January 18, 2015

Dr. Weber

An interview of Moffitt Cancer Center's Dr. Jeffrey Weber, M.D., Ph.D. by OncLive's Andrew Roth, Expert Discusses Integration of PD-1 Inhibitors Into Clinical Practice, was published last week. I found several of Weber's answers to Roth's questions separately notable by themselves and germane to PV-10 (when viewed in the context of his involvement with the drug).

Dr. Weber's public positions on intralesional therapies and PV-10 are interesting, as has been his work with Provectus' drug when one considers his other clinical work. I have not been able to find disclosure statements for him that included Provectus—if you find any, let me know. Into November 2014 sample Weber disclosures included:
Click to enlarge. ESMO 2014-related (i.e., September)

Click to enlarge. November 6, 2014
Moffitt and Dr. Weber's work with PD-1s pembrolizumab and nivolumab are:
  • Moffitt Cancer Center Plays Pivotal Role in FDA Approval of New Anti-PD-1 Inhibitor Keytruda for Metastatic Melanoma (Moffitt press release, September 2014): "Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at Moffitt Cancer Center, was one of the lead investigators of the PD-1 clinical trial which led to the drug receiving breakthrough status from the FDA. “Pembrolizumab is the first PD-1 drug to be approved by the FDA, and it is a clearly effective drug that will prolong survival for many patients with metastatic melanoma.  This approval is a real advance, and a major milestone in the treatment of the disease,” Weber said."
  • Bristol-Myers Squibb Receives Accelerated Approval of Opdivo (nivolumab) from the U.S. Food and Drug Administration (Bristol-Myers press release, December 2014): "“The approval of Opdivo gives patients and physicians an important new treatment option for a population where they were once very limited,” said Jeffrey S. Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center. “For the first time, a PD-1 blocking antibody has shown a response rate of 32% in a Phase 3 randomized clinical trial of patients with unresectable or metastatic melanoma, who have progressed following first line therapy.”"
Click to enlarge. Source link
Moffitt and Dr. Weber also have been involved in three other melanoma approvals, ipilimumab, vemurafenib, and the combination of dabrafenib and trametinib:
  • (2011) "Researchers at several NCI-designated cancer centers were lead investigators in the pivotal phase III clinical trial that ultimately led to FDA approval in March 2011of ipilimumab as a treatment for advanced melanoma. These researchers included Dr. F. Stephen Hodi Exit Disclaimer of the Dana-Farber/Harvard Cancer Center, Dr. Jeffrey A. Sosman Exit Disclaimer of the Vanderbilt-Ingram Cancer Center, Dr. Jedd D. Wolchok Exit Disclaimer of the Memorial Sloan-Kettering Cancer Center, and Dr. Jeffrey S. Weber Exit Disclaimer of the Moffitt Cancer Center and Research Institute."
  • FDA Approves Personalized Medicine Drug For Melanoma (Moffitt press release, August 2011): From Moffitt's website, "Jeffrey S. Weber, M.D., Ph.D., and others at Moffitt contributed significantly to the approval and testing of the melanoma drug Vemurafenib, including important laboratory work in developing an inhibitor to overcome resistance to the drug that has led to improved outcomes."
  • Moffitt Cancer Center Instrumental in FDA Approval of Revolutionary Two-Drug Combo to Treat Advanced Melanoma (Moffitt press release, January 2014): "“Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease,” said Jeffrey S. Weber, M.D., Ph.D., director of Moffitt’s Melanoma Research Center of Excellence. “This new combination therapy is a huge step in the right direction for the treatment of melanoma, and our researchers played a large role in bringing this treatment option to patients.”"
Of seven drugs the FDA has approved for melanoma since 2011, according to Moffitt and Dr. Weber, they have been instrumental or significantly participated in six approvals.

To date Dr. Weber has publicly associated himself (so to speak) with PV-10 two times, both around ASCO 2014 (June).
To add context to the above, however, he:
  • Does not believe intralesional ("IL") therapies have a singular role in treating late-stage melanoma with heavy tumor burden and spread of the disease to visceral organs. See Debating Systemic Intralesional Therapies (April 16, 2014) on the blog's Archived News I, and
In the moment, as it relates to Provectus' upcoming pivotal Phase 3 trial for locally cutaneous advanced melanoma, the company has an initial pathway to licensure. When they finally start their trial, management finally would have advanced their drug candidate to the final clinical stage prior to approval (pending of course a positive outcome for the trial). A "fully FDA-approved" and fully operational Phase 3 protocol should be tantamount to a prospective drug label; that is, who to treat and how to treat them.

Returning to Dr. Weber's OncLive interview:
OncLive interview, Figure 1
Takeaway: He notes three approved drugs (ipi, pembro and nivo), and the IL agent (T-Vec) that has begun testing in combination with ipi and will be combined with pembro. Anti-CTLA-4 and PD-1 drugs do not sufficiently work singularly for late-stage patients. Combinations now are the order of the day for this patient population where drug permutations would be graded based on a combination of safety ("keep toxicity down") and efficacy ("boost the response rate). Combining two checkpoint inhibitors, or drugs that release the brakes of the immune system, does not make sense (you're further releasing the brake?) from safety, efficacy and cost perspectives. Combining a stimulatory agent (starting the engine) with an inhibitory one (i.e., a checkpoint blockade agent) makes more sense in order to garner a better grade.
OncLive interview, Figure 2
Takeaway: The role of chemotherapy is being diminished and presumably eventually eliminated as drugs are approved for different melanoma patient populations as safer and more effective alternatives to chemo. He notes three approved immunotherapies (ipi, pembro and nivo). IL-2, also an immunotherapy, was approved in 1998. If and when T-Vec is approved (for metastatic melanoma), it would be an alternative for certain patients. If and when PV-10 is approved (for locally advanced cutaneous melanoma), it would be an option for another segment of melanoma patients.
OncLive interview, Figure 3
Takeaway: I found this answer interesting because Provectus principal investigator and St. Luke's University Health Network medical oncologist Dr. Sanjiv Agarwala said at ECC 2013, "[d]iscussing the interest in the use of PV-10 by his surgical colleagues, Dr. Agarwala added other potential benefits of pre-surgical intralesional injection—turning unresectable lesions into resectable ones and stimulating the immune system to lower the odds of recurrence." Neoadjuvant therapy refers to treatment given prior to the primary one (i.e., in this context, surgery—turn an unresectable lesion into a resectable one so it may be removed with surgery or excision). PV-10 achieved a 71% objective response and 50% complete response in the subgroup of 28 patients from Provectus' melanoma Phase 2 trial who received PV-10 into all existing melanoma lesions (i.e., no un-injected lesions).
OncLive interview, Figure 4
Takeaway: I don't believe Moffitt has commented on progress it may have made in determining a biomarker for PV-10. At this year's J.P. Morgan Health Care Conference, Roche's Chief Financial Officer Dr. Alan Hippe, Ph.D. said 70% of the company's projects in development have a biomarker hypothesis, which underscores Roche's deal with Foundation Medicine. Provectus's upcoming pivotal Phase 3 trial would include patients with "indolent, low-burden, low bulk with normal LDH."

Should Dr. Weber lend his voice—appropriately and in context—to the process of approving PV-10, his could be an important one to the FDA, and one that could help frame the drug's initial and potential eventual roles in treating advanced melanoma in particular and melanoma in general.

January 9, 2015


Image source
I found the following while monitoring my curated Twitter feed for this project (h/t Tom Silver, ‏@TomSilver39):
"Does anyone have early access to inside information?  There is another way that CytRx’s clinical results are made available to big pharmaceutical companies, and that is CytRx’s “black box” website. This website is designed to provide big pharma with inside information, with the objective of interesting them in possible partnerships, which can enhance shareholder value by providing cash to accelerate and/or expand the pipeline without selling more shares.  Big pharma companies who wish to monitor research results as they occur, can sign a nondisclosure agreement, and are then granted access to this restricted site. There, they can view results at almost the same time that CytRx receives them from the clinical testing centers.  Now, if it is a double-blind study, they will still not know which patients received Aldox, and which received the control drug(s) or placebo. Still, it is not difficult to calculate the therapeutic benefit of Aldox, using known historical data on the control drug, and the ratio by which patients are assigned to each arm of the trial. For example, suppose that Aldox is being compared to Dox, and every 3 patients are randomly assigned in a 2:1 ratio Aldox:Dox. If Dox gives a progression-free survival of 10 months, and the average PFS for all of the patients is 20 months, we can calculate that the PFS for Aldox is 25 months because (25 + 25 + 10) /3 = 20." Source link: CytRx Corporation Overlooked News {Bold emphasis is mine}
There are two topics here. First, there is subject of collecting clinical trial data in real-time, which should come as no surprise to anyone (given the advent of information technology now on its umpteenth wave of progress). It also goes without saying that if you can collect data in real-time, or as clinical sites send these data in, you also can analyze and share it. A sample paper on the topic: Harnessing technology to improve clinical trials: study of real-time informatics to collect data, toxicities, image response assessments, and patient-reported outcomes in a phase II clinical trial, Pietanza et al., J Clin Oncol. 2013 Jun 1;31(16):2004-9. doi: 10.1200/JCO.2012.45.8117. Epub 2013 Apr 29.

Second, there is the subject of sharing the data with third parties. See Pharma Compliance Monitor's December 29, 2014 blog post entitled Clinical Trial Data Sharing: Landscape, Trends, and Risks by Robin Jenkins of Sanofi U.S. and Joe Morrell of Huron Life Sciences:
"The potential benefit of sharing clinical trial data (patient-level data and clinical documentation) has been recognized by various industry groups over the past several years, but the reality of sharing data is emerging...[D]ata sharing initiatives can be categorized into three fairly broad data sharing models[1]; Black Box, Gatekeeper, and Open Access."
[1] refers to Mello, JD, PhD, Michelle, “Potential Models for Data Sharing.” Issues and Case Studies in Clinical Trial Data Sharing: Lessons and Solutions; Cambridge, MA, May 17, 2013. The slides below better inform on the black box reference above in the CytRx blog post, which is the name of one of several models of data sharing noted above in the Pharma Compliance Monitor blog post.
Click to enlarge.
Click to enlarge.
Click to enlarge.
The conference above speaks to a much larger topic about leveraging data sharing to accelerate biopharmaceuticals development.
Click to enlarge.
My blog post is more focused on what I learned:
  • That all companies running any clinical trial and certain pre-clinical ones can share data with third parties,
  • That to gain access to such data, the parties would have to enter into non-disclosure agreements ("NDAs"),
  • That software platforms and packages exist to facilitate sharing. INC Research has such a product, and other large global contract research organizations ("CROs") have proprietary ones as well,
  • That Big Pharma do enter into NDAs with companies when the former are interested in one of latter's trials, and
  • That providing data access to certain melanoma advocacy groups might assist in the effort to bring more visibility to the Stage 3 melanoma patient (progress is gained for constituents when the oncology community is better educated and good public policy is facilitated).
Let's say, merely for the sake of argument of course, that you're Pfizer (or any interested Big Pharma), and you want to look at data generated from Provectus's upcoming pivotal Phase 3 trial for locally advanced cutaneous melanoma. Let's assume:
  • The above mentioned process for clinical trial data sharing with third parties is real, appropriate and indeed happens, etc.,
  • You sign an NDA with Provectus, and
  • Progression-free survival ("PFS") for systemic chemotherapy (dacarbazine or DTIC) is [2-]3 months.
If DTIC gives a progression-free survival of 3 months, and the average PFS for all of the patients is 9 months, we can calculate that the PFS for PV-10 is 12 months because (12 + 12 + 3) /3 = 9. [Randomization is 2-to-1]

Let me frame the analysis another way, using the knowledge gleaned by Eric and Provectus from the compassionate use program ("CUP") and sub-set of the metastatic melanoma Phase 2 trial patients who had all of their disease treated: hit the injectable disease early, often and repetitively until is goes away (i.e., a complete response, or partial response until the complete response is achieved). This approach could (would) suggest a PFS of 1.0 for the pool of suitably treated PV-10 patients (i.e., the PV-10 arm of the upcoming pivotal trial). Let's now assume you re-use the assumption above that the PFS for systemic chemotherapy is 3 months (i.e., the pivotal trial's control arm). A graph of months after treatment vs. PFS in months might look like this:
Click to enlarge.
A graph of months after treatment vs. PFS (as a % or fraction of 1) might look like this:
Click to enlarge.
None of the above graphs are dependent on N, the total number of patients treated at a given point in time. Real-time data collection, or data collection as clinical trial sites provide the data to the CRO running the trial and, thus, the data sharing software sharing package, would simply yield lines, graphs and trends that would change over time as N changes (increases) and the results of treatment on each N changes.

Different thresholds of N would have different meanings for statistical significance and relevance. N-1 might be the number of patients for the divergence of the PV-10 (blue above) and chemo (red above) arms to reach statistical significance. N-2 might be the number of patients for the trial to reach its assigned hazard ratio. N-3 might be the number of patients/responses to trigger the interim analysis.

A Big Pharma with a basic-to-good understanding of PV-10 (e.g., pre-clinical data, prior clinical data, mechanism of action, mechanism of immune response, intralesional therapies, etc.) that also had signed an NDA to access some level of pivotal trial data would observe the trends of the trial's data—positive or negative—before or as the different N thresholds are reached and/or passed.

Then what?

January 4, 2015

The Emergence of PV-10, and Provectus Biopharmaceuticals

Sayaka Ganz, Reclaimed Creations, Silence
In several respects 2014 saw the emergence of Provectus Biopharmaceuticals, much as I as a long-time shareholder would have thought this development could have begun earlier, say in the 2010-2011 time period.

Nevertheless, PV-10's recent emergence reflects growing awareness of the drug—with the FDA, Big Pharma, key opinion leaders ("KOLs") and members of the medical community at large—and the role of dual mechanisms (one ablative, the other immunological) in the approaches to and outcomes of treating cancer, especially given the backdrop of cancer immunotherapy (or "immuno-oncology").

Figure 1
Of course the story is not just about the drug. It's also about the management team and publicly traded company and, thus, the stock and share price. PVCT's' historical performance (see Figure 1) remains the single most contrary point to arguing for the emergence of PV-10 and Provectus, and ostensibly challenges recognition of positive identifiers of progress last year.

The larger argument for the other side of the Provectus trade is that the market is always right ("...any one person can be wrong about the market—indeed, everyone can be—but the market as a whole is always right"). The efficient-market hypothesis ("EMH") "...asserts that financial markets are 'informationally efficient'" (Quote sources: Efficient-market hypothesis, Wikipedia). The price is what it is because the stock, company and drug are what they are, and the share price reflects it.

The larger argument against the argument of the other side of the trade is, "...it is hard to reject the claim that prices are right unless you have a theory of how prices are supposed to behave," which is a quote from an August 2009 article by Richard Thaler in The Financial Times entitled Markets can be wrong and the price is not always right. He also wrote:
"For many years the EMH was “taken as a fact of life” by economists, as Michael Jensen, a Harvard professor, put it, but the evidence for the price is right component was always hard to assess. Some economists took the fact that prices were unpredictable to infer that prices were in fact “right”. However, as early as 1984 Robert Shiller, the economist, correctly and boldly called this “one of the most remarkable errors in the history of economic thought”. The reason this is an error is that prices can be unpredictable and still wrong; the difference between the random walk fluctuations of correct asset prices and the unpredictable wanderings of a drunk are not discernable."
The above is a convenient way of rationalizing my very positive beliefs about the drug and its potential addressable market, positive views of the company and its management team, and extremely upbeat prospects of its stock with the current share price. It's sort of like saying, "I'm right because you can't prove I'm wrong, until I am [right] or you can [prove me wrong]."

When the "other side of the trade" arguers argue the argument in more detail—I have tried to actively curate the other sides since inception of my diligence on Provectus, PV-10 and management, and continue to do so—the intellectual honesty of their veracity ultimately dissolves into fragments I certainly acknowledge. Arguments for PV-10's irrelevance include:
  • The current generation of approved checkpoint blockade therapies (i.e., Merck's pembrolizumab or Keytruda, and Bristol-Myers' nivolumab or Opdivo) will make PV-10 obsolete,
  • Amgen's Talimogene laherparepvec ("T-Vec") is a better intralesional agent than PV-10, or
  • Next generation CAR T cell ("Chimeric Antigen Receptor T cell") companies (i.e., Bluebird Bio, Juno, Kite) will make PD-1s obsolete, which should make PV-10 doubly or squaredly obsolete.
Rather than use PV-10 to talk down these drugs and companies, there are more general counterpoints:
  • While PD-1s clearly have utility, are viable options for cancer patients, and backed by Big Pharma, they are limited (tumor immunogenicity is providing more knowledge about what does and does not work, and where and when it does) and expensive (on both absolute and relative [cost per unit success] bases). The FDA's approval letters for Keytrua and Opdivo (here and here, respectively) are not commensurate with the "excitement" for PD-1s.
  • T-Vec's success and Amgen's marketing muscle ("oncolytic immunotherapy") should help build the category of intralesional cancer agents. Any and all T-Vec success (i.e., approval as a monotherapy, clinical trials and data from combination with checkpoint blockades) is good for PV-10. An oncolytic virus engineered from herpes simplex 1 that is far from simple to store, handle, and use and reuse, however, does not sound like the ideal intralesional agent.
  • CAR T cell companies' multi-billion market capitalizations should be considered in the context of preliminary clinical results, likely high treatment price tags, likely product gross margins that probably will be comparable to if not less than Dendreon's Provenge, more articles about their offerings in the lay press than in scientific literature, and a focus only on T cells (what about NK cells, among other things?).
So, if PV-10 and Provectus management both are bad, well, then we're dealing with that intellectual honesty thingie. If the drug is bad, has no merit or lacks opportunity, it's reasonable to such a position ignores available data and commentary that, while not overly conclusive in some quarters, at the very least speaks to a greater medical and thus financial opportunity than the share price currently reflects. If the drug is good, has merit or presents opportunity but Provectus management is lacking, I would not disagree. They have strengths, weaknesses and blindspots. You may recall my comments about them in my September 2013 investment letter Why I'm Long Provectus Pharmaceuticals):
"Management historically has relied on the input of a stable of high and low quality advisors and consultants in its decision-making, making many good and several questionable decisions and choices along the way. Provectus has eschewed playing Wall Street's game for the most part, and has suffered to some degree because of it. Some company wounds, non-fatal as they are, however, have been self-inflicted. Management possesses a sufficient threshold level of competence and integrity to warrant my support, and seeks to sufficiently protect the economics of Provectus's innovation for shareholders to warrant my continued holding of Company stock."
Until recently, few could dispute management's overall lack of success in properly managing the FDA. Credible people now are entirely focused on the data and clinical development details, and on management's execution and generation of them. Wall Street promotes what it can sell. Provectus has been a difficult promotion for the Street for several reasons, some substantive, some superficial, but none fatal, and thus PVCT has not been sold. Wall Street's interest in the company should change as the immense opportunity of the drug and for the company more fully emerges in 2015. Both sides of the trade also could agree that no one of relevance and substance—neither the FDA, nor Big Pharma nor KOLs—truly spoke up meaningfully about the drug (in word or by action) until 2014.

Entering 2015 I believe my investment thesis not only remains intact, but has grown stronger (below, from my September 2013 investment letter):
"PV-10, a novel oncology compound being developed by Knoxville, Tennessee-based Provectus Biopharmaceuticals, Inc., exemplifies innovation over incrementalism, meaningful over marginal, productized technology over hypothetical, and changing the world over accepting the status quo, with not an insignificant amount of serendipity over contrivance. In sum, these form the quintessential essence of a paradigm shift in the treatment of cancer. 
This is where my investment thesis begins and ends: a novel drug compound with a pristine safety profile, a treatment well tolerated by and easily administered to patients, a readymade product inexpensively produced at scale, and a vast addressable market of unmet need that should be fully and very profitably met over time. 
My thesis comprises compelling clinical, regulatory, business and stock value propositions in a pharmaceutical industry ravenous for safe and effective oncology solutions, with the prospect of annual market growth rates exceeding other therapeutic areas, that following approval(s) should deliver a lucrative monetization for shareholders." {Bold emphasis is mine.}
One simple way to assess emergence merely could be to measure the growth of PV-10's digital awareness over time, in this case by counting visitation to and readership of this blog. See Figures 2 and 3 below.
Figure 2
Figure 3
(Average session duration is measured in seconds.)
Another way to consider emergence would be to assess view points and behavior of key constituencies over time: the regulator, the immune system, KOLs and Big Pharma. See Figure 4 below.
Figure 4, click to enlarge
The Regulator (The FDA): The company seemed be mired in its regulatory trek in 2012, with no agreement with the FDA on indication and patient population, nor clinical trial endpoints. See, for example, Provectus' May 23, 2014 conference call transcript, which in hindsight helped explain Eric's cryptic "oncology presents a moving playing field" comment from the May 2013 annual CEO letter. In 2013, the company seemed to reach an important mile marker towards the end of the year with its December Type C FDA meeting, which established locally advanced cutaneous melanoma as PV-10's initial path to licensure. In 2014 the May BTD denial letter revealed key Agency acknowledgements as well as the need for more data:
"We have reviewed your request and while we have determined that treatment of “locally advanced cutaneous melanoma” meets the criteria for a serious or life-threatening disease or condition, the preliminary clinical evidence you submitted does not indicate that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. Therefore, designation as a Breakthrough Therapy cannot be granted at this time. 
The preliminary clinical data provided in your request for Breakthrough Therapy designation are indicative of drug activity in the treatment of local, satellite or in-transit recurrence of malignant melanoma; however, the preliminary clinical data do not demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. This determination is based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding) and our inability to determine the clinical significance of the reduction in the size in one to 10 target lesions in patients with locally advanced melanoma, who may have additional untreated cutaneous, subcutaneous, or visceral sites of disease." {Bold emphasis is mine.}
The FDA then announced in October the opportunity for public comment related to the Agency's patient-focused drug development initiative that nominated "Melanoma, specifically unresectable loco-regional disease" to the preliminary list of candidates. In December the Phase 3 trial was accepted by the FDA.

The Immune System (Immuno-Oncology): In 2012 Moffitt Cancer Center began publishing their pre-clinical work on PV-10 that revealed the production of tumor-specific interferon gamma (IFN-γ). In 2013 this work expanded to show T cells played a critical role. In 2014 the cancer center began publishing their clinical work that discerned the involvement of different T cell populations (e.g., CD3+, CD4+ and CD8+), including NK T cells.

Key Opinion Leaders (Moffitt Cancer Center): While Moffitt started their work on PV-10 in 2011, 2013 provided a quizzical press release, quizzical because there has been no comparable public follow-up: Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows. In 2014 Moffitt opined further and nearly as boldly. Dr. Jeffrey Weber, M.D., Ph.D. saying PV-10 might offer the perfect way to prime the immune system (at ASCO). Dr. Vernon Sondak, M.D. said [in a conference presentation] PV-10 was the ideal intralesional agent (at the 4th European Post-Chicago Melanoma Meeting).

Big Pharma (Pfizer)

In 2012 Provectus had one Pfizer executive on its strategic advisory board ("SAB"), who joined in 2011. By 2014 the company had three of them.

Image source

For Provectus' emergence in 2014 to more fully translate into a more reflective share price, there are clear milestones that clearly must be achieved:

1. Commence enrollment of the pivotal Phase 3 trial for locally advanced cutaneous melanoma.

2. Consummate a China regional transaction. If there is a China deal, there will be an Indian one.

3. File the Phase 1b/2 protocol for liver cancer. Enrollment should begin this year; however, a China transaction likely would be a condition precedent to a trial start.

4. File a Phase 1b/2 protocol for a combination therapy of PV-10 and a checkpoint blockade for advanced melanoma. If Pfizer's first touchpoint was its first SAB member, the second was the joint patent application for combination therapies involving PV-10, and the third and fourth were the second and third SAB members, then the fifth could be a co-development arrangement to combine Pfizer's PD-L1 agent with PV-10.

5. File a Phase 1b/2 protocol for triple negative breast cancer. Maybe...?

December 21, 2014

Let Me Tell You A Story About Pfizer

Provectus issued a press release and filed an associated 8-K this past week regarding the addition of a third Pfizer executive to its strategic advisory board ("SAB"), Deanna Angello, Director, Commercial Strategy and New Business Planning of Pfizer's Global Established Pharma business. As an aside, there are two other businesses in the reorganized company: Global Innovative Pharma and Global Vaccines, Oncology and Consumer Healthcare.

It would seem reasonable to say there Pfizer's interest in Provectus has existed since at least 2011 (and likely before, probably starting in 2010) and continues to exist, led by Pfizer's Dr. Craig Eagle, M.D. Eagle's last reported position at the firm was Vice President of Strategic Alliances and Partnerships for the Oncology unit. His professional background includes patient care (he was a hematologist-oncologist), and both managerial and participatory experiences in pharmaceutical research, drug development, regulatory affairs, pricing, reimbursement, and post-merger integration. Until I believe relatively recently, it hasn't included profit/loss ("P&L") experience.

Dr. Eagle also appears to be a forward-thinker about oncology, and the role and opportunity of the immune system to restrain, if not defeat, cancer. Consider, for example, a snippet of an Oncology Business Dynamics interview of Eagle following ASCO 2007:
"Oncology Business Dynamics: And the other investigational agent we seemed to hear a lot about was CP675,206. What’s new with this one? 
Craig Eagle: This is a very interesting compound which essentially releases the brakes on the immune system. CTLA-4 is a molecule which normally puts the brakes on the immune system and stops it from attacking tumors. CP-675,206 is an antibody which works on CTLA-4 and renders it inactive so that the immune system can attack the tumor. We presented results from a phase 2 study with 89 patients in which we saw survival times 10.3 to 11 months, which is longer than historical data. While this is preliminary data it was also encouraging enough that we are going to further our investment in the development of The CP-675,206 Phase 3 study in metastatic melanoma has completed enrollment and we are awaiting the data In this study CP-675,206 was used as a single agent administered once every three weeks." {Underlined emphasis is mine.}
CP-675,206 was Pfizer's initial label for its monoclonal antibody and immunotherapy tremelimumab, which is related to Bristol-Myers' approved immunotherapy ipilimumab (trade name Yervoy). Pfizer out-licensed tremelimumab to AstranZeneca's MedImmune in 2011.

Eagle's longstanding interest in PV-10 is a second example; a local drug that is very safe and kills cancer locally, and has demonstrated the ability to systemically kill cancer. A third example would be his contribution to and involvement in Provectus' patent application Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer, which covers and protects the combination of PV-10 and other therapeutic agents, particularly all checkpoint blockade categories (i.e., anti-CTLA-4, anti-PD-1 and anti-PD-L1), and of which he is a co-author (Pfizer is a co-assignee). He probably saw much earlier than most the eventual trend of the FDA and pharmaceutical industry towards the use of combinations of drugs to treat late-stage cancer.

His interest and, by extension, Pfizer's, however, has not translated into an increase in Provectus' share price. The stock price on the date of the first public Pfizer touchpoint, Eagle's addition as the first Pfizer executive on the SAB on August 30, 2011, was $0.92. The price on the date of the fourth public touchpoint, Angello's addition on December 17, 2014, was $0.88. The stock market has placed no premium on a Pfizer-Provectus relationship or association.

The historical touch points between Pfizer and Provectus, starting in 2011 -- three Pfizer executives on Provectus' SAB, and the companies as co-assignees of a combination therapy patent application that includes the pairing of PV-10 and different categories of checkpoint inhibitors -- might encourage one to ask: "Given Pfizer's interest in Provectus, why hasn't it invested in and/or acquired the company yet?"

One answer, it would seem, is not for lack of "trying." I believe Pfizer (Eagle) has tried three times. For two of those times, Provectus management would not have found the valuation proposition sufficiently compelling and thus worthwhile to pursue. In the third instance, Craig et al. likely concurred with valuation but fell short in their efforts to reciprocate Pfizer's interest to formalize the relationship/association.

Transactions, whether venture capital, private equity or portfolio management, typically stem from an underlying value proposition and, more often than not, require a catalyst. PV-10's clinical value proposition, together with the drug's ease of administration and low cost to manufacture, ship and store, is both very clear and attractive. See, for example, my blog post PV-10 (Rose Bengal) Clinical Value Proposition. The historical record of fact and "fiction" paints a picture of potential catalysts that may have provided context for either an acquisition of Provectus or an equity investment in the company by Pfizer. The facts are the addition of three Pfizer executives to Provectus' SAB, and the joint oncology combination therapy patent application the two companies made. The "fiction" includes:
  • A rumored 2011 bid for the company for the same $1 billion valuation as and around the same time when Amgen acquired Boston (Woburn), Massachusetts-based, privately held, intralesional oncology company Biovex,
  • A rumored equity investment that may have led or co-led Provectus' preferred stock "IPO (using the NASDAQ ticker symbol PVCTP) in 2012, which was to have been predicated on or catalyzed by a special protocol assessment ("SPA") for a melanoma Phase 3 trial. The "IPO" might have been contemplated at a $1 billion pre-money valuation that, while yielding a minority ownership in Provectus for Pfizer, could have provide the impetus and opportunity for Provectus to grow its market capitalization much higher, and
  • The rumored 2014 bid for the company for a valuation of more than $2 billion prior to the company's submission of its breakthrough therapy application ("BTD").

Provectus presented preliminary, full, melanoma Phase 2 results at the Society for Melanoma Research's Melanoma 2010 Congress (see Provectus' press release Provectus Reports Full Phase 2 Study Data on PV-10 for Metastatic Melanoma). Prior to that, competing intralesional oncology therapy company Biovex, venture-backed and Boston-based, began enrolling patients in its pivotal melanoma Phase 3 trial for OncoVEX GM-CSF in 2009 (the press release is here, and clinical trial information is here). In 2011 Amgen acquired BioVex for a top-line amount of $1 billion, and renamed the drug talimogene laherparepvec ("T-Vec").

Without reference to a specific timeframe but sometime in 2011 it is possible Dr. Eagle had a casual conversation with Provectus about their interest to be acquired. He may have understood PV-10's value proposition, and Amgen's acquisition of BioVex could have been a direct or indirect catalyst. In M&A parlance the acquisition would have been a precedent transaction used to provide a datapoint establishing price. Provectus management, believing they knew what PV-10 and thus the company were worth, then may have rebuffed Eagle's informal overture.

Given his work with tremelimumab, his interest in PV-10 and its potential in combination with other drugs, and/or possibly a positive opinion of Provectus' early-stage trial effectiveness and capital efficiency, all underscoring a desire to continue working with the company if he could not acquire them, it is possible Eagle tried to out-license Pfizer's anti-CTLA-4 agent to Provectus.

Eagle joined the SAB in August 2011. Pfizer out-licensed tremelimumab to MedImmune (AstraZeneca) in October.
Figure 1. Click to enlarge.

It has been said biotechnology companies typically are acquired when they are in Phase 3 trials. BioVex was acquired by Amgen after beginning its pivotal melanoma Phase 3 trial for intralesional oncology agent T-Vec (formerly OncoVEX) but before an interim analysis was read out.

In 2011 Provectus seemed like it would commence a pivotal melanoma Phase 3 trial. The company had held a meeting with the FDA in October 2011. In January 2012 management issued press release Provectus Receives Guidance From FDA On Pathway to Approval for Phase 3 Trial of PV-10 For Metastatic Melanoma noting they would seek an SPA for the trial. In July Peter filed a $100 million mixed securities shelf of both common and preferred stock; he filed the prospectus for the "IPO," an offering of preferred shares with warrants, in September (the related SEC filings are here and here, respectively). The fundraising round was to have totaled $30 million, if I recall properly, with a "fictional" pre-money valuation of somewhere around or between $800 million and $1 billion.

The situation made sense. While Provectus management may not have been willing to sell the company (i.e., give up all ownership) for a BioVex-like amount of a $1 billion, they might have been prepared to give up a percentage to Pfizer and the round's other investors to cement a relationship with the Big Pharma company. In return, however, Pfizer likely would have required Provectus to be on a firm pathway towards the commencement of a Phase 3 trial. Unfortunately, as we finally learned on the company's May 23rd conference call in the wake of the FDA's denial of Provectus' BTD application, Eric had been unable to agree upon a trial design (endpoints and patient population) with the Agency. There ended up being no investment by Pfizer because there ended up being no catalyst (i.e., no Phase 3 trial design, no Phase 3 trial).

The "IPO" was cancelled in October 2012 amid monstrous volatility in the share price.
Figure 2. Click to enlarge.

Finally, during Provectus' December 16, 2013 Type C meeting with the FDA, Provectus appeared to establish its initial pathway to the licensure of PV-10 with the Agency. See, for example, January 2014 press release Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes, which was locally advanced cutaneous melanoma. The day after the meeting the company issued press release Provectus Announces Name Change to Provectus Biopharmaceuticals, Inc. and Reincorporates in Delaware in which they seemingly buried the addition of the second Pfizer executive to Provectus' SAB, Bob Miglani. Miglani appeared to have substantive international pharmaceutical business experience, and a corporate functional role (as opposed to Dr. Eagle's operational and oncology-focused role). In the same January press release above management noted they also would apply for BTD.

Sometime before Provectus submitted its BTD application it is possible Dr. Eagle had a casual conversation with Provectus about their interest to be acquired this time for $2 billion or thereabouts. He may have been more comfortable with PV-10's regulatory pathway -- albeit not completely certain about it -- and the company's BTD application could have been a direct catalyst (a successful application would have made Provectus much more expensive to buy in his mind). Provectus management, believing PV-10 and the company were worth more, would have rebuffed Eagle's second presumably informal overture.

Provectus' BTD application was denied in May 2014.
Figure 3. Click to enlarge.
2014 And Beyond

In early-November 2014 Moffitt Cancer Center presented preclinical combination therapy work at SITC 2014. Around mid-November Pfizer seemingly jumped into the middle of the immuno-oncology pool with their own anti-PD-1 agent in one hand and Merck KGaA's anti-PD-L1 agent in the other. According to the immediately linked Pfizer press release, Albert Bourla, Group President of Pfizer's [Global] Vaccines, Oncology and Consumer Healthcare business said "Immuno-oncology is a top priority for Pfizer."

Last week, on December 17, Provectus issued press release Provectus Biopharmaceuticals To Sponsor American Association of Physicians of Indian Origin in which they seemingly buried, yet again, the addition of a third Pfizer executive to Provectus' SAB, Deanna Angello. Angello appears to have substantive commercial strategy experience, which notably includes "...formulating robust business cases, and performing due diligence to thoroughly assess the commercial value and fit of in-licensing and acquisition opportunities," and an operational role in Pfizer's Global Established Pharma business, which presumably is not where the bulk of the Big Pharma company's oncology assets lie. Wouldn't they reside in Global Vaccines, Oncology and Consumer Healthcare?

Returning to the concept that many biotechnology companies or assets are acquired or licensed during their respective Phase 3 trials, Provectus soon should announce the company will begin enrolling patients in its own pivotal melanoma Phase 3 trial. Interestingly, Pfizer, but more likely Dr. Eagle, has added a colleague with experience constructing and making the business case to license a therapeutic or buy the company that owns it. It would appear, however, Angello is in a different Pfizer business than Eagle. Wouldn't his visible title put him in Global Vaccines, Oncology and Consumer Healthcare?

I speculate Eagle currently is tied (or has moved) to Pfizer Injectables, which is part of the Global Established Pharma, because he probably needs to add P&L responsibility to his resume to further his career prospects at Pfizer. The division's portfolio of products includes oncologics (PV-10 is an injectable compound of course). Additionally, if someone is going to be tapped to assess the commercial value of the drug, why would he or she come from an ostensibly different Pfizer business. Eagle may be augmenting his professional background while at the same time maintaining his running start on trying to acquire Provectus for Pfizer.
Figure 4. Click to enlarge.
The answer to the question "Given Pfizer's interest in Provectus, why hasn't it invested in and/or acquired the company yet?," if you believe my "fiction," might be that the stars -- valuation and catalyst -- have not yet aligned for both Pfizer and Provectus. It would seem to me Eagle has a reasonably long-standing belief in how to more effectively treat cancer, and a long-standing interest and belief in Provectus and their treatment approach. Craig et al. are and have been focused on protecting the economics of their fully owned cancer asset, and have not been nor currently appear inclined to give the company away. It would also appear Pfizer (Eagle) has been prepared in the past to offer a very healthy premium to the then market capitalization of the company.

While it is not a foregone conclusion Pfizer will acquire Provectus, it would appear the Big Pharma company may be in the pole position (also see my July 2012 Pole Position post). The better question to ask Provectus management, and a key question existing and prospective investors in the company should pose to themselves, might be "Can Provectus get its price?"

December 8, 2014

PV-10 (Rose Bengal) Clinical Value Proposition

Updated 12/10/14: Bigger font (particularly for the footnotes)
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Original post below.
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December 1, 2014

November Blog Stats, and other bits and bobs

Bits and Bobs.
Blog readership mostly rose from October depending on the statistic. I wrote 22 blog posts (7) and news items (15) in November, versus 22 during the previous month (5 and 17, respectively). November month-over-month changes were:
  • +8% for the number of unique visitors (2,255 v. 2,085),
  • +4% for page views (18,851 v. 18,106),
  • +5% for visits (8,591 v. 8,173),
  • -10% for U.S. cities [from where visitors came] (584 v. 649),
  • -16% for world cities (137 v. 163), and
  • No change for countries (51 v. 51).
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 Roche's Genentech's Dr. Daniel Chen, M.D., Ph.D., PD-L1 Global Development Leader, noted in May 2014 that:
"One theory about immunotherapies is that they could work for everyone, with any type of cancer. The data to date show that this isn’t the case. Even though everyone has an immune system, not all patients will respond to the same medicine in the same way. 
Our immunotherapy program at Genentech has a large biomarker and diagnostic focus so we can find those who are most likely to experience a meaningful benefit. 
But what about those who do respond, but not well enough? 
Perhaps those people with a small to moderate response should be candidates for combination trials. Some immunotherapies may be more effective if they are combined with different types of medicines, including chemotherapies, personalized medicines and even other immunotherapies. 
In this way, biomarkers for cancer immunotherapy don’t just tell us who will or will not respond. Rather, they could help guide treatment strategies involving one or more medicines."
I recently asked Eric about this. He commented (paraphrasing):
Biomarker (i.e., targeted) therapies have proven quite successful in a number of cases, such as vemurafenib (trade name Zelboraf) and imatinib (trade name Gleevec). But these generally have limited time before escape* occurs since they target one or a few mutations, and cancer cells, which are generally highly adept at mutating, mutate to circumvent the therapy. 
Our understanding of immune targets relevant to cancer is still very primitive along with our ability to devise drugs specific to unique targets. Part of the problem is that "unique" targets are generally conserved**, just as molecular pathways are, in other kinds of cells and thus we get "off-target" effects (e.g., cholitis, secondary tumors, etc). 
Craig would say that PV-10 works by training our very sophisticated immune system to recognize complex patterns of targets that are expressed but sequestered by cancers. This is a bit like grabbing a very carefully selected handful of biomarkers and deploying them simultaneously.
* "Time before escape" is akin to survival time.
** "Conserved" means similar or identical.

 Peter updated Provectus' website to include information about the number and diversity of people and vendors working for the company. See About Us, Management, and scroll to the bottom of the page. It is a competent first step that provides some useful, basic insight into company operations.
Click to enlarge.
Of the 50 FTE figure in the bottom left hand corner, Eric's consultants and contract labor (see "consulting and contract labor" in Provectus' quarterly and annual SEC filings) comprise 36 FTEs (not including himself). The balance of 14 FTEs comprise Provectus' four principals and employees, and 10 FTEs that Peter characterizes as the full-time equivalents of the 134 people servicing and supporting his "corporate infrastructure."

 I recently asked Peter about the possible impact of a potential approval (i.e., a speculative PDUFA date of April 2015) of Amgen's intralesional oncology agent talimogene laherparepvec ("T-Vec") as a monotherapy for metastatic melanoma. He commented (paraphrasing):
People seem to like the idea of intralesional agents becoming appropriate to treat disease, and it is believed both T-Vec and PV-10 are helping to establish the relevancy of and build the intralesional agent category. People like having options as well, so two intralesional agents are better than one, in general. No matter what happens with T-Vec as a monotherapy, it is already believed T-Vec used in combination with ipilimumab is synergistic, and further builds the intralesional agent category.
 According to Neuroscience For Kids, the blood-brain barrier is semi-permeable, allowing some materials to cross, but preventing others from crossing. Further:
"More than 100 years ago it was discovered that if blue dye was injected into the bloodstream of an animal, that tissues of the whole body EXCEPT the brain and spinal cord would turn blue. To explain this, scientists thought that a "Blood-Brain-Barrier" (BBB) which prevents materials from the blood from entering the brain existed."
According to BrainFacts.org:
"The brain is the only organ known to have its own security system, a network of blood vessels that allows the entry of essential nutrients while blocking other substances. Unfortunately, this barrier is so effective at protecting against the passage of foreign substances that it often prevents life-saving drugs from being able to repair the injured or diseased brain."
Very small amounts of rose bengal cross the blood-brain barrier. See, for example, Table 3 of Klaassen's Pharmacokinetics of rose bengal in the rat, rabbit, dog and guinea pig (October 1976).
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Some patients in Provectus' melanoma Phase 2 trial had visceral disease, including brain metastases. How many patients with brain mets is unclear. Provectus has publicly discussed one such patient at medical conferences (Subject 0907 with Stage IV M1c disease), noting "“Near complete resolution” of pulmonary nodules observed at Week 12" during an ASCO 2010 clinical development update presentation.

If the brain is on the other side of the blood-brain barrier (and the immune system is on the other, so to speak), and PV-10 is injected into visible lesions on the skin, how were these brain tumors (nodules) positively impacted?

Blood Brain Barrier, Margaret Reece, Ph.D. (November 2013):
"The blood brain barrier is designed to exclude both pathogens and the cells of the immune system. It also excludes large proteins including immune system antibodies. It is only after viruses and bacteria are able to trigger a breakdown of the blood brain barrier that immune system responders gain entrance. And, when it occurs, it seldom turns out well."
The small amounts of rose bengal that may permeate the barrier are very unlikely to be able to reduce or destroy tumors, and the drug was not systemically administered (just injected into the skin at the location of a cutaneous or subcutaneous lesion). As Craig would say, Mother Nature's immune system knows how to get to brain tumors without destroying the normal brain tissue. But how?
"The brain has often been considered an immunologically privileged organ. This was based on early studies that found few antigen-presenting cells in the central nervous system. In addition, there was a perceived lack of a lymphatic system within the brain to carry immunogenic material in the central nervous system to lymph nodes where a humoral immune response could be initiated. And finally, the presence of the blood-brain barrier (BBB) was thought to prevent the entry of immune cells from the peripheral circulation into the brain. However, there is increasing evidence to suggest that the brain is under immunological surveillance." (Miller, Immunobiology of the blood-brain barrier, December 1999)

November 28, 2014

Safely specific (a.k.a a diseased tissue-specific way of generating a systemic response)

An August 2014 Drug Discovery Today article entitled Loco-regional cancer drug therapy: present approaches and rapidly reversible hydrophobization (RRH) summarized the shortcoming of systemic chemotherapy:
"Insufficient drug uptake by solid tumors remains the major problem for systemic chemotherapy. Many studies have demonstrated anticancer drug effects to be dose-dependent, although dose-escalation studies have resulted in limited survival benefit with increased systemic toxicities."
A similar criticism -- that is, the cost-benefit of systemic toxicity and greater survival -- could be made of checkpoint inhibitors (e.g., anti-CTLA-4s, anti-PD-1s, anti-PD-L1s), although there presumably is greater drug intake of these immunotherapies than chemotherapies.

Craig has long said (paraphrasing) one of the keys to solving the problem of cancer -- to generating correct, sustainable and thus successful systemic responses -- was to solve the problem of specificity. Other contributors to this proper response included route of delivery, and how the therapeutic or therapy in question induced cells to die. Specificity, manner of cell death, and route of delivery all importantly contribute to the safety, robustness and durability of a therapeutic or therapy's correct and successful systemic response.

The Drug Discovery Today article above continues:
"One solution to this has been the idea of loco-regional drug treatments, which offer dramatically higher drug concentrations in tumor tissues while minimizing systemic toxicity." {Underlined emphasis is mine}
Once they knew rose bengal (PV-10) had the necessary kind of specificity (and thus solved this problem) -- destroying only diseased tissue while leaving healthy tissue untouched or unaffected -- Craig contends they knew the main problem mostly was solved.

Other agents induce autophagy (where cells eat themselves). Can those agents induce this action only in cancerous cells, and not normal ones too?

Other agents can be delivered intralesionally or intratumorally, with the goal of delivering more drug product into the tumor. Without specificity, however, would not both the tumor and its surrounding normal tissue be affected, leaving a confused immune system to try and sort out what it must and must not do?

Craig believed a loco-regional agent could generate the correct systemic response, but needed a diseased tissue-specific way of doing so to make it practically effective and sufficiently safe: PV-10 (rose bengal).