalties Bristol-Myers and Ono's way(s).

Merck could, however, circumvent paying the other parties by meaningfully combining pembrolizumab/Keytruda with PV-10. Directionally speaking, immuno oncology is trending towards combination therapies for late-stage cancer treatment. Strategically, PV-10 should permit Merck's PD-1 to achieve greater tumor destruction and immunological signaling, and be the perfect front end for an immunologic back-end like Keytruda for the ultimate and better benefit of patients than what the PD-1 alone could achieve as a monotherapy. This combination proposition of course would require a sound scientific and medical data-based foundation, which one hopes Moffitt Cancer Center will present and convey at the Society for the Immunotherapy of Cancer's annual meeting in early-November. Tactically, an effective Keytruda/PV-10 combination with a compelling clinical value proposition should obviate the need for royalty payments to Bristol-Myers/Ono because the '336 combination patent would not be infringed. Increasing anti-PD-1 antibody patent opposition and litigation could tip Merck's decision-making scales in favor of embarking on a near-term combination study of Keytruda and PV-10, with perhaps an eye to a longer-term combination.

September 6, 2014

Moffitt

H. Lee Moffitt Cancer Center & Research Institute has issued strongly worded press releases related to recent pre-clinical and clinical cancer trial work and research successes.

Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows
August 22, 2013, Tampa, Fla. – A new study at Moffitt Cancer Center could offer hope to people with melanoma, the deadliest form of skin cancer. Researchers are investigating whether an injectable known as PV-10 can shrink tumors and reduce the spread of cancer. PV-10 is a solution developed from Rose Bengal, a water-soluble dye commonly used to stain damaged cells in the eye. Early clinical trials show PV-10 can boost immune response in melanoma tumors, as well as the blood stream.
Moffitt Cancer Center Instrumental in FDA Approval of Revolutionary Two-Drug Combo to Treat Advanced Melanoma
January 23, 2014, Tampa, Fla. – Moffitt Cancer Center researchers have laid the groundwork for a revolutionary new combination therapy for the treatment of advanced melanoma – melanoma that cannot be removed surgically or has spread to other areas of the body. The newly FDA-approved therapy, Mekinist (trametinib) in combination with Tafinlar (dabrafenib), is one of the biggest advancements in melanoma treatment in the past 30 years.
Moffitt Cancer Center Plays Pivotal Role in FDA Approval of New Anti-PD-1 Inhibitor Keytruda for Metastatic Melanoma
September 4, 2014, Tampa Fla. – The U.S. Food and Drug Administration (FDA) announced the approval of a new cancer immunotherapy today to treat patients with metastatic melanoma, Keytruda (pembrolizumab) by Merck & Co.

Quotes and statements from Moffitt about PV-10
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September 2, 2014

A China Tale, and Process

From the traditional folksong of Tiger Woman,
adapted by Laurence Yep
From Peter's first trip to China in November 2012 when he began to engage Chinese pharmaceutical companies for a regional partnership, to Eric and Peter's recent trip in August 2014 (the former's first) to sign a memorandum of understanding ("MOU") with one of them, Provectus principals have made five trips to China. These also include February, September and December 2013. 

The November 2012 trip comprised introductory meetings with companies of varying size and geographic scope. Subsequent follow-ups with some additional initial get-togethers too, essentially trips in 2013, comprised gradually more serious meetings with a short-list of more interested companies and increasing senior levels of their leadership. These introductions were facilitated by a number of individuals, agents and third parties that included strategic advisory board members, Network 1 Financial, and Maxim Group. Potential partners have interacted with Provectus in the interim via e-mail and phone, and conducted due diligence via the company's electronic data room. The culmination of these efforts and trips resulted in a first MOU for a China regional partnership with two subsidiaries of Sinopharm Group in August.

Generally speaking, an MOU is to a licensing deal or business relationship what a term sheet is to a venture capital investment and a letter of intent ("LOI") is to an acquisition: formalizations and acknowledgements of serious discussions towards the above mentioned ends, frameworks or outlines of business-investment-acquisition terms, conditions, rights, etc., and lists or mentions of other customary and perfunctory ifs, ands or buts.

Provectus noted in their press release:
During the next three months, the parties will seek to enter into a definitive licensing contract, subject to additional negotiation, due diligence, and any required regulatory and corporate approvals. The parties will further address the details of the license; the use of the technology from Provectus to Sinopharm A-THINK in China; the process for commercialization; and payments to Provectus (upfront, milestone and royalties). Provectus intends to manufacture PV-10 in the USA and Sinopharm A-THINK will distribute PV-10 in China. {Underlined emphasis is mine}
I'm reminded of our corporate venture capital process back in the day (our process flow is below), which I believe is a reasonable facsimile of Provectus' process and the process from Sinopharm's perspective in this situation.
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Preliminary analysis/assessment. Prior to Peter's trip, third parties introducers would have pre-submitted information about Provectus, PV-10, summary and previously public information about pre-clinical and clinical data, regulatory interactions, etc. to potential Chinese pharmaceutical company partners for their analysis and assessment, and to gauge any interest to learn more.

Management team meeting(s). The parties would have had an initial meeting, and potentially or eventually other more serious ones.

Due diligence. Although the graph above is linear and discrete in its steps, some actions are undertaken in parallel and are continuous, like due diligence, even after engagement is formalized. The potential licensee-investor-acquirer conducts due diligence in advance of and after the initial management team meeting, and as more meetings are conducted. As Provectus mentioned on several of its conference calls this year, Chinese companies (among others) have visited the electronic data room to review the various different types of documents stored there.

Due diligence of course goes beyond reading introductory collateral material, meeting management, and visiting data rooms. It extends to on-site visits of the business (Provectus), where clinical work is carried out (e.g., St. Luke’s Cancer Network, Moffitt Cancer Center) and with the people carrying this work out (e.g., Dr. Sanjiv Agarwala, M.D., Moffitt personnel), and other relevant and germane people, companies and institutions, and places. I imagine these due diligence activities are to come.

Term sheet negotiations. At some point, interest rises to a level where the parties can discuss price expectations and their associated structure, terms and conditions. If the parties can reach sufficient preliminary consensus they feel could ultimately lead to a transaction (but with no certainty nor obligation [unless they elect to bind themselves] to do so), they enter into or agree to an MOU-term sheet-LOI. As the jargon goes, MOUs are agreed to by the parties, while term sheets and LOIs are extended by one party to the other.

Negotiations of definitive agreements. When continuing due diligence is satisfactorily wrapped up, should the consensus remains the consensus, and if the broad and not so broad strokes of the MOU-term sheet-LOI are conveyed to definitive agreements, a definitive license-investment-purchase agreement may be struck for signing.

Deal closing. Documents are signed. Signatures are swapped. Money, securities, licenses, etc. change hands.

The process.

MOUs can be serious documents, and they can be far from serious. Sometimes also known as "Barney agreements" (i.e., "I love you, you love me") during the dot com era, Internet companies would enter into them with more established companies or other like venture-backed firms in hopes of demonstrating or simply giving the illusion of progress, business value creation, and rationale for increased valuation.

In the past management has garnered license and acquisition interest, in hand or through conversation, but nothing that rose to the level of both seriousness (met price expectations) and tangibleness (was on paper). For example*:
  • Galderma's rumored 2010 interest in Provectus' dermatology business (on paper, but not serious),
  • A Big Pharma's rumored 2011 interest to buy the intralesional drug compound company (not serious, and not on paper),
  • Orbimed and Domain Associates-backed Eddingpharm's rumored 2013 interest to license PV-10 for sale in China and its territories (on paper, but not serious), and
  • The above Big Pharma's rumored 2014 interest to acquire Provectus for twice its 2011 bid (still not serious enough, and still not on paper).
Provectus' MOU with Sinopharm is the first serious commercial interest the company has tangibly garnered. Tangibly serious because (i) it met management's price expectations as translated into potential payments to Provectus (i.e., upfront, milestone and royalties) and (ii) it was on paper.

To what, if anything, will/could the MOU between Provectus and the Sinopharm subsidiaries lead? The easiest way to answer this question of course is to wait and see if/when a license deal transaction is consummated between the parties. In the interim, I look at the situation this way: Provectus agreed to sign a document that formalized their discussions with Sinopharm towards the end of consummating a license deal and business relationship with the Chinese healthcare company under a framework of financial and business terms and conditions that may good to great [for Provectus], and we should know by mid-November or earlier if the parties ultimately do something together.

Finally, I wanted to comment on some of the verbiage in the MOU PR:
The MOU contains customary provisions regarding confidential information, publicity, and intellectual property, and is non-binding upon the parties (except for certain non-material provisions). The MOU shall continue in effect until the earliest of the replacement of the MOU with a definitive agreement, one month prior written notice by either Provectus or Sinopharm, or ninety days from the signing of the MOU.
In order to facilitate my comments, I also provided a sample or model venture capital investment term sheet below, which I utilized during my corporate venture capital investment days.


Click to enlarge. Sample venture capital investment term sheet, page 1.
Click to enlarge. Sample venture capital investment term sheet, page 2.
Click to enlarge. Sample venture capital investment term sheet, page 3.
Click to enlarge. Sample venture capital investment term sheet, page 4.
Click to enlarge. Sample venture capital investment term sheet, page 5.
Click to enlarge. Sample venture capital investment term sheet, page 6.
Click to enlarge. Sample venture capital investment term sheet, page 7. 
Click to enlarge. Sample venture capital investment term sheet, page 8.
Click to enlarge. Sample venture capital investment term sheet, page 9 (of 9).
Provectus' MOU PR naturally did not discuss "price," or payments to Provectus (upfront, milestone and royalties). Management would not have signed an MOU if those elements were neither to their liking nor codified (summarily or specifically) in the document. The first page of a term sheet (i.e., page 1 above) or the first paragraph of an LOI, aside from pleasantries, typically addresses the headline numbers of a prospective deal. I previously have commented on this blog about Provectus' price expectations for a China partnership. One wouldn't have expected the company to detail price agreements with Sinopharm in either the PR or the associated 8-K filing. Additional MOUs maybe forthcoming, and there may be competitive interest. Then again, there may not be dueling interest that pushes price upwards, and I would presume Provectus then would be comfortable with price as outlined in the Sinopharm MOU (with perhaps some further wrangling to finalize agreement on the timing of payments).

The MOU PR discussed "customary provisions regarding confidential information, publicity, and intellectual property," some of which find commonality with the venture capital investment term sheet (i.e., page 7, Confidentiality). Later versions of my terms sheets included sections dealing with publicity, and intellectual property (of the target company) as and when appropriate.

MOUs, term sheets and LOIs are broadly binding (i.e., material and non-material provisions) when the parties agree to be so bound, or when one party wants the other party to be bound and the other party agrees to such binding. Usually, as illustrated by the sample or model term sheet above, these relationship documents generally aren't binding in any meaningful way (to allow an out for either party, but many times the the one wanting to partner, invest or purchase). For non-material binding provisions see page 8, Binding Provisions. For outs, see page 7, Conditions to Closing.

As the MOU PR noted, the term sheet often references the definitive investment (or securities purchase) agreement that replaces the MOU or term sheet. See page 7, Purchase Agreement or page 1, introduction, for example.

Term sheets often include a target closing date (see page 7, Closing Date) by which time the parties hope or seek to complete their negotiations to consummate a transaction (i.e., finalize definitive agreements, sign them, exchange whatever). The parties mutually agree on a timeframe; however, the closing date is not set in stone and can be mutually modified through subsequent revisions to the term sheet (in large part to maintain exclusivity until a transaction is done). Provectus MOU PR noted a ninety-day period, which should be the target or contemplated closing date.

Exclusivity clauses almost always are part of terms sheets and LOIs to provide sufficient timing for the parties (especially the motivated one) to consummate a transaction. They may be part of an MOU in terms of the transaction (i.e., Sinopharm may exclusively negotiate with Provectus until such time as a deal is done, or the parties part ways). I imagine if the MOU had an exclusivity clause, the MOU PR would have mentioned it (not saying anything about it says something too). Exclusivity certainly may be part of the business terms; in this case it is: "Sinopharm-CSIPI and Sinopharm A-THINK desire to obtain an exclusive license to commercialize PV-10 within [the People's Republic of] China territory, and PVCT is willing to grant such license to Sinopharm."

* Listen to Provectus' echo chamber long enough, do some due diligence and, pardon the pun, connect some dots, and you eventually make out what the original voice that started the echo said or meant to convey. And while it doesn't mean a hill of beans if it's not translated into share price, the sound nevertheless is informative and instructive.

August 31, 2014

Potential Catalysts

Potential catalysts through 1Q15 could include:
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Commencing enrollment of its pivotal late-stage trial for melanoma (locally advanced unresectable/unresected cutaneous melanoma) is a key milestone and important catalyst for Provectus because the eventual outcome should provide clarity about the prospects for PV-10's regulatory validation (i.e., the drug's initial pathway to approval).

Securing a good-to-great regional transaction or two, in these cases for the world's two most populous countries, among other things (i) validates the drug's commercial prospects, (ii) more than bolsters Provectus' balance sheet with non-dilutive monies, (iii) brings partners to the fore that can facilitate late-stage trials in their respective geographies for primary liver cancer (and potentially breast cancer), further strengthening PV-10's multi-indication viability, and (iv) establishes a viable non-U.S. centric go-to-market strategy.

Moffitt Cancer Center's presentation of pre-clinical work underscoring their contention (initially conveyed at the 2014 annual meeting of the American Society of Clinical Oncology, and later at the 4th European Post-Chicago Melanoma & Skin Cancer Meeting) -- intralesional PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma, and PV-10 would be a good candidate to evaluate in conjunction with available systemic therapies and new agents in development (respectively) -- could be the catalyst for a drug combination study of PV-10 and an anti-PD-1 agent like nivolumab or pembrolizumab. I think a study only materializes if (because) the data is sufficiently compelling to encourage one of the Big Pharmas to accede to more favorable non-clinical-related terms and conditions than to what other combo study partners have agreed. This data should be presented by Moffitt at the 2014 annual meeting of the Society for Immunotherapy of Cancer in early-November.

August 22, 2014

Notepad

1. DAMPs. Following up on my Damage-Associated Molecular Patterns, and Immunogenic Cell Death (August 21, 2014) news item, I'm curious (fascinated) by PV-10's potential role in immunogenic cell death, and thus the release and surface expression of damage-associated molecular patterns ("DAMPs"). DAMPs "..link the dying tumor cell with innate immunity, culminating in adaptive anticancer memory responses."

The recent paper by Panzarini et al. (2014), Rose Bengal Acetate PhotoDynamic Therapy (RBAc-PDT) Induces Exposure and Release of Damage-Associated Molecular Patterns (DAMPs) in Human HeLa Cells, observed that key DAMPs -- ATP, HSP70, HSP90, HMGB1 and CRT -- were exposed and/or released after treatment of cell lines with Rose Bengal acetate and photodynamic therapy. I understand this work involved using PDT and a functional RB derivative, and was carried out on cell lines; however, what interests me about it is the study's goal, which was to determine if RB could trigger apoptosis and autophagy -- cell death -- and thus expose and/or release pivotal DAMPs.

Very interestingly, in my view, the researchers also noted their data represented the fourth demonstration of the exposure of the HSP90 DAMP by indication and third demonstration by drug compound: "In fact, exposure of HSP90 was shown only in lung cancer [36] and myeloma [37] treated with Bortezomib and in bladder cancer cells treated with capsaicin [38]." Bortezomib is a proteasome inhibitor (Millennium Pharmaceuticals [Velcade]/Venus Remedies [Cytomib]). Capsaicin is a neurotoxin and active component of chili peppers.

Moffitt previously showed PV-10 (Rose Bengal) in their murine model work released HMGB1.

2. Innate and Adaptive Immunity. As I wrote above, DAMPs, or their impact once exposed and/or released, form a bridge between the body's innate and adaptive immune systems (or non-specific and specific, respectively). See my blog post PV-10 is not bigger than Mother Nature for a discussion of the immune system; "The immune system protects organisms from infection with layered defenses of increasing specificity."

In 1994, "[t]wo papers appearing in the same year presaged the deeper understanding of innate immune reactivity, dictating the subsequent nature of the adaptive immune response. The first...speculated...free radical-mediated reperfusion injury-was seen to contribute to the process of innate and subsequent adaptive immune responses. The second...suggested the possibility that the immune system detected "danger", through a series of what we would now call damage associated molecular pattern molecules (DAMPs), working in concert with both positive and negative signals derived from other tissues." {Underlined emphasis is mine}
  • Land W, Schneeberger H, Schleibner S, et al. (January 1994). "The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants." Transplantation 57 (2): 211–7.
  • Matzinger P (1994). "Tolerance, danger, and the extended family." Annu. Rev. Immunol. 12: 991–1045.
I've written that PV-10 harnesses the immune system, rather than restraining, blocking, manipulating, etc. parts of it. Note that Chen & Mellman (2013) title step 3 of their cancer immunity cycle illustration "Priming and activation." {Underlined emphasis is mine}

3. It's A Small World. The authors of the RBa-PDT paper come from Italy's University of Salento, and do not appear to have any disclosures related to Provectus. While the company has engaged certain principal investigators and their respective hospitals in Australia and the United States, as well as Moffitt Cancer Center, there is a body of work from researchers espousing Rose Bengal's potential as a cancer therapeutic who are currently or not at all unaffiliated (or appear to be unaffiliated) with the company. They are, among others (representative papers below):
4. Amgen's talimogene laherparepvec ("T-Vec"). Related to Amgen's T-Vec, the FDA announced a November 6th advisory committee ("AdComm") meeting (Cellular, Tissue and Gene Therapies Advisory Committee) to discuss the draft guidance for industry entitled "Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products." Does this bode well or poorly for T-Vec in regards to its ease of administration and use, or lack thereof?

5. Info. An interview with Peter formed the basis for today's Seeking Alpha article Provectus' Latest Developments Spark Investor Interest -- CFO/COO Culpepper Explains Why. Of note to me was his answer to the interviewer's question "What is the anticipated market trajectory for PV-10?"
Peter: "We anticipate PV-10 phase 3 for melanoma to be one path for PV-10 approval. We anticipate also combining PV-10 to treat patients with disease inaccessible to direct injections. We also anticipate treating primary liver cancer patients in an upcoming randomized phase 2 study and seeking an expedited approval path in that important indication as well."
Taking this response at face value would suggest the upcoming (anticipated) liver Phase 2 trial would be for primary liver cancer (hepatocellular carcinoma), and not include cancers metastatic to the liver. A subsequent or concurrent study might examine this aspect of liver cancer, but the contemplated Phase 2 trial would not, or so it seems to me. Liver cancer of course is a very large unmet need in Asia. One would hope Eric garnered the feedback he required [from his recent Asia trip] to finalize and file the liver Phase 2 trial protocol.