April 18, 2014

“The study shows...the bystander response observed in patients...[is] a bona fide immunological response”

"The studies showed that immunohistochemical staining of biopsy specimens for mel A (an immunohistochemical marker of melanoma viability) demonstrated the complete disappearance of viable melanoma cells in both the injected and bystander tumours."
(PV-10 decreases melanoma cells in tumours, ecancer reporter Janet Fricker)
{Underlined emphasis is mine}

The article from which the above quote comes contributes to the picture of PV-10's systemic properties and benefit, and the very meaningful implications of which, becoming clearer. I briefly noted these under the blog's news tab in "...it’s a bona fide immunological response" (April 17, 2014).

"...the complete disappearance of viable melanoma cells in both the injected and bystander tumours"

In my post "Ironically, the original aim of the trial to assess tumor-infiltrating lymphocytes was thwarted when biopsies of patient tumors collected just 7-14 days after PV-10 injection no longer contained viable tumor tissue" I wrote PV-10's clinical value proposition as (see my September 2013 investment letter Why I'm Long Provectus Biopharmaceuticals):
Oncology compound PV-10 is very safe, is very efficacious locally and systemically, robustly stimulates the immune system locally and systemically, creates systemic anti-tumor immunity, is both a targeted therapy and immunotherapy, works on multiple solid tumor cancers, and could be used anywhere from a pre-neoadjuvant to a combination therapy with other cancer treatments.
Provectus clinical studies to date, particularly the 28-patient subset from the metastatic melanoma ("MM") Phase 2 trial who had all disease treated (i.e., all tumors or lesions were injected with PV-10), clearly have demonstrated the drug's ability to destroy injected tumors through rapid ablation (step #1 of the drug's mechanism of action, or MOA). In other words, locally (or loco-regionally) effective. In my post What PV-10 is doing is “unprecedented” I wrote inject PV-10 and the tumor goes away, and does not come back.

Moffitt Cancer Center's Dr. Jeffrey Weber, M.D., Ph.D., a medical oncologist, said patients who die of melanoma die of distant metastatic disease, not locoregional, cutaneous, dermal or soft tissue disease. Well, if you can establish loco-regional control -- PV-10 does this by mostly destroying tumors, rather than just shrinking them -- you have a very good chance of preventing metastatic disease, which should mean you have a very good chance of preventing people from subsequently dying of distant metastatic disease. There is tremendous value in this: local (loco-regional) efficacy.

The MM Phase 2, 28-patient subset used for Provectus' breakthrough therapy designation ("BTD") application, all disease treated, achieved a 71% objective response or OR (complete response, or CR, plus partial response, or PR) and an 82% loco-regional disease control (CR + PR plus stable disease, or SD). 50% (CR) + 21% (PR) and 50% (CR) + 21% (PR) + 11% (SD), respectively. The poster from where this data is taken is hereEffective (true) loco-regional disease control can forestall or prevent metastatic disease.

What has been less established, by virtue a not complete understanding of PV-10's MOA, more questions, great astonishment, and certainly lots of skepticism, is the drug's affect on non-injected lesions (so-called bystander lesions distant or removed from injected lesion sites). These distant non-injected sites can range from bad to worse to evil (i.e., visceral disease). The relevance and importance of PV-10's bystander effect frames and establishes the drug's systemic properties and benefit. Because an injected lesion rapidly ablates -- is destroyed -- the goal of a physician treating a melanoma patient (or any other patient with a solid tumor cancer) would be to inject as many lesions as the oncologist can find and inject. Win as many battles as you can.

But cancer is, to most, viewed as a systemic disease. The evil of cancer is not in what we can see or find or image, but in what we cannot see or find. How do we win the war? How do we kill (cure) cancer wherever it lies in the human body.

Truly demonstrating the bystander effect is one of several ways to establish PV-10's systemic properties, benefits and chops. For example, the MM Phase 2 trial, bystanders untreated, achieved a 54% OR and an 85% loco-regional disease control. 23% (CR) + 31% (PR) and 23% (CR) + 31% (PR) + 31% (SD), respectively. 

The bystander effect is real. Another way one can show this is by the work of a third party like Moffitt, which can reproduce, repeat and validate Provectus' work. In Moffitt's Phase 1 feasibility study, injected and non-injected lesions of an initial group of 8 patients completely disappeared. Thus, Moffitt confirms PV-10's rapid ablative effect and the effective immunological activity of the drug.

"Studies are now underway in an additional seven patients to take biopsies and blood samples at more frequent time intervals after PV-10 injection to elucidate the pathways more clearly."

Since Moffitt unexpectedly missed the window of where the activated T-cells attacked and destroyed both injected and non-injected tumor (which in itself is unexpected given Moffitt's great experience with adoptive cell transfer technology and trials) they’re now taking more frequent blood sampling of these seven additional Stage IV patients as well as more frequent core needle biopsies of areas in question.

Moffitt changed the trial protocol of its feasibility on January 9, 2014 according to ClinicalTrials.gov, and began enrolling the next seven patients later in the month. It is now mid-April. The cancer center should have had sufficient time to process and view tissue samples as well as get blood results of the second group of feasibility study patients.

This information unquestionably should be part of Moffitt's poster presentation and its poster highlights session at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO").

“The study shows that there are plausible immunological processes that explain the bystander response observed in patients. This isn’t a spurious event, it’s a bona fide immunological response”

Eric's quote, in my view, foretells Moffitt's ASCO 2014 poster. Moffitt should know the results of the additional seven patients. I have to believe Provectus management does as well. Explaining the bystander response is critical to the steps #2a and 2b of PV-10's MOA. Step #2a is the destruction of non-injected lesions. Step #2b is the provision of immunity to the patients thereafter. Spurious, in a medical context, means "simulating a symptom or condition without being pathologically or morphologically genuine."  A bona fide immunological response means that lesions or tumors inaccessible to injection can be shrunk or more likely destroyed (assuming not too heavy tumor burden in the patient) with PV-10.

For most patients whose disease has not progressed to a metastatic stage, winning the war with PV-10 may appear to be in sight. This would be accomplished because PV-10 harnesses the immune system to do what it, the immune system, was intended to do, and kill cancer where we cannot access or see it (i.e., microscopic traces or non-visceral disease). The drug of course must first gain approval, and thus management must manage the regulatory approval process and path.

But what about the war for patients with metastatic disease, and visceral disease. Recall Eric's quote from the company's June 2013 white paper PV-10 Moves Forward by W. Alexander, which discussed Moffitt's translational research work: "“What we learn from leveraging the clinical data with these new nonclinical results highlights the crucial role translational medicine can play in clinical development,” observed Dr. Wachter in an interview. While more frequent dosing could potentially improve outcomes, for patients with extensive tumor burden inaccessible to PV-10 injections a combination therapy strategy may be attractive, he said."

The article went on to frame management's belief of the robustness of PV-10's immunological activity for visceral disease (i.e., in melanoma, Dr. Weber's Stage IV M1c patients): "PV-10 murine research demonstrated unambiguously, Dr. Wachter noted, that tumor burden is a critical variable in predicting response to a combination therapy. It has been suggested that earlier research into therapeutic melanoma vaccines faltered because tumor burden grew beyond the immune system’s capacity for control before the vaccine could develop its full effect. “We think that the combination of PV-10 with something like a kinase-inhibitor has the potential to dial back or reduce tumor burden even better than an anti-CTLA-4 agent while the systemic PV-10 immunologic effect is developing. The kinase inhibitor would do the early work against visceral disease until PV-10 can catch up and take the baton across the finish line.”"

The story behind PV-10's immunological activity has yet to fully unfold. Winning the war on cancer means helping all stages of cancer patients defeat their affliction.

April 10, 2014

"Ironically, the original aim of the trial to assess tumor-infiltrating lymphocytes was thwarted when biopsies of patient tumors collected just 7-14 days after PV-10 injection no longer contained viable tumor tissue."

Data at ASCO becomes increasingly more anticipated
as Moffitt Cancer Center tells PV-10's immuno-oncology story

If I had to boil my curiosity of Moffitt's clinical work down to one question, it would be what happened to the eight melanoma patients about whom the cancer center presented clinical data at the 2014 annual meeting of the American Association of Cancer Research ("AACR") this past Sunday. Moffitt will provide more data at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO") in early-June. The patients had metastatic melanoma per the study protocol, and while they should be Stage IV patients, their specific staging (e.g., M1a, b or c) is as yet unknown.

I'd like to thank @bradpalm1, an internist and shareholder, for collaborative thoughts that form some of this blog post's bases.

As a follow-up to my post What PV-10 is doing is “unprecedented” about Moffitt's AACR 2014 poster presentation, here are some additional questions and thoughts. Quoted remarks come from the company's April 7th press release.
a. Why hasn't Moffitt's AACR 2014 poster been released by Provectus
In the past when Moffitt presented PV-10 data, at the 2012 annual meeting of the Society of Surgical Oncology ("SSO") and AACR 2013, the company has made posters available after the conferences end. This approach seems in keeping with conference rules about the timing of disseminating material presented at the conference. AACR 2014 ended on Wednesday, April 9th. Provectus provided comments by Moffitt's Dr. Pilon-Thomas, but no poster. What's the big deal? The big deal [on the poster I guessing and/or what it may imply and one could infer] should be (a) clinical detail of the eight patients and (b) the broadening and deepening of PV-10's overall mechanism of action.

By "embargoing" the poster for a time, presumably after ASCO, Moffitt focuses attention on its clinical work at the Chicago cancer conference and ensures it has greater impact when unveiled in early-June. I'm guessing Moffitt, in addition to presenting a poster at ASCO, may publish the results of their Phase 1 feasibility study in a medical journal.
b. "...clinical data on 8 melanoma patients that demonstrated significant decreases in melanoma cells in injected tumors and uninjected bystander tumors 7-14 days after PV-10 injection as evidenced by pathologic evaluation confirmed with immunohistochemical staining of biopsy specimens for melA (a marker of melanoma)."
Notable: significant decreases in melanoma cells in injected and non-injected tumors, in 7-14 days after injection

In this human feasibility study Moffitt confirmed what they previously found in their murine model work:
"Recently, PV-10 has been used as an IL therapy for malignancies including melanoma. In initial clinical testing, PV-10 therapy induced regression of both uninjected as well as injected melanoma lesions [10]. Intralesional BCG has been associated with patient fatalities due to anaphylactic hypersensitivity reactions that have not been reported with PV-10 [20]–[24]. In mice, it has been shown that repeated injections of high dose BCG by the s.c route led to mortality [25], indicating that PV-10 may be safer than BCG for intralesional therapy. In this study, we verified that IL PV-10 resulted in regression of untreated bystander lesions in breast cancer and melanoma mouse models. In both models, IL PV-10 was associated with enhanced tumor-specific interferon-γ secretion. These results confirm that IL PV-10 can induce a systemic anti-tumor immune response that can mediate the regression of untreated lesions." {Bold emphasis is mine} Source: Moffitt's July 2013 PLoS One paper Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer
And, PV-10 acts rapidly, directly on tumors into which it is injected as well as indirectly (i.e., manifested by the acts of the immune system) on distant non-injected tumors.
c. "The researchers showed that these changes in tumors were accompanied by increased populations of CD3+, CD4+ and CD8+ T cells along with NKT cells in peripheral blood. T cells from one patient were purified and exhibited increased interferon-gamma expression when exposed to the patient's pre-treatment melanoma cells."
Notable: NKT cells in peripheral blood

This is the first time Moffitt has broached the topic of NKT cells, which (together with dendritic cells) are thought of as a bridge between innate and adaptive immunity. @bradpalm1 calls NKT cells the assassins of the immune system. See my blog post PV-10 is not bigger than Mother Nature.

"Natural killer T (NKT) cells are a heterogeneous group of T cells that share properties of both T cells and natural killer (NK) cells." The role of NKT cells in tumor immunity: "NKT cells are a relatively newly recognized member of the immune community, with profound effects on the rest of the immune system despite their small numbers. They are true T cells with a T cell receptor (TCR), but unlike conventional T cells that detect peptide antigens presented by conventional major histocompatibility (MHC) molecules, NKT cells recognize lipid antigens presented by CD1d, a nonclassical MHC molecule. As members of both the innate and adaptive immune systems, they bridge the gap between these, and respond rapidly to set the tone for subsequent immune responses. They fill a unique niche in providing the immune system a cellular arm to recognize lipid antigens. They play both effector and regulatory roles in infectious and autoimmune diseases. Furthermore, subsets of NKT cells can play distinct and sometimes opposing roles. In cancer, type I NKT cells, defined by their invariant TCR using Valpha14Jalpha18 in mice and Valpha24Jalpha18 in humans, are mostly protective, by producing interferon-gamma to activate NK and CD8(+) T cells and by activating dendritic cells to make IL-12. In contrast, type II NKT cells, characterized by more diverse TCRs recognizing lipids presented by CD1d, primarily inhibit tumor immunity. Moreover, type I and type II NKT cells counter-regulate each other, forming a new immunoregulatory axis. Because NKT cells respond rapidly, the balance along this axis can greatly influence other immune responses that follow. Therefore, learning to manipulate the balance along the NKT regulatory axis may be critical to devising successful immunotherapies for cancer." {Bold and underlined emphasis is mine}
d. "These data are exciting and illustrate successful translation of our pre-clinical work in mice to clinical results in melanoma patients. With only 8 patients we've been able to clearly observe statistically significant increases in beneficial T cell populations in peripheral blood."
Notable: successful translation, statistically significant, beneficial T cell populations in peripheral blood

Moffitt confirmed in humans what they previously found in mice, which underscores this notion or concept of successful translational cancer research.
“Translational research can be pictured in the following way,” explains Nobel prizewinner Phillip Sharp, PhD, in an interview with SU2C. “I have a scientific insight. I develop a drug for that scientific insight, or a new therapeutic approach . . . You have to find the cancer patient who would respond to this drug, and you have to deliver it to that cancer patient in a compassionate and reasonable way to see if you can get maximal response.” Source: What Is Translational Research by Cat Vasko
e. "Ironically, the original aim of the trial to assess tumor-infiltrating lymphocytes was thwarted when biopsies of patient tumors collected just 7-14 days after PV-10 injection no longer contained viable tumor tissue."
Notable: ironically, no longer contained viable tumor tissue

I wonder if "ironically" refers to management's initial guidance to Moffitt about how PV-10 would work, and what they (Moffitt) would see by way of tumor destruction behavior and other pre-clinical and clinical features of PV-10, all of which they ultimately reproduced, repeated, verified and validated. More importantly, if PV-10 induced increased populations of CD3+, CD4+, CD8+ and NK T cells but no tumor-infiltrating lymphocytes ("TILs") were found in resected injected and non-injected tumors in patients after 7 to 14 days, where did all the T-cells go?

PV-10 is injected into an accessible cancerous lesion or tumor. The drug rapidly ablates the tumor (MOA step #1), which go away. At ECC 2013 management noted "...transient cutaneous loco-regional blistering...consistent with the novel tumor-specific immune mediated mechanism of action of PV-10": a sign [?] of MOA step "#2a:" an immune response at the injected site. Bystander tumors, that is non-injected tumors, go away too: MOA step "#2b:" an immune response at distant sites. MOA step #3, in my reworking of the two-step MOA for PV-10, would be longer-term, tumor specific immunity. It would seem reasonable, through the process of steps #1, 2a and 2b, that T cells are fighting the good fight first at the injected and non-injected lesion sites. After winning the fight, I presume they leave (dissipate from?) these sites. Where do they go? Into the [peripheral] blood (or blood stream) and/or the tumor draining lymph nodes ("TDLNs"), which are lymph nodes downstream from the lesions or tumors? It would seem they first stand up to fight the good fight. Then, second, stand down and hang out in their TDLN barracks or factories (my analogy may be getting thin here), and/or travel around the body over time via the blood stream looking to beat up on cancer [in the distant and not so distant future] of the form or substance they previously beat up in the injected lesion (having learned about what to beat up in the injected tumors' microenvironments).
f. "We are following up both the human data and continuing to design more experiments in mice to better explain the systemic immune effects elicited by PV-10 ablation."
Notable: following up, continuing to design

The study protocol was first put up on ClinicalTrials.gov in December 2012. The per patient treatment and evaluation protocol steps appear to be have a one-month time frame: t = 0 or baseline, 7-14 days after treatment, and 21-28 days after treatment. Were all of a patient's lesions injected and characterized as non-injected, or were only a subset studied? Were there multiple study rounds (e.g., 20% of lesions were studies, and then another 20% and then...), or was only round completed for study purposes? Even though the feasibility study was not a clinical trial with endpoints, was survival monitored and measured in some way? The anticipated study completion date was extended to December 2014. Rather than recruit more patients (subjects upon whom to experiment), which Moffitt also may be doing, is the cancer center observing and monitoring the success or failure (remission) states of the eight patients to see how they're doing (including holistic aspects of treatment a patient's primary oncologist might conduct as a matter of course)?

As for "continuing to design," it would seem Moffitt has further murine model work to do to figure out PV-10's immunological MOA. More immune system components and processes like NKT cells are involved (antibody-dependent cell-mediated cytotoxicity ("ADCC") too?) and the immune response is more robust (read: faster, like 3-5 days and not 7-28 days) than they expected.
g. "Provectus is thrilled to collaborate with the immunology and translational medicine experts Moffitt."
Notable: the immunology and translational medicine experts

In regards to ipilimumab (Yervoy) and its anti-CTLA-4 activity: "The achievement has recently won Allison a raft of awards that M.D. Anderson President Dr. Ron DePinho thinks will culminate in the Nobel Prize. "By creating this brilliant approach that treats the immune system rather than the tumor, Jim Allison opened a completely new avenue for treating cancers that's the most exciting and promising area of cancer research today," DePinho says." It was thought "blocking CTLA-4 stimulates the innate immune system, with subsequent activation of adaptive tumor-specific immunity." It's not clear how robust this really is.

Nevertheless, if one follows DePinho's logic, would Craig, Tim and Eric (and Moffitt, although they neither made the discovery nor translated it into a drug) be candidates for the Nobel at some point, perhaps after drug approval, one or two billion dollars of drug sales, near-100% complete responses (assuming properly and sufficiently injected PV-10) and the passage of time, too?
h. "As more data become available on the 'bystander effect' we've consistently observed in our therapeutic trials, we can better position PV-10 to help the most patients."
Notable: we've consistently observed, most patients

Chemoablation with PV-10,
6th International Symposium
on Melanoma, New York City 2009
PV-10's immune response in humans has been observed since the beginning of the company's clinical trial journey (see a slide from a 2009 Provectus principal investigator presentation at a medical conference using metastatic melanoma Phase 1 trial results). Moffitt's AACR 2014 poster presentation, as a snapshot in time of the sum total of their work to date, adds to the body of pre-clinical and clinical work that underscores PV-10's clinical value proposition (see my September 2013 investment letter Why I'm Long Provectus Biopharmaceuticals):
Oncology compound PV-10 is very safe, is very efficacious locally and systemically, robustly stimulates the immune system locally and systemically, creates systemic anti-tumor immunity, is both a targeted therapy and immunotherapy, works on multiple solid tumor cancers, and could be used anywhere from a pre-neoadjuvant to a combination therapy with other cancer treatments.

April 7, 2014

What PV-10 is doing is “unprecedented”

"...under investigation as a non-surgical option
to induce tumor regression of cutaneous neoplasms."

No poster was provided in the PR. According to management, it will be available after the American Society of Clinical Oncology ("ASCO") meeting that runs from May 30th to June 3rd. Interestingly and previously, the company has PRed Moffitt's Society of Surgical Oncology 2012 and AACR 2013 posters once the conferences ended (AACR 2014 ends June 9th).

My takeaways and questions include:

1. Inject PV-10 and the tumor goes away, and does not come back
2. PV-10 injection [effectively] is equivalent to surgery (i.e., a non-surgical treatment option)
    When melanoma is identified in Stages 0-III melanoma, excision of a sort (e.g., small, wide, deep, etc.) typically is the primary, initial or main treatment. More specifically, surgery is a therapeutic and diagnostic biopsy: remove the diseased tissue and take samples around the surgical margins to ensure the surgeon has removed the cancer, all within a few days.

    At AAC 2014 Moffitt found in and around the injected lesions:
    • No viable tumor tissue,
    • Healthy tissue around the margins, and
    • No tumor-infiltrating lymphocytes because the injected tumor went away faster (probably measured in a few days like three) than the planned for 7-14 follow-up period.
    A cutaneous neoplasm is a cancerous lesion on the skin. A skin cancer equals a skin neoplasm.

    Given this, how is PV-10 injection not equivalent to or better than surgery? PV-10 injection accomplishes the same goals as a diagnostic and therapeutic biopsy, but spares the tissue.

    Moffitt's study investigated whether PV-10 was a non-surgical option. Is it not now?

    3. The FDA, and a bridging study post-approval
      Moffitt's data very likely should have been provided to the FDA. Moffitt's documentation of PV-10 effect on injected lesions in their 8-patient study clearly builds on Provectus' metastatic melanoma Phase 2 trial 28-patient subset that had all disease treated. "...[I]f you inject PV-10 into melanoma tumors, the tumors go away."

      Given this, how could the bridging study not be done post-approval?

      4. We know more, and less
        AACR 2014 revealed Moffitt knows more about the whats of PV-10 injection on treated and untreated melanoma lesions. It also revealed they still don't fully know the whys. But what happened to the patients in Moffitt's feasibility study? The study protocol required the patients to be [essentially] experimented upon within a few days. If PV-10 worked so well requiring Moffitt to change their study design to re-examine injection sites much sooner than 7-14 days, were other lesions in these metastatic melanoma (Stage IV) patients subsequently and/or all treated too, following the initial study of or experimentation on intended to treat and not intended to treat lesions?

        The AACR 2014 poster is effectively embargoed until ASCO 2014 (and thus preventing us from seeing further detail of the study, results and patients). I can only wonder if (speculate whether) Moffitt's ASCO abstract's title Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions means patient follow-up will be discussed at ASCO.

        5. Melanoma
          The PR noted Provectus' breakthrough therapy designation ("BTD") submission again: Provectus has applied to the FDA for breakthrough therapy designation of PV-10 for the treatment of melanoma based on a 7 center international single-arm trial." {Underlined emphasis is mine above}.

          As I wrote under the blog's News tab for "Trial design endpoints should be tailored to the strength of your drug" (April 5, 2014), PV-10 is being considered for approval for local (non-metastatic) disease. Local (including local regional or loco-regional) disease represents more than 95% of the addressable melanoma market (see, for example, Recurrent Loco-Regionally Advanced Melanoma Market > Metastatic Melanoma Market (January 25, 2014) below).

          I believe management is making a point in today's PR about the implications of the resultant outcome from a BTD award.

          April 4, 2014

          The company PV-10 keeps

          There is a saying "you are the company you keep," or perhaps "you're only as good as the company you keep." PV-10's company? MPDL3280A (Roche),  Yervoy and nivolumab (Bristol Myers), MK-3475 (Merck), T-Vec (Amgen), Abraxane (Celgene), etc.

          Over the next three months, April to June, PV-10 data will be presented and/or discussed in at least 6 presentations at five medical conferences. Never in Provectus' history has data been presented at so many venues in such a short period of time.
          Click on the figure to enlarge it.
          First, on April 6th, Moffitt Cancer Center presents a poster at the 2014 annual meeting of the American Academy of Cancer Research ("AACR") entitled Induction of anti-melanoma immunity after intralesional ablative therapy. The focus likely should be on the second step of PV-10's two-step mechanism of action ("MOA"), and perhaps further explanation of the drug's viability for multiple indications like breast cancer, on which I think Moffitt and Provectus may further collaborate.

          Second, on April 11th, "PV-10 will be an integral part of..." the HemOnc Today - Melanoma and Cutaneous Malignancies Conference's Session 4: Local and Regional Therapy. The session will include Amgen's T-Vec, Vical's failed Allovectin-7, other intralesional therapies, and a debate about the role of systemic intralesional therapy.

          Third, on May 7th, St. Luke's University Health Network's and Provectus principal investigator Dr. Sanjiv Agarwala will participate in a plenary session at the 10th European Association of Dermato-Oncology ("EADO") congress entitled New Drugs and new trials. Other drugs on the agenda include:
          • Amgen's T-Vec,
          • Bristol-Myer's Yervoy (ipilimumab, an anti-CTLA4 agent),
          • Roche's MPDL3280A (an anti-PD-L1 agent),
          • BMS' nivolumab (an anti-PD-1 agent),
          • BMS' combination of Yervoy and nivolumab,
          • Merck's MK-3475 (an anti-PD-1 agent), and
          • OncoSec's ImmunoPulse.
          Click on the figure to enlarge it.
          Amgen, Bristol-Myers, Roche, Merck and...Provectus.

          Fourth, on June 2nd, Dr. Agarwala will present a poster at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO") during the day's Poster Highlight Session (in addition to the regular poster presentation day and time) entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions. The focus likely should be on the 28-patient data subset of Provectus' metastatic melanoma Phase 2 trial that formed the basis of the company's breakthrough therapy designation ("BTD") application.

          You know, the BTD submission stated or commented on publicly by management [at least] 11 times thus far --five press releases, three Provectus News items (to be fair, BTD submission was picked up by third parties),  two 8-Ks, one 10-K, and a partridge in a pear tree -- and on the website.
          I'm obviously poking fun at management. For a company with a history of being somewhat opaque or obtuse in communications regarding clinical data, regulatory interaction, and other matters, it's not unreasonable for the casual observer to think Provectus currently is promotional in regards to their BTD submission. The change in stride certainly is notable. Once or twice, in an SEC filing, I get. But, more than ten times? The same casual observer might think it strange; however, long-time investors who have done their due diligence on Eric's historical interactions with the FDA along the company's regulatory approval journey understand, and I think the company has said as much in its PRs: the Agency appears to have (has) agreed tumor-based endpoints (i.e., complete response: "...if you inject PV-10 into melanoma tumors, the tumors go away...") and not survival-based endpoints (e.g., overall survival, progression free survival, etc.) are appropriate for approving this drug. If you assume this Agency embracing of PV-10 and hurdle-clearing of endpoints, and I cannot fault folks if they don't, one could understand management's confidence in securing BTD, and then (and only then) these many BTD submission mentions.

          BTD, in some respects, marks the beginning of a potentially speedy pathway to approval. The decision tree might be one of the FDA either (a) requiring the company to conduct a bridging study in order to file a new drug application ("NDA") for PV-10 -- "...before...we have approval to sell PV-10..." -- or (b) permitting the study to be a post-marketing requirement/commitment -- "...after we have approval to sell PV-10..."
          Click on the figure to enlarge it.
          Managing our investment in Provectus of course requires me to manage risk. Even as a presumably well-informed investor, it's still very hard for me to assume a BTD award is in the bag. Probable, yes. Certain, no. The FDA may say no, and the company (like others turned down before them) very likely would have been told by the Agency to obtain more clinical data. But, as I wrote in my post Provectus Submits Application to FDA for Breakthrough Therapy Designation, the FDA doesn't want nor does it encourage companies to submit BTD applications that are more likely to be turned down than accepted. One would imagine the boldness with which management speaks of BTD suggests they very strongly believe they'll attain it (because of interactions with the Agency that suggest so) on, before or well before May 23rd.

          Fifth, also on June 2nd, Moffitt will present a poster at ASCO, also during the day's Poster Highlight Session (again, in addition to the regular poster presentation day and time) entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions. This presentation should elaborate on both the clinical (MOA step #1, ablation/destruction of injected lesions) and immune (MOA step #2, immune response/destruction of non-injected lesions) efficacy observed in patients enrolled in the cancer center's feasibility study, where Moffitt essentially experimented on them.

          Sixth, on June 27th, Moffitt's Dr. Vernon Sondak will participate in a symposium session at the 4th European Post-Chicago Melanoma/Skin Cancer Meeting entitled New drugs and trials: An update on immunotherapy and chemotherapy. Other drugs on the agenda include:
          • Bristol-Myer's Yervoy (ipilimumab),
          • BMS' nivolumab,
          • Merck's MK-3475,
          • GlaxoSmithKline's failed MAGE-A3 (a cancer vaccine),
          • Amgen's T-Vec,
          • OncoSec's ImmunoPulse, and
          • Celgene's Abraxane (chemotherapy nab-paclitaxel).
          Click on the figure to enlarge it.
          Bristol-Myers, Merck, GlaxoSmithKline, Amgen, Celgene and...Provectus.

          This month and over the next two, we can expect a lot of pre-clinical and clinical PV-10 data, and potentially a positive BTD decision. More data and MOA elucidation is good (and I am very much looking forward to reading them). Regulatory clarity and steps (i.e., BTD and what comes with it) is better, and very, very necessary for this company.

          But how now China? And/or other regional transactions? And/or the endgame?

          If management believes it will get BTD for PV-10 for locally advanced melanoma, thinks they might have to conduct a bridging study prior to filing the NDA (i.e., in this case de facto approval) "at worst," has about $16 million of cash on the balance sheet (see the company's March 24th PR), and possibly estimates the cost of a bridging study at $5-$10 million or thereabouts (comparable or less if the trial is terminated early, and some patient number overlap is acceptable to the various geographical regulatory agencies), why consummate a deal with a Chinese partner or any partner for that matter until after a BTD decision and clarity is achieved as to the step(s) toward and after approval?

          I'm particularly interested in Dr. Agarwala's ASCO presentation, which will focus on the 28-patient subset that formed the basis for Provectus' BTD application and in all likelihood its awarding. This data was first broken out at the 2013 European Cancer Congress in September: Exploratory Data Analyses of Intralesional PV-10 Clinical Phase 2 Study Results Presented at ECC 2013 Demonstrate Effective Locoregional Disease Control and Support Systemic Immunologic Activity in Refractory Metastatic Melanoma:
          Click the table to enlarge it. Poster source is here.
          If one were to not consider the non-evaluable subjects (NEV above), loco-regional control of the disease -- the value proposition underscoring approval of PV-10 for locally advanced melanoma: the drug forestalls or defeats the spread of the disease to a metastatic stage, or alternatively "...if you inject PV-10 into melanoma tumors, the tumors go away..." -- increases to 88%.
          Craig would tell you the residual percentage, 12% w/o NEV (or 18% as presented at ECC 2013 for the full subset), is more than likely due to physicians not injecting the lesions properly and thus not getting the expected result. The results PV-10 and PH-10 generate appear to be startlingly consistent from properly injected lesion (volume of drug per unit volume of tumor, proper administration) to properly injected lesion.

          88% loco-regional control, and you want to do a deal now? Wouldn't it make sense to wait or seriously contemplate waiting until after a decision (unless a counter party aggressively bids for a deal, which doesn't appear to be the case at the moment)? There is of course risk in doing so; however, if you're supremely confident based on clinical data and regulatory interaction heretofore, you wait. Wait for the bigger regional check as milestone payments turn into upfront payments based on what transpires regulatory-wise. Wait to submit a BTD application or two for your liver program (e.g., in combination with maintenance sorafenib, cancers metastatic to the liver). Wait until impatient Big Pharma with drugs and compounds that are not sufficiently efficacious or safe, and very expensive, see their respective Kodak moment coming and decide to deal. By Kodak moment, I specifically mean technology disruption that could end in a near-zero sum game in the case of PV-10. If you own it you survive, and flourish. If you don't...

          As folks line up to associate themselves with Provectus, and/or deal with the company, Pfizer might lose first mover advantage. Provectus has three executives from two Top 15 ranked (by pharmaceutical sales) companies on its strategic advisory board. It may add executives from up to three more Top 15 firms.
          Click on the figure to enlarge it. The table source is here.
          There is much for the company to accomplish before thoughts of the end-game can and should percolate. And although I've written often on this blog that I think Pfizer will be the end-game acquirer, and a topic for another post, it's not a given the company with the biggest checkbook (and the nose under the tent for the longest time) wins. Vision, strategic rationale, ambitiousness and, ultimately, verve, together with a not inconsequential balance sheet should win the M&A day.

          April 1, 2014

          In Support of the Initial Label

          Today's press release about Provectus' poster presentation at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO"), Provectus Biopharmaceuticals' PV-10 Data to Be Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, provided several items of useful information,

          More detailed subset data to come. As the company has said in the past, it is relying on a 28-patient subset of its metastatic melanoma Phase 2 trial to seek breakthrough therapy designation ("BTD") and an initial pathway to approval. More information about the presentation should be forthcoming on May 14th when abstracts are released by ASCO; however, the title is informative: "Efficacy of intralesional Rose Bengal in patients receiving injection of all existing melanoma in phase II study PV-10-MM-02."

          Data from the 28-patient subset of Phase 2 enrollees where all disease was treated was first highlighted at the 2013 European Cancer Congress in September (Exploratory Data Analyses of Intralesional PV-10 Clinical Phase 2 Study Results Presented at ECC 2013 Demonstrate Effective Locoregional Disease Control and Support Systemic Immunologic Activity in Refractory Metastatic Melanoma): "Results showed that for all subjects, BORR was 51% (26% CR, 25% PR) with the amount of tumor burden accessible to PV-10 injection prognostic for outcome. In the majority of subjects (68%) the lesions treated with PV-10, together with the up to two untreated bystander lesions, constituted all disease present, and these subjects achieved a BORR of 63%. In subjects where all disease was treated (35% of subjects) BORR further increased to 71% (with 50% achieving CR)." {Bold emphasis is mine}
          Click the table to enlarge it. Poster source is here.
          Following Provectus' December 16th meeting with the FDA, the company further discussed this 28-patient subset in its January 24th PR Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes.

          First: "The meeting and official meeting minutes provided valuable guidance on a number of issues surrounding the approval path of PV-10:...In reference to discussions on the potential for breakthrough therapy designation, 'FDA advised Provectus to provide objective response rates with adequate information to evaluate the symptomatic treatment effects (e.g. pain, infection, bleeding) in patients presenting with locally advanced cutaneous melanoma who received PV-10 to all lesions.'" {Bold emphasis is mine}

          Second: "The Phase 2 study of PV-10 showed:...In the subgroup of melanoma patients that received PV-10 injection into all known disease (28 of the 80 ITT patients), 50% achieved a complete response (71% ORR, CI 51-87%)."

          Third, on a per-tumor basis for an expanded subset (all or ostensibly all disease treated): "In the subgroup of melanoma patients with locally advanced cutaneous melanoma that received PV-10 injection into all known disease or only had 1 or 2 designated bystander tumors untreated (54 of the 80 ITT patients), a complete response was achieved in 232 of 363 injected tumors (64% of lesions) with the vast majority of these tumors requiring only 1 or 2 injections." {Bold and underlined emphasis is mine}

          Finally, fourth: "Dees continued, 'Measurement of tumor shrinkage via objective response criteria has been considered direct clinical benefit in drug approvals for other skin cancers and we believe a similar case can be made for PV-10 in locally advanced cutaneous melanoma. As advised by the Agency, we will submit data from the 28 patients in our Phase 2 study who had all existing disease treated in a formal BTD request this quarter, and should receive a decision within 60 days of receipt of that request.'" {Bold emphasis is mine}

          The company continued to consistently communicate the narrative of PV-10 injected into all disease as the basis for its initial approval pathway in its March 24th PR Provectus Biopharmaceuticals Inc. Submits Application to FDA to Receive Breakthrough Therapy Designation for PV-10 for Treatment of Melanoma.

          First: "Craig Dees, PhD, CEO of Provectus said, 'The decision to apply for BTD stems from our Type C meeting held with the FDA's Division of Oncology Products 2 in December 2013. At the meeting FDA expressed willingness to work with Provectus toward initial approval for the novel investigational oncology drug PV-10 in locally advanced cutaneous melanoma. This included a statement in the minutes that data in a cohort of patients that received PV-10 to all existing lesions should be submitted in a formal BTD application.'" {Bold emphasis is mine}

          Second: "Dees continued, 'I want to make clear to our shareholders, the media and the market as a whole that BTD is not guaranteed and if the designation is conferred on PV-10 for melanoma, it does not bypass the need for a new drug application (NDA) and review, as both are required for commercialization of any drug. As I have stated previously, the Agency may yet recommend and it may be in the best interest of Provectus to undertake a small, short bridging study in patients where all tumor burden can be injected. This could occur either before or after we have approval to sell PV-10. Provectus has over $16 million in cash reserves and would not require additional capital or the resources of a partner to conduct such a study. If such a study is conducted, it also fits with needs for an international study supportive of licensure in Australia, Europe, China and India.'" {Bold emphasis is mine}

          And third: "Dees concluded, 'We are confident that the studies done thus far illustrate the effectiveness and safety of PV-10: if you inject PV-10 into melanoma tumors, the tumors go away. For recurrent, aggressive skin cancers this unique mechanism confers tangible benefit to patients.'" {Bold emphasis is mine}

          I imagine Provectus' ASCO poster (as well as their 2-5 slides that would be included in their poster highlight session) will provide more detailed per tumor data, and make clear the rationale the FDA appears to have embraced regarding treating all disease for locally advanced melanoma.

          Poster Highlights Session selection. As noted in today's PR, the company's abstract was selected for this session, which should take place from 8 am to 12:45 pm CST on Monday, June 2nd. Dr. Agarwala (the probable discussant) likely will present a few slides during the session.

          Breakthrough Therapy Designation. Selection to the poster highlight session must only have happened because the data underlying Provectus' abstract, the 28-patient "cohort," is being used to support BTD. While ASCO acceptance and highlighting certainly doesn't influence whether the company will secure the designation from the FDA, I think it is another measure of growing industry acceptance of the drug, the local nature of its use, and the initial indication for which it should (will) be applied. The "friendly reminder" in the PR that the company recently submitted a BTD application for melanoma may reflect management's supremely confident belief regarding successfully attaining the designation, Craig's "I want to make clear to our shareholders, the media and the market as a whole that BTD is not guaranteed..." notwithstanding.

          March 30, 2014

          The Biggest Risk [Updated-2]

          When I periodically review and assess the risks I wrote about in my September 2013 investment letter, whether here on the blog or at Seeking Alpha (i.e., the scenarios in which I could be wrong, and if so by how much), I also try to contemplate and consider new potential and possible risks. I've moved beyond clinical questions (e.g., could there be unexpected adverse events and/or poor clinical results in the future) and almost past regulatory questions (e.g., could more time be required to confirm the regulatory path) to commercial ones (e.g., could management be unable to monetize the company at a valuation commensurate with their innovation).

          For me, the biggest risk, and very likely the source of disappointment if there is to be one, is whether management can sell Provectus at their desired price, let alone at the worth I see. It's a risk I have focused on almost from the beginning; a question of will they, rather than can they. A simplistic analysis (with no supporting material at this time by intent) might yield an interim assessment of "yes" or thereabouts, potentially pointing to a probable "yes" when the endgame arrives. Note that the analysis below does not contemplate contingent payments.
          Click to enlarge the table
          We may receive more clinical, regulatory and commercial information during the next 60 to 90 days to better assess risk-reward:
          • Mechanism of action (Moffitt at AACR),
          • Liver program (enrollment & trial progress),
          • Additional indications (maybe breast and/or colorectal),
          • MM Phase 2 results (durability of response I really hope, and finally),
          • A breakthrough therapy designation decision from the FDA,
          • Combination therapy potential (most likely murine model work of a leading research facility at a major oncology conference),
          • PH-10 mechanism of action (maybe), and
          • A NASDAQ up-listing and/or regional license transactions.
          Updated 3/30/14: If the stock market ultimately does not reward the company with a market capitalization such that an acquisition premium by Big Pharma (to the then market cap) cannot reach Provectus' management expectation of price and value, the principals face two obvious choices at that time: Sell, or don't sell (and build until the decision is re-visited).

          Intrinsic value, as I've written on this blog in the past, is the value of an asset (in this case the company) determined by fundamental analysis (in this case my analysis) without reference to its market value (in this case the share price). Extrinsic value, borrowing terminology from option pricing, is worth or value assigned or determined by external factors. The stock market is an example of an external factor (market capitalization is the result). An M&A transaction is another example.

          You'll recall in January 2014 I argued for a worth of $150 per share or a total of $30 billion, my estimate of the company’s intrinsic value on a net present value, an amount that could accrue to Provectus shareholders upon an M&A transaction and over time through an earn out.

          One measure of extrinsic value is the company's approximately $400 million market capitalization as of Friday's closing price (although I would prefer to adjust the number to accommodate a fully diluted shares outstanding figure). Another measure would be the price at which Big Pharma might bid to management to buy the company today, formally or informally. Management can turn them down (and re-inform them of their price expectations), but the price point is an extrinsic value point. 

          Another way to come at the outcome of the simplistic analysis above is to evaluate stock price appreciation adjusted for dilution over time. Interestingly, on a percentage change basis, adjusted market cap roughly mirrors that of Big Pharma's apparent assessment of value.
          Click to enlarge the table
          The larger point of the blog post is that having the bigger or biggest risk to my investment thesis as management not being able to sell the company for the price they want (assuming there are no other bigger risks, and management's expectations of price are appropriately and sufficiently high enough) is a "good" problem to have. That the stock market doesn't currently value Provectus anywhere close to these price level discussions is no small thing. The stock market as a snapshot in time, however, is just one measure of extrinsic value.

          Updated 3/31/14: Using figures provided by management on Provectus' corporate website presentation for common stock, and stock options & warrants outstanding (approximately 173 and 37 million, respectively), the above tables then would appear as:
          Click to enlarge the table