November 23, 2016


Source of tweet image below: Paul D. Rennert (@PDRennert).
Click to enlarge
On the SITC slide above, I imagine PV-10 (in combination with a/the PD/PDL1 "backbone") would fall under "oncolytic" in the pembrolizumab column (second from the left). The slide clearly illustrates an amazing amount of work underway to augment this fundamental concept of combination therapy or treatment in cancer.

The slide reinforces an important theme of Provectus' Dr. Eric Wachter, PhD's November 14th presentation (as part of the 3Q16 business update call): there is considerable interest and clinical activity in melanoma, and while he believes there is no doubt about the relevance of PV-10, cutting through the crowd to the front of the pack will require continued effort on Provectus' part. See, for example, the slides below from his presentation:
Click to enlarge
Click to enlarge
Under Additive: 1 + 1 < 2. Synergistic: 1 + 1 > 2 (best case, >> 2) (June 25, 2016) on the blog's Archived News VI page I co-opted a slide from MD Anderson's Dr. Merrick Ross, MD's presentation -- see ASCO 2016: "The Role of Immunotherapy in the Medical Management of Melanoma: An Overview for the Oncologist" (June 22, 2016) -- that provided results from various combination therapy studies for advanced or metastaic melanoma slide in order illustratively model the difference between additivity and synergism:
Click to enlarge
The table above was updated to include recent combination therapy data of oncolytic virus CVA21 (Coxsackievirus A21, a cold virus) and anti-PD-1 drug pembrolizumab (Keytruda) presented at SITC 2016: "According to the preliminary data from the first 10 patients evaluable for best overall tumour response assessment, a disease control rate (DCR) of 100 percent (10/10 patients) was demonstrated, including seven patients (70 percent) with an objective tumour response and three patients (30 percent) with stable disease" {Viralytics’ CAVATAK™ in Combination with KEYTRUDA® Provides Promising Results in Advanced Melanoma from the CAPRA 1b study}.

Interestingly, however, Viralytics' combination therapy above yielded no complete responses in its Best irRC Overall Response (see the SITC poster here), and did not use RECIST 1.1 in its tumor response measurement. Median doses of CVA21 and pembrolizumab (for the ten patients noted above) were 8 (range 6-11) and 6 (3-11), respectively. CVA21, like T-Vec, has to be delivered often for its effect to manifest, weak or weaker (than PV-10's immunologic signalling) as it is.

Viralytics previously established a collaboration with Merck & Co. in November 2015 to combine CVA21 and pembro in either advanced stage non-small cell lung cancer (NSCLC) or metastatic bladder cancer. In June 2016 the parties initiated a Phase 1b study, one-site (Australia) program for NSCLC where CVA21 would be delivered intravenously (three different dosing levels of CVA21), and not intralesionally or intratumorally.

In his November 21st article "Viralytics' anticancer virus aces checkpoint inhibitor combo trials," FierceBiotech's Phil Taylor provides or references several examples of funded or acquired oncolytic virus companies:

  • 2011: Amgen's acquisition of BioVex (U.S.), and thus T-Vec (Imlygic) (formerly OncoVEX) ($1 billion: $425 million upfront and a $575 million earn out), which was approved in 2015,
Edison Investment Research's Dennis Hulme and Lala Gregorek's November 21st equity research note on Viralytics entitled "Cavatak data continue to impress" presents the valuation rationale below:
Click to enlarge.
"Notable changes in immune cell infiltrates and expression of PD-L1 within the CVA21-treated NMIBC tissue were also observed. Increased urinary levels of the chemokine, HMGB1, was observed in six of eleven patients following exposure to CVA21."
Moffitt Cancer Center noted increased HMGB1 levels in sera of melanoma patients after intralesional PV-10 treatment.
Click to enlarge. Image source
Moffitt did not report the number of patients with elevation, but rather the change in mean. Inspection of Figure 6 in Liu et al. suggests most patients (n = 14) exhibited increased HMGB1.

Oncolytic, as a label or category, can be somewhat deceiving.

Intralesional (IL) oncolytic virus (e.g., T-Vec, CVA21, HF10, etc.) is different than IL chemical small molecule (i.e., PV-10), both of which might be referred to as oncolytic immunotherapy.

Oncolytic virus immunotherapy however delivered (e.g., intralesionally/intratumorally, intravenously) is different from ablative immunotherapy (i.e., PV-10).

Takeaway: There's a real opportunity for Provectus and PV-10. There is no doubt about the relevance of PV-10, but cutting through the crowd to the front of the pack will require continued effort on the company's part.

November 8, 2016

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

Updated below: 11/8/16 {thrice}.

Source link

Intralesional injection with Rose Bengal and systemic chemotherapy induces anti-tumor immunity in a murine model of pancreatic cancer

Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A Sarnaik H. Lee Moffitt Cancer Center, Tampa, FL, USA

Journal for ImmunoTherapy of Cancer 2016, 4(Suppl 1):P256

Rose Bengal is a xanthene dye that has been utilized for liver function studies and is currently used topically in ophthalmology. Intralesional (IL) Rose Bengal (PV-10) has been shown in murine models and melanoma clinical trials to induce regression of treated melanoma lesions and uninjected bystander lesions. This study was undertaken to measure whether IL PV-10 can induce systemic anti-tumor effects alone or in combination with gemcitabine (Gem) therapy in a murine model of pancreatic cancer.

C57BL/6 mice received Panc02 pancreatic tumor cells subcutaneously (SC) on one flank to establish a single tumor. On day 7, tumor was treated with IL PV-10. Control mice received IL phosphate
buffered saline (PBS). Tumor growth was measured. Splenic T cells were collected and co-cultured with Panc02 or irrelevant B16 cells. Supernatants were collected to measure Panc02-specific T cell responses by IFN-gamma ELISA. To measure the effect of IL PV-10 on the growth of an untreated, bystander tumor, mice received Panc02 cells in bilateral flanks. The resulting right tumor was injected IL with PV-10 or PBS. Tumor sizes were measured for both the right (treated) and left (untreated/bystander) tumors. To determine the efficacy of combination therapy with IL PV-10 and systemic Gem, mice bearing a single or bilateral Panc02 tumors were treated with PV-10 alone or in combination with Gem. Mice received 60 mg/kg Gem intraperitoneally (IP) twice per week.

C57BL/6 mice bearing Panc02 tumors treated with IL PV-10 had significantly smaller tumors than mice treated with PBS (p < 0.001). A significant increase in the IFN-gamma production in response to Panc02 was measured in the splenocytes of mice treated with PV-10 as compared to mice treated with PBS (p < 0.05). Mice with bilateral tumors had a significant regression of tumors injected IL with PV- 10 and there was a reduction in the untreated (bystander) flank Panc02 tumor (p < 0.01). Gem therapy in combination with IL PV-10 injection led to enhanced tumor regression (p < 0.05) compared to IL PV-10 or Gem alone in both a single tumor model and a bilateral tumor model.

Regression of untreated pancreatic tumors by IL injection of PV-10 in concomitant tumor supports the induction of a systemic anti-tumor response. Addition of Gem chemotherapy enhances the effects of IL PV-10 therapy. Given that patients with metastatic pancreatic cancer have a dismal prognosis, combination therapy of IL PV-10 combined with Gem may benefit patients with metastatic pancreatic cancer.

Updated (11/8/16).1: My underlined emphasis above. Note PV-10 use in the above murine model work as a monotherapy, and in combination with systemic chemotherapy.

Updated (11/8/16).2: H/t @bradpalm1:

Click to enlarge. Tweet image source
"Gemcitabine reduces MDSCs, tregs and TGFβ-1 while restoring the teff/treg ratio in patients with pancreatic cancer," Eriksson et al., Journal of Translational Medicine 2016 14:282
Gemcitabine regulates the immune system in patients with pancreatic cancer including MDSCs, Tregs and molecules such as TGFβ-1 but does not hamper the ability of effector lymphocytes to expand to stimuli. Hence, it may be of high interest to use gemcitabine as a conditioning strategy together with immunotherapy."
Updated (11/8/16).3: Unlike some, I do not read too much into Moffitt's abstract with respect to the additivity or synergism of PV-10 and gemcitabine (systemic chemotherapy) based on the cancer center's murine model work (i.e., p values of PV-10 alone, and in combination with chemo). And, I'd like to see the poster if Provectus facilitates its release (e.g., the company did not facilitate the release of Moffitt's AACR 2016 poster, which I believe may lead to a peer-reviewed publication).

I believe the point of this mousie work, which of course is beyond cell line (in vitro) work but behind clinical studies, is to demonstrate in principle that (a) intralesional (IL) PV-10 could be used to treat pancreatic cancer (i.e., tumor type, leading to a suitable cancer indication) via (i) ablation/destruction of an injected tumor and (ii) the subsequent triggering of the immune response to reduce or destroy an untreated one, and (b) IL PV-10 plus chemo sees enhanced untreated tumor reduction or destruction.

These principles of (x) ablation/destruction by injection and (y) immunologic signalling (immune system harnessing) already have been shown preclinically by Moffitt for PV-10 as a monotherapy in melanoma (also clinically) and breast cancer (AACR 2013), and in combination with checkpoint inhibition for melanoma (SITC 2014).

So, this continues Rose Bengal, PV-10 and Provectus' theme of (A) agnosticism (ablation, immunologic signalling), (B) synergism (in that one therapy enhances another; "induce and boost"), (C) orthogonality (although this would be better shown in clinical work to emphasize no greater toxicity, if not less to far less), and...

(D) PV-10 is an immunotherapy. See January 19, 2016 blog post PV-10 is an immunotherapy.

November 3, 2016

It will take more than just checkpoint inhibition to achieve the next step forward in oncology

Image source
Updated below: 11/3/16 {twice} and 11/5/16.

(alternative blog post title: Can Clever Chronological Combos Cure Cancer?)

Clinicians and medical researchers around the world are growing in their realization that current immuno-oncology is not mission accomplished. It will take more than just checkpoint inhibition to achieve the next step forward in oncology.

Even immunologist Dr. James Allison, PhD, whose work led to the development of anti-CTLA-4 drug ipilimumab (Yervoy), highlighted this "look forward" in Laura Panjwani's October 31st OncLive article entitled "James Allison Says Rational Combinations Key to Immunotherapy Success in "Cold" Tumors:"
"The success of immunotherapies in those cancers—which are likely seeing a better rate of response due to their high mutational burden—is now paving the way for what are known as “cold” tumors, those that don’t have a heavy mutational burden or significant T-cell infiltration. 
There is enough progress being made across the board that I think we can start thinking about some of the colder tumors responding if we just keep studying and making rational combination decisions. As we understand this better, we can rationally put two things together that won’t just duplicate or cancel each other out, but will do different things that can at least be additive, if not synergistic."
Among various combinations of therapies and therapeutics with checkpoint inhibition, Dr. Allison discussed radiation, chemotherapy and targeted therapy in the OncLive article:
"Most of the activity now, at least that I know about, is in radiation...There is also some chemotherapy combination research going on... 
Relatively few targeted therapies are being investigated with immunotherapies, although that research is happening. One of the problems is that there are so many options for combinations; the temptation is there to just combine something from column A, something from column B, and something from column C, and see if it works. That is the way it used to be done back in the empirical days of chemotherapy, but we know enough now to not do that."
PV-10's (Rose Bengal's) clinical & pharmacoeconomic value proposition is clear, simple and straightforward:
Click to enlarge. Sample image source, Sidoti Fall 2016
Germane to this blog post is the value proposition PV-10 provides a combination partner: agnosticism, orthogonality, and synergism:
Click to enlarge. Same sample source as above.
PV-10's combinatorics drug development program/portfolio to date comprises chemotherapy, radiotherapy, and checkpoint inhibition in pancreatic cancer, melanoma, and liver cancer:
  • November 2016, SITC: preclinical (murine models), PV-10 + chemotherapy (gemcitabine/Gemzar®), pancreatic cancer, Moffitt Cancer Center,
  • November 2014, SITC: preclinical (murine models), PV-10 + co-inhibitory blockade [checkpoint inhibition] (anti-CTLA-4, anti-PD-1, anti-PD-L1), melanoma, Moffitt Cancer Center,
  • April 2013, AACR: preclinical (murine models), PV-10 + anti-CTLA-4 [checkpoint inhibition], melanoma, Provectus,
  • November 2012, SITC: preclinical (murine models), PV-10 + chemotherapy (5-fluorouracil/5-FU, Adrucil®), hepatocellular carcinoma (HCC), Provectus, and
* There is not yet sufficient information to suggest patients on a course sorafenib have been treated with PV-10 (see May 10, 2016 1Q16 business update conference call, pp 44-45).

Updated (11/3/16).2: A table of the bullet points above is below.
Click to enlarge
Updated (11/5/16).3: Speaking of old oncology therapeutics and therapies ("In cancer, it’s back to the future as old treatments make cutting-edge ones more effective," Stat, Sharon Begley, August 4th):
"New cancer drugs that unleash the immune system on tumors are all the rage, getting credit for curing former President Jimmy Carter’s advanced melanoma and inspiring tech billionaire Sean Parker to pledge $250 million to cancer research. Behind the excitement, however, is the hard truth that these therapies work in only a minority of patients. 
Now scientists are finding hints of a solution in an unexpected place: Older, out-of-favor cancer treatments such as chemotherapy and radiation may make the cutting-edge immune-based drugs effective against more cancers — even hard-to-treat ovarian and pancreatic tumors... 
One answer: through chemotherapy or radiation. When these old-line treatments begin to kill tumor cells, those cells release molecules that can attract T cells to join in the attack. “They have the potential to prime the pump for immunotherapies,” said Dr. Gary Gilliland, president of the Fred Hutchinson Cancer Research Center in Seattle... 
Radiation, which was first used against cancer at the turn of the 20th century, can also turn cold tumors hot. In a study published in June, scientists led by radiation oncologist Dr. Ralph Weichselbaum of the University of Chicago Medical Center found exactly that in mice with pancreatic cancer, which is notorious for being nearly untreatable, as well as for not attracting tumor-destroying T cells. (The only immunotherapy having any effect on pancreatic cancer in people slowed tumor growth in a mere 8 percent of them.) 
“We think radiation turned a cold tumor into one that attracts T cells, while the immunotherapy kept the T cells from being disabled,” Weichselbaum said. “I think some cancers that aren’t now treated with radiation might be,” as long as immunotherapy follows." {my underlined emphasis} 
Dr. Weichselbaum's paper is here: "Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance," Oncotarget, Zheng et al., June 7, 2016.
The majority of cancer patients respond poorly to either vaccine or checkpoint blockade, and even to the combination of both. They are often resistant to high doses of radiation therapy as well. We examined prognostic markers of immune cell infiltration in pancreatic cancer. Patients with low CD8+ T cell infiltration and high PD-L1 expression (CD8+ TloPD-L1hi) experienced poor outcomes. We developed a mouse tumor fragment model with a trackable model antigen (SIYRYYGL or SIY) to mimic CD8+ TloPD-L1hi cancers. Tumors arising from fragments contained few T cells, even after vaccination. Fragment tumors responded poorly to PD-L1 blockade, SIY vaccination or radiation individually. By contrast, local ionizing radiation coupled with vaccination increased CD8+ T cell infiltration that was associated with upregulation of CXCL10 and CCL5 chemokines in the tumor, but demonstrated modest inhibition of tumor growth. The addition of an anti-PD-L1 antibody enhanced the effector function of tumor-infiltrating T cells, leading to significantly improved tumor regression and increased survival compared to vaccination and radiation. These results indicate that sequential combination of radiation, vaccination and checkpoint blockade converts non-T cell-inflamed cancers to T cell-inflamed cancers, and mediates regression of established pancreatic tumors with an initial CD8+ TloPD-L1hi phenotype. This study has opened a new strategy for shifting “cold” to hot tumors that will respond to immunotherapy."
In Moffitt Cancer Center's upcoming SITC 2016 poster presentation of its PV-10-related work, "Intralesional injection with rose bengal and systemic chemotherapy induces anti-tumor immunity in a murine model of pancreatic cancer," (Provectus press release) (a) Rose Bengal more than likely was administer before chemotherapy (not after, like in Weichselbaum's murine model work of radiation plus checkpoint inhibition), and (b) PV-10 plus chemotherapy induced, elicited, generated, etc. anti-tumor immunity, unlike Weichselbaum's work.

October 19, 2016

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

Image source
Updated below: 10/19/16.

What is PV-10's clinical value proposition to Merck & Co. (pembrolizumab, Keytruda®) and Bristol-Myers (nivolumab, Opdivo®), among other Big Pharma in the oncology space? In no particular order, is it, among other things:
  • As a primer, front-end, turner-on-of-the-engine, stepper-on-the-gas pedal, [insert your favorite over-, weakly- or wrongly-used analogy or metaphor],
  • Synergism, where from an efficacy perspective 1 + 1 >> 2,
  • Agnosticism to tumor type/cancer indication,
  • Safety profile, and/or
  • Turning cold tumors hot, and hot tumors hotter?
Industry discussion appears to recognize immune checkpoint inhibitors work — when/where they do work — in a portion of cancer patients. Is the summary clinical value proposition of PV-10 in combination with Keytruda/Opdivo to make the latter (i.e., these anti-PD-1 drugs) work better when and where they work? Or is PV-10's proposition, the more powerful one, to show it can make Keytruda/Opdivo work better where they do not work?

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

For this blog post, consider, among other things, two combinations with pembrolizumab (for advanced melanoma):
  • Intralesional* agent electroporation with plasmid interleukin-12 (epIL-12) (ImmunoPulse, OncoSec), the combination of a medical device and an investigational agent, and
  • Intratumoral* agent toll-like receptor 9 (TLR9) agonist SD-101 (Dynavax), an investigational agent too.
* Intralesional = intratumoral

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

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

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

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

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

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

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

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

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

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

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

October 4, 2016


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

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

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

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

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

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

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

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

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

September 26, 2016

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

Updated below: 9/26/16 {twice}, 9/28/16 and 9/30/16.

Click to enlarge
Updated (9/26/16): According to the Pancreatic Cancer Action Network, there are three chemotherapy drugs approved by the United States Food and Drug Administration (FDA) for the treatment of pancreatic cancer: albumin-bound paclitaxel (ABRAXANE®), gemcitabine (Gemzar®) and fluorouracil (5-FU).
"Gemcitabine (Gemzar®) was approved in 1996 for the treatment of unresectable pancreatic cancer. Studies have also shown that there is a benefit to using gemcitabine after surgery for pancreatic cancer. Prior to gemcitabine, fluorouracil (5-FU) was used as the standard treatment for unresectable pancreatic cancer. Both of these drugs are still used today. 
Most recently, in September 2013, albumin-bound paclitaxel (ABRAXANE®) was approved to be used in combination with gemcitabine (Gemzar®) as first-line treatment for metastatic pancreatic adenocarcinoma, the most common type of pancreatic cancer. 
In addition to the three FDA-approved drugs, FOLFIRINOX, a combination of three chemotherapy drugs (5-FU/leucovorin, irinotecan, and oxaliplatin) is commonly used in the treatment of metastatic pancreatic adenocarcinoma. In 2010, a Phase III clinical trial showed positive results for patients treated with FOLFIRINOX. Due to the results of this study, FOLFIRINOX is also considered a standard treatment option for patients with metastatic pancreatic cancer. However, patients treated with FOLFIRINOX may experience more severe side effects than those treated with gemcitabine alone, so this combination is usually given to patients who are healthy enough to tolerate the potential side effects."
Abraxane is made by Celgene. Gemzar is made by Eli Lilly. Provectus previously showed the combination of 5-FU and PV-10 for hepatocellular carcinoma in murine model work (SITC 2012).

Updated (9/26/16): I believe the systemic chemotherapy used in Moffitt's work is gemcitabine (Gemzar®), which by now is produced by generics manufacturers.

Some recent information on the competitive landscape for pancreatic cancer:
  • "Eli Lilly's chemotherapy drug Gemzar (gemcitabine) is widely considered the standard of care for pancreatic cancer. Generic gemcitabine is available from numerous companies" {January 2014 source},
  • "In the past, companies have combined various targeted treatments with gemcitabine in an attempt to increase their survival benefit. These efforts include Bristol-Myers Squibb/Eli Lilly's Erbitux, Roche's Avastin, Pfizer's Inlyta, and Amgen/Bayer's Nexavar, among others. Unfortunately, none of these drugs has shown a significant survival benefit when combined with gemcitabine" {above source},
    • "Frontline therapies for patients with metastatic pancreatic cancer have advanced in the past 5 years, with the FDA approval of nab-paclitaxel (Abraxane) plus gemcitabine (Gemzar). These advancements branch off the established treatment paradigm of gemcitabine monotherapy, which showed a significant extension in overall survival (OS) compared with 5-FU alone in a phase III study."
  • "Pancreatic cancer is a particularly tough cancer to treat and a number of other companies have failed in their efforts to develop an effective treatment. In February, Incyte halted trials of its drug Jakafi in solid tumors, after a Phase 3 study in pancreatic cancer failed to show efficacy. And this past May saw pancreatic cancer immunotherapies from NewLink Genetics and Aduro Biotech fall short of goal in Phase 3 and Phase 2b trials, respectively" {September 2016 source}, and
  • Momenta Pharmaceuticals has decided to end development of necuparanib, an experimental drug for advanced pancreatic cancer and the biotech's lead clinical candidate, according to a regulatory filing submitted Thursday. Enrollment in a Phase 2 trial testing necuparanib in combination with Celgene's Abraxane was halted earlier this month after an independent data safety monitoring board concluded treatment didn't demonstrate a sufficient level of efficacy {above source}.
Updated (9/28/16): In 2011 co-founder and former Chairman and CEO Dr. Craig Dees, PhD presented Provectus' murine model work examining PV-10's "immunologic potential in treating melanoma and other cancer indications including liver, pancreatic and colorectal cancer." See several pertinent slides below.
Click to enlarge
Click to enlarge
Click to enlarge
Updated (9/30/16): H/t @bradpalm1: Vitamin D + immunotherapy + chemotherapy..."Physicians and Physicists Join Forces to Fight Pancreatic Cancer," The Wall Street Journal, September 25th, Ron Winslow
"The team is planning a clinical trial soon in which patients who are candidates for pancreatic-cancer surgery first will be treated with synthetic vitamin D, chemotherapy and Bristol-Myers Squibb Co.’s cancer immunotherapy Opdivo. Opdivo is one of the new so-called checkpoint inhibitors that are transforming treatment of cancers such as melanoma and lung cancer. The drugs work by releasing brakes on immune-system T cells, enabling them to pursue tumor cells." 
Bristol-Myers also is combining Opdivo with several other companies and drugs to treat pancreatic cancer, such as Celgene (Abraxane/Paclitaxel protein-bound) and Aduro Biotech (CRS-207 and GVAX)*. Opdivo combination trials for pancreatic cancer on include at least eight studies.

* CRS-207 and GVAX failed as a regimen for pancreatic cancer.

September 14, 2016

Life & Death, and the Biggest Checkbook

Without being in the situation (because, um, close to doesn't cut it), a Provectus shareholder cannot fully evaluate the possible quality/quantity of potential introductory, follow-up and/or advanced meetings Provectus could/may have had, and/or could/may be having, with prospective Big Pharma partners about combination or cocktail therapy for end-stage cancer patients. The question a shareholder asks of course is to what extent is Big Pharma interested in and/or kicking the tires of chemical small molecule, ablative immunotherapy PV-10 for potential combination with their respective systemic immunomodulatory or targeted cancer agents, with the goal of such discussions being to hopefully and eventually arrive at a clinical combination and business collaboration.

Some shareholders may have read about or heard rumors of recent discussions with Big Pharma that on the surface seem to denote interest. I cannot speak to that; all I can observe are the single or multiple, domestic or international, visitors and visits to or brush bys this blog via corporate-named routers from Amgen, Astellas Pharma, Bristol-Myers, F. Hoffmann-La Roche, Genentech (Roche), Gilead Sciences, Johnson & Johnson, MedImmune (AstraZeneca), Merck and Co., Novartis, Onxeo, and Pfizer. Visits could suggest blog reading. Brush bys may be the result of Internet search engine keyword searches. There could be other or more visits from Big Pharma and/or biotech folks via visitors' Internet service providers but I have no way of telling other than the occasional, reasoned guess about a location, such as Kenilworth, New Jersey (possibly for Merck and Co.) or Abingdon, Oxfordshire, UK (possibly for PsiOxus Therapeutics).

What is it that we really know about Provectus' progress, if any, towards a so-called co-development transaction that company management has insinuated, implied, suggested or said is imminent, around the corner, near-term, close, etc. for several years now (the volume of which seems to have grown louder this quarter)?

As early as the summer of 2014, I recall hearing of entreaties regarding combination studies to Merck and Co. by a strategic advisory board member and an oncology key opinion leader on behalf of Provectus. There also were rumors of several possible related interactions over time, such as a visit by a Merck executive to a medical conference to hear a Moffitt Cancer Center speaker talk about PV-10, and preclinical oncology work by the Big Pharma using off-the-shelf Rose Bengal.

As 2015 turned to fall, with apparently no partner(s) in sight, let alone in hand, to pay for a checkpoint inhibitor-based clinical combination study involving PV-10, Provectus issued press release "Announces Initiation of Phase 1b/2 Clinical Trial to Study PV-10 in Combination with Immune Check Point Inhibitor Pembrolizumab" in September to commence its own clinical combination work on advanced (metastatic; Stage IV) melanoma. The trial protocol for this study obviously was developed well before the announcement. There was no need for a supply agreement with Merck (i.e., no official collaboration) because pembro already was approved for the solid tumor cancer indication under investigation, and its trial cost thus would have been reimbursed. Provectus was going to be the sole sponsor of the clinical work.

The press release laid out management's then preclinical, clinical and intellectual property management plan to present and protect PV-10 as the ideal (perfect?) primer or front-end for Big Pharma's so-called checkpoint inhibitor backbone for treating end-stage cancer patients:
At the time Provectus management seemed to have a heightened sense of expectation Pfizer would make a big deal of the patent award, which did not materialize save for a tortured inclusion of Pfizer's name in a press release. This perspective of "let's not undermine Pfizer" emanated at the time from both COO and Interim CEO Peter Culpepper and CTO Dr. Eric Wachter, PhD, who preferred I not blog about the patent award date (that I had learned about several weeks earlier via the US PTO's Patent Application Information Retrieval website) until after the patent award was awarded (patent awards are made on Tuesdays by the PTO). See Pfizer's Just Not That Into You (August 21, 2015) and Intellectual Property (August 18, 2015) on the blog's Archived V News page,
  • The initiation of the company's own melanoma combination therapy study program in September was Step #2.
By sponsoring/conducting the trial by itself, Provectus owns all study data (per standard contract language applicable to clinical investigators, trial sites, CROs, etc. involved in the study). It will be customary to report top-line data in public venues like biomedical conferences and journals (e.g., potentially a 1Q17 conference); however, the full data set remains under the company's control, which is typical of any sponsored clinical trial. The detailed clinical data regulators ultimately would review, however, remains solely the property of Provectus, unless the company enters into a deal that affords access or rights to a third party, and
  • Step #3 was the completion/publication in May 2016 of Moffitt Cancer Center's mechanism of action work in melanoma on PV-10.
Entitled "Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1," Eric noted its importance and context on Provectus' August 10th 2Q16 business update call, saying that after "...years of work conducted by Moffitt Cancer Center both in animals and is now clearly accepted that tumor ablation with PV-10 can lead to stimulation of a useful anti-tumor immune response." In other words, PV-10 is an immunotherapy. See January 19, 2016 blog post PV-10 is an immunotherapy and May 12, 2016 blog post Moffitt: IL RB in melanoma elicits tumor immunity via activation of DCs by the release of HMGB1.
But by this time, the spring of 2016, there still was no co-development transaction (let alone multiple ones the company thought, and still thinks, could materialize). Possible explanations, aside from simply lack of interest on the part of Big Pharma, might have included to a greater or lesser degree:
  • The September 30, 2015 approval of the combination of nivolumab and ipilimumab for patients with advanced melanoma (BRAF V600 wild-type), which may have temporarily stymied interest in combination therapies for this indication,
  • The need to at least wait for the October 2015 approval of fellow intralesional (IL) or oncolytic therapy talimogene laherparepvec (T-Vec, Imlygic®),
  • Pfizer saying, at the January 2016 JP Morgan Healthcare conference, that is would bypass melanoma for its checkpoint inhibitor, anti-PD-L1 agent avelumab, to pursue "less competitive" cancer indications. If Pfizer were uninterested in melanoma for avelumab as a monotherapy, it would seem to suggest the Big Pharma also would be uninterested in combination therapy just for melanoma too, and
  • The growing realization checkpoint inhibitors no longer were/are the panacea the pharmaceutical industry and its constituent sycophants first thought they were. Clear, unequivocal limitations include:
    • Applicability to 20-30% of cancer patient population,
    • Ineffectiveness in less immunogenic cancer indications (i.e., cold or colder tumors),
    • Reaching toxicity and adverse event limits of checkpoint inhibitors (and targeted therapies) as both monotherapies and combination therapies (but since they are better than chemotherapies, management of such has grown acceptable), and
    • Realizing another set of tools, so-called primers or front-ends (i.e., co-stimulatory, agonists, "turn on the engine," "press the gas pedal," etc.), were necessary to combine with "back-end" co-inhibitory blockade.
If I had to summarize the above "explanations" in hopes of elucidating why a co-development transaction has not yet materialized for Provectus, I now might solely focus on the need for Provectus to:
  • Move beyond melanoma to show combinatorial, primer or front-end relevance in other solid tumor cancer indications, and
  • Establish predictive tools or measures of treatment success in a nascent, overhyped era of precision medicine, like immune biomarkers derived from both peripheral blood and tumor tissue, also in multiple solid tumor cancer indications.
Nevertheless, one could reasonably argue Provectus and other biomedical researchers have made preclinical, clinical and intellectual property management progress toward presenting and protecting PV-10 as the perfect primer or most complementary front-end to most if not every major cancer treatment category: chemotherapy, radiation therapy, targeted therapy, and immunotherapy.
  • Preclinical data related to combination therapy
  • Clinical data related to combination therapy
    • PV-10 + radiotherapy
  • Intellectual property related to combination therapy
It is possible at least three Big Pharma could have some level of interest in pairing PV-10 with their immunotherapy agents: Pfizer (anti-PD-L1 with Merck KGaA), Merck & Co. (anti-PD-1), and Bristol-Myers Squibb (anti-PD-1).

Pfizer Inc. Over at least the last five years Pfizer has been consistently wrong or late to the oncology/immuno-oncology (I-O) game:
  • November 2014: Pfizer buys (out-licenses) an anti-PD-L1 agent, later named avelumab, from Merck KGaA for an $850 million upfront payment and other considerations. Merck gets anti-PD-1 drug pembrolizumab approved for metastatic melanoma as Keytruda® in September 2014, while Bristol-Myers gets its anti-PD-1 relative nivolumab approved for the same indication as Opdivo® in December of the same year,
  • September 2015: Bristol-Myers gets its combination of anti-CTLA-4 Yervoy® and anti-PD-1 Opdivo® approved for metastatic melanoma. Following Bristol-Myers' non-small cell lung cancer trial failure of Opdivo as a monotherapy, Wall Street analysts peg AstraZeneca's combination of anti-CTLA-4 tremelimumab (previously in-licensed from Pfizer) and anti-PD-L1 durvalumab as capable of potentially taking market share away eventually from Bristol-Myers' approved combination therapy. See Pfizer sale/outlicense above,
Click to enlarge
  • January 2016: Having admitted the company was late to immuno-oncology, Pfizer says during the JPMorgan Healthcare Conference that it will be "a leading player in the second wave of combinations." As of this writing, Pfizer has 8 open oncology combination studies, compared to 180 for Merck and 132 for Bristol-Myers, and
  • August 2016: Pfizer buys Medivation for $14 billion, more than 50% higher than Sanofi's initial April bid in April.
But, Pfizer is the one of these three Big Pharmas with the biggest checkbook, and into August 2016 still was working with Provectus to advance their joint oncology combination therapy patent portfolio (one patent and two patent applications). See More Intellectual Property Management (September 11, 2016) and Is Pfizer paying more [IP] attention to Provectus? (September 2, 2016) on the blog's Current News page.

Pfizer seemed to have entered Provectus' picture around late-2010 to early-2011 when Provectus and it appeared to have begun writing and then initially filing (in March 2011) the combination therapy patent application that eventually would be jointly awarded to them by the U.S. Patent and Trademark Office (US PTO) in August 2015 as "Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer" noted above.

Initial interest in and the rationale for combining an immunomodulatory agent (anti-CTLA-4 compound tremelimumab) with PV-10 began with Provectus strategic advisory board member and Pfizer executive Dr. Craig Eagle, MD, who apparently conceived of the idea apart from Provectus' co-founders. Eagle reasoned an antigen cascade or "storm" ("antigenization") would be kicked off or initiated by the substantial size and scope of tumor destruction initially caused by PV-10 ablation (injection). The subsequent PV-10-based antigenization would induce an immune response -- otherwise known as priming -- that then could be boosted by the immunomodulatory (or targeted) agent. CTO Dr. Eric Wachter, PhD noted as much in a recent US PTO filing when he wrote "President" and co-founder Dr. Tim Scott, PhD did not anticipate tumor ablation would have "a downstream immune system priming systemic effect" and that this systemic priming effect could "synergize with known systemic agents."

Ironically, from today's perspective and pharmaceutical industry focus on oncology combinations and cocktails, it would seem Eagle thought enough of PV-10 to suggest its combination with anti-CTLA-4 agent and ipilimumab relative tremelimumab, but not enough to expansively protect Pfizer's interest in the ensuing combination therapy patent. According to Provectus, Pfizer does not benefit from its co-ownership of the combination therapy patent portfolio unless it acquires the company.

But, as I wrote before, Pfizer has the biggest checkbook -- if it wishes to open it -- in the event it again is late to the I-O game by not initially entering into a co-development relationship with Provectus before another Big Pharma does.

Merck & Co. Anti-PD-1 drug pembrolizumab (trade name: Keytruda®), first approved in for patients with advanced melanoma in September 2014, breathed new life into Merck's oncology franchise almost 18 months after current head of R&D Dr. Roger Perlmutter, MD, PhD re-joined this company from Amgen in March 2013.

In a Barron's August 31st article entitled "Merck: Lung Cancer Lead Depends On “How Smart It Plays Its Hand,”" Bernstein analyst Tim Anderson said:
"One of the frequent criticisms with MRK’s I/O program has been that, relative to competitors like BMY/AZN and Roche, its “combination” strategy is less clear, with many believing MRK could be left in the cold over the long run because of this. This is too simplistic of a view, in our opinion. 
MRK has already placed its bets on “chemo combo” through the earlier initiation of trials like Keynote-189 and Keynote-407. In the area of CTLA4 combinations, we believe the chances are high that MRK will soon initiate a phase 3 development program (exact scope unclear) if only to hedge its bets in the event that trials like Checkmate-227 and MYSTIC/NEPTUNE are positive. 
While the onus is on BMY and AZN to fully validate CTLA4 combinations, all MRK has to do is imitate given its sudden lead in the monotherapy 1L lung cancer market that came about through the very different fates of Keynote-024 and Checkmate-026. 
In other potential combination areas with anti-PDx therapies and “3rd generation” agents (e.g. OX40, GITR, IDO, and more) the playing field is more level across the different drug companies. Like its competitors, MRK already has various assets in development – either owned in entirety or accessed through partnership. Progress with almost all of these later generation drugs, across all companies, has seemed to be on the slower side; activity in a single-agent setting, for example, has often seemed underwhelming, in contrast to the single agent activity seen with the anti-PDx’s and anti-CTLa4′s. 
Lastly, even if “combination therapy” comes to fruition and the data is compelling (whatever the regimen), there will likely be the attendant trade-offs of incremental toxicity and higher cost. Therefore, it seems likely that some segment of the 1L lung cancer market will continue to exist for anti-PDx monotherapy, where MRK has a first-mover advantage. 
On balance, we continue to think investors under-appreciate the potential durability (and value) of MRK’s coming lead in 1L lung cancer. Part of this depends on how smart MRK plays its hand from here."
I recounted above what I believe is Merck's historical curiosity or interest (is there a better descriptor?) in PV-10. Below is a quickly constructed, cursory overview of combination collaborations (e.g., announced, supply agreements only, etc.) between Merck and other companies for pembrolizumab in advanced melanoma.
Click to enlarge.
A search of for "pembrolizumab combination melanoma intratumoral" yields six open studies; there are three other trials for different indications (a total of 9). "Pembrolizumab combination intralesional" yields two trials (PV-10, T-Vec).

What kind of agent is Merck searching for to pair with pembrolizumab? What defines an ideal drug partner for pembro? One way to answer these questions is to consider former Moffitt and current NYU Langone Medical Center key opinion leader's comments to me that (paraphrasing) the utility of a primer is simply its ability to synergize with the immune agent in question in terms of clinical effect when given prior to the second agent. Moffitt data showing the strength of the systemic responses PV-10 can stimulate (i.e., efficacy of PV-10 plus a checkpoint inhibitor >> efficacy of the checkpoint inhibitor alone) should make this/his point). See August 17, 2014 Immune Surveillance.

Another way is to recount Moffitt's Dr. Vernon Sondak, MD's (and Provectus consultant's) characterization of PV-10; see June 29, 2014 blog post Properties of PV-10:
  • Simple to store, handle and use and reuse,
  • Modest local toxicity and minimal to no systemic toxicity,
  • Rapid and complete induction of necrosis/antigen release in injected lesions,
  • Excellent healing of the injected site after tumor necrosis, and
  • Reliable and reproducible induction of regional and systemic immune effects capable of destroying occult tumor cells, "bystander lesions" and distant metastatic lesions regardless of prior treatments.
If Merck settles on what it believes to be a more ideal partner for pembrolizumab, it further breathes life into its cancer immunotherapy franchise. As such, I am intrigued by Merck's most recent collaboration with Biothera, which pairs pembro with a pathogen-associated molecular pattern-based (PAMP-based) compound. PAMPs are "molecules associated with groups of pathogens, that are recognized by cells of the innate immune system." It would seem Merck is creeping closer and closer to understanding how to turn (induce) cold or cold tumors hotter (via Biothera's PAMP) so as to boost the immune response subsequently generated by pembro.

Well, PV-10 could be called a DAMP-based compound. "Damage-associated molecular pattern molecules (DAMPs) also known as danger-associated molecular pattern molecules, are host molecules that can initiate and perpetuate a noninfectious inflammatory response." And, DAMPS are recognized by both the innate and adaptive immune systems. See Immunological “ignition switch” (August 26, 2016) on the blog's Current News page.

Click to enlarge. Image source
Bristol-Myers Squibb. And then there's Bristol-Myers, which has the most to lose of these three Big Pharmas with its interchangeable, anti-PD-1 drug nivolumab (Opdivo®), also approved initially for melanoma shortly after Merck's version. Bristol executives faced a "near-death experience" on August 5th that continues by virtue of a declining share price that currently shows no sign of abating. See August 30, 2016
The Day Big Pharma's Earth Stood Still, which was visited by several times by Bristol-Myers Internet Protocol addresses (among other visits to this blog).

If nivolumab and pembrolizumab are interchangeable, and Bristol-Myers has no meaningfully different marketing department than Merck's, Bristol-Myers' "death" potential remains viable so long as it does not find an ideal combination partner for Opdivo® and Merck does. Should cancer combinations (or cocktails) rule the day for late-stage cancer patients for the time being, the ideal primer or most complementary front-end for a combination therapy would seem to be the greater or greatest differentiation. See February 18, 2015 The Early Obsolescence of Checkpoint Inhibitors. Own it, live. Lose it, die.