[We] now believe...[we] have sufficient information to seek regulatory approval

Expectations. Last week, in the news related to Provectus, an article appearing in the November/December 2013 issue of Oncology News on the final analysis of PV-10 Phase 2 melanoma study data presented at the European Cancer Congress ("ECC") 2013 meeting, PV-10 continues to show robust effect in cutaneous Stage III-IV melanoma, noted "Provectus Pharmaceuticals, Inc, (Knoxville, Tennessee, USA), the company developing PV-10, believes they now have sufficient information to seek regulatory approval." The belief and sentence are nothing new. The same author who wrote the above article penned two more following the ECC meeting, and wrote the same thing in early-October: "Provectus Pharmaceuticals believe they now have sufficient data to seek regulatory approval for PV-10." When I asked her who told her this, she said the company did (not Dr. Agarwala, who was interviewed at the conference for these articles).

A bold belief, and bolder words. But nothing new of late, nor inconsistent with recent company communications.

Recall the recently filed prospectus supplement: "We believe regulatory clarity is determined by specifying the expected approval pathways of both PV-10 and PH-10. This may include the potential for breakthrough therapy designation for PV-10 to treat metastatic melanoma and an accelerated approval path for PV-10 to treat refractory recurrent melanoma."

It must seem odd to casual observers and shareholders of Provectus, and the greater biotech market (and the general stock market at large) that expectations for the coming weeks are very high. At a closing share price on November 22nd of 82.5 cents, and a market capitalization and enterprise value of $106.11 million and $107.27 million, respectively, with no regulatory clarity yet, how can the company be an exceptional long idea?

Because of the very expectation of regulatory clarity and guidance many shareholders believe is forthcoming. The expectation is not ambiguous, but rather clear: Management expects the FDA to make and convey and its decision by year-end.

In one those ECC 2013 articles about Provectus Dr. Agarwala was quoted as saying: "First, it might be used in patients who are refractory to all other therapies and who have injectable disease. Second, it might be used in patients who have injectable lesions but who are not eligible for systemic therapy (e.g., the elderly or those with comorbidities). Third, it might be used in combination with other therapies (e.g., ipilimumab or nivolumab or both)."

In my And the decision(s) is(are)... post I wrote "The company has asked for AA/OA and BTD, and probably thinks they have a very good chance at attaining both asks." The accelerated approval ("AA")/outright approval ("OA") ask likely is for patients who are refractory to all other therapies and who have injectable disease. The breakthrough therapy designation ("BTD") ask likely for use in combination with other therapies; however, I think what comes with BTD is an evolving topic.

Quantum Immunology. Provectus' science's kung fu is strong. I previously wrote several blog posts on or related to the topic of Korn et al.'s 2008 meta-analysis of 42 MM phase 2 metastatic melanoma ("MM") studies (70 arms and 2,100 patients): Overall Survival, PV-10 vs. OncoVEX, Allovectin-7, and Blog Reader Comment. I wanted to compare what OS data was available for PV-10 at the time to other studies, fully understanding the caveats of comparing trials and comparisons themselves. Comparisons provide useful information, but of course one does not digest them in a vacuum. All three intralesional therapies above, PV-10, OncoVEX (now T-Vec) and Allovectin-7 placed well outside the solid blue lines below, which are 95% confidence bounds. The dotted line is the overall 1-year survival rate (25%) or the overall 6-month PFS rate (15%).

Click on the figure to enlarge it.

PV-10's intralesional therapy competitors initiated Phase 3 trials with primary endpoints of durable response after 6 months (BioVex's OncoVex, later Amgen's talimogene laherparepvec or T-vec) and objective response after 24 weeks [6 months] (Vical's Allovectin-7). We now know T-vec met is primary endpoint and Allovectin-7 did not.

I read an interesting abstract at the 2013 Society for Immunotherapy of Cancer ("SITC") Annual Meeting, co-authored by Martin Ashdown and Provectus principal investigator Brendon Coventry: Mathematical modeling of immune kinetics in advanced cancer through meta-analyses of complete response rates: immune synchronisation emerges as the likely key determinant of clinical response. Ashdown et al.'s work comprised a meta-analysis of 130 clinical trials, 8,000 patients, different solid tumor cancers, and standard chemotherapy, targeted therapy and iimmunomodulatory therapy compounds IL-2, ipilimumab, tremelimumab, cytotoxic agents, TMZ, dabrafenib, vemurafenib, PD-1s (BMS, Merck) and a PDL-1 (Genentech).

Ashdown et al., Poster Presentation,
SITC 2013 Annual Meeting

As I looked to examine PV-10's efficacy in the context of approved and other promising therapies, I was reminded by Craig's comments that eliminating the tumor (complete response, or "CR") was the relevant focus, and not just shrinking it (partial response, or "PR") or overall response ("OR") where a high PR but a low CR still would result in a high and potentially misleading OR. At the time, his comments seemed non-obvious, or perhaps I didn't fully appreciate the essence of what he was trying to message by simplifying what should be the focus of any cancer drug: Kill the cancer. This led me to think about tumor heterogeneity.

You may recall my May 2013 $PVCT: #Tumor Heterogeneity post.

I’ve tried to understand the issue, problem and challenge of tumor heterogeneity, and why and how PV-10 works so well. I’ve previously written that to understand PV-10 is to understand the relationship between chemoablation and immune-mediated signaling. It's what Craig means when he says the immune system responds in direct proportion to the degree of insult. Think of PV-10 chemoablation as the proxy for the degree of insult, which is rapid, complete and durable in the case of PV-10. But when Craig describes his approach in this way, what is he really getting at? How did he approach tackling or solving tumor heterogeneity?  

(Moffitt, 2009) There have been well documented but exceedingly rare cases of spontaneous or post-infection remissions in melanoma that appear to be immunologically mediated. There is a correlation between treatment-associated autoimmune depigmentation, or vitiligo, and favorable melanoma outcomes. Regression of uninjected melanoma modules after intralesional BCG therapy had been demonstrated. Results with conventional therapy for metastatic melanoma up to that point remained poor. Melanoma patients at high risk of recurrence are readily identifiable. Tumor-induced immunosuppression increases with tumor burden. Immunotherapy should be more effective the earlier it is applied. But there are major obstacles to overcome: patient heterogeneity (variable outcomes for patients within similar stages, HLA haplotype differences), tumor antigenic heterogeneity (not all tumors express the same antigens), antigen loss (most immunogenic proteins are not essential to survival), tumor-induced immunosuppression, and the length of time needed for an immune response. A weak or partial immune response to the tumor selects for more virulent tumor cells to survive, akin to antibiotic resistance in microbial infections. Vaccines are inducing “tolerance” by repeated exposure to antigen, convincing the immune system not to react to tumor-associated antigens and/or stimulating the generation of “suppressor” cells. 

Tumor heterogeneity is a critical problem. In any given cell there are, say, 15,000 unique mRNAs at any given second. A few seconds later, illustratively, 15,000 new ones. There are, for example, at least 15,000 to 20,000 unique proteins on a membrane surface at any one time. These change continuously. Does picking one of them to form the basis of a cancer vaccine make sense? Does targeting a specific antigen as a holistic solution make sense? Heterogeneity is so wide, trying to target a specific antigen might be tough if not hopeless task. A needle in a haystack? Maybe a needle in an entire whole galaxy. Treating as many tumors as you can with PV-10 intratumorally achieves two significant positive outcomes. First, you lower the patient's overall tumor burden so as to allow the immune system to work better. Second, you allow more of the heterogeneous antigens (from the injected heterogeneous tumor) to be seen by the immune system. The more tumors treated by PV-10 the better. PV-10: 1. Lower tumor burden. 2. Cover the antigenic spectrum as broad as one can.

My very early due diligence uncovered a useful table (below) from a March 2010 BioVex presentation entitled OPTiM Trial in Stage IIIb/c and IV Advanced Melanoma (slide number 7).

Click on the figure to enlarge it.

Now, Craig also cautioned (and has repeatedly) about comparing clinical trial results. I understand, and used the exercise at the time as an informative and instructive one. I was struck by OncoVEX's CR; OncoVex, following BioVex's acquisition by Amgen, now is called T-Vec. Vical's CR (for it's Phase 2 trial) was 3%.

Ashdown and Conventry concluded:"Mathematical analyses of over 130 clinical trials, inclusive of over 8000 patients, has demonstrated that the CR rate for patients treated with widely divergent therapies is remarkably fixed at between 5 and 10%. The probability of this occurring by chance alone is extremely close to zero, and is both scientifically and clinically implausible. Therefore, an underlying predictive operative biological mechanism must apply. It is highly likely that the known principles of immune kinetics between effector and regulatory homeostatic functions must therefore determine a degree of immune synchronization to produce these observed CR’s. We have derived a mathematical model and equation using the principles of controlled homeostatic systems, which can be used to explain our meta-analysis findings, and the clinical efficacy." Bold and underlined emphasis is that of Ashdown et al. from their SITC poster presentation.

Ashdown et al., Poster Presentation,
SITC 2013 Annual Meeting

They further conclude: "The principal determinant of CR efficacy is constrained by the probability of fortuitous therapeutic Immune Synchronization and Modulation in the Time Domain. A conjunction of events, including the random timing of therapy, with respect to an endogenous homeostatical oscillating tumor immune response creates recurring narrow "therapeutic windows," and thus restricts this CR efficacy to approximately a random 7% of patients. We propose that intentional immune synchronization therapy will lead to a significant increase in the Complete Response Rates." Bold emphasis is that of Ashdown et al. from their SITC poster presentation.

In Dutcher and Wiernik's June 2013's Kidney Cancer Journal's article Deconstructing and Reinventing the IL-2 Paradigm: Can Alternate Dosing Schedules Enhance Tumor Effect?, the authors write: "[Coventry and Ashdown]...describe a sequential, time-dependent, homeostatic, (Figures 1, 2) physiological process, requiring the coordinated and timely interaction of cytokines, their receptors, and the responding cell populations. According to their review, these cytokine/receptor interactions have half-lives of minutes to hours. Both T effector cells and T regulatory cells transiently express the IL-2 receptor for only about 8-12 hours, and both require IL-2 for their activation/expansion and maintenance.5  With this in mind, they hypothesize that alterations in IL-2 administration schedule may impact more positively on the induction of cytotoxicity." Bold emphasis is mine.

Click on the figure to enlarge it.

Click on the figure to enlarge it.

Dutcher and Wiernik further write: "The impetus behind the new thinking is the view that IL-2 may be more than just an immune stimulator, ie the bimodal effect described earlier. Recently IL-2 has been advanced as a potential immune modulator able to “tweak” the immune response selectively to aid transplant tolerance, while others reported this in graft vs host disease and chronic hepatitis C infection. Despite the prevailing view in numerous reports that  IL-2 activates or augments immune response, the expanded hypothesis suggests an apparent paradoxical role for IL-2 both as a cytokine to drive the immune response in an activated and an inhibitory direction. Coventry and Ashdown refer to the “bimodality” of IL-2 that has created a paradox for understanding its activity.

Seeking to resolve the paradox, Coventry and Ashdown  suggest how the immune response needs to be revisited as a “dynamic” entity as opposed to a static process. The response, once triggered, is known to be a sequential, time-dependent, homeostatic, physiological process. This process, note the authors, requires the coordinated and timely interaction of cytokines, their receptors, and the responding cell populations. The half-lives of these interactions are minutes to hours. The coordinated cellular expansions can take several days to rise and fall, a process during which the immune response rises and ends. Both T effector cells and T regulatory cells transiently express the IL-2 receptor for only about 8 to 12 hours, and both require IL-2 for their activation/expansion and maintenance." 

I am struck by the interaction half-lives that measure in the minutes and hours, particularly when you consider PV-10's proposed mechanism of action below.

Click on the figure to enlarge it.

To be fair, Ashdown et al.'s SITC 2013 multi-trial, multi-indication CR analysis was centered around late stage patient trials (Stage IV). So, in the case of PV-10's MM Phase 2 trial, the comparable results (i.e., Stage IV melanoma patients) would be consistent with Ashdown and Coventry's findings that "...the CR rate for patients treated with widely divergent therapies is remarkably fixed at between 5 and 10%." The table below is drawn from Provectus' ESMO 2012 poster presentation.

Click on the figure to enlarge it.

The authors, aware of PV-10's large local-regional CR rate, note the relationship between systems and sub-systems, systemic and local benefits, and thus, I believe, the extension of their conclusion that timing therapy governs efficacy systemically to efficacy local-regionally. In doing so, PV-10's clearly outlier result contributes to its novelty and uniqueness.

Ashdown and Coventry think any efficacious immune modulating therapy theoretically can be taken close to 100% success, with caveats of course, by immune synchronization: monitoring the patient's immune fluctuations and synchronizing treatment with the correct phase of the patient's immune cycle.

Heady stuff, and an emerging field the authors say is called "quantum immunology.

Perhaps immune synchronization can make PV-10's efficacy, like the efficacy of other therapies, better. Or perhaps PV-10's mechanism of action, and the short time frames of tumor lysosomal accumulation and rupture, coincides with cytokine/receptor interaction half-lives, for which other therapies may not easily or structurally achieve.

Merck & Co.’s PD-1 Agent. Interestingly, this past week Merck said its PD-1 agent MK-3475 only achieved 9% CR for melanoma patients.

Vical & Allovectin-7/Amgen & T-Vec. Doubly interestingly, both Vical and Amgen released information about their respective intralesional agents, Allovectin-7 and T-Vec, respectively. Allovectin-7 has become Allovectin-0, while T-Vec continues to show some promise as a potential treatment.

"In interim results, patients taking T-Vec, short for talimogene laherparepvec, posted a median overall survival rate of 23.3 months, besting the 19 months for those treated with the white blood cell-spurring GM-CSF."

Allovectin's Phase 3 trial's objective response rate was about a third of the comparator arm's standard chemotherapy treatment.

It feels a little (a lot) like... The company is seeking outright approval of PV-10 for use in patients who are refractory to all other therapies and who have injectable disease (rather than "just" accelerated approval for this patient population).

...The date for the special shareholder meeting of December 16th to approve the company's name change to Provectus Biopharmaceuticals and re-jurisdiction of Provectus from Nevada to Delaware has more than nominal relevance, suggesting the week of December 16th, which is a Monday, bears watching.

...Provectus would receive regulatory guidance and clarity before year-end.

...Regional and/or worldwide deals would be consummated after clarity arrives, which means January bears watching to see if deals are inked with China, India, Japan, etc.

...A BTD application for liver would be submitted early in the new year.

Danger, expectations.