The Early Obsolescence of Checkpoint Inhibitors

Image source

Take as a starting point Inman et al.’s 2007 article entitled Costimulation, coinhibition and cancer, and their statement therein: (underlined emphasis is mine):

“If sufficient co-stimulation is provided in the presence of adequate tumor-associated antigenic stimulation, the immune system will act against tumor antigen and, thus, destroy early tumors before they become fully established. Contrarily, if co-inhibitory signaling dominates, the immune system will be tolerized to tumor antigens, and the tumor will be permitted to grow unfettered and unmolested by the immune system. If neither co-stimulatory nor co-inhibitory signals dominate, the adaptive immune system may remain in a tenuous state of equilibrium, militating against tumor outgrowth with varying degrees of success.”

The essence of the authors’ view might be that the immune system is capable of decisively acting against cancer only in the situation where or circumstance that co-stimulation dominates co-inhibition. Take also as context to this starting point, however, that what we don’t know about the immune system probably dwarfs what we know about it.

The notion of “releasing the brakes” in the medical literature and mainstream press describes the approach of inhibiting cancer’s ability to suppress or block the body’s immune system from acting, and thus to evade attack. Although possibly coined in the early-2000s (see, for example, Tirapu et al.’s 2002 article entitled Effective tumor immunotherapy: start the engine, release the brakes, step on the gas pedal,...and get ready to face autoimmunity), use of the releasing-the-brakes phrase may have grown more widespread starting in the late-2000s and around the time of Dr. James Allison, Ph.D’s seminal work of blocking (inhibiting) the CTLA-4 protein receptor (using Bristol-Myers’ ipilimumab) and, later, the follow-up scientific exploration of blocking (inhibiting) PD-1 and PD-L1 ligands too (and associated PD-1 therapeutics pembrolizumab and nivolumab, for example, from Merck and Bristol-Myers, respectively).

Medical literature has more sparsely touched on, and mainstream press much less so, the other two components of the get-the-car-moving analogy (where the car is the immune system), “starting the engine” and “stepping on the gas pedal,” where these phrases relate to different aspects of stimulating the body’s immune system.

Possibly over-using the car analogy further, with the potential risk of over-simplifying it inappropriately, consider T cell immunity as a car at rest. More immunogenic tumors and their associated cancers like melanoma are like a car sitting on a slight incline. Release its brakes by treating the tumors (and thus the cancer) with checkpoint inhibitors, and the car may roll forward move some distance, notable or otherwise. With other less or non-immunogenic cancers, think of the car as sitting on a flat surface. Releasing the brakes does not enable the car to move any meaningful distance, if at all.

If you want to get the car to really move, you have to start its engine, and then step on its gas pedal. Releasing the brakes might help the car move farther and faster, but it also is quite possible the car may be able to move sufficiently without the need for further action other than to start its engine and/or stepping on its gas pedal.

The continued use of get-the-car-moving analogy of course requires the assumption the car can drive by itself; that is, the immune system can handle its own business once it has been started, and is appropriately up and running from stepping on the gas pedal.

Now consider Winograd et al.’s 2015 article entitled Induction of T cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. In particular, note the underlined sentences (my emphasis) from the article’s abstract:

“Disabling the function of immune checkpoint molecules can unlock T cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4 resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFN-γin this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with PD-1 mAb, with or without CTLA-4 mAb, failed in well-established tumors, recapitulating clinical results. Agonist CD40 mAb with chemotherapy induced T cell immunity and reversed the complete resistance of pancreatic tumors to PD-1 and CTLA-4. The combination of αCD40/chemotherapy plus PD-1 and/or CTLA-4 induced regression of subcutaneous tumors, improved overall survival, and confered curative protection from multiple rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers although no cures were observed. Our findings suggest that in pancreatic carcinoma, a non-immunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T cell response with αCD40/chemotherapy.”

CD40 is a co-stimulatory protein, while chemotherapy has been understood to act in a stimulatory fashion through the subsequent release of cancer antigens.

Achieving T cell immunity almost if not actually by definition should mean overcoming resistance to cancer, thus overcoming checkpoint blockade and mitigating the need to artificially release the brakes.

Should stimulation via stimulatory therapeutics and therapies start the engine and enables the gas pedal to be stepped on sufficiently and appropriately (i.e., with minimal or manageable side effects or adverse events) so as to achieve T cell immunity, brakes may not be necessary once the car is moving (in context, and given the car [the immune system] can drive itself and not careen off the road because it then should know what it is doing).

Over time, however, road friction may start slowing the car down to the point where waning immunosurveillance (the immune system recognizing and eliminating continuously arising cancerous cells) no longer can protect the patient from relapse (analogous to how waning varicella zoster antibody titers may result in a bout of shingles). Keeping the brakes disengaged, especially with non-immunogenic tumors, should have some role going forward, making Merck, Bristol-Myers, Roche, AstraZeneca, Pfizer and other companies’ checkpoint inhibitors not necessarily obsolete as much as persnickety.

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.

Click to enlarge.

Click to enlarge.

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.

Pfizer adds a 2nd executive to Provectus' advisory board

"Alright, move on. Nothing to see here. Please disperse. Nothing to see here. Please."

Pfizer added a second executive to Provectus' corporate advisory board ("CAB"), Bob Miglani, Senior Director, External Medical Affairs (PR here).

In August 2011 Pfizer oncology executive Dr. Craig Eagle joined the CAB. At the time Eagle was Vice President of Strategic Alliances and Partnerships for Pfizer's Oncology Business Unit.

Provectus also announced it had received sufficient shareholder support to reincorporate in Delaware (from its original incorporation in Nevada) and change its name to Provectus Biopharmaceuticals, Inc. (from Provectus Pharmaceuticals, Inc.).

Updated [12/17/13]: With Miglani's CAB announcement placed at the end of today's PR and having no separate PR, I have to wonder whether the Pfizer mothership and/or its corporate legal department, possibly concerned about appearing to endorse the company (and/or, perhaps, not wanting to reveal interest in Provectus (rom a worldwide license and/or M&A perspectives), prevented Craig et al. from issuing a separate PR on the matter.

After all, Eagle's addition to the CAB 28 months ago came with its own PR and appropriate title: "Dr. Craig Eagle of Pfizer Joins Provectus Pharmaceuticals's Corporate Advisory Board." Underline emphasis is mine. For Miglani, today's PR's byline merely said: "Bob Miglani Joins Corporate Advisory Board."

In September 2012 Provectus issued a PR regarding its patent application for combining local and systemic therapies 15 months ago, co-authored with Eagle and assigned jointly to the company and Pfizer (and which looks for all intents and purposes to be approved). The PR made no mention of Pfizer. Here again, I think Pfizer did not allow Provectus to include its name in the PR.

I suppose allowing two executives of varying corporate influence to join a tiny biotechnology company's corporate advisory board and agreeing to jointly submit a combination therapy patent could be construed as not-an-endorsement-of-said-biotech. To me, it (and other dots) more than suggest interest to acquire the biotech.

Well, Did You or Didn't You...?

It's been a few days of quite the price action and trading volume since Moffitt issued its press release Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows, following low to moderate volume within a roughly $0.60 to $0.70 per share trading range since about mid-April.

The PR was followed by a positive piece in Agora Financial's investment newsletter Breakthrough Technology Alert on August 27th entitled Study Shows Provectus' Compound Makes Cancer "Dye" and an article in Seeking Alpha today (September 6th) entitled Provectus Pharmaceuticals: Small Cap, Huge Upside.

Last 3 months

Last 12 months

Into the buying interest that ensued convertible preferred shares were sold (i.e., preferred stock were converted into common stock, and then sold) dampening the upward share price move: a close of $0.64 on August 21st, a high of $0.89 on the 28th, and a close of $0.74 on September 6th -- moves of 15-40%. Not bad.

Like a coiled spring, a "little bit of good news" goes a long way when it comes to Provectus' share price.

But, this is where the capital structure hurts. The overhang of shares ready, able and willing to be sold weighs heavily on the share price for the time being. While there certainly has been buying interest, it is no where near the levels to overcome the amount of shares available for sale by folks who are more than content to sell their common and/or preferred stock and wait for their warrants to become the primary driver of value in their portfolios.

You might think of the 75-cent share level as a key "resistance level" because the preferred shares issued in 2010 and 2013 were priced at this figure. As at June 30, 2013, there were 1,481,665 2010s and 3,400,001 2013s. Somewhere between 750,000 and 1 million 2010s may have been converted and sold into the recent share price bump. Sustained selling may ensue of more 2010 preferred, if not the remainder of them, should buying interest continue.

The next key resistance level may be around $1.05 for warrants and their potential exercise.

I hope there is continued news of progress that would drive greater and greater awareness of the drug, Provectus and, thus, the share price.

As I wrote above, a Seeking Alpha article on Provectus was published today:

"Given that PV-10 has an outstanding safety profile, no debilitating treatment side effects, and has been effective in treating solid tumors that normally have a high mortality rate, the remarkably low market capitalization makes the investment premise obvious."

The blog received a mention (see the red underlined sentence portion in the illustration above), which I appreciated.

Peter has been in China, ostensibly (obviously) to try and secure/agree to a regional license transaction. I hope this process, which began last spring or summer (I think), followed by his first trip to the country in November 2012, a second trip in February 2013, meetings in Washington, DC at AACR in April 2013 and several meetings (I think) in New York, will culminate in a transaction or transaction agreement with this September visit. The two leading parties for a regional deal appear to be Pfizer joint venture Hisun-Pfizer Pharmaceuticals and pharmaceutical marketing company Eddingpharm (Hong Kong and Shanghai).

Very recent speculation has been that an MOU has been secured; proof only will be pudding'ed when Provectus files an 8-K for this material event (and issues a subsequent PR). For now, we wait.

It is quite possible a regional transaction with an Indian pharmaceutical company follows very quickly on the heels of a China transaction (if one ultimately is consummated). I do not believe Peter would have to fly back to India, which he initially visited in June, to close this deal. The two leading parties for a deal on the sub-continent appear to be Dr. Reddy Laboratories and Japanese pharmaceutical company Daiichi Sankyo's Indian subsidiary Ranbaxy Laboratories.

I often wonder about the status of Provectus' November 2010 discussion with Australia's Therapeutic Goods Administration ("TGA") regarding the use of interim data from the first half of metastatic melanoma Phase 3 study subjects (when such a trial would be run), in conjunction with safety data collected in earlier studies of PV-10 for melanoma, to allow early evaluation for marketing approval for MM. If Moffitt's results thus far, such as the cancer center's work published in PLoS, have moved the FDA, it would not be unreasonable to think it also has moved the TGA. When the FDA provides the much needed and long awaited regulatory clarity for PV-10, TGA may approve PV-10.

In July I learned (diligenced) the second liver trial site, Tampa, Florida's Southeastern Center for Digestive Disorders & Pancreatic Cancer, had not yet enrolled patients. It appears patients now have been enrolled, and I would expect a near-term PR from Provectus to mark this milestone.

Abstracts for ECCO 2013, the European cancer conference at which the company will present MM Phase 2 trial data, should be available online on September 12th.

The #OhShit Provectus Moment

Bell lap. You may recall I wrote in early-June, a couple of months ago, that I believed the focus of Eric and his regulatory affairs team was on getting PV-10 approved (my post entitled $PVCT: Do You Understand the Words That Are Coming Out of My Mouth?). I thought Eric et al. were working collaboratively with the FDA to provide what additional information was required by the Agency to achieve accelerated approval ("AA"). I felt to me the situation wasn't/isn't about SPA or BTD applications or submissions, or timing, anymore. Rather, I felt, it was/now is just about getting PV-10 approved (e.g., label, patient population, remaining boxes to check, etc.).

But, all drug development companies and their management teams try to get their drug candidates approved. You follow steps in (i.e., meetings with and submissions to the FDA) and out (e.g., conferences, peer-review publications, meeting with and engaging key opinion leaders, etc.) of the regulatory process and the investment one (e.g., soliciting or seeking out investment sponsors, playing nice with Wall Street, etc.).

Provectus hasn't really followed a lot of those "recommended" steps. Typical of an atypical biotechnology company management team, but I think typical of the best folks coming out of this country's national labs (at least, the several I met in a previous lifetime), they followed a data-driven process rather than one driven necessarily by convention or tradition.

In doing so, you make choices and decisions that don't always work out or that require changing course or that take more time than you would have liked. You learn, you get better, you adapt, you continue your pursuit, especially when the data gets better and more expansive over time.

So when I write "Eric is focused on getting the drug approved" I mean his efforts, and those of his team and the rest of management, to answer all of the FDA's questions from 2010 through this year that previously had resulted in Provectus getting "shot down" or put off when they first asked for AA.

As such, there will come, I think and hope very soon, an "oh shit" moment when, in my view, Provectus gets breakthrough therapy designation ("BTD") for PV-10 and metastatic melanoma ("MM").

The investment community, broadly speaking, says "oh shit" as a natural reaction to four guys from Tennessee innovating PV-10, getting BTD for MM, an investment opportunity seemingly out of nowhere and not on most investors' radar screens or in their stock filters, impressive clinical and business value propositions that beg for more exploration and examination, and so on.

Perhaps "oh shit" also comes from a realization that PV-10, a 10% solution of small molecule Rose Bengal, is a very safe and efficacious therapy that when injected into accessible cancerous lesions rapidly reduces local tumor burden and stimulates the immune system to systemically shrink or eliminate non-injected distant tumors and visceral metastases. Broadly applicable to several solid tumor cancer indications, the drug generates tumor-specific immunity that is tantamount to in situ vaccination against cancer.

Or from the understanding that Provectus and its management team exemplify innovation over incrementalism, meaningful over marginal, productized technology over hypothesis, changing the world over accepting the status quo – all of which combine to form the quintessential essence of a paradigm shift.

Or from the construction that the paradigm shift in cancer treatment that is PV-10 is where a compelling investment thesis begins and ends: a novel compound, a ready made product, a vast addressable market of unmet need easily, profitably and fully met over time. The thesis comprises compelling clinical, regulatory, business and stock value propositions in a pharmaceutical industry ravenous for safe and effective oncology product offerings, facing an addressable market with an annual growth rate exceeding other therapeutic areas, that following drug approval delivers a lucrative monetization for shareholders.

As for timing, well, you won't get a revealing word from management on the topic, other than encouragement to read May's CEO letter. I think it's reasonable to speculate around or before The European Cancer Congress 2013, as I've previously written in blog posts "Raising the Curtain on $PVCT, Finally" and "$PVCT's Word out of the 8th World Congress of Melanoma," because you can't help but think, after observations following the 8th World Congress and during this week in New York, that the BTD application has been completed and/or submitted.

Pfizer. Peter was said to have been in several meetings with folks at Pfizer this week. As you know, Pfizer announced this week it would reorganize "its commercial operations into three new units, with one division focused on products that are losing patent protection, one division that will handle drugs with years of patent protection remaining, and a third that will sell vaccines, cancer treatments, and consumer products."

What positive or negative effects does or could Pfizer's reorganization have on Provectus? I am interested to learn of corporate advisory board member Craig Eagle's go forward role, if any, in the new corporate structure at Pfizer. I had asked a former senior executive at a global brand for the internal view of Dr. Eagle within Pfizer. It was interesting to compare notes in the context of what emerged this week from shareholders who were updated in New York. I also learned of a "closer relationship" (that I do not believe includes any monetary concepts) being contemplated between the two companies. I'll dish next weekend on this, and on things Pfizer because I'm interested in (albeit, as a non-biotechnology investor, a tad perplexed by) the tapestry apparently being woven. You can't help but think there's not a small amount of table setting going on, which isn't to say other options, outcomes or relationships with others are being foreclosed.

PH-10. Why was/is Eric also in New York this week? It is possible he was involved in continued due diligence by regional and/or global pharmaceutical companies. His portfolio of responsibilities at Provectus of course comprise clinical trials, biostatistics, intellectual property, regulatory affairs, and manufacturing.

With regulatory affairs resources having been recently shifted towards PH-10 and the company's inflammatory dermatoses opportunity, he also may have been visiting with researchers at Rockefeller University's Laboratory for Investigative Dermatology (where toxicity-related work, among other things, was being conducted) and principal investigators at Mount Sinai School of Medicine (PIs for the company's atopic dermatitis and psoriasis trials).

A change to the layout of the blog. As you will have seen, I made a layout change by adding a pane on the left hand side to provide snippets of news, information, data, rumors, etc. I find, glean, learn of or hear.

$PVCT & $PFE's Hisun-Pfizer Pharmaceuticals Co., Ltd.

In my blog post "I think the situation with $PFE and $PVCT has escalated," I wrote the injection of PV-10 and its subsequent chemoablative action creates lots of antigens. The creation of lots of antigens is the key to the successful, sustainable treatment of cancer and, thus, its cure. Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells. PV-10 creates an "antigen storm," the creation of many antigens, much more than than any other antigen-creating material currently available. One would think Dr. Eagle is well are of this.

In the context of Provectus' white paper describing PV-10's systemic immuno-stimulatory effects, it is interesting to read Dr. Eagle's comments about stimulating the immune system and doing so to in a specific way. What follows is a transcript of a Generex conference call from October 2010, where Dr. Eagle had sat on this company's scientific advisory board ("SAB"). Interestingly, in November 2010, Dr. Eagle visited with and viewed Provectus's presentation of its preliminary MM Phase 2 results at an Australian conference.

Bold emphasis below is mine. The "Eric" below refers to/is Dr. Eric Von Hofe, President of Antigen Express, Generex's wholly owned subsidiary (and not Provectus' Dr. Eric Wachter).

Thanks Eric. For the people on the phone, my name is Craig Eagle, and I’m an MD by training in Australia, and I’ve been working with Generex for the last six to nine months as part of its Scientific Advisory Board, and really what I want to do and discuss today was two very high-level concepts particularly around Antigen Express and the immune portfolio.  And the first is around the science. We all every day depend upon the immune system to protect us from diseases whether it be cancer or infections. And we know, and certainly many companies in the field of cancer technology are looking at ways to augment the immune system to attack cancer. One of the things that Antigen Express is working on is looking at it from two angles. One is to stimulate the immune system in itself, that’s (two key) protein, and the other is to (inaudible) direct and stimulate the immune system to a specific target. Now the beauty of this approach and the reason that I think there’s a lot of potential research required here to prove whether these compounds achieve treatment in cancer centers around the fact that, as Eric mentioned, the platform. 

In particular the platform of stimulating the immune system and directing it is a platform that has been recommended in the scientific world of (immuno-) oncology, and at the moment, the forerunner is looking at HERC2 breast cancer. Now the beauty of looking at HERC2 breast cancer as the forerunner is that Antigen Express, I believe, has designed the right experiments to test whether the vaccine works, but also HERC2 expression breast cancer is an area that has already shown and been well defined to have benefit from treatment, in particular, people may be familiar with a product called Herceptin, and Herceptin was a breakthrough for treating patients with that particular cancer.
And so the vaccine will then add and be able to augment potentially the immune system in a (robified) cancer population that still needs further treatment.  Also, what makes it exciting from the Antigen Express point of view, in my view, is related to the fact that they can build on that cancer immunology to then branch out to other cancers where there could be positive results.  In particular, the signs would suggest that the HERC2 expression, just like Herceptin, has been used in other cancers, could be explored with further research on its benefit there.

Finally I just want to move along to other areas, and Eric mentioned those, and that is the immune system could be used in (antigen effectives (ph) or as an immune modulator for areas like diabetes.  So now when you look across multiple and different biotech companies, and certainly from a research point of view, there are probably three criteria that are key to remember. The first is that, as Eric mentioned, in the Antigen Express space there’s a platform. A platform to stimulate the immune system to achieve what it needs to achieve to control cancer, infections and other diseases, and it’s just a case of producing, testing and doing the right research to develop those products forward.  The second area, then, is to do the right experiments and the right testing, and Eric and the team at Antigen Express have been working very hard to make sure that the trials that they are doing are trials that we (to the) right questions from a scientific point of view.

So the quality of the trials has to be paramount and above all very important to show whether the (products) worth or not.  And finally the third area is actually an overall direction for the potential treatment of patients in a (robified) population.  So I’ve already mentioned that HERC2 breast cancer is well defined and there is a very significant unmet medical need with women with cancer of the breast who get their cancer progressing despite the best standard of care, and so there’s certainly potential here to actually save lives and help women with breast cancer.  So all in all I think that Antigen Express creates a great, stable platform to actually explore and research these compounds moving forward.  I’ll hand over now to Gerry Bernstein who can then further discuss the metabolic aspects of Generex. Gerry?

Dr. Eagle's interest in or perspective of stimulating the immune system with great specificity seems very consistent with Provectus' path to immuno-oncology.

As an aside, in checking Generex's SAB website page and the SAB website page of it's subsidiary Antigen Express for links to use in this post, it would appear Dr. Eagle is not mentioned on either site's SAB pages anymore. I believe he still is a director on the boards of Regenicin and Assured Pharmacy.

Pfizer announced the signing of a memorandum of understanding ("MOU") with Hisun Pharmaceuticals in June 2011 to establish their joint venture ("JV"), Hisun-Pfizer Pharmaceuticals, which no doubt took many months to construct before signing. The JV was contributed to/funded in September 2012, nearly 15 months later.

Recent articles about Hisun-Pfizer suggest a very independent company from Pfizer. The economics of the JV are notable for Pfizer, which owns 49% of it versus Hisun's 51% controlling stake. Kevin Xiao is CEO of Hisun-Pfizer, with whom Peter interacted this week.

Whether a deal gets done with Hisun-Pfizer for China more than likely is up to the Chinese, and not exclusively Pfizer, who I think are encouraging a transaction for this geography between the JV and Provectus parties. I think that because I think, after Peter and Eric's recent trip to New York and various meetings with Pfizer there, Dr. Eagle has more recently taken a more active role in his interactions with Provectus (although I'm sure he's been a contributing SAB member since he joined).

I think the situation with $PFE and $PVCT has escalated

Following the week of June 10th, during which Peter spent a considerable amount of time in New York and Eric later did as well, it appears to me the situation with Pfizer, the relationship, such as it was and now is, changed.

Call it what you wish: The situation or relationship evolved. The relationship was taken to a new level. The situation escalated in a positive way. Etc.

However you wish to describe or frame it, Eric being brought further into the picture points to a discussion that very likely broadened and deepened from what it only was the week before when Peter and Eric were at ASCO with Pfizer's Craig Eagle.

From what I have discerned thus far, and I certainly do not have anywhere near the entire picture, Peter again met with Dr. Eagle, a member of Pfizer's Oncology Business Unit ("OBU"), which is part of the Specialty Care and Oncology organization that also includes the Specialty Care Business Unit ("SCBU"). Eric's visit included, at least, meetings with OBU senior leadership. Peter also met with senior corporate leadership (not, however, Pfizer's Chairman and CEO Ian Read).

There were more meetings, too.

Peter's role encompasses represents the first-line of and continuing business development interaction and communications with potential license partners, both regional and global. Given the demands on Eric's time, bringing him into New York City for further discussions with Pfizer is not atypical of a relationship that has grown, poised to grow or being considered for growth.

The question for me is the nature of the discussions, both the ones Peter had and the one(s) Peter and Eric had. Did discussions include or address regulatory clarity, commercial validation, and/or business strategy of one sort or another? Time only will tell.

◦    ●    ◦    ●    ◦    ●    ◦    ●    ◦    ●    ◦    ●    ◦    ●    ◦    ●    ◦

Click to enlarge the picture.

I also understand Peter met with the company's Chinese intermediaries. I believe Pfizer is encouraging, as best it can or in a manner consistent with and in its own interests, a relationship between Hisun-Pfizer Pharmaceuticals, Pfizer's Chinese joint venture with Zhejiang Hisun Pharmaceuticals, and Provectus.

Since no press release was made nor 8-K filed last week, it would seem more work is needed and/or more time is required for a relationship to be consummated, if at all.

Peter leaves for his trip to Japan next week. If a deal is to be had, it will require him to take a side trip to Taizhou Zhejiang, China, where Zhejiang Hisun Pharmaceuticals is headquartered (and where I presume Pfizer-Hisun has its China location, although not necessarily). I think it is more likely Peter returns with an MOU and no upfront payment. Recent chatter suggests the upfront payment is lower than I first expected, at $10 million, but with two healthy-sized, regulatory-oriented milestone payments of $50 million each.

Should Peter secure the MOU, it is possible the company announces the event via a PR on June 18 at the earliest. If this happens, I would not be surprised if Maxim Group equity research analyst Dr. Echo Yinghui He, MD, PhD, then issues a research note describing the deal and valuing it at $1 billion on a net present value (i.e., taking into account upfront and milestone payments, royalties, market penetration, indications, cash flows).

If we hear nothing upon or shortly after his return, then follow-up is required.

◦    ●    ◦    ●    ◦    ●    ◦    ●    ◦    ●    ◦    ●    ◦    ●    ◦    ●    ◦

Moffitt Cancer Center has definitively and unambiguously concluded PV-10 has systemic properties and benefits, which the FDA wanted to understand before considering accelerated approval.

We're now trying to digest a larger truth, that local chemoablation of a cutaneous lesion with PV-10 leads to transferable immunity. As described in Provectus' recent white paper, according to Moffitt's Dr. Shari Pilon-Thomas, "We think that when you inject PV-10 into a tumor, it  destroys the tumor, releasing tumor fragments that are then taken up by immune cells. The immune cells travel to the lymph nodes where they ‘educate’ or activate T-cells which can in turn travel anywhere in the body."

The question of PV-10's systemic properties and benefits has been answered. Academics and researchers will read it in a peer-reviewed journal in the coming months, now that the manuscript has been approved for publication.

The next question for Moffitt is how does it maximize the process by which PV-10 generates immunity. Moffitt's Dr. Jeffrey Weber, the driving force behind the approvals of immunotherapy treatments ipilimumab (Yervoy) and vemurafenib (Zelboraf) for Stage IV metastatic melanoma patients (and considered a/the "god" of immunotherapy), is now firmly behind PV-10. The landscape for treatment therapies for Stage III patients is barren, and wide open for PV-10, which is and has been the point of the regulatory path Provectus chose for its drug. Stage I, II and IV are, of course, also in play.

Dr. Pilon-Thomas now searches for answers to questions like “Is it just because you inject the drug and it goes everywhere and then kills tumor cells at other sites? Or is injecting PV-10 inducing
a T-cell response, such that T-cells travel throughout the body and kill tumors in their various locations?”

To Pfizer's Dr. Eagle and his Big Pharma counterparts, none of what Dr. Pilon-Thomas asks matters as much as the massive creation of antigens that PV-10 causes, and how can PV-10 be optimized to treat and cure all stages of cancer.

PV-10 creates antigens. It creates a lot of them. The creation of lots of antigens is the key to the successful, sustainable treatment of cancer and, thus, its cure.

Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells.

PV-10 creates an "antigen storm." Provectus' drug compound is more powerful than any other antigen-creating material for the expression of antigens to the immune system.

Dr. Eagle knows this, and his counterparts at Big Pharma are quickly learning this too.

The not-so-incremental innovation of Abraxane's nanotechnology delivery system -- the albumin-bound formulation of, say, paclitaxel may help you understand the paradigm shift that is PV-10 better. PV-10's genius and innovation is its stimulation of the immune system. PV-10's storm of antigen creation is singularly unique.

For Dr. Eagle and others, the question now is how to optimize the use of PV-10 by itself and in combination with other therapies, when, and with what specific therapies for what situation. How. When. With what.

Even when  PV-10 is an approved, Pfizer will be use it in combination (typically for late/end stage patients) until it does not have to because PV-10 is then able to run the entire race and not be handed the baton to cross the finish line. Thus, the very intent of the joint Pfizer-Provectus combination patent application is strategic, financial and commercial.

The Pfizer-Provectus relationship has changed. How much is the question now.

$PVCT: More $MRK's Perlmutter

A Dark Horse For $PVCT: $MRK

As global Big Pharma interest in the company accelerates, Merck is a dark horse for Provectus.

Article link here.

Article link here.

Article link here.

How Could A $PVCT-$PFE Story Unfold?

I hope to have some fun with the first part of this three-part post. Indulge me.

As you know, I beat the drum from time to time about Provectus and Pfizer. The relationship, as I see it, has steadily grown in depth, but has not yet been consummated.

November 2010: Craig Eagle first engaged Provectus when he traveled to Australia for Dr. Agarwala's presentation of preliminary MM Phase 2 trial data.

Early-2011: Pfizer and Dr. Eagle proffered a unique deal to Provectus that ultimately did not materialize.

Summer/Fall-2011: There is/was the rumor of a cash bid by Pfizer for the company, which management denied (to me) was made and that would have valued Provectus at approximately $1B ($7 in cash per share) at the time. Earlier that year, BioVex (T-Vec) and Plexxikon (Zelboraf) were acquired by Amgen and Daiichi Sankyo, respectively, for approximately $1B (top-line figure) each.

August 2011: Craig Eagle joined the company's corporate advisory board.

March-October 2012: The joint patent application, for combining local and systemic immunomodulative therapies, worked its way through Pfizer (legal) before being filed.

September 2012: The company made an SEC filing for a preferred stock offering, the rationale and structure of which purportedly was to facilitate a strategic equity investment by Pfizer in Provectus.

October 2012: Pfizer supposed role as co-lead on the PVCTP "IPO" did not materialize.

Yet, the stock price has refused to budge upwards, and in actuality has fallen a lot. I previously wrote about disbelief.

The stock market, some/many in the Wall Street community, some/many potential investors and some/many existing shareholders do not believe in nor trust management, and thus do not believe in the data. If they did, they would buy or buy more shares. These disbeliefs, the first more problematic and resulting in the second, have led to the obscuring of value that clearly exists in Provectus and that Big Pharma very much sees and desires. 

Although disbelief in or lack of trust in management mostly results from self-inflicted wounds, these wounds are far from fatal, and there should be no doubt about the immense value management has created in its innovation of PV-10. 

Simple, angelic or divine regulatory clarity will transform disbelief in both management and PV-10 overnight.

One has to assume disbelief of Provectus extends to or has enveloped the notion and reality of a Pfizer relationship, too. Clarity about a monetary relationship with this Big Pharma also will additively transform disbelief in both management and PV-10 overnight.

June 2013: Which brings us to last week and Provectus' Empire State of Mind, where there apparently/purportedly were several meetings between Provectus principals (Peter, Peter and Eric) and Pfizer folks (broadly speaking), as there has been since the relationship began. I think I have a good idea of who, what, where and when, but not why.

It's fair to say there is no small amount of anticipation or expectation brewing for something to happen, soon, whether it is some portion of regulatory clarity or commercial validation through a regional license transaction.

I can't help but think of, anticipate or expect a monetary relationship finally being put into place between Provectus and Pfizer. Without regulatory clarity of any sort (e.g., SPA, breakthrough therapy designation, accelerated approval), it's too early for a global license with or the end game by Pfizer.

But how does Provectus get from here to there, from Friday's 63 cent share price to a multi-billion dollar upfront payment from Pfizer? I wrote the Empire State of Mind post to clarify some things. I also understand there was some chatter about a strategic equity investment by Pfizer last week. I would have to believe the topic of investment has been a longstanding discussion between the two companies.

Maybe, now, whenever now becomes today, and today becomes a PR, there might/could/will be an investment in Provectus by Pfizer (or possibly but less likely some other Big Pharma). Why "now?" With regularity clarity in the offing, potentially simple leading to angelic or divine, an investment from Pfizer assists Provectus to get from here to there.

A substantial investment (say, $25-$75MM) investment by Pfizer at a significantly higher share price (say, $3.50-4 per share) should put a floor under the stock.

The upcoming annual meeting of shareholders on June 27 potentially will help resolve the issue and company proposal to increase the number of shares of common stock Provectus is authorized to issue from 200-250 million shares. As of March 31, the total shares of common stock issued and outstanding and reserved for issuance for outstanding warrants, options and preferred stock totaled 188 million (no shares of common stock are held in treasury), leaving about 12 million shares for a strategic equity investment by Pfizer (or another Big Pharma). Maybe 11,853,076 unreserved shares of common stock available for issuance is enough.

If an equity investment starts the ball rolling, then one hopes that event is followed by some regulatory clarity, like the receipt of the SPA. Leveraging Provectus board member Al Smith, among others, to build greater awareness in the financial and investment management communities creates more momentum. A regional license deal or two, next, like for India and then China, or for China and then India, helps more. More regulatory clarity, like BTD or AA, speeds up the ball's rolling. And then...

But it's very early Sunday morning at my favorite Starbucks (this blog will post Monday morning at midnight EST), it's just the here and now, and I'm having a little fun.

▫     ▪     ▫     ▪     ▫     ▪     ▫     ▪     ▫     ▪     ▫

A Chicago stockbroker organized a conference call for his clients holding Provectus stock with Peter before ASCO 2013. The broker also invited me to join the call, which lasted about an hour. There were about 50 people on the call. Peter used the company’s website presentation as his talking points, providing informative comments about the company's progress or situation on several fronts. Below are notes that, while not meant to be an exhaustive description of the call or a transcript of it, essentially were a list of things Peter said that I found to be interesting to varying degrees.

Peter used the company’s website presentation as his talking points, providing informative comments about where the company is several fronts as well as some very candid commentary.

The mechanisms of action of PV-10 for oncology and PH-10 for dermatology are not the same but have interesting similarities and high profile researchers are currently investigating.

The synthesis patent application has been approved. Peter described some of the implications of the now approved patent. Provectus will issue a press release next week where I expect the company will describe several key aspects that drive significant shareholder value.

A Phase 3 trial under the SPA that should be agreed to with the FDA, should such a trial ultimately be run, would have treatment without any limits of any concern (i.e., as many retreatments of as many visible tumors as necessary).

In addition to breast cancer and melanoma for which Moffitt (a) confirmed from its murine studies that PV-10 chemoablation resulted in both a direct effect on injected lesions as well as a systemic response that leads to regression of uninjected subcutaneous and lung lesions and (b) concluded intralesional PV-10 treatment led to the induction of tumor-specific immunity, Moffitt also has done work in other indications.

Moffitt seeks to finish its Phase 1 feasibility study of human patients as quickly as possible.

The FDA and Big Pharma realize that to kill cancer one has to effectively kill tumors in a clinically relevant manner.  PV-10 is singularly unique in the approved and emerging cancer agent universe.

Peter mentioned they are having license talks with global and regional pharmaceutical companies, including active dialogue with Dr. Craig Eagle of Pfizer.

▫     ▪     ▫     ▪     ▫     ▪     ▫     ▪     ▫     ▪     ▫

The follow-up to my regulatory clarity and commercial validation pathways post is below.