July 19, 2016

It's the small molecule chemical, stupid

Original image source
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.

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.
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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...?

Notes:
  • 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

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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

    Shapeshifter

    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.
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    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:
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    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:
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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.

    June 1, 2016

    Intralesional PV-10 for In-Transit Melanoma—A Single-Center Experience

    Article: Lippey et al., "Intralesional PV-10 for in-transit melanoma-A single-center experience," J Surg Oncol, 2016 May 30.

    H/t a shareholder and regular hatter for access to the above paper. Bolding-in-paragraph and underlined emphasis below is mine.

    [From the end of the paper] "Synopsis: This paper reviews a single metropolitan cancer hospitals experience with PV-10 for the treatment of in-transit melanoma. Over a 4-year period, we have treated 19 patients with PV-10 for melanoma and achieved disease control in 68% of patients. We find it a helpful tool in our armory for local control of this often-difficult clinical scenario."
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    "Toxicity: The majority of treatments (73%, 24/33) were well tolerated without any reported side effects. Edema, pain and erythema were the most common side effects, although these were minor in severity, limited in duration, and easily managed by simple analgesia. Five patients required opiate analgesia for pain associated with PV-10 injection.

    One patient was readmitted to hospital 1 week following treatment with lower limb cellulitis requiring intravenous antibiotics for 2 days. This patient was obese and elderly and the cellulitis arose in the area of recent injection."

    "Treatment Response: After a median follow up of 11.7 months, disease control was achieved in 63% of patients. Five patients (26%) achieved a complete response, another five (26%) patients achieved a partial response, and two patients had stable disease (11%) at the time of last follow-up. Seventy-four percent (14/19) of patients had a clinical response at time of first follow-up (median time 21 days); range 8–91 days. Younger patients and those with smaller lesions were more likely to respond to treatment (Table III). The number of injected lesions and the time from primary diagnosis to treatment were not predictive of response.
    Click to enlarge.
    Ten patients did not have all lesions injected, primarily due to the number of lesions present. A bystander response was noted in un-injected lesions in 50% of patients who did not have all their lesions directly injected (Table II). After a median follow up of 11.7 months, eight patients had died
    from metastatic melanoma."

    "DISCUSSION: This single-center retrospective review demonstrates that intralesional PV-10 is an effective, safe, and well-tolerated treatment option for patients with ITMs and loco-regional recurrence of melanoma. Treatment was delivered to a group of patients who were elderly (median age 82 years) and in many cases considered inappropriate for more aggressive and potentially toxic therapies such as ipilimumab or isolated limb infusion.

    There have been several previous reports of success with intratumoral injection of PV-10, providing local control in this group of patients with an acceptable toxicity profile. There is still a lack of data about durability of PV-10 as well as a lack of long-term survival data. The largest published study assessing the use of PV-10 in the setting of refractory melanoma published in 2014 analyzed 80 patients from seven international sites. In this study, a 52% overall response rate and 26% complete response rate were described which is comparable to the overall response rate of 63% and complete response rate of 26% in the current series as well as in another previously published single-center series (Table IV).

    The effective treatment options for metastatic and locoregional inoperable disease melanoma have rapidly improved over the last 5 years. With the introduction of novel systemic agents targeting immune checkpoints (ipilimumab, pembrolizumab, nivolumab), and mutations in the MAP kinase
    pathway (dabrafenib and trametinib), the treatment options for patients with unresectable metastases have increased and the prognosis for these patients has significantly improved. However, these agents may be associated with significant toxicity and in the case of PD-1 targeted therapy require frequent hospital visits for infusions. Intralesional PV-10 compares favorably with other
    intralesional therapies including talimogene laherparepvec (T-VEC) which in the recently published OPTiM study demonstrated on overall response rate of 26.1%. It is important to note that the
    patient population in the OPTiM study had more advanced disease than the population in the current study, and the response rate for patients with all lesions injected lesions with T-VEC was 33%. For an
    elderly patient with ITM, a simple and effective local therapy with minimal side effects is an attractive option. In our center, the use of ILI has steeply decreased with the availability of PV-10.

    In the modern era of effective systemic therapies, patient selection for intralesional therapy is critical. Previously described factors predictive of response include the presence of ulceration, blistering, eschar, or pain following injection. In the current study, lesion size was also found to be predictive. Of the five patients who achieved a complete response, the average lesion diameter was 3 mm compared to the cohort average size of 6.3 mm. We did not specifically collect data on eschar formation but anecdotally have seen significant ulceration and eschar in most responders which may represent a brisk immune response to treatment or a direct toxic
    effect.

    Aside from the local toxicity of pain and edema and an isolated report of photosensitivity, PV-10 remains a very safe treatment option. As compared to radiotherapy, PV-10 has the advantages of allowing a wider field of treatment which may be repeated if necessary. A successful combination of radiotherapy and intralesional PV-10 has been reported and may warrant further
    investigation.

    The limitations to this study are the retrospective nature and the variable treatment regimens which were tailored to patients according to social, geographic, and oncological factors. As our cohort consisted of elderly and comorbid patients, we often limited their required visits to hospital which is reflected in the short follow-up intervals.

    There are a growing number of options for the treatment of unresectable in-transit disease and choice depends on many factors including availability of treatment, patient suitability, and disease factors. Intralesional PV-10 compares favorably in that it is well tolerated especially in an elderly patient or one with significant comorbidities.

    May 25, 2016

    Checkpoint Inhibition Differentiation or Death: Proprietary Combinations with Protectable Agents

    Updated below.

    From this project's Twitter feed: Dr. Sally Church, PhD, ‏@MaverickNY
    Click to enlarge. Tweet image source
    How would Big Pharma distinguish each of its immune checkpoint inhibitors (CIs) from another? Efficacy? Tolerability? Cancer indication? Cost? Within groups (e.g., PD-1s, PD-L1s, etc.), efficacy and safety should equivalent. Different antibodies — for example, with the PD-1s, like nivolumab/Opdivo and pembrolizumab/Keytruda — function in almost identical fashion and differ only by means of manufacture and corporate decisions made with regards to clinical development (e.g., dose schedule, target indication). Magically, there is parity in pricing.

    Based on drug sales to date and sales projections thus far, captured in part by @grhyasen's tweet graphic above, Bristol-Myers (nivolumab/Opdivo) and Merck & Co. (pembrolizumab/Keytruda) may be in no serious rush to differentiate their CIs beyond their current, respective corporate strategies. But Roche (atezolizumab/Tecentriq), AstraZeneca (durvalumab) and Merck KGaA/Pfizer (avelumab), all with "late to market" CIs, surely must be thinking about ways to differentiate their respective compounds.

    Does meaningful, sustainable and profitable differentiation come in the form of combination, and thus in the form of a partner compound for a CI? In other words, could combination create branded differentiation — ultimately based on efficacy, tolerability, indication and cost of the combination. Proprietary combinations with protectable agents.

    Novartis, one Big Pharma without a "lead CI" but having PD-1, TIM-3, LAG-3 and PD-L1 CIs within its pipeline, seems to have begun its brand differentiation by expanding its strategic thinking to include or focus on first-in-class combinations. See Pharmaceuticals and Oncology Business Units, Meet Novartis Management, May 24-25, 2016:
    Click to enlarge. Fuzzy orange rectangle is mine
    Click to enlarge. Fuzzy orange rectangle is mine
    PV-10's, and thus Provectus', value proposition to the likes of Roche, AstraZeneca, Merck KGaA, Novartis, etc. might be to (a) combine their CI with PV-10 and (b) use Provectus' combo patent* to defend the unique combination thus formed — a proprietary combination with a protected agent.

    * United States Patent No. 9,107,887, Eagle et al., August 18, 2015, Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer

    Updated (6/11/16): Deena Beasley, Reuters, June 11th, Regulator says too many drugmakers chasing same cancer strategy:
    "A new type of cancer drug that takes the brakes off the body's immune system has given drugmakers some remarkable wins against the deadly disease, but a top U.S. regulator says too many companies are focused on the same approach. 
    Dr. Richard Pazdur, head of the Food and Drug Administration's office of oncology products, was referring to therapies designed to disable the PD-1 protein that tumors use to evade the immune system...  
    "People should ask themselves ... would we be better off spending those resources into looking at more novel drugs?" Pazdur told Reuters during the annual American Society of Clinical Oncology (ASCO) meeting in Chicago this week.... 
    "As with everything in drug development, it is about reduction of risk," he said. But the number of similar drugs in development at the same time is a first in the oncology field, and latecomers to the PD-1 market will likely be relegated to "niche" indications, he added. 
    Drug company executives disputed Pazdur's critique. In interviews with Reuters, they argued that the science around cancer is advancing rapidly, with a focus on how to best combine therapies to attack multiple mechanisms of the disease, determine which patients are most likely to respond to them and how long patients will need to be treated."
    Blumenthal and Pazdur, Response Rate as an Approval End Point in OncologyJAMA Oncol. 2016;2(6):780-781.
    "Overall response rate (ORR) as a surrogate end point in oncology drug approval has a long history. In the 1970s, the US Food and Drug Administration (FDA) usually approved drugs on the basis of ORR. In the 1980s, after discussions with the Oncologic Drug Advisory Committee, the FDA determined that cancer drug approval should be based on more direct evidence of clinical benefit, such as improvements in overall survival (OS), tumor-related symptoms, or physical function.1 In the past decade, due to an improved understanding of the genomic underpinnings of cancer, better molecular characterization of tumors, and more precisely targeted agents, unprecedented rates of response have radically altered the therapeutic landscape in a number of malignant neoplasms. Therefore, ORR and duration of response as assessed in single-arm trials has served as the basis of accelerated approval and at times regular approval in a number of refractory malignant neoplasms, including non–small-cell lung cancer (NSCLC), lymphoma, melanoma, and myeloma."
    This presumably works [very well] only for systemic drugs using standard RECIST. Provectus' pivotal melanoma Phase 3 is employing [standard] RECIST 1.1.

    Road tripping:
    My proxy vote should be posted by June 14th.

    May 21, 2016

    Could PV-10 (Rose Bengal) be implicated in different kinds of cell death?

    Image source
    Reference article: Garg et al., Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translationCell Death and Differentiation (2016) 23, 938–951.

    N.B. There is no reference to Rose Bengal (generic name) or PV-10 (proprietary name) in the February 2015 Garg et al. article.
    Article Abstract: Phagocytosis of dying cells is a major homeostatic process that represents the final stage of cell death in a tissue context. Under basal conditions, in a diseased tissue (such as cancer) or after treatment with cytotoxic therapies (such as anticancer therapies), phagocytosis has a major role in avoiding toxic accumulation of cellular corpses. Recognition and phagocytosis of dying cancer cells dictate the eventual immunological consequences (i.e., tolerogenic, inflammatory or immunogenic) depending on a series of factors, including the type of ‘eat me’ signals. Homeostatic clearance of dying cancer cells (i.e., tolerogenic phagocytosis) tends to facilitate pro-tumorigenic processes and actively suppress antitumour immunity. Conversely, cancer cells killed by immunogenic anticancer therapies may stimulate non-homeostatic clearance by antigen-presenting cells and drive cancer antigen-directed immunity. On the other hand, (a general) inflammatory clearance of dying cancer cells could have pro-tumorigenic or antitumorigenic consequences depending on the context. Interestingly, the immunosuppressive consequences that accompany tolerogenic phagocytosis can be reversed through immune-checkpoint therapies. In the present review, we discuss the pivotal role of phagocytosis in regulating responses to anticancer therapy. We give particular attention to the role of phagocytosis following treatment with immunogenic or immune-checkpoint therapies, the clinical prognostic and predictive significance of phagocytic signals for cancer patients and the therapeutic strategies that can be employed for direct targeting of phagocytic determinants.
    Provectus says PV-10/Rose Bengal:
    • Does not rely on a single pathway to work [I assume 'signalling pathway'],
    • Does not focus on a single receptor to work [I assume 'cell receptor'], and
    • Has no known resistance [I assume little no cancer drug resistance].
    A highly specific compound in its targeting of only diseased (cancerous) tumors/lesions, tissue and cells, sparing healthy ones in the process, might the veracity of PV-10/Rose Bengal's "multiplicity" be based in its lack of "specificity" in regards to cell death?

    That is, might Provectus' investigational compound's apparent implication in different kinds of cell death help explain why PV-10/Rose Bengal does not rely on a single pathway or focus on a single receptor to work, and has no known resistance?

    Of note in Garg et al.'s article are (a) a table describing "major cell death pathways and their immunobiological" profiles and (b) a figure illustrating "therapeutic exploitation of phagocytosis of dying cancer cells for T-cell-mediated cancer cell elimination."

    The table of major cell death pathways includes (i) apoptosis, (ii) autophagy (autophagic cell death) and (iii) immunogenic cell death.
    Click to enlarge. Image source
    The illustration appears to draw three paths to anti-tumor immunity; one that is direct (e.g., DAMPs like HMGB1), and two that additionally employ co-stimulatory signals such as TLR agonists or co-inhibitory signals such as immune checkpoint therapy.
    Click to enlarge. Image source
    A sampling of Provectus and independent medical researcher work implicates PV-10 in apoptosis, autophagy, necrosis, and immunogenic cell death:
    Garg et al. observe "The mechanisms of cancer cell death elicited by anticancer therapy and the type of phagocytes (e.g., tumour-resident versus therapy-recruited) interacting with dying cells are decisive factors in making a difference between anti-inflammatory or pro-inflammatory responses."

    Some cell death via PV-10 occurs in the injected lesion or tumor (i.e., tumor-resident), which is the upstream trigger of subsequent cell death via a tumor-specific immune response (i.e., therapy-recruited).