August 30, 2016

The Day Big Pharma's Earth Stood Still

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Prior to Bristol-Myers' failure of its anti-PD-1 drug and cancer immunotherapy nivolumab/Opdivo as a monotherapy for patients with advanced non-small-cell lung cancer (NSCLC), when in the "era" of anti-PD-1/PD-L1 therapy had one of these drugs or drug compounds failed a pivotal clinical trial.

Since the Big Pharma's announcement on August 5th of this "shocking" or "stunning" outcome, as of this writing, BMS' share price has fallen about 25% (while MRK's has risen about 7%, with a roughly flat S&P 500), which would be equivalent to a loss in market capitalization of about $30 billion.

The "era" of course can be measured in a mere handful of years. It was not that long ago, in 2011, when anti-CTLA-4 drug ipilimumab (Yervoy, Bristol-Myers) was approved for metastatic or advanced melanoma, while "relative" tremelimumab (Pfizer, subsequently licensed to AstraZeneca and MedImmune) failed its own pivotal melanoma trials.

Bristol's failure was attributed by some (or many) to a failure in trial design, and its share price was treated like that of a small biotechnology company that failed its pivotal study. When has that happened? Was failure really attributable simply and strictly to trial design, or was there a calculated risk-reward calculation that merely did not pan out? Consider that Bristol-Myers was running two pivotal trials essentially for the same indication and patient population; one of nivo as a monotherapy, and one of nivo and ipi as a combination regimen.

Nivolumab's August failure may have the exposed anti-PD-1/PD-L1 therapy in at least two ways. First, anti-PD-1/PD-L1 drugs need help. And second, combinations (two therapies and/or treatments) and cocktails (three or more) "now" are the order of the day for end-stage cancer patients.

What started out a few years ago as throwing poop on a wall and observing what stuck in regards to exploring combinations and cocktails for end-stage patients appears to have evolved into or towards thinking more about the poop before it is thrown and wondering what each poop in the pairing or triplet brings to the table individually and collectively in regards to baseline immunologic signalling, biomarkers, pharmacokinetics, etc. -- that is, clear, definable, understandable, synergistic value. See, for example, Immunological “ignition switch” (August 26, 2016) on the blog's Current News page.

What happens to a Big Pharma owner of an anti-PD-1/PD-L1 drug or agent if it doesn't find the right (i.e., synergistic) partner for its checkpoint inhibitor, and when a/one competitor does?

August 15, 2016

Seeking Co-Development

Updated below: 8/17/16.

The company's CTO, board of directors member and a co-founder Dr. Eric Wachter, PhD said several things in regard to PV-10 as an immunotherapy on Provectus' August 10th 2Q16 business update conference call.

Among them, in no particular order:
  • "After a long haul, it is now clearly accepted that tumor ablation with PV-10 can lead to stimulation of a useful anti-tumor immune response."
  • "...over the last several years we have worked with colleagues at Moffitt Cancer Center, we have done some work internally, and we have done some work at the University of Illinois-Chicago to show that PV-10 unambiguously triggers that first step, the destruction of tumor. And that event performs all of the expected downstream signaling of the immune system, leading eventually to a functional immune response against an untreated tumor."
  • "So, when we started this work in Australia in the clinic in 2005, we described that as a an bystander response, which was the common terminology at the time. Immuno-oncology was not particularly well regarded at that period. It got to be even less of an important area of investigation as we approached the end of the first decade of the 21st century. And then, it became a very hot area with the approval of anti-CTLA drug Urvay [sp] and subsequent approvals of a number of anti-PD-1s and presumably eventually anti-PD-L1s, all drugs that harness T cells to have a functional--or improve their functional response against tumor tissue."
  • "So, I think that the story [that ] is now very well documented in the literature. We have shown that this occurs in [unintelligible] models of melanoma. We have shown this occurs in [unintelligible] models of colorectal carcinoma. We have evidence to show that this happens in [unintelligible] breast carcinoma. And, most importantly, we have shown that key elements of this signaling are occurring in melanoma patients."
    • "Our next tumor on the radar will be hepatocellular carcinoma because there are challenges in HCC that are comparable to those in melanoma. We already know that we can destroy HCC with this ablative process and the hypothesis that that should lead to similar signaling, which can have implications for--well, single-agent therapy [unintelligible] HCC, but more importantly for combination with things like anti-PD-1 [unintelligible] . We have already shown that the basic immunology occurs in HCC models, so I would say that--one of the things I’m highly confident in, I’m highly confident that we will show that this same functional immune signaling functions in HCC."
    As I noted under Church (August 15, 2016) on the blog's Current News pageDr. Sally Church, PhD wrote a Biotech Strategy Blog post entitled "Beyond T-Vec - a look at oncolytic viral immunotherapy." Dr. Church does not appear to be either an innovator or an early adopter (as labeled on the technology adoption life cycle). Rather, her professional experience, among other things, biases her (which is neither "right" nor "wrong") towards early or late majorities (I'd lean towards early). I think it is worth paying attention when she begins to opine on a newer or novel category of drug. In the case of oncolytic viruses (OVs) (she does not categorize them explicitly as intralesional or intratumoral presumably because OVs have been explored via both intralesional and intravenous administration), she is commenting as the majorities begin to pick up on what the innovators and early adopters (e.g., Agarwala, Andtbacka, Weber, etc.) have been saying for a while. She is, however, rightfully wanting to know more about durability of responses and survivability, which these innovators and early adopters also have been wanting to see as well.

    Two thoughts crystallized quickly [in my head] but only after reading Dr. Church's blog post. The second one is the field of melanoma, and for Provectus, what immunology in other indications they must show to secure a co-development transaction more on their terms than not. This is represented by the screenshot from her post below, and which is the subject or focus of this blog post.
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    First, the threshold for differentiating one's combination therapy for melanoma appears to be, in Dr. Church's mind, is the approved combination of anti-CTLA-4 ipilimumab (Yervoy) and anti-PD-1 nivolumab (Opdivo).

    Second, is combination data of PV-10 and pembrolizumab in advanced melanoma sufficient to get any co-development deal for Provectus, let alone the deal management presumably desires? Probably not, and I believe they already have recognized such. Big Pharma also may want certain immunology (and not just ablation) data for other indications, such as hepatocellular carcinoma.

    Updated (8/17/16): For some time Provectus' COO and interim CEO Peter Culpepper has publicly and routinely described the kinds of co-development combination therapy deals there could be and he seeks. As recently as the 2Q16 quarterly financial statements filing, the company noted:
    "An interim transaction could be a co-development deal like Roche-NewLink, Bristol-Celldex or AstraZeneca-Incyte. The Company is not in discussions regarding the sale of its business, and there can be no assurance that the Company will be able to monetize PV-10 or PH-10 in the manner described herein."
    Setting aside both Peter and Eric's immense historical difficulties with expectation setting (e.g., in the case of co-dev combo deals as early as June 2014 that one could be/was coming), the above quote is endemic of their historical challenge with guidance (see Forward Guidance (August 14, 2016) on the blog's Current News page).

    What is it that you mean? What do you want to say, and why do you want to say it?

    I don't believe they are saying things that are not true, or that they don't believe; however, in trying to communicate strategy and tactics, Provectus management often conflates the desire to provide genuine insight into what is going on (Peter, Eric) with poorly set or communicating expectations (Eric, Peter) and ineffective (Peter) or ideological-driven approach to providing (Eric) guidance. Eric's comments on the August 10th 2Q16 business update conference call regarding PH-10 are another example:
    "Turning to PH-10, we're sorting through the immunologic and histopathologic data from our mechanism of action study of topical PH-10. I, unfortunately, can't go into detail yet about what we're learning, but in general, my assessment is that these results will be as important to PH-10 as the Moffett work has been to PV-10. 
    When new kinds of therapy come along, everyone likes to understand the biologic story underlying clinical observations, and it appears that this may be a very interesting story that explains observations we've made throughout clinical development of the drug. I look forward to sharing details on this with our stakeholders in the next few months."
    While Eric's first paragraph is more appropriate to describe his perspective of the PH-10 mechanism of action (MOA) results that Rockefeller University's Dr. James G. Krueger, MD, PhD and his Laboratory for Investigative Dermatology have arrived at thus far, Eric's second paragraph conveys his excitement about the results (imprecise as those comments are by phraseology like "very interesting"). Eric is saying Rockefeller's MOA work and results should be as important to PH-10 as Moffitt's work/results were to PV-10, which established the oncology use of Rose Bengal as immunotherapeutic (i.e., "After a long haul, it is now clearly accepted that tumor ablation with PV-10 can lead to stimulation of a useful anti-tumor immune response") and that is of assistance in discussions with Big Pharma (among other preclinical and clinical work/data).

    So, when Peter "talks" Bristol-Celldex, AstraZeneca-Incyte and Roche-NewLink (in chronological order), what does he mean? What does he want to say, and why does he want to say it?

    Whether you agree with this or not (I agree with him in context), to the get the valuation he wants for Provectus Peter believes the company requires an interim value-creating (-recognizing) transaction. This transaction, in his view, is more likely a co-dev combo deal/relationship rather than a geographic license deal/relationship because of factors such as size, scope, validation, etc.
    Click to enlarge.
    His illustrative co-dev combo deals provide a range of potential outcomes for Provectus and the prospective Big Pharma partner, and thus for Provectus shareholders:
    • Deal type A (Bristol-Myers/Celldex), where there would be clear recognition of the partner's interest in Rose Bengal as a promising component of the pairing/combination regimen. A combo collaboration begins,
    • Deal type B (Genentech-Roche/NewLink), where there would be much, much stronger recognition of the partner's interest by its licensing of PV-10 for cancer combo therapy, or
    • Deal type C (MedImmune-AstraZeneca/Incyte), where there would be overt or tacit recognition of the partner's interest or acquiescence but with no strings attached.
    Provectus of course understands there is no reason now to enter into a type C because the company's combination therapy study work already is underway (i.e., PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma), together with prior work such as that of Moffitt's (e.g., "Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma"). A recent type C deal (August 15th) is Bavarian Nordic's drug supply agreement with Bristol-Myers of anti-PD-1 nivolumab (Opdivo) for use in a combination therapy clinical study of the former's vaccine CV301 and the latter's checkpoint inhibitor for patients with previously treated non-small cell lung cancer (NSCLC).

    The difference between type A and B deals is the prospective partner's interest to dip a toe into the pool, or to dive into it. The decision of how wet to get probably depends on how much data each Big Pharma requires for whatever degree of waterlogged-ness they seek or with which they are comfortable. Both types, however, can co-exist with an eventual transaction to buy the company because Provectus management wants to advance the therapeutic use of PV-10 as a monotherapy and in combination with other cancer treatments.

    The co-dev combo relationship Peter has been seeking for some time (i.e., the company ineffectively stated strategy) comprises something to the effect of:
    • A multi-indication collaboration (e.g., melanoma, HCC, NSCLC, etc.),
    • An upfront payment and/or paid-for study/development costs. No upfront payment but paid-for costs could be a nice second. Peter understands the stock market and industry recognize validation is seen with Big Pharma dollars in the deal, whether soft, hard or both,
    • Trial sponsorship is an interesting topic because I would imagine Eric would want to have Provectus conduct (control) it; however, Big Pharma might want to do it in a more expeditious manner than for which Eric has been known,
    • Non-exclusive clinical combination would be preferable to Provectus since PV-10 is orthogonal to the class of PD-1s (and PD-L1s); that is, PV-10 would be synergistic to any checkpoint inhibitor, as management has publicly stated of Keytruda and Opdivo. Why not do combination therapy trials with both PD-1s? Because non-exclusivity might/would not be preferable to the prospective partner, and
    • Time-limited right of exclusive negotiation for licensing rights likely would be a given. If Provectus can get what it wants (vis a vis core business terms), the prospective partner would like a right of first something.
    The 2016 "version" of the 2014 Bristol-Myers-Celldex type A deal (aside from some stuff related to the historical relationship prior to the combo co-dev transaction that may have manifested themselves in the co-dev deal) would appear to be the Bristol-Myers-PsiOxus transaction. The latter essentially is the sentiment and structure of what Peter is seeking on behalf of Provectus. There will be continue to be an open question from many-to-most company shareholders (and I would imagine the Street, the stock market, and the industry ecosystem at large) about whether he can get the deal Peter wants for Provectus, however, until he answers the question and does.

    August 13, 2016

    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 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)
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    July 19, 2016

    It's the small molecule chemical, stupid

    Original image source
    Updated below.

    Sometimes it takes a piece of news to (again) put things into almost complete perspective.

    Consider today's press release Oncorus®, Inc. Launches with $57 Million Series A Financing. This was a topical, straightforward, sizable, early-stage (Series A) biotechnology startup company financing by notable financial (MPM) and corporate (Celgene) life sciences investors of a cancer treatment approach akin to Provectus'. The scientific basis for the company and financing (the "scientific founders," or foundation, so to speak) is the work by Drs. Joseph Glorioso III, PhD and Paola Grandi, PhD around oncolytic viruses, intralesional or intratumoral injection, and immunotherapy.

    Also consider a PubMed search of "glorioso grandi." From this search, further consider, for example, (from where the basis for Oncorus may have come) Grandi et al., "Design and application of oncolytic HSV vectors for glioblastoma therapy," Expert Rev Neurother. 2009 Apr; 9(4): 505–517. Aside from improvements over injectable oncolytic viruses, it's still intratumoral injection as the route of delivery.
    Updated (7/31/16): The trend towards immuno-oncology (I-O) via oncolytic virus continues — the first in this class being the October 2015 approval of Amgen's (BioVex's) talimogene laherparepvec (OncoVEXGM-CSF) — with a license transaction between Western Oncolytics and Pfizer for the former's version, this time a smallpox-related oncolytic virus: "Pfizer bags option on oncolytic virus, partners up to advance through PhI" (Nick Paul Taylor, FierceBiotech, July 29, 2016).
    Gloriosio's (and Grandi's) work above, and his/their intellectual property, references the same base patent/patent application material BioVex did. See here, here (2008) and here (2011).
    The scientific founder of, or the science foundation supporting, Western Oncolytics is Dr. Stephen Thorne, PhD, who comes from the same entity/organization/program — the University of Pittsburgh Cancer Institute's Cancer Virology Program — as Drs. Glorioso and Grandi. Thorne's work has been around as early as 2009 (and probably before; I have not done a thorough desk-based review of this work, but merely am observing the key details and the apparent trend): "Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer," Kirn et al.,, January 2009.
    There are several things of note to me in regards to Pfizer's involvement and certain other aspects of the deal/technology, such as: (i) no financial deal terms were announced (there's usually a reason for such); (ii) upside beyond "today" is gone; (iii) Western Oncolytics appears to only have raised a few million dollars; (iv) see the UPitt relationship/lineage above; (v) one could argue the trend is oncolytic virus, but one also could argue the trend is the tumor microenvironment (TME) as the gateway and route of delivery as the way to enter the gateway; (vi) there is no mention of Pfizer/Merck KGaA's anti-PD-L1 avelumab; (vii) more interest in the gateway, and the use of intralesional (IL) agents to enter it, and the value IL agents in combination with other therapies, especially immune checkpoint inhibitors; (viii) one could argue that Pfizer, a laggard in the immuno-oncology space, is slowing getting up to speed on where the possibility exists to catch-up (e.g., via TME, injection, oncolytic immunotherapy, etc.); and (ix) was Pfizer late again, beaten to the better UPitt oncolytic immunotherapeutic assets by Celgene and others?
    It also is still injection of a biologic, and therein lies the "rub." Said another way: What I know now could be what I wished I knew then. Or perhaps said even another way: An entire pharmaceutical industry unsure or unable to consider or contemplate that the injection of a chemical (Rose Bengal/PV-10/a halogenated xanthene) -- not a biologic (e.g., a Rous sarcoma virus, a herpes simplex virus, a common cold virus, a CpG oligodeoxynucleotide, an avian paramyxovirus, etc.) -- can elicit a systemic immune response.

    Recall St. Luke's Dr. Sanjiv Agarwala's presentation at 6th European Post-Chicago Melanoma/Skin Cancer Meeting. Setting aside Rose Bengal and chemotherapy cisplatin, I believe, everything other oncolytic agent is a biologic.
    Click to enlarge. Image source
    Rose Bengal to the pharmaceutical industry might as well be battery acid. An intralesional or intratumoral injection of this chemical (sulfuric acid) should kill the injected lesion or tumor. As a I wrote under Do Dr. Jedd Wolchok/Sloan Kettering Understand Immunotherapy's History? (July 12, 2016) on the blog's Current News page, the father of cancer immunotherapy, Dr. William Coley, MD injected dead bacteria -- a biologic -- into the cancer tumors of his patients.

    Oncorus' algorithmic creation (by the VC MPM) and funding (by financial and corporate investors) in today's environment is proof positive the immuno-oncology space still remains wanting for a solution to vast amounts of unmet patient need, and that solution (or an important contributor to it) could be intralesional/intratumoral cancer therapy. Of course, what Oncorus is injecting is a biologic.

    Provectus' data, in context, necessary and presumably sufficient to assuage the industry's concern over a [small molecule] chemical being capable of generating a systemic immune response are the results of the company's two ongoing melanoma trials, one of PV-10 as a monotherapy or single agent, and the other of PV-10 in combination with an immune checkpoint inhibitor.

    Management teams, boards of directors, addressable markets, worth, valuation, etc.; those are all straightforward, and cut across industry sectors. But as a non-life sciences investor, perhaps I did not fully appreciate the apparent very high hurdle of the intralesional therapy of a small molecule chemical. Knowing what I know now, how would I have invested differently, if [I would have invested differently] at all...?

    • Rous sarcoma virus: Allovectin-7 (Vical)
    • Herpes simplex virus: talimogene laherparepvec/T-Vec/Imlygic (BioVex/Amgen), HF10 (Takara Bio)
    • Common cold virus: CAVATAK/Coxsackievirus (Viralytics)
    • CpG oligodeoxynucleotide: SD-101 (DynaVax)
    • Avian paramyxovirus (Wolchok, Allison, etc.)

    July 11, 2016

    Clash of Clans

    Image source
    Every drug or drug compound, and drug category or class has a clan.

    Clan members comprise all manner of biopharmaceutical industry constituency or stakeholder; from physicians, clinicians and medical researchers to global regulatory agency staff to Big Pharma/Biotech executives and employees to pharma and biotech investors and traders to media, journalists and commentators to medical conferences to...

    Whether one's "schtick" are immune checkpoint inhibitors, targeted therapies, radiation or radiotherapy, intralesional therapies, etc., we've all got our clan or tribe.

    I believe, by virtue of this blog and talking our book, that our clan(s) is(are):
    • First, PV-10, and Rose Bengal, which fall into the category of small [chemical] molecules that rely on their physical (and not biological) chemistry properties, and
    • Second, intralesional (IL) or intratumoral (IL) therapies (aka local, loco-regional or local-regional, and regional therapies), because route of delivery matters.
    But there is good reason for the biopharmaceutical industry ecosystem to be skeptical of the class of IL therapies. First, until very recently (October 2015 for talimogene laherparepvec or T-Vec), there had been no history of clinical success and, thus, regulatory approval. Second, what promising, approved therapy there has been (T-Vec) has turned out to be a marginal product with an uncompelling clinical value proposition. Before Amgen's T-Vec was approved in 2015 as Imlygic for advanced melanoma, failure preceded it more than two year before in the form of Vical's IL agent velimogene aliplasmid (Allovectin-7) in August 2013 for the same indication. Before Vical, there was the failure of IL agent bacillus Calmette-Guérin (BCG) in 1978, also for advanced melanoma. Taken together, IL therapies would have a modest-to-no history of regulatory validation for nearly 40 years.

    Now consider HemOnc Today's July 10, 2016 article entitled "Intralesional agents show promise in melanoma but may serve ‘narrow clientele.’" After reading it, I am struck by what seems to be physician clan members -- of the IL therapy clan -- endeavoring to frame the potentially notable clinical benefits and patient outcomes IL cancer therapies could generate or yield if only there was a better IL therapy to be their flagbearer. T-Vec was the first guy through the wall, opening the regulatory and commercial doors for IL therapies. The article made me think these clan members were waiting for PV-10 to bust through the door, breaking its frame in the process.
    • HemOnc Today's article's page links
    • Quoted physicians
      • Sanjiv S. Agarwala, MD (medical oncologist, aka Dr. Rose Bengal) —a T-Vec and PV-10 clinical trial investigator from St. Luke's University Health Network in Bethlehem, Pennsylvania,
      • Robert H.I. Andtbacka, MD (surgical oncologist) — a T-Vec and PV-10 clinical trial investigator from Huntsman Cancer Institute in Salt Lake City, Utah,
      • Dale Han, MD (surgical oncologist) — no affiliations were disclosed, and from Yale School of Medicine in New Haven, Connecticut,
      • Vernon K. Sondak, MD (surgical oncologist) — a consultant to Amgen and Provectus from Moffitt Cancer Center in Tampa, Florida, and
      • Jeffrey S. Weber, MD, PhD (medical oncologist) — an advisor to Amgen and a PV-10 clinical researcher from NYU Langone Medical Center.
    Article paragraphs and quotes of interest to me:
    • "HemOnc Today spoke with medical and surgical melanoma specialists about the future of intralesional agents for melanoma, whether oncolytic agents likely will be used as single agents or in combination with immunotherapies, and the lingering questions surrounding T-VEC’s efficacy based on the OPTiM trial."
    • "“If you look specifically at patients with stage IIIB or stage IIIC disease on the OPTiM trial, their response rate was 52%,” Robert H.I. Andtbacka, MD, CM, FACS, FRCSC, associate professor of surgery at Huntsman Cancer Institute at University of Utah, as well as a HemOnc Today Editorial Board member, told HemOnc Today. “None of the other immunotherapies and checkpoint inhibitors have come close to having that response rate in that patient population.” 
    Andtbacka, who served as an investigator on the OPTiM trial, said the positive outcome and FDA approval signal the utility of intralesional agents in the rapidly expanding melanoma landscape."
    • "The relatively mild toxicity profile of T-VEC may make it more appealing to some patients than immunotherapies, which can produce virulent adverse events, Sondak added.
    “Adverse events can be quite modest when you are just injecting a [lesion], rather than trying to treat the entire patient,” Sondak said. “If we can get the immune system to pay attention to the melanoma and do something good because of it, then you are looking at a low-toxicity means of producing an important, clinically relevant immune response.”" 
    • "Although most oncologists agree T-VEC has a role in the melanoma treatment armamentarium, the design of the OPTiM trial has prompted a number of clinicians to question how large that role should be.
    The primary reason for concern is the use of GM-CSF as the control. 
    “T-VEC was approved on the basis of a clinical trial design that will certainly never be replicated,” Sondak said. “The control arm was basically a placebo, with no basis in why one would choose to use that particular regimen. I don’t know if that design would be approved today by the FDA.” 
    OPTiM researchers enrolled patients between May 2009 and July 2011. The majority of new melanoma therapeutic options were approved after that period, leaving some oncologists to wonder how the results might differ if the trial were conducted now."
    • "“There are many patients who have tumors that do not have tumor-infiltrating lymphocytes, and checkpoint inhibitors cannot work unless those lymphocytes are there,” Andtbacka said. “Using an oncolytic therapy can actually change the tumor microenvironment, and essentially make a ‘cold’ tumor become a ‘hot’ tumor. When we do that, it appears that we can make a nonresponder into a responder.”"
    • "“The preliminary data for T-VEC combinations look promising,” Han said. “The whole idea of treating systemic melanoma has really blossomed into the idea of combination therapy. Combining T-VEC with other effective systemic treatments was the natural next step to see if we could further improve outcomes.”"
    • "“The beauty of combinations is that you can take a patient who has an in situ tumor reachable by a needle and inject it with something that makes the tumor more immunogenic,” Agarwala said. “If you throw in a confirmed immunotherapy that works well, you have the potential for synergy.”
      Because melanoma has been shown to respond to combinations, the use of these regimens should be considered when possible, Agarwala added. 
      “I like to say, ‘Make the tumor your friend, and make it your ally,’” he said. “If you can’t remove the tumor — if you’ve tried everything and it keeps coming back — instead of just trying to remove it again or giving systemic therapy, why not add an intralesional agent that gets into the microenvironment and releases antigens? That is a concept that highly appeals to me.”"
      • "The labor involved in preparing a T-VEC injection may drive cost-related considerations.
      “The biggest cost factor with an intralesional therapy, aside from the drug, is time,” Agarwala said. “It’s not just a nurse hanging a bag. You have to have a doctor or a provider actually do a procedure, and that procedure is billable. It taxes the provider’s time. I am not sure if anyone has studied the total cost yet, but the short answer is that it’s an issue.” 
      Weber agreed. 
      “An injection like this can take up a room for 20 minutes and might be viewed as a hassle by a doctor with a busy practice,” Weber said. “If a nurse practitioner is doing the injection, that’s time she or he is not seeing other patients. I do not think it is unreasonable to say that some busy oncologists view it as more work than it is worth.”"
      • "T-VEC is the first intralesional agent to be approved as monotherapy for the treatment of advanced melanoma. However, it is far from the only oncolytic agent under investigation.
      “These agents are safe and produce good response rates,” Agarwala said. “Some of the ongoing trials of new oncolytic agents can address the concerns left over from the OPTiM trial.” 
      Agarwala serves as an investigator on a phase 3 study investigating PV-10 (Provectus Biopharmaceuticals), an injectable form of rose bengal disodium that received FDA orphan drug designation for melanoma and hepatocellular carcinoma."
      • "“The current PV-10 randomized trial only includes patients who have failed immunotherapy or are not candidates,” Agarwala said. “In that sense, it is much more of a real-world trial [than OPTiM]. The control arm of the trial is chemotherapy, which is reasonable, because if you have tried everything else, it is a fair comparator.”"
      • "“These agents may have theoretical or practical advantages compared with T-VEC,” Sondak said. “They are all worthy of investigation, without question, and some could be real advances. There is value to having T-VEC available, but it will also be important for these other agents to have their chance to show what they can do.”"
      For the first time that I can recall, an article discussing by therapies addressed treatment administration by non-physician providers (e.g., nurse practitioners, physician's assistants, nurses). See page 6 of the article here.

      The article's author should have discussed this topic with Dr. Agarwala's NPs, PAs and/or RNs, and solicited their opinions of PV-10.

      July 2, 2016


      Image source
      Rose Bengal is a molecule that has been around for a long time and used in several very different ways. In addition to being an industrial dye and a food dye (i.e., Red Food Dye No. 105), the molecule has a long history as a diagnostic agent with an established safety history. Use as a diagnostic was Rose Bengal's original and first medicinal use (i.e., an intravenous hepatic diagnostic: 131I-radiolabeled Rose Bengal/Robengatope®; a topical ophthalmic diagnostic: Rosettes®, Minims®).

      Rose Bengal's second medicinal use is as a therapeutic, which is being advanced by Provectus in both oncology (PV-10) and dermatology (PH-10). There are other halogenated xanthenes the company owns.

      Note the concentrations: intralesionally (intratumorally) injected PV-10 for oncology is a 10% solution of Rose Bengal, and topically applied PH-10 for dermatology is a 0.001% to 0.01% gel of the active pharmaceutical ingredient (API) Rose Bengal. PV-10 up-regulates or stimulates, while PH-10 appears to locally down-regulate.

      This is a blog page I update from time to time as information is gathered about Rose Bengal's shape changing (transformation) abilities; h/t a shareholder hatter.

      For now, first consider Xu et al., "Aggregation of Rose Bengal Molecules in Solution," Journal of Photochemistry and Photobiology, A: Chemistry, 40 (1987) 361-370.
      Click to enlarge.
      The authors note (my underlined emphasis):
      "Rose bengal is a bis anionic dye and it has been suggested that it also has a tendency to aggregate in solution. It does not follow Beer’s law at concentrations above 10e5 M and the spectra are both of different shape and shifted at higher concentrations. Thus the aggregation phenomena of rose bengal and the other xanthenes have been previously studied in solution by means of absorption spectroscopy 171. The absorption spectrum of rose bengal in dilute solution consists of two peaks separated by about 30 nm. In more concentrated solution the shorter wavelength of these peaks grows and shifts several nanometers toward the blue. We can now assign the longer wavelength band exclusively to the monomer while the shorter-wavelength band derives from a combination of the monomer and the dimer respectively and its size as well as its shape depend on concentration."
      There has been some discussion of the pH environment in a tumor cell, and surrounding healthy tissue. There are differences in the nutritional and metabolic environment of cancerous and healthy tissues.

      Pathobiology of Cell Membranes, Volume 2, edited by Benjamin F. Trump, Antti U. Arstila (1980), discuss, among other things, the effect of pH, and mechanism:
      Click to enlarge.
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      Click to enlarge.
      Red Cell Shape: Physiology, Pathology, Ultrastructure, edited by M. Bessis, R. I. Weed, P. F. Leblond (1973), note the factors that facilitate shape transformation (sphering) to varying degrees include pH, temperature, ionic composition, and concentration:
      Click to enlarge.
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      June 14, 2016

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