Turning [more anti-PD-1] non-responders into responders

Image source

Updated below: 10/19/16.

What is PV-10's clinical value proposition to Merck & Co. (pembrolizumab, Keytruda®) and Bristol-Myers (nivolumab, Opdivo®), among other Big Pharma in the oncology space? In no particular order, is it, among other things:

• As a primer, front-end, turner-on-of-the-engine, stepper-on-the-gas pedal, [insert your favorite over-, weakly- or wrongly-used analogy or metaphor],

• Synergism, where from an efficacy perspective 1 + 1 >> 2,

• Agnosticism to tumor type/cancer indication,

• Safety profile, and/or

• Turning cold tumors hot, and hot tumors hotter?

Industry discussion appears to recognize immune checkpoint inhibitors work — when/where they do work — in a portion of cancer patients. Is the summary clinical value proposition of PV-10 in combination with Keytruda/Opdivo to make the latter (i.e., these anti-PD-1 drugs) work better when and where they work? Or is PV-10's proposition, the more powerful one, to show it can make Keytruda/Opdivo work better where they do not work?

PV-10's clinical value proposition to Merck & Co. (pembrolizumab, Keytruda®) and Bristol-Myers (nivolumab, Opdivo®) is that it (PV-10) can turn more anti-PD-1 non-responders into responders than any other partner drug or investigational compound.

For this blog post, consider, among other things, two combinations with pembrolizumab (for advanced melanoma):

• Intralesional* agent electroporation with plasmid interleukin-12 (epIL-12) (ImmunoPulse, OncoSec), the combination of a medical device and an investigational agent, and

• Intratumoral* agent toll-like receptor 9 (TLR9) agonist SD-101 (Dynavax), an investigational agent too.

* Intralesional = intratumoral

OncoSec. OncoSec announced in November 2014 it would combine ImmunoPulse and pembrolizumab, UC San Francisco and OncoSec Medical Collaborate to Evaluate Investigational Combination of ImmunoPulse and Anti-PD-1 Treatment. Data from this investigator-initiated study were presented at AACR 2016 (April), "Positive Melanoma Clinical Data at American Association for Cancer Research (AACR) Annual Meeting 2016," where patients initially were treated with ImmunoPulse and, then, some went to receive systemic anti-PD-1/PD-L1 therapy. Notably, however, OncoSec announced this month data from the same study would be presented at SITC 2016 (November), "Acceptance of Late Breaking Abstract at Upcoming Society for Immunotherapy of Cancer (SITC) Annual Meeting 2016," where the focus would be on [clinical data from] patients with a low likelihood of response to an anti-PD-1 alone (i.e., anti-PD-1 failures).

Dynavax. Dynavax and Merck & Co. announced a collaboration in June 2015, Investigating the Combination of Immuno-Oncology Therapies. Initial clinical data of the combination of SD-101 and pembrolizumab in patients with metastatic melanoma was presented at ESMO 2016, "Phase 1b/2, Open-Label, Multicenter, Dose-Escalation and Expansion Trial of Intratumoral SD-101 in Combination With Pembrolizumab in Patients with Metastatic Melanoma." Preclinical work on SD-101 was presented at AACR 2016 by Dynavax observed, "These data provide a strong rationale for the clinical assessment of SD-101 in combination with agents blocking the PD-1/PD-L1 pathway in patients unresponsive to PD-1 blockade alone." Dynavax and Merck jointly observed on their ESMO 2016 poster, "Preclinical studies suggest that the immunostimulatory effects of SD-101 might also boost the activity of PD-1 checkpoint inhibitor therapy. In mouse models, SD-101 converted anti-PD-1 non-responders into responders by increasing the quantity and quality of tumor-specific T cells." {my underlined emphasis}

In order for Provectus CTO Dr. Eric Wachter, PhD to put Provectus in a position to garner a collaboration with a Big Pharma and its immune checkpoint inhibitor, he has to provide a compelling demonstration of the features of PV-10 in combination with an anti-PD-1 drug like pembrolizumab (e.g., clinical trial PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma). The features of this demonstration would include (a) preliminary safety and efficacy results, (b) immune biomarkers to facilitate appropriate patient selection if and when the combination is approved, and, presumably, (c) the ability of PV-10 to better turn anti-PD-1 non-responders into responders.

Contesting anti-PD-1 non-responders into responders should be a big deal for Merck and Bristol-Myers because such contestation is all about eating more of the rest of the pie, much more so than fighting over the same sliver of it.

Updated (10/19/16): OncoSec. ref. "OncoSec (ONCS) Q4 2016 Earnings Call Transcript," Seeking Alpha

I referenced epIL-12 (and OncoSec) above because of the useful information regarding anti-PD-1 failures or non-responders. The oncology playing field continues to evolve, and combination therapy approaches clearly are evolving as well across multiple dimensions, like (i) determining which patients when and how [immune biomarkers], and (ii) expanding the addressable market from responders to non-responders.

Among other aspects of an analysis of epIL-12 (and OncoSec), which historically has been mentioned together with Amgen's T-Vec and Provectus' PV-10, like at ASCO 2014 (see "Expert Point of View: Axel Hauschild, MD," The ASCO Post, Caroline Helwick, July 25, 2014), (a) there does not appear to be an initial pathway to approval yet (if at all) for epIL-12 as a monotherapy and (b) the investigator-initiated study was neither designed nor powered to transition to a pivotal trial as a combination therapy. OncoSec hopes to secure agreement with (acquiescence by) the FDA on a pivotal/registration trial design by the end of the year. Initial pathways to approval, like what Provectus has with PV-10 as a monotherapy for locally advanced cutaneous melanoma, as with valuable beachfront property, is valuable drug treatment "real estate." Nevertheless, it is a good strategy for OncoSec to focus on PD-1 failures; using emerging biomarker data to select "likely" PD-1 failures, however, is likely to prove somewhat more challenging. It will be interesting to see how this plays out.

Dynavax. This is a true treatment combination and company collaboration (compared to the OncoSec treatment combination, for which the clinical trial protocol is here). The results are interesting, if not very preliminary (e.g., efficacy from 5 patients, measurement [for purposes of the ESMO 2016 abstract] was made after only 12 weeks). One would have hoped they could have provided a few more details (e.g, the number of injections of SD-101 [presumably 11 in total], more details on patient stage [particularly Stage IV, like M1a, M1b and/or M1c], what the grade 4 SAE was, etc.).

A 25% serious adverse event (SAE) rate seems a bit high, and this is kind of an odd way to report safety data; usually this is reported as CTCAE Grade 3 or higher events since this includes both severe AEs and the subset of those that qualify as SAEs. Robert et al. reported 10.1-13.3% rate of Grade 3 or higher AEs for pembrolizumab alone (NEJM 2015;372:26).

Notably, investigators/clinical sites on the poster included Agarwala/St. Luke's. The trial itself also is recruiting at Huntsman Cancer Institute (Andtbacka).

Since this is a collaboration with Merck, it would appear the Big Pharma is not requiring rigorous safety testing before the project moves to Phase 2 (a Merck staffer is a co-author on the ESMO 2016 poster). The poster's Methods section notes the trial is a dose-escalation and dose expansion study. It shows data from dose-escalation (i.e., 2 mg, 4 mg, 8 mg), but does appear to refer to the dose expansion portion, which normally would be additional patients at the highest tolerated dose. The N = 6 at 8 mg is dose expansion but, again, if Merck wants to green light this work to a Phase 2 trial, [as a Big Pharma] they probably are not going to get significant push-back from the FDA or institutional review boards (IRBs). If a small biotechnology company has a major player backing it, it is possible to do things that are not plausible for outsiders (i.e., the golden rule). Finally, this study might give Amgen pause, since SD-101 appears to function similarly to T-Vec, may produce a more robust effect than T-Vec and, most importantly, is not a live virus.

Immunity

Edited (by me) image above; original image source

Let us take as given, finally in and by 2016, that PV-10 (chemical small [but heavy] molecule and halogenated xanthene Rose Bengal) is an immunotherapy

That is, the investigational compound is potentially capable of inducing the human body's immune system to mount a possibly worthy defense against solid tumor cancer after first being injected into lesions and tumors of said cancer.

That PV-10 has been independently shown to be that immunotherapy, at arms length from Provectus separately by both Moffitt Cancer Center (Moffitt) and the University of Illinois at Chicago (UIC) — reproducibility, the hallmark of Western Science— should make the claims about and data on PV-10 that much more veracious. See footnotes 1-5 below.

But let's now examine the notion, and growing preclinical and clinical evidence, that PV-10 treatment — singularly or in combination — potentially may lead to something greater and more profound than just the inducement or generation of an immune response....immunity.

AACR 2016 (April), Moffitt: T cell mediated immunity after combination therapy with intralesional PV-10 and co-inhibitory blockade in a melanoma model

2016 (May) peer-reviewed publication, Moffitt: Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1

SITC 2016 (November), Moffitt: Intralesional injection with Rose Bengal and systemic chemotherapy induces anti-tumor immunity in a murine model of pancreatic cancer



Footnotes of non-Provectus biomedical research for "PV-10 is an immunotherapy:"

1. SSO 2012, Moffitt: Intralesional Injection of Melanoma with Rose Bengal Induces Regression of Untreated Synchronous Melanoma In a Murine Model,
2. 2013 peer-reviewed publication, Moffitt: Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer,
3. SSO 2015, UIC: Intralesional Injection of Rose Bengal Induces an Anti-tumor Immune Response and Potent Tumor Regressions in a Murine Model of Colon Cancer,
4. 2015 peer-reviewed publication, UIC: The Potential of Intralesional Rose Bengal to Stimulate T-Cell Mediated Anti-Tumor Responses, and
5. ASO 2016, UIC: PV-10 Induces Potent Immunogenic Apoptosis in Colon Cancer Cells,

April 2016: Grant McArthur Discusses the Memory of Our Immune System

The Untrigger

Updated below: 8/15/16.

I have written a lot about the so-called clinical trial math of Provectus' ongoing pivotal Phase 3 study entitled PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma (official title). The company's CTO, board of directors member and a co-founder Dr. Eric Wachter, PhD discussed some of this math on Provectus' August 10th 2Q16 business update conference call.

Eric said the number (not the percentage) of disease progression events required to trigger the interim and full study analyses were 81 and 162, respectively. I discussed this as item 5. Clinical trial math under Quick: 2Q16 (August 9, 2016) on the blog's Current News page.

It was helpful and insightful, but disappointing, to hear Eric say the trial does not have a scheduled assessment (a prescribed time trigger):

"So, when we began designing the study several years ago, we looked at the issue of how to schedule an interim assessment. And while that was a rather uncommon idea, we looked at that very carefully. We even had discussions with FDA on that topic. And they were adamant that they were strongly opposed to any sort of effort to schedule an interim assessment. Our hypothesis at the time was that, for example, because the interim assessment and the final assessment are based on a number of progressions, they're modeled using standard statistical models. If there was a longer progression-free survival in the PV-10 arm than expected, there would not be the required number of progressions in that arm to add up to the required number of events."

As such, as I hear and read it, one should consider that there only is one trigger (a prescribed event trigger), stated on the trial's CT.gov page as "[a]n interim assessment of efficacy and safety will be performed by the IRC when 50% of the events required for the primary endpoint have occurred." As a number, rather than a percentage, this figure is 81.

Eric said on the call that "one of our crown jewels is our study protocols because they represent everything that we've invested in the company up to the point that that protocol is issued." He certainly is reluctant to show his jewels if he doesn't have to (although it is possible he may fondle them from time to time). He "teased" two sections of the Phase 3 trial protocol. First, section 4.9 (with my underlined emphasis):

"An interim assessment of efficacy and safety will be performed when the IRC--that's Independent Root [sp] Committee--will be performed by the IRC when 50 percent of the events required for the primary endpoint, that is 81 disease progressions as defined in the study protocol, have occurred. And so, that explains to you that there's a set number. It's designed at the beginning of the study, and that's the point when that number of progressions have occurred."

Second, section 4.10 (with my underlined emphasis):

"It doesn't matter if they're all in the PV-10 arm, if they're all in the comparator arm, which isn't possibly because there aren't enough patients in the comparator arm. We have to have enough progressions to hit that metric. Now, we had hoped, as I said, to have some sort of a mechanism in the study that would allow that to be triggered early if, for example, we're going along and we're not seeing progressions as we expected. And so, while we worked on that with the agency, as I said, they're adamant that that was not appropriate for a pivotal study. So, what we managed to compromise on was that in Section 4.10, which is captioned "Study Duration", that subjects will be monitored until survival--for survival until death, loss to follow up, withdrawal of consent, or study termination by the sponsor."

Rather than hash out or re-hash my work/writing about prescribed event and time triggers, the number of patients needed to be enrolled to hit 81 events, etc., I'd like to state (speculate) the following -- [I believe] there is a trigger Eric does not want to explicitly speak about or affirm, which could/would be an imbalance in the number of events between the treatment and control arms, which could/would cause a statistical and ethical dilemma for the study's IRC. What would an imbalance look like or comprise? In the extreme, or potentially actually, there would be no events in the PV-10 treatment arm, and events of whatever frequency or magnitude in the chemotherapy/oncolytic virus control arm. Takeaway: The pivotal trial does not have to reach 81 events for the interim analysis to be triggered.

In his own special way I believe Eric said this on the call (with my underlined emphasis):

"And so, we are able to monitor at the terminal end of the study, and if the clinical trial data monitoring committee determines that it's in the best interest to end the study, it could end before we had all of the progression events occurring. I doubt that'll happen. It will be a very unusual circumstance, but it would probably be positive for the drug because it would suggest that a large number of patients weren't progressing because of the majority of the patients in a two-to-one randomized study are from the PV-10 arm, and that probably would imply that the PV-10 patients weren't progressing. 

But, this is all speculation."

The statistical dilemma is having a treatment arm with no or very few events, and a control arm with many, many more (like 0 and 15, or 0 and 20). The ethical dilemma is a treatment arm that works and works very, very well (i.e., no disease progression), and a control arm that demonstrates what everyone already predicted (i.e., everybody progresses).

The question then would be, "how many events in total and across the two arms would be required for the IRC to recognize an imbalance, and thus trigger the interim analysis?" Twenty events in the control arm (and none in the treatment arm)? Thirty? A two-to-one study randomization then would suggest enrollment and treatment of 60 patients. Or 90.

Math, math, math.

Updated (8/15/16): My projection for enrollment in the pivotal melanoma Phase 3 trial is below (having adjusted only for 5 months of no enrollment as a result of the major amendment related to Amgen's intralesional (IL) drug Imlygic, and also differentiating enrollment rates between medical and surgical oncology sites). The study may generate enough events to highlight the imbalance between the two arms in 1Q16, where the idea is that most-to-all of the control arm patients generate events, and few-to-none of the treatment arm ones do.

Click to enlarge.

What proportion of events in each arm ("proportion"), and what number of events in each arm ("sample size") gets you to a sufficiently low p-value?

If 75-100% of the control arm generate events, and 0-25% of the treatment do too, who you got?! Using this calculator, which is a simple analysis, and may even be simplistic, may require upwards of 30 patients; however, this may be too low.

E.g., Sample 1: Proportion of Control Arm Events (Number of events generated in the control arm ÷ Number of control arm patients); Sample 2: Proportion of Treatment Arm Events (Number of events generated in the treatment arm ÷ Number of treatment arm patients)

Click to enlarge

Click to enlarge

Proxy Vote

Provectus’ 2016 annual meeting of stockholders is scheduled for Thursday, June 16th at 4 pm EDT in New York, New York. Shareholders of record as of April 25th's close of business should have until the annual meeting to vote. Practically, however, votes probably should be received at least 48 hours ahead of the meeting (i.e., no later than Tuesday, June 14th at 4 pm EDT). This year Provectus asked shareholders to vote on three proposals:

1. A slate of five directors to serve on the company's board for a one-year term,
2. An advisory vote to approve Provectus' named executive officers’ compensation, and
3. The selection of accounting firm Marcum LLP as the company's independent auditor for 2016.

You can read about my 2015 proxy vote and rationale in May 30, 2015 blog post Proxy Vote. I will vote all of our shares for/against as noted below in the sample/illustrative ballot. See Still [road] trippin' (June 13, 2016) on the blog's Current News page.

My Ballot

Click to enlarge.

In a world different than the one Provectus and its shareholders currently inhabit, things could or would be more better — sooner rather than later — for the company and its investigational oncology compound PV-10 (and dermatology compound PH-10):

• The category of intralesional (IL)/intratumoral (IT)/local cancer agents would not have been abject failures for so long,

• See Class of Drug (May 20, 2016) on the blog's Archived News V page.

• There would have been earlier regulatory agency comfort with IL/IT/local agents that could treat the systemic disease that is cancer,

• See April 29, 2015 blog post The first guy through the wall.

• Perhaps, what once may have been an industry (the pharmaceutical industry, that is) of regular, real innovation would not have become one of mostly me-toos and followers,

• See, for example, "Regulator says too many drugmakers chasing same cancer strategy," Deena Beasley, Reuters, June 10, 2016.

• There would have been a better balance between Provectus management arrogance/confidence and humility; or, said (written) another, more cliched way: "Hoping for the best, prepared for the worst, and unsurprised by anything in between,"

• For example, former Provectus Chairman, CEO and a co-founder Dr. Craig Dees, PhD's belief (my assumption) that the pharmaceutical industry would immediately beat a path to the company's and his door because of how well Rose Bengal and PV-10 (and PH-10) worked therapeutically. How well, of course, was based on his contextual view of the "necessary amount" of preclinical and clinical data. Well, what happens (what was your plan and approach) if they (Big Pharma) did not do so, immediately?

• And/or company CTO, board member and a co-founder Dr. Eric Wachter, PhD's belief (again, my assumption) that the FDA, a/the key regulatory agency, would immediately embrace (approve?) Rose Bengal and PV-10 for therapeutic use because of how well Rose Bengal and PV-10 (and PH-10) worked.  How well, of course, was based on Eric's contextual view of the "necessary amount" of preclinical and clinical data. Well, what happens (what was your plan and approach) if it (the Agency) did not do so, immediately?

• There would have been real Provectus board members.

• Both Craig and company President, board member and a co-founder Dr. Tim Scott, PhD had insufficient innate or learned ability to be Provectus board members. Founding a company is not a long-term reason or mandate for board membership.

• In my view, Eric possesses/has had the ability to be a quality board member of this company if so developed, coached and immersed over time on/in a real, thoughtful, intelligent board and board culture.

• Past and present independent/outside board members have not contributed enough leadership in principled and/or intelligent manners.

• There would have been more effort and experience by company management and the board to surround themselves/associate with a higher quality of non-clinical advisors across several operational functions.

But the world in which Provectus and its shareholders currently live is all that it/they/we have until it changes for the better, and hopefully in a sustainably, much more positively manner.

If I had to sum up or more cogently articulate my sense of Provectus' singular, primary and key deficit, it would be, generally speaking, a lack or vacuum of quality leadership, at both company management and board levels. Prior and certain current company "leadership" created an unacceptable culture, potentially paradigm-shifting innovation notwithstanding. Independent/outside directors appear to have done little-to-nothing to change or improve this culture for the better.

Proposal #1, A slate of five directors to serve on the company's board for a one-year term

The rationale for my WITHHOLD vote for board member Dr. Scott, consistent with how I voted our shares in 2015 (a Withhold vote), includes his insufficient leadership at the board level and, at a minimum, his disqualification as a board member resulting from the Dees debacle (i.e., Provectus' March 16, 2016 press release Announces Results of Internal Investigation).

My FOR vote for board member Eric, who replaced Craig on the board, is based on my belief that he is capable of being a quality board member with the potential to display better leadership at the board level, and my thinking that his clinical development program experience (among other clinical operational roles and responsibilities) would be an important and necessary contribution to an eventual, hoped for, board level discussion of a company buyout in the future.

The rationale for my FOR votes for board Chairman Al Smith IV and board members Dr. Kelly McMasters, MD, PhD and Jan Koe includes my thinking that they should be in place at the present time for business continuity reasons (such as but not limited to the CEO search process). I acknowledge the potentially inconsistency of this vote given they have not acted like real board members (i.e., they have displayed insufficient leadership). I believe they should transition themselves off Provectus' board at the appropriate time and be replaced by board members committed to doing "it" properly.

While one might argue that good board leadership could include meaningful [to a board member in context and based on his or her individual circumstance] stock ownership, consistent with Provectus' proposed guidelines on corporate governance, section IV.l {badly numbered], it is not the only consideration. Nevertheless, consider that two independent/outside directors (Dr. McMasters, Mr. Smith) own no common stock despite having joined the board in 2008 and 2011, respectively. Consider also that Peter has acquired (purchased) all of his stock ownership, compared to Dr. Scott who purchased (for money) fractions of what Eric and Peter themselves have bought over time.

My FOR vote for Jan Koe in 2016 is different from my vote in 2015, which was Withhold. At the time I wrote:

"Jan Koe originally was added to Provectus' board of directors in May 2012 to facilitate the forming of an independent board to meet corporate governance requirements in advance of uplisting onto a major U.S. stock exchange (i.e., more independent members than insiders). Up until that point, company insiders/founders (i.e., Dees, Scott and Wachter ) outnumbered independent members. As a result, Provectus' Chief Technology Officer Dr. Eric Wachter, PhD stepped off the board. 

I met Mr. Koe for the first time briefly at a Provectus shareholder event during ASCO 2014. I recall he immediately sounded like he had no substantive technology (let alone life sciences) knowledge. A quick check of his background at the time of his board appointment revealed no biopharmaceutical industry experience (presumably save for his investment in Provectus). He struck me as someone who would not offer a principled, intelligent counterbalance to the company's insider directors (i.e., Craig and Dr. Scott). To be fair to Mr. Koe, Provectus' board has never struck me as an active or engaged entity, but more of a rubber stamping "authority." Board independence is not insignificant of course, but his contribution in this regard no longer is required. The time to upgrade this independent director position with someone with both substantial industry and board experience is overdue."

I have recently spoken to Jan on a couple of occasions in regards to the CEO search process — see CEO Search Committee (June 13, 2016) on the blog's Current News page — and believe his heart and intent is in the right place even though I do not believe he can fully/properly execute on his goals and this process.

I believe both COO and interim CEO Peter Culpepper and Eric are important to the current process of generating sufficient clinical trial data in context, and engaging prospective licensees/co-development partners/[eventual] acquirers. Neither of them, however, is a suitable CEO candidate. I do believe both of them would agree that a good-to-great candidate would be a medical doctor who has a proven track record of leading a successful biopharmaceutical company.

In regards to the CEO search process, I tried to convey not only the above to Jan, but also the following. First, the person the search committee and board may pick today might not be the person they would pick in, say, 6 months (round number) when more clinical data potentially were available. I do not believe a deal person with fundraising experience is necessary or an important qualification.

Second, the CEO search process might be a two-step or two-stage one, where the first step/stage would be the concurrent following of Eric’s process/path (together with Peter's non-clinical business/corporate development) efforts as data are generated in context and continuing of interviewing CEO candidates to get smarter about who the committee and board are looking for and why. The second step/stage is, assuming they do not find an A+ candidate during first step/stage, would be to determine whether the company is on a clear and present trajectory to be sold at a/the proper price as data in context becomes available, or whether the board would want to transition to a new board and CEO who could take the valuation level Eric and Peter may have helped build to a much higher amount.

Proposal #2, An advisory vote to approve Provectus' named executive officers’ compensation

The rationale for my AGAINST vote includes, repetitiously, the poor or lacking leadership of current independent/outside board members (i.e., those on the compensation committee, and of course on the full board), and the tone deafness of management to accept enhanced compensation at this point in time, irrespective of the company's compensation committee and its policies, reviews, deliberations, plans, etc.

I voted Abstain in 2015. At the time I wrote:

"As an advisory vote I'm inclined to believe the final decision carries little weight with management despite language to the contrary in the SEC filings (see for example, page 10 of the proxy statement). I do not believe historic share price performance and very significant share dilution has fully warranted historic levels of compensation. I also am of the opinion a negative vote is not commensurate with my net positive assessment of management's progress to date to achieve what I believe is a paradigm shift in the treatment of solid tumor cancer. Abstention in my opinion reflects a wait-and-see attitude for the next 12 months."

The board and management continued to fail to show leadership by granting and accepting compensation in 2015 based on commercial and operational performance milestones, peer company compensation data, and the achievement of specific scientific, medical and clinical milestones while not acknowledging poor share price (and market capitalization so as to address the notion of fully diluted) performance as a major component of their thinking.

I do not believe compensation committee members (or the full board) would be any more real or intelligent in 2016. Show me meaningful success on the share price and market capitalization fronts, and I would very much and very easily consider, in context, substantial enhanced compensation for Eric and Peter.

Proposal #3, The selection of accounting firm Marcum LLP as the company's independent auditor for 2016

My FOR vote for this proposal is pretty much a perfunctory one. At a basic level Provectus needs this, in context, to eliminate questions over being a going concern and all that might or could come from not being one or operating without such an opinion.

Accounting professionals (and those who dig into this due diligence topic) may assess firm and individual account leadership (and team) reputations. Recent rankings, primarily revenue-based, would place Marcum as a Top 20 accounting firm. See, for example, below.

Click to enlarge. The 2015 Inside Public Accounting (IPA) 100 Firms

Click to enlarge. The 2014 accountingTODAY Top 100 Firms

Relating this proposal to the blog post's theme of a vacuum/lack of leadership, Provectus' former independent auditor BDO USA LLP (like the company's internal auditor vendor that was terminated earlier this year) clearly displayed insufficient leadership by not identifying Craig's potentially or purported inappropriate actions and activities sooner.

Image source

Road trippin': I would have got this post out sooner, but I was dealing with car troubles in cheese country.

Advancing from “occasional cures” to “routine cures”

On the blog's Current News today I compared an article in The Australian from last month, April 2016, "Melanoma drug Keytruda denied full listing on PBS," to one in The ABC from June 2015, about a year later, "'Revolutionary' melanoma drug worth $150,000 a year listed on PBS, saving Australian patients thousands."

Last year, Australian patients with advanced melanoma gained access to Merck & Co.'s anti-PD-1 or immune checkpoint inhibitor drug pembrolizumab (Keytruda) following its initial, "partial" listing on the country's Pharmaceutical Benefits Scheme (PBS). This year Keytruda was denied full listing on the PBS because there was insufficient evidence of clinical benefit to justify its cost — with The Australian calling Keytruda "a much-hyped melanoma drug."

The above dialog from Australia is one part of an ongoing, maturing, global discussion with respect to this topic: whether current “revolutionary” drugs are truly revolutionary, and ultimately worth the requested price. A paragraph from The Australian's article goes to the very heart of this topic:

"The knock-back comes less than a year after the PBAC flagged concerns about a “substantial mismatch” between the public’s expectations for the so-called “breakthrough drug” and the supporting scientific data." [PBAC is Australia's Pharmaceutical Benefits Advisory Committee]

Keytruda (aka lambrolizumab) received the FDA's breakthrough therapy designation (BTD) for advanced melanoma in 2013.

Since the beginning of 2016 there has been an increasing realization that declaring “mission accomplished” in the fight against cancer might be premature. At the Vatican's recent 2016 healthcare conference, Cellular Horizons: How Science, Technology, Information and Communication will Impact Society, it was noted that the current immuno-oncology (I-O) drugs lead to “occasional cures,” but that this outcome is not good enough. Part-and-parcel with this view is the realization that combinations — combinations of different cancer treatments, whether therapies or therapeutics — likely will be paramount to advancing from occasional cures to routine cures.

The global oncology community is actually now talking about cures, realizes the immune system is crucial for this (as was first noted by the Society for Immunotherapy of Cancer in 2013), and is looking at cancer with a markedly increased sophistication in the search for necessary treatment algorithms for various tumors and tumor subtypes.

As with the rest of the oncology community, Provectus has challenges ahead, but PV-10 appears to be congruent with the mainstream more and more daily.

Click to enlarge. Image source

Catching On

Updated below.

Takeaways and a Question:

• Getting T cells into cancer tumors is important to more successfully fighting the disease.

• Traditional cancer treatments do not kill enough cancer cells. Immunotherapies like immune checkpoint inhibitors kill more cells than traditional treatments, but they still do not kill enough.

• Ways of getting T cells into tumors include chemotherapy, radiotherapy, targeted therapies and intralesional (IL) or intratumoral (IT) agents like Amgen's talimogene laherparepvec (T-Vec) (Imylgic®) [approved as a single agent], Provectus' PV-10 [in a pivotal Phase 3 trial as a single agent], Viralytics' Cavatak (another oncolytic virus) [having done Phase 2 trial work as a single agent], etc.

• The more (quantity) and better (quality) T cells that get into cancer tumors, the greater the immunologic signalling of the drug or drug compound (immunotherapy) that led to said infiltration.

• If a drug or drug compound's immunologic signalling is so powerful and broad as to enable the Cancer Immunity Cycle to cycle more sustainably and durably, what would have come first, the chicken or the egg (i.e., the left-hand side, or the right-hand side, the antigen cascader or the checkpoint inhibitor)?

Big Pharma-oriented blogger and publisher, and industry consultant, Dr. Sally Church, MD recently wrote a post (on her blog Biotech Strategy Blog; subscription required) asking if chemotherapy was immunotherapy: "Controversy: Is Chemotherapy Immunotherapy?" Her thoughts derived, in part or in whole, from her visit to AACR 2016. She noted in this post (alluding to a prior one) that one of the rate limiting steps in the Cancer Immunity Cycle was "getting more T cells into the tumours so that subsequent immunotherapy can be even more effective." One way to get more T cells into tumors, according to Dr. Church, was chemotherapy.

Click to enlarge. Tweet image source

Getting T cells into cancer tumors, from the perspective of a traditional treatment like chemotherapy, begins with generating antigens caused by killing cancer cells.

Click to enlarge. Figure 3, Chen and Mellman. Immunity 2013; 39: 1-10.

Utilizing therapeutics or therapies (immunotherapies) from the left-hand side of the Cycle to facilitate the infiltration of presumably educated and trained T cells into cancer tumors, therapeutics (immunotherapies) from the right-hand side can be, to use Dr. Church's words "even more effective."

Following Dr. Church's writing, primarily her tweets (and related or associated material) on Twitter (@maverickNY), is necessary for this investment project. She was kind enough to answer some basic questions of mine early on in my due diligence (basic for her, not so basic for me at the time). With 20 years of experience in the pharmaceutical industry that included the development and launch of Gleevec by Novartis (bios here and here), Dr. Church is smart, intelligent, thoughtful, and (I believe) a weather vane of Big Pharma's market/marketing (and, possibly, R&D) interest and direction. For example, she was and presumably remains a fan of checkpoint inhibitors, but has evolved her views (as I believe them to have developed) in regards to treating late-stage disease from such agents strictly as stand-alone, single agent therapies to their greater relevance and effectiveness in combination with other therapeutics and therapies (presumably stimulatory ones complementary to these inhibitory agents).

AACR 2016 not only discussed chemotherapy as a "potential immunotherapy" (viewing this through Dr. Church's prism), the conference also considered and contemplated radiation therapy or radiotherapy — but fractionated treatment, where radiation treatment is given in several, small doses over a period of time. This is about killing cancer cells to begin the antigen cascade (immunogenic cell death). This is about harnessing the cancer patient's tumor(s) to become a vaccine, so to speak (in situ vaccination).

PV-10 + Chemotherapy. Ironically, as an aside, at SITC 2012 (October), three-and-a-half years before AACR 2016 (April), Provectus presented the results of murine model work combining PV-10 and chemotherapy that generated the best response in non-injected (untreated) tumors {underlined emphasis below is mine}:

"The mechanism by which PV-10's bystander effect is produced was investigated using hepatocellular carcinoma (HCC) and melanoma tumors in immunocompetent and immunodeficient mice. In one set of experiments using immunocompetent mice with bilateral HCC tumors (i.e., two HCC tumors in opposite flanks), intralesional injection of PV-10 into one of the two tumors led not only to eradication of the injected tumor, but also to regression of the uninjected tumor. Controls treated with saline exhibited no effect in either tumor. Treatment of mice with systemic chemotherapy (i.e., 5-fluorouracil, "5-FU") had minimal effect on either tumor, while combination of intralesional PV-10 with systemic 5-FU elicited maximal response in uninjected tumors. Data were analyzed by tumor (i.e., injected tumor, uninjected tumor and total tumor burden) for time to progression and for tumor growth. PV-10 alone was favorable to saline control in all categories, while PV-10 combination therapy produced highly significant advantage vs. control for time to progression of treated tumors (p = 0.010), untreated tumors (p = 0.011) and total tumor burden (p = 0.004)." (Source: Provectus press release, October 2012)

Click to enlarge. Image source

Click to enlarge. Image source

PV-10 + Radiation. Even more ironic, and as a further aside, Provectus shareholders await the presentation or publication of an investigator-initiated study in Australia combining PV-10 and radiotherapy in patients with advanced melanoma. You know...what the company's CTO Dr. Eric Wachter, PhD said more than a year ago in response to a question of mine.

As background, Radiation therapy has been combined with PV-10 in two situations. First, in 2010, Foote et al. reported on their combination work on 3 patients in A novel treatment for metastatic melanoma with intralesional rose bengal and radiotherapy: a case series, Melanoma Research, 20:48, Jan 2010. All of the patients originally were enrolled in Provectus' metastatic melanoma Phase 2 trial (I believe). All patients achieved complete response (CR) (note detailed descriptions in the article's text); however, no discussion was provided regarding survival (that is, keep in the mind the difference or differentiation between [objective] response rate and overall survival). Note: PV-10 was administered first, followed by radiation.

Click to enlarge. Fuzzy purple underlined emphasis is mine.

Later, in 2013, Tan and Neuhaus reported on their combination work on 2 patients in Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcoma, ANZ Journal of Surgery, 83:1-2:93, Jan 2013. Both patients were treated in the company's compassionate use/expanded access program (I believe). One patient achieved a complete response, while the other enjoyed "good" clinical effect before progressing again. Also, no discussion was provided regarding survival of the patient achieving CR. Note: Here, radiation was administered first, followed by PV-10.

During the 4Q15/CY 2014 business update conference call on March 11, 2015, I asked about the timing, and possibly the potential venue(s) (medical conference, journal), of Foote et al.'s clinical follow-up work combining PV-10 and radiotherapy? Eric said: "But regarding the radiation therapy publication by Foote, that is of record as having led to an investigator-initiated study that you mentioned, 25 patients. That study has been enrolling slowly. It had very specific eligibility criteria at a single center. We have had discussions over the last several months with the investigator about ways to get data from that study available publicly and we anticipate that sometime in the coming months, that is sometime this year, that there will be some presentation of interim data from that study" {my underlined emphasis; this year = 2015}.

Step #5, Infiltration of T cells into Tumors. PV-10 has been potentially implicated in each and every step of the Cancer Immunity Cycle, with data on Step #5 to come.

Click to enlarge. Image source

Click to enlarge. Image source

If PV-10/Rose Bengal can (has) overcome one of the Cancer Immunity Cycle's rate limiting steps (of getting T cells into cancer tumors) in greater quantity and better quality (than other treatments), would Dr. Church then refer to PV-10 as immunotherapy?

Updated (5/20/16): Dr. Church updated or extended her thinking with one of her Blue Ice Publishing episodes at Novel Targets entitled Episode 12: Of Mice and Men. In it she further expands on chemotherapy as immunotherapy, and potentially a partner for other immunomodulatory agents like checkpoint inhibitors.

Click to enlarge. Tweet image source

Inception to date: PV-10 + [something else]

Click to enlarge.

Burning Down The House

Wikipedia's tumor infiltrating lymphocytes (TILs) page describes TILs as "a type of white blood cell found in tumors." It goes on to say that "TILs are implicated in killing tumor cells. The presence of lymphocytes in tumors is often associated with better clinical outcomes." The National Cancer Institute's Dr. Steve Rosenberg, MD, PhD pioneered the approach of using TILs via adoptive cell transfer (ACT) to treat cancer patients. The American Cancer Society notes that TILs are "immune system cells deep inside some tumors...These T cells can be removed from tumor samples taken from patients and multiplied in the lab by treating them with IL-2. When injected back into the patient, these cells can be active cancer fighters." One company taking this approach of ACT via TILs is Lion Biotechnologies (NASDAQ: LBIO).

Another variation on this concept of ACT is where immune cells originating from a patient's blood (as opposed to his or her tumor) are extracted, altered and put back "with the goal of transferring improved immune functionality and characteristics along with the cells." Peripheral blood T cells are genetically engineered to express tumor-antigen specific T-cell receptors. Companies using this approach include Bluebird Bio (BLUE), Juno Therapeutics (JUNO) and Kite Pharma (KITE).

Autologous (below left) and genetically engineered (below right) ACT are illustrated below from W. Joost Lesterhuis and Cornelis J. A. Punt, “Harnessing the immune system to combat cancer,” 2012, Nature Reviews/Drug Discovery, supplement to Nature Publishing Group Journals.

Click to enlarge.

Harnessing the immune system to combat cancer, in the context of intralesional (IL) or intratumoral (IT) compounds like Bacillus Calmette–Guérin (BCG), Interleukin-2 (IL-2), talimogene laherparepvec (T-Vec, Imylgic), velimogene aliplasmid (Allovectin-7), Rose Bengal (PV-10), CAVATAK, Newcastle Virus Disease, HF-10, etc., means more than just destroying the lesion or tumor into which these agents are directly injected —it also means, more critically, the potential to generate a robust immune response, to activate, educate, train and thus enable (collectively, "harness") the immune system to attack cancer elsewhere in circulation.

Mechanism of action (MOA) would explain how an IL or IT agent destroys an injected lesion or tumor. Immune mechanism of action (IMOA?) or mechanism of immune action (MOIA?) would explain how the IL/IT agent harnesses the immune system to destroy uninjected, distant or so-called bystander lesions or tumors. PV-10's IMOA/MOIA also would be very relevant in the context of combining the IL/IT agent with other immunotherapies.

Provectus' CTO Dr. Eric Wachter, PhD analogizes PV-10's systemic response to fire, smoke and ash —where there's smoke and ash, there also is fire. T cells in the [peripheral] blood is the smoke. Regressed tumors are the ash. TILs are what interested observers want to see; that is, the fire.

From here, travel back to February 2013's Cancer Watch article about PV-10 and Moffitt Cancer Center's IMOA/MOIA work (which began in December 2012 [protocol first received date]) in this regard. The article is entitled "Back to Phase 1: Understanding Systemic Effects of PV-10;" Moffitt's work is entitled Detection of Immune Cell Infiltration Into Melanomas Treated by PV-10, a Feasibility Study (lead investigators: Dr. Amod Sarnaik, MD and Dr. Shari Pilon-Thomas, PhD).

Moffitt's work in mice in 2012, and presented and published in 2013, concluded that IL/IT PV-10 treatment led (after lesions/tumors were injected and then destroyed or shrunk) to a systemic response. The Cancer Watch article noted:

"Seeking an immune cell infiltrate 

To find direct evidence of such a systemic immune response is part of the motive behind heading back to the bench—although this time involving human subjects. “A further impetus toward teasing out the precise mechanism of how PV-10 can exert a systemic immune response in patients,” said Dr. Sarnaik in an interview, “is to allow us to rationally combine PV-10 treatment with some of the exciting emerging immunotherapies for metastatic melanoma.” 

The focus at Moffitt, Dr. Sarnaik continued, is on discerning the presence of immune cell infiltrate in untreated tumors after PV-10 injections into other lesions. “We are really interested in harnessing immune cell infiltrate as a form of treatment,” he said, noting also that while creating cancer vaccines has been thought of traditionally as one of the Holy Grails of cancer research, cancer vaccines have turned out to be not strong enough to generate an adequate immune response."

The article then went on to note {underlined emphasis and inserted commentary is mine}:

"Adoptive cell transfer 

The strategy of adoptive cell transfer potentially overcomes the weak vaccine response. With adoptive cell transfer, antigen-specific effector cells are taken from the patient’s tumor and expanded ex vivo under laboratory conditions favoring growth of T-lymphocytes and then re-infused to the patient. This precludes the need to provide antigens or to activate antigen-presenting cells. 

ACT via TILs: In melanoma, T-cells from the tumor are cultured from tumor resection specimens in the presence of interleukin-2. ACT via T cell re-engineering: A second strategy infuses peripheral blood T-cells that have been genetically engineered to express tumor-antigen specific T-cell receptors. 

While adoptive cell transfer offers the advantage that enough T cells can be obtained for infusion in all patients, the T-cell receptors transfected into the T cells have a limited antigen-specificity. The strategy works, Dr. Sarnaik said, only about half the time. “We generate large numbers of T-lymphocytes, but we don’t have control over their quality. 

We think one of the limitations is that the T cells you get out of the tumor just aren’t good enough.” PV-10, however, does cause an immune response, suggesting that a combination treatment may improve the quality of the T-lymphocytes and have a greater impact on the disease. 

When Shari Pilon-Thomas, PhD, also a Moffitt researcher, demonstrated that T-lymphocytes recovered from mice treated with PV-10 do appear to be of a higher quality, as evidenced by stronger tumor reactivity, the stage was set for Dr. Sarnaik’s current 15-patient pilot study. In it, one of two resectable melanoma tumors is injected with PV-10. Both are removed several weeks later. Serum is assessed before and after treatment to look for changes in the infiltration of immune cells. In patients with an immune response, PV-10 therapy can be continued."

Unfortunately, Moffitt's IMOA/MOIA/combination therapy relevancy work was waylaid because PV-10 worked too well — both injected and uninjected lesions or tumors were destroyed too well (pathologic complete response [pCR]) and too quickly (sooner than the study protocol patient biopsy period of 7-14 days post-PV-10 injection).

In April 2014 at AACR, Dr. Pilon-Thomas noted about their human work up to that point (the poster was not released by either Moffitt or Provectus, see the company's press release here):

Too quickly, and "smoke:" "These data are exciting and illustrate successful translation of our pre-clinical work in mice to clinical results in melanoma patients. With only 8 patients we've been able to clearly observe statistically significant increases in beneficial T cell populations in peripheral blood. Ironically, the original aim of the trial to assess tumor-infiltrating lymphocytes was thwarted when biopsies of patient tumors collected just 7-14 days after PV-10 injection no longer contained viable tumor tissue. We are following up both the human data and continuing to design more experiments in mice to better explain the systemic immune effects elicited by PV-10 ablation."

In June 2014 at ASCO, Moffitt further noted:

Too well, and "ash:" "Treatment with IL PV-10 led to pCR in the post-treatment biopsies of both PV10-injected and uninjected study lesions in 4 of the 8 patients, and all 8 exhibited at least partial regression of the injected lesion."

Really, ironically, some of the injected and uninjected going away too quickly in Moffitt's work is reminiscent of Provectus' metastatic melanoma Phase 2 trial, and Eric's argument to the FDA to grant PV-10 breakthrough therapy designation for PV-10 in patients (who would have all of their disease treated) with locally advanced cutaneous melanoma:

"Because of the lack of requirements for patients to have pain symptoms upon enrollment, only a small fraction of patients had clinically significant pain at baseline. So, we analyzed those patients, uh, and presented them that analysis of those data in context of the objective response data. We found that there was a strong relationship between the two types of data, that there was simply not enough of the symptomatic, or symptomology data to show a statistical function. I have to conclude that that’s the principal basis for the rejection of the application. I'd say that it was our assumption going into the application that improvement in symptoms, if we made the patient’s symptoms go away was tantamount to -- I’m sorry -- if we make the patient’s lesions go away that’s tantamount to making the patient’s symptoms of that disease go away. We don’t seem to have been successful in convincing the Agency of that."

Nevertheless, Moffitt found, in humans, smoke — T cells in peripheral blood — and ash — regressed tumors.

The Cancer Watch article went on to note:

"“This is a straightforward study that will give a yes or no answer,” Dr. Sarnaik said. 

If the hypothesis that PV-10 will produce a better immune cell infiltrate is borne out, that would justify testing of combination treatments, Dr. Sarniak said. Likely candidates are adoptive cell therapy, approved drugs like ipilimumab that boost immune response, or PD-1- blocking antibodies (none approved yet)."

Moffitt should have found, in humans, the fire, presumably through the following 7 patients of their originally planned 15-patient study. In November 2015 at SITC they showed they found more smoke: "Increased tumor-specific response was found from those circulating T cells of 5 out of 7 tested patients after IL RB treatment."

The Cancer Watch article concluded:

"What kind of therapy is PV-10? 

Echoing Dr. Sarnaik, Eric Wachter, PhD, Provectus chief technology officer, said that he hopes that the findings of Dr. Sarnaik’s study will point toward rational judgments about combining PV-10 with other documented therapies. “We then might want to try two or more orthogonal therapies to stress tumor cells from several different angles simultaneously, for example an immune therapy plus a metabolic therapy (e.g., a kinase inhibitor), or in a rationally designed sequence.” In a hepatocellular carcinoma model, he added, PV-10 showed significant potential for synergy with 5-fluorouracil. Provectus recently initiated clinical testing of PV-10 with the multikinase inhibitor sorafenib, again bringing in two therapies with divergent mechanisms of action. 

Which category does PV-10 fall into? “I think we are getting a clearer picture of how it might be classified, but it has features of several previously unrelated categories, such as of adoptive cell transfer and vaccination,” Dr. Wachter said. “PV-10 initially reduces tumor burden through chemoablation—but then activates the immune system bringing in capacities completely orthogonal to the ablative tumor destruction,” he added." 

“Amod Sarnaik’s work may give us the molecular basis for closing the loop on one of the founding concepts for going into the clinic in the first place,” Dr. Wachter commented. “Back in the preclinical days at Provectus, Craig Dees, PhD, theorized that ablation of tumors with PV-10 might lead to unmasking of tumor antigenic material. I don’t think he anticipated that it would work as well as it does.”

Trying to Understand Provectus' Clinical Development Program (e.g., trial design, protocols, data, etc.)

Reference article: "How to Spot Red Flags in Clinical Trial Data," Adam Feuerstein, Biotech Stock Mailbag, TheStreet.com, March 24, 2016

Adam Feuerstein wrote the above article, which resulted from a conference call he held with Dr. Mark Ratain, MD on March 22nd (conference link in the article) to discuss "a checklist of things to think about when a biotech or drug company announces clinical trial results." Feuerstein and Rattain covered, presumably among other things:

• Single arm vs. randomized controlled trials (SATs vs. RCTs),

• Communication of trial results (press releases, and the information contained therein),

• Changes to trial protocols, and

• The importance of N (the number of patients enrolled in a trial).

Feuerstein concluded with a comment on the importance of more and further questions, research and due diligence, but noted: "Despite all that work, you can still end up being totally wrong."

Given the potential of a promising investigational oncology drug like PV-10 (active pharmaceutical ingredient [API]: Rose Bengal), together with key intellectual property (IP) protection (e.g., patents and trade secrets covering Rose Bengal's second medicinal use as a therapeutic, method of use, formulation, synthesis, and combination with other therapeutics), clinical trial protocols could be viewed as a biotechnology company's crown jewels. Well-designed clinical trials could be prognostic of outcome; should, as successful early-stage studies, facilitate the transition to pivotal trials; and should, as successful later-stage registration studies, provide eventual labels for drug compounds if and when approved by the FDA.

Diligencing clinical development programs (CDPs) precedes the generation and communication of clinical trial data. So, it's very important to understand Provectus' decision-making, choices and execution of solid tumor cancer indications, supporting preclinical murine model work, eventual patient populations, clinical trial designs and protocols, etc. in advance of sought after study results.

CDPs are intertwined with the FDA, and vice versa. Opaque as the Agency's process may appear to be, and generalized as my analogy below is, it is an understatement to say Provectus' past, present and future has been, is and will be about the company's CDP process. Current emphasis is, of course, finally on the step of generating and presenting more and randomized trial data. This is especially so for a molecule like PV-10 (and API Rose Bengal), and Provectus' approach to treating cancer; the former being very novel and the latter being historically unsuccessful (that is, treating disease locally [i.e., making the tumor your friend] in order to defeat it locally and then, in so doing, systemically) until now.

A door is built when a company achieves a consensus design for a pivotal trial with the FDA. The door is closed of course. But, with its design and construction complete, the drug company can commence a registration study in pursuit of the key the regulator holds to open it. A successful study that also leads to drug approval yields the key from the Agency to unlock the door, opening into the room of a market opportunity for the company to commercialize its therapeutic. Drugs fall down before they reach their doors' respective thresholds by failing their pivotal studies, and thus they are unable to obtain the key.

Designing and building the door, traveling the path to secure the key from the FDA, opening of the door, and entering the room are just steps in the Agency's process. Everyone does not follow the process all of the time. When they do, and if they are successful, the process works, in my view. The FDA's process could be observed as nearly agnostic to the investigational drug going through it. See August 12, 2015 blog post The Door.

Takeaways:

In 2016 Provectus should generate and present data for each PV-10 CDP:

• As a monotherapy for advanced melanoma,

• In combination (also: as part of a combination regimen) with pembrolizumab (Keytruda) for metastatic melanoma, and

• As a monotherapy for hepatic cancers.

Also in 2016 the company should produce mechanism of action (MOA) data that may enable Provectus to advance its investigational dermatology drug PH-10 into pivotal Phase 3 trials for psoriasis and/or atopic dermatitis.

Summary:

• Melanoma CDP, part 1. Provectus' pivotal Phase 3 trial (a registration study) of PV-10 as a monotherapy (a single agent) for patients with locally advanced cutaneous melanoma (AJCC* Stages III B-C and IV M1a):

• It is a well-designed trial with a unique feature (clinical assessments every 4 weeks), and

• Recent protocol changes, made as the study enrolls and treats patients, potentially make it easier to recruit into. 

• Melanoma, CDP, part 2. The company's Phase 1b trial of PV-10 and Merck & Co.'s immune checkpoint blockade drug pembrolizumab for patients with metastatic melanoma (AJCC Stage IV):

• It is a well-designed trial that is "enrolling well," 

• The study's design is flexible enough to pair another checkpoint blockade drug or drug compound with PV-10, like ipilimumab, nivolumab, other anti-PD-1 agents, anti-PD-L1 agents, etc., utilizing their respective prescribing or potential prescribing information,

• The design also is flexible enough to pair PV-10 with a targeted therapy,

• It is possible by now that a Phase 1b safety assessment has been successfully completed (or is nearing completion), which then would allow for advancement into an expanded Phase 2 RCT of PV-10 + pembrolizumab vs. pembrolizumab alone; that is, PV-10 + standard of care (SOC) vs. SOC, and

• A Phase 2 RCT (very likely a registration study) would be well-positioned in a post-monotherapy approval world of PV-10.

• Liver CDP. Provectus' original clinical (Phase 1) testing of PV-10 in liver cancer explored unresectable hepatocellular carcinoma (HCC) and hepatic metastases in an initial group of patients: 13 patients, or 15 patient-tumors -- a single hepatic lesion was treated [injected] with PV-10; two patients with multiple tumors were enrolled twice to allow additional treatment of their second tumors.

• At July 2015, 10 of 13 patients were alive after up to 54 months. Three deaths occurred; one due to cardiac comorbidity, one due to a serious adverse event (possibly thromboembolism), and one due to HCC progression,

Click to enlarge. ESMO 17th World Congress on Gastrointestinal Cancer, Abstract #P-116, July 2015

• The company expects to present more data from this Phase 1 study in July 2016,

• Initial clinical testing was expanded to (a) continue assessing HCC and potential tumor indications in additional patients and (b) begin assessing HCC patients on a stable dose of sorafenib, with patients still receiving PV-10 treatment of a single hepatic lesion,

• The advancement of the expanded Phase 1 trial should take the form of a Phase 1b/2 clinical trial approach similar to that Provectus' melanoma CDP (i.e., PV-10 + SOC of pembrolizumab), where after and assuming a Phase 1b safety assessment is successfully completed, the CDP would advance into a Phase 2 RCT of PV-10 + SOC vs. SOC, where SOC would depend on geography (e.g., sorafenib, local ablation technologies like TACE or RFA, etc.).

• Dermatology CDP: This CDP and its potential advancement into one or two pivotal trials fpr psoriasis and/or atopic dermatitis very likely wholly depends on the results of Provectus' mechanism of action study A Phase 2 Study of Cellular and Immunologic Changes in the Skin of Subjects Receiving PH-10, for which data and results are expected to be communicated in 1H16 (management recently guided to April).

* AJCC = American Joint Committee on Cancer

Provectus' overall CDP, led from inception (I believe) by the company's CTO Dr. Eric Wachter, PhD, is comprised of at least 5 parts:

• Oncology (PV-10, a 10% solution of Rose Bengal) (parts 1 to 3)

• Melanoma

• Earlier stages of advanced melanoma: Stage III B-C and IV M1a

• Later stage: Stage IV (visceral: IV M1b-c)

• Mechanism of action

• Hepatic cancers

• HCC (aka primary liver cancer)

• Cancers metastatic to the liver (aka secondary liver cancer)

• MOA

• Other solid tumor cancers (e.g., breast cancer, etc.)

• An active compassionate use program (CUP)/expanded access protocol (EAP) for cutaneous or subcutaneous tumors (mostly, but not limited to, melanoma) (part 4)

• Dermatology (PH-10, a 0.001% to 0.01% gel of Rose Bengal) (part 5)

• Psoriasis

• Atopic dermatitis

• MOA

Quotations below are drawn from the above mentioned Feuerstein article. Bolded, underlined and/or italicized emphases in them, or in quotations of other people, are mine. As background, Provectus' two-prong approach to treating cancer comprises, first, making the cancer patient's tumors his or her friends by treating all accessible (injectable) lesions and tumors with PV-10. Second, this direct attack on the patient's tumor burden educates or awakens the immune system to fight back, hold off or destroy cancer elsewhere in the body.

[Quote A]

"Generally speaking, single-arm clinical trials are difficult to interpret because they lack a comparator arm. A single-arm study could produce credible evidence of drug activity in certain circumstances -- a study measuring response rate in deeply refractory cancer patients, for example. Be very skeptical, however, of single-arm studies with progression-free survival or overall survival endpoints. Likewise, the use of an historical control is suspect."

Eric's approach with the FDA prior to the approval of immunotherapy ipilimumab (Yervoy) in 2011 was to seek accelerated approval on the basis of PV-10's "robust response" in metastatic melanoma patients from a Phase 2 SAT. Response rate means objective response (OR) rate (ORR), which equals complete response (CR) rate (CRR) plus partial response (PR) rate: OR = CR + PR. Company presentations from 2009 and 2010 outlined this, prior to agreement with the Agency to undertake a Phase 3 RCT. Relevant slides from these presentations are below:

Click to enlarge

Click to enlarge.

Click to enlarge.

Click to enlarge

Click to enlarge

Co-opting Feuerstein's language from Quote A above: Eric initially sought drug approval on the basis of an SAT that produced credible evidence of drug activity by measuring response rate in deeply refractory cancer patients. It should be noted in addressing Feuerstein's comments that Provectus' SAT, Phase 2 Study of Intralesional PV-10 for Metastatic Melanoma, had:

• A primary endpoint of ORR (modified RECIST v 1.0**), and 

• Secondary endpoints of ORR of untreated bystander lesions (see **), progression-free survival (PFS) (see **) (measured for only 52 weeks), and 1-year overall survival (OS).

The following excerpt is from Provectus' November 2010 press release Reports Full Phase 2 Study Data on PV-10 for Metastatic Melanoma. Presentation of preliminary clinical trial results was made at SMR [November] 2010.

"A Complete Response (CR) of PV-10 injected lesions was achieved in 24% of subjects, Partial Response (PR, requiring at least a 30% reduction in tumor volume) in 25% of subjects and Stable Disease (SD, requiring less than 20% increase in tumor volume) in 18% of subjects, with 23% of subjects experiencing disease progression (PD, 20% or greater increase in tumor volume); 

Response was considerably higher in the 55 subjects with cutaneous or nodal disease only (55% OR and locoregional disease control in 78% of subjects) than in the 25 subjects with visceral metastases (35% OR with a 56% rate of disease control); 

An OR was achieved in untreated bystander lesions in 37% of subjects having an evaluable bystander lesion at baseline, with 55% of subjects achieving locoregional disease control in their bystander lesions; 

Bystander response was closely correlated with successful ablation of injected lesions, with 67% of subjects achieving an OR of their bystander lesions if they achieved an OR in their injected lesions vs. 5% in subjects who did not achieve an OR in their injected lesions; 

Mean Progression Free Survival was 8.2 months for all subjects, while the OR cohort had a significantly longer PFS estimated to be 11.7 months vs. 4.1 months for SD or PD subjects; subjects with cutaneous or nodal disease achieved a mean PFS of 8.8 months vs. 6.2 months for subjects with visceral metastases: 

Adverse Experiences ("AE") during the study interval were generally mild to moderate, locoregional and transient, with no deaths or life-threatening experiences attributable to PV-10."

All patients in this Phase 2 trial "had recurrent, locally advanced melanoma after a median of 6 previous interventions (range 1–19), and most had received multiple classes of treatment" (source: journal article below), such as surgical excision, nodal biopsy, regional chemotherapy, immunotherapy, radiotherapy, investigational agents, systemic chemotherapy, distal amputation, and other. Related references include:

• ESMO [September/October] 2012 poster "Immuno-chemoablation of metastatic melanoma with intralesional rose bengal" (which presented final study results), and

• July 2014 peer-reviewed publication in Annals of Surgical Oncology "Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma."

The underlined portion of the Phase 2 trial results press release above will be relevant to another Feuerstein comment as well as later in this blog post; that is, the subgroup analysis of the patient population of PV-10's initial pathway to approval. Returning to our story and saga, the FDA directed Provectus to undertake a Phase 3 RCT. Relevant slides from a 2010 company presentation are below:

Click to enlarge.

Click to enlarge.

See also April 2010 press release Reports on Successful End-of-Phase 2 Meeting with U.S. FDA and Gains Clarity for Licensure of PV-10 for Metastatic Melanoma.

Recall comments of melanoma, intralesional agent (IL) and PV-10 key opinion leader (KOL) Dr. Sanjiv Agarwala, MD of St. Luke's Cancer Center at the 2016 HemOnc Today Melanoma and Cutaneous Malignancies conference and in March 19th article "Intralesional therapy ‘here to stay’ for melanoma:"

"“If we’re going to show monotherapy with PV-10 works, you have to design a randomized trial,” Agarwala said. “It is not easy to design a randomized trial for a monotherapy intralesional agent, when you have all of these drugs available. This trial is designed in a very specific way, and it will be very interesting to see the results of this trial compared to the talimogene laherparepvec [Imlygic, Amgen] trial, because that trial was designed in a different era.”"

The primary endpoint identified in the slide immediately above (Phase 3 Study Overview) is durable response (DR) rate (DRR) for at least 6 months, which was the primary endpoint of BioVex's (Amgen's) Phase 3 RCT for intralesional (IL) agent OncoVEX (GM-CSF) (talimogene laherparepvec), A Randomized Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of Treatment With OncoVEX^GM-CSF Compared to Subcutaneously Administered GM-CSF in Melanoma Patients With Unresectable Stage IIIb, IIIc and IV Disease. BioVex's pivotal trial (prior this company's acquisition in 2011 by Amgen) started in 2009, which was about a year before the FDA directed Provectus towards a Phase 3 RCT of IL PV-10.

Returning briefly to Feuerstein's comment of "credible evidence of drug activity," the Agency acknowledged such activity while at the same time denying Provectus' breakthrough therapy designation (BTD) application in May 2014 for patients with locally advanced cutaneous melanoma, the sub-group noted in the November 2010 press release above (but by a different name). BTD was denied because Eric's Phase 2 SAT, designed in c. 2009, did not collect sufficient quality of life and/or patient reported outcome data:

"The preliminary clinical data provided in your request for Breakthrough Therapy designation are indicative of drug activity in the treatment of local, satellite or in-transit recurrence of malignant melanoma; however, the preliminary clinical data do not demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. This determination is based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding) and our inability to determine the clinical significance of the reduction in the size in one to 10 target lesions in patients with locally advanced melanoma, who may have additional untreated cutaneous, subcutaneous, or visceral sites of disease. " (Source: FDA BTD denial letter, May 16, 2014; see also May 24, 2014 blog post The FDA Response)

Paucity means not enough data. Paucity does not mean the data are not good or not good enough.

It is also important to note, with the benefit of hindsight, that Eric's discussions with the FDA on a prospective Phase 3 RCT were hindered to no small degree (I believe he was reluctant to agree with the Agency) because, first, there was no agreement on the patient population he thought appropriate and applicable. Second, I think he felt there was insufficient IP protection of the therapeutic use of Rose Bengal (and thus PV-10) as well as their (Rose Bengal and PV-10's) manufacture for therapeutic use. Third, I think Eric felt there was inadequate supply of both drug substance (Rose Bengal) and drug product (PV-10) for a pivotal trial and in a post-approval world. See May 30, 2014 blog post "Why did it take four years...to arrive at this point?". I still also think in a post-ipilimumab approval world and pre-Provectus December 2013 Type C meeting with the FDA, there still was debate over the role and utility of an IL agent for treating cancer.

[Quote B]

"Ratain very much likes randomized, controlled studies (preferably blinded as well) for the converse of the reasons stated above."

Almost four years to the date of presenting Phase 2 SAT data (November 4, 2010), Provectus initiated its pivotal melanoma RCT (November 10, 2014) for Stage III B-C disease, PV-10 Intralesional Injection vs Systemic Chemotherapy for Treatment of Locally Advanced Cutaneous Melanoma Without Distant Metastases. Elements of this design were communicated by company management as early as 2013; see the relevant slide below from a March investor presentation:

Click to enlarge.

Provectus understood there was a difference between (a) treating earlier stages of advanced melanoma (Stage III B-C and IV M1a), where all of the disease's lesions and tumors should be accessible to a PV-10-filled needle (e.g., manifested in or pursued by the on-going Phase 3 RCT of PV-10 as a monotherapy or a single agent) and (b) treating much later stages (Stage IV M1b-c), where disease has spread out of the reach of the needle (e.g., now manifested in or pursued by the ongoing Phase 1b/2 program combining PV-10 and immunotherapy pembrolizumab, A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination With Systemic Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma). Relevant slides from Dr. Argawala's SMR 2010 presentation show:

Click to enlarge.

Click to enlarge.

The trial's patient population was expanded from Stage III B-C to include IV M1a in March 2016, via a new trial protocol, when Eric added fellow IL drug talimogene laherparepvec (T-Vec), which was approved in October 2015, as a comparator, PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma Without Distant Metastases.

[Quote C]

"When the company's press release hits the tape, do these things:

Read the press release. The whole thing. If the headline of the press release states results are "positive," "outstanding" or uses some other superlative, assume there are problems hidden somewhere in the waning paragraphs until proven otherwise. Read the press release again.

The design of the clinical trial, including number of patients enrolled, the type of patient enrolled and the endpoints (primary, secondary), should be explained clearly. There will be a paragraph discussing the study results. Look for these re-assuring words/terms: Intent-to-treat analysis, statistical significance, achieved the primary endpoint. More details, more specific data are better than less.

Be wary of companies which describe "positive" clinical trial results using wishy-washy adjectives."

Although not a comprehensive list of Provectus press releases about preclinical and clinical PV-10 data, let's look at some press releases for melanoma, liver cancer, breast cancer, and dermatology:

• September 2007: Releases Summary Results of Phase 1 Metastatic Melanoma Study

• 4th paragraph: "At final evaluation after injection with a single dose of PV-10, the following results were obtained: 20% of subjects achieved CR of their injected tumors, 20% achieved PR, 35% achieved SD and 25% achieved PD, corresponding to an objective response (CR+PR) in 40% of subjects and local disease control (CR+PR+SD) in 75% of subjects. Among those subjects achieving an objective response of their treated tumors, 25% achieved an objective response of their untreated bystander tumors, and 100% exhibited disease control in their bystander tumors. In contrast, for those subjects failing to achieve an objective response of their treated tumors, only 8% achieved an objective response of their bystander tumors, and 92% exhibited progressive disease in their bystander tumors. These differences in response of bystander lesions as a function of response of target lesions were statistically significant and support the occurrence of a bystander effect in subjects whose target lesions have been responsive to PV-10 chemoablation."

• October 2008: Announces Completion of Phase 1 Clinical Trial of PV-10 in Recurrent Breast Cancer

• June 2009 (for ASCO 2009, interim results of half of the Phase 2 trial's enrollment figure): REPORTS ENCOURAGING CLINICAL DATA AT ASCO ON TREATMENT OF METASTATIC MELANOMA WITH PV-10

• 2nd paragraph: "Key interim data from the first 40 subjects in the Phase 2 study included: Objective response of PV-10 treated lesions was observed in 60% of subjects. Locoregional disease control of treated lesions was observed in 75% of subjects. Response of untreated bystander lesions was consistent with observations from Phase 1 testing. Interim safety data were comparable to Phase 1, with transient mild to moderate locoregional pain, vesicles, edema or swelling most common."

• June 2010 (for ASCO 2010, results of Phase 2 patients with visceral disease): Encouraging Data on Visceral Metastases Presented at ASCO

• 3rd paragraph: "Summary data on 20 subjects, including initial data on 4 subjects from the final 40 subjects in the study, who had evidence of macroscopic metastases of the lung, liver, brain or lymph nodes at screening, were presented. Among the first 40 study participants, 7 of the 16 subjects (44%) with visceral or macroscopic nodal metastases at screening exhibited stasis or regression of their lesions, including complete regression of multiple pulmonary metastases measuring up to 1.1 cm in one subject. Detailed data were presented on one Stage IV subject who experienced complete regression of multiple lung metastases and partial regression of multiple brain metastases over the study interval."

• November 2010 (for SMR 2010, preliminary full Phase 2 data): Reports Full Phase 2 Study Data on PV-10 for Metastatic Melanoma

• 2nd paragraph: See above.

• May 2014 (for ASCO 2014, a subgroup analysis of Phase 2 data): PV-10 Data Show Exceptional Complete Response Rates in Refractory Melanoma Patients

• 4th paragraph: "Dr. Agarwala and co-authors from 7 prominent melanoma centers in the United States and Australia studied the safety and efficacy of IL PV-10 in an 80 patient international, multicenter, single arm phase 2 trial. A subgroup analysis of 28 patients with all existing melanoma lesions injected and an additional 26 patients with only 1-2 uninjected bystander lesions showed that these patients experienced an exceptionally high rate of response. The best overall response rate (BORR) in the 28-patient "all treated" subgroup was 71% (confidence interval of 51-87%), with 50% complete response (CI 31-69%). Among the 54 patients in both of these subgroups (i.e., patients who had all of their disease monitored in the study), CR (Complete Response) was achieved in 232 of 363 injected lesions (64% CR). Furthermore, CR was achieved in 121 lesions after a single injection of PV-10; 84 lesions required 2 injections to achieve CR; 22 lesions required 3 injections; and 5 lesions required all four allowed injections."

• July 2015: Data on PV-10 for Chemoablation of Liver Cancers Presented at ESMO 17th World Congress on Gastrointestinal Cancer

• Data was presented on the poster; however, the press release noted in its 4th and 5th paragraphs: "In the initial study cohort, six subjects received PV-10 injections in two successive escalating dose cohorts of 0.25 and 0.50 mL per cm3 lesion volume. Significant adverse events were limited to injection site and photosensitivity reactions that resolved without sequelae. All injected tumors were stable in size at 28 days, and among four of the initial six tumors that had longer-term assessment, two had partial response. Based on these data, the researchers concluded that preliminary efficacy in treatment of liver tumors with PV-10 was observed with acceptable tolerability. The study is continuing at three study centers with two expansion cohorts to further assess safety and response in HCC and other cancers metastatic to the liver."

Provectus' approach to communication of clinical trial progress and data via press release headlines and content could be described as mixed: sometimes wanting, proper or silent, while at times inconsistent and confusing. For example:

• Some of the releases above used superlatives, such as "encouraging," capitalization, and "exceptional." Others did not. As to whether the headline superlatives matched the clinical results in the releases, one's stock position (i.e., long, short or none) could dictate or lead one's interpretation,

• For the company's metastatic melanoma Phase 2 SAT, Provectus press released the opening of each of the trial's seven trial sites, as well as the trial's commencement, enrollments of 25%, 50% and all of the trial's 80 patients, and completion of treatment,

• Aside from July 2015 medical conference presentations of initial hepatic cancers data (where the company disclosed treatment of 13 patients or 15 patient-tumors), Provectus has not yet communicated the progress of its liver CDP, such as the total number of patients enrolled and treated to date, in which expansion cohorts these patients were treated, etc., and

• The company felt the need to issue a press release in January 2016 to confirm patients were being treated in its melanoma trials, Confirms First Patients Dosed in Trials of PV-10 for Melanoma, after beginning recruitment for the pivotal Phase 3 RCT in April 2015, Opens Patient Enrollment; Begins Phase 3 International FDA Comparative Clinical Trial of PV-10 for Melanoma, and initiating the Phase 1b SAT in September, Announces Initiation of Phase 1b/2 Clinical Trial to Study PV-10 in Combination with Immune Check Point Inhibitor Pembrolizumab, and recruiting at this trial's first site in October.

[Quote D] 

"Other red flag words/terms to watch for: per protocol, retrospective analysis, responder analysis, subgroup(s), modified intent-to-treat, trend, grade five toxicity (that means a patient died.) 

Were any changes made to the trial design, including endpoints? Did the company fully enroll the study as planned? Don't rely on the company to tell you. Compare the company's description of the trial with information listed on ClinicalTrials.gov. You'd be amazed how many times they don't match up."

In the intervening years between (a) the presentation of preliminary full metastatic melanoma Phase 2 trial data (November 2010) and (b) an agreement between the FDA and Provectus on the applicable patient population for PV-10 as a monotherapy (December 2013, see January 2014 press release PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes) and who would form the basis for the Phase 3 RCT, the company undertook retrospective/subgroup/certain responder analyses of the subset of patients in the metastatic melanoma Phase 2 SAT who had all of their disease treated:

• September 2012: Presents Final Phase 2 Melanoma Data at ESMO 2012

• 2nd paragraph: "The data presented on response rate and progression free survival corroborated previously presented preliminary data on these topics. Key results include: An Objective Response Rate (OR) of 51% in subjects' target lesions (25% Complete Response and 26% Partial Response); 69% disease control in these lesions (combined Complete, Partial and Stable Response subjects); 33% of subjects having an untreated bystander melanoma lesion achieved an OR in their bystander lesions while 50% achieved disease control in these lesions; Response of bystander lesions was highly correlated with outcome in treated target lesions, with a bystander lesion OR of 61% in subjects achieving complete or partial response in their target lesions versus 18% bystander lesion OR in subjects that did not achieve this level or response in their target lesions; Stage III subjects experienced a substantially higher target lesion response rate (60% OR and 79% disease control) versus Stage IV subjects (22% and 33%, respectively); Similar trends were noted in response metrics for bystander lesions between these two subpopulations; Analysis of temporal data showed that Stage III subjects also experienced significantly greater mean Progression Free Survival (PFS) of at least 9.7 months, versus 3.1 months for Stage IV subjects (median PFS for Stage III subjects was not reached during the 12-month study interval); Overall survival (OS) data were also presented by disease stage, with Stage III subjects achieving a mean overall survival of at least 12.6 months (median not reached during the study interval) versus 7.3 months for Stage IV subjects. Case studies on several subjects illustrated potential stasis or regression of untreated visceral lesions following PV-10 treatment of their cutaneous lesions, while data on long-term treatment of one study participant demonstrated successful management of the disease over a period exceeding 3 years."

• September 2013: Exploratory Data Analyses of Intralesional PV-10 Clinical Phase 2 Study Results Presented at ECC 2013 Demonstrate Effective Locoregional Disease Control and Support Systemic Immunologic Activity in Refractory Metastatic Melanoma

• 6th and 7th paragraphs: "Results showed that for all subjects, BORR was 51% (26% CR, 25% PR) with the amount of tumor burden accessible to PV-10 injection prognostic for outcome. In the majority of subjects (68%) the lesions treated with PV-10, together with the up to two untreated bystander lesions, constituted all disease present, and these subjects achieved a BORR of 63%. In subjects where all disease was treated (35% of subjects) BORR further increased to 71% (with 50% achieving CR). Additional new data analyses explored response rates relative to locoregional blistering, a specific reaction observed in 40% of subjects. This phenomenon generally occurred within seven days of PV-10 injection but with no clear pattern of incidence, and typically resolved within four weeks. Appearance of this potentially immune-mediated effect was strongly predictive of outcome. Subjects who developed blisters had 66% BORR (44% CR) vs. 42% (15% CR) for those not developing blisters. The correlation between occurrence of blisters and locoregional disease control was even stronger: among subjects with blisters, 91% achieved stable disease or better vs. 54% of subjects without blisters."

• June 2014 (post-Phase 3 RCT consensus with the FDA): PV-10 Data Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting Defines Path Forward

• 4th and 5th paragraphs: "In the phase 2 PV-10 trial, when all existing lesions were injected with PV-10, tumors were no longer detectable (complete response) in 50% of the patients (Confidence Interval: 31-69%). This subgroup analysis supports the potential of PV-10 as a single agent and provides a rationale for a PV-10 phase 3 randomized controlled trial in locally advanced melanoma patients. This phase 3 randomized controlled trial of PV-10 in patients with unresectable locally advanced cutaneous melanoma will assess response to PV-10 vs that of systemic chemotherapy in patients who have disease limited to cutaneous and subcutaneous sites and who have failed or are ineligible for systemic immunotherapy. Progression-free survival and complete response rate will be assessed using standard criteria (RECIST 1.1). Overall survival and exploratory assessment of patient reported outcomes related to lesion pain and other melanoma symptoms will also be assessed. The study is expected to commence this year, and will allow for interim assessment when 50% of the required events have occurred (i.e., disease progressions)."

As noted above, the pivotal melanoma Phase 3 RCT design was changed, expanding the trial's patient population from its initial population of Stage III B-C patients (November 2014) to include those with Stage IV M1a disease (March 2016).

[Quote E]

"Assuming the study was enrolled fully, can you track all the patients from beginning to end? I always pay attention to the "Ns" -- slang for the number of patients in each arm of the study. Look out for patients missing from analyses for inexplicable reasons. It's not unusual for patients to drop out of a study, but they still need to be accounted for in whatever efficacy analysis is being used. Patients "disappeared" are a red flag."

In Provectus' metastatic melanoma Phase 2 SAT the company noted the number and impact on efficacy of patients withdrawing from the trial.

More importantly, N has been, is and continues to be a critical letter and number for PV-10 and Provectus trials, primarily as it relates to the potential treatment effect or effect size of PV-10 when compared to control drugs in the Phase RCT of systemic chemotherapy and IL T-Vec, and the eventual Phase 2 RCTs of pembrolizumab (compared to PV-10 + pembrolizumab) and sorafenib (cf. PV-10 + sorafenib).

Big Pharma beats multi-efficacy look pivotal clinical trials of somewhat better drugs  (i.e., having smaller effect sizes) by using large numbers of patients. The immune checkpoint inhibitors represent notable relative improvement over prior patient options; however, patient trial numbers were not insubstantial. Effect size is a measure of strength (of something over something else). In the context of a clinical trial where the responses of two groups (a control group and a test drug one) are being compared, the difference in response between that of the control group and that of the test drug group is known as the effect size.

Should the control and test (treatment) groups be close in response, and thus the test drug has a small effect (i.e., it is a less efficacious agent), a large or larger number of patients are needed in order for the test drug to distinguish itself; that is, for the confidence interval (say 90% or 95% interval) of the test drug to not overlap or run into the confidence interval of the control. Conversely, if the test drug is very effective, a large effect size may anticipated, and thus a relatively small number of trial patients are needed; that is, the confidence interval of the test arm, in this case, may be large without overlapping the confidence interval of the control arm. The fact Provectus only is utilizing 225 patients in its pivotal Phase 3 trial signals this study assumes a relatively large effect size for PV-10 (i.e., PV-10 is very efficacious). Generally speaking, the more effective a drug is the less patients would be needed (without taking into account other factors that might influence clinical trial design) in a trial.

A more effective drug, less study or trial patients are needed. Less effective, more patients needed. See June 23, 2014 blog post Trial Math: Meeting the Primary Endpoint, Pt. 1 and July 16, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part II.

Feuerstein's comments about N are made in the context of communicating trial results. When Eric changed the melanoma Phase 3 RCT's protocol to include patients with Stage IV M1a disease, and allow T-Vec as a comparator, better interpretation for "not candidates for" and less restrictive lesion size entry criteria, he did not change the trial's N of 225 at the time. It is possible he could change this figure in the future, although I doubt it.

Eric's original N=180 (when his initial patient population was Stage III B-C), with a hazard ratio (HR) of 0.545; see the slide entitled Planned Phase 3 trial under Quote B. Eric's "final" N=225 was 25% higher. Did he subsequently increase his "final" HR too? Higher HRs are worse than lower HRs. The goal of a clinical trial is to generate an actual HR that is lower than the projected HR for the study. As I noted above, higher Ns make it easier for trials to win and meet endpoints. But PV-10's efficacy, all things being equal (e.g., the Phase RCT protocol for patient treatment of and follow-up with PV-10), would not have changed between the time of his original N and his final one -- thus potentially lowering the trial's hurdle by some, most or all of the 25% associated with the increase in N.

[Quote F]

"A lot of clinical trials fail. This is the bane of biotech... 

Not every subgroup analysis is fraudulent. But getting comfortable with the potential credibility of a subgroup analysis requires asking a lot more questions and research. The press release will only be the start of that journey. This is an incomplete list, but it should get you started. I'll end with a depressing truth. You can work through this checklist and do a lot more in-depth research that validates your investment thesis. 

Despite all that work, you can still end up being totally wrong. This is why we love and curse biotech stocks." 

In June 2014, on an investor conference call, Eric said in regards to Provectus' Phase 3 RCT:

"We firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome. It's critical to understand what the drug is doing, which patients are most likely to benefit, what other options those patients have, and which endpoints would be most convincing for government agencies to approved the labelled indication for the drug."

Time will tell.