It's 2016: Intralesional therapy [for oncology] is "here to stay"

(H/t a regular hatter for the article heads-up and link)

Melanoma, intralesional (IL) agent for oncology, and PV-10 key opinion leader Dr. Sanjiv Agarwala, MD of St. Luke’s Cancer Center (and a HemOnc Today editorial board member) made his presentation Current Trials with Oncolytic Agents at the HemOnc Today Melanoma and Cutaneous Malignancies conference on Friday in New York.

In a March 19th article by Alexandra Todak entitled Intralesional therapy ‘here to stay’ for melanoma, Agarwala said the following.

About Provectus' pivotal Phase 3 trial entitled PV-10 vs Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma:

“If we’re going to show monotherapy with PV-10 works, you have to design a randomized trial. It is not easy to design a randomized trial for a monotherapy intralesional agent, when you have all of these drugs available. This trial is designed in a very specific way, and it will be very interesting to see the results of this trial compared to the talimogene laherparepvec [Imlygic, Amgen] trial, because that trial was designed in a different era.”

About the role of IL agents in a physician's toolkit:

“There is no getting away from the fact that even monotherapy with intralesional agents for the right patient population produces good clinical results. The question is, in what setting are you going to use it? For us, in the medical oncology world, whether we will pick this first or not is a bit of a question.”

About the utility of IL agents for later-stage (i.e., advanced or metastatic) melanoma patients:

“We’ve been able to now make an intralesional therapy applicable to not only patients with M1a disease, but also to patients with M1b and M1c disease. So, patients with multiple metastatic sites might be able to benefit.”

About the combination of IL agents with other cancer therapeutics and therapies like immune checkpoint inhibitors; Provectus' Phase 1b/2 program in this regard is entitled PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma:

“Combinations will be the future. Why not find a way to combine modalities that have different mechanisms of action and have, very importantly, nonoverlapping toxicities?” 

And:

“We have to realize intralesional therapy is not going anywhere, it is here to stay. It is a new paradigm for potential combinations, and perhaps in the future the ultimate melanoma regimen is going to be with an intralesional therapy with a systemic, checkpoint inhibitor. Monotherapy also is applicable to specific patients.”

@MoffittNews' PR of its work (study) on $PVCT's PV-10 trending of Twitter

Click to enlarge figure.

Moffitt Cancer Center's PR from yesterday -- Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows -- is trending on Twitter. A screen shot of a recent portion of it is on the left (click the picture to enlarge it). You also can observe it yourself by searching for "Moffitt" and "cancer" and looking at "All" Tweets (this link should do this for you, but it may not).

Several news and web sites have picked up Moffitt's PR thus far; however, I'm more interested in how the PR and story, brief as it currently is (since the only available information for most folks is from the PR), is circulating within and across social media.

At the moment, while the story is trending, it has not yet reached so-called biotech Twitter pros, such as those mentioned in Xconomy's Luke Timmerman's article Who Should Biotech Pros Follow on Twitter? An Update for 2013, and other more recognized names.

As a reminder, the blog is on Twitter here: @PVCTinvestor. Please follow!


Moffitt's PR, in my view, was very compelling, if not astounding. Among other things:

• The use of a single treatment (i.e., injection) of PV-10, which is not [I think] to say one injection, but rather one treatment cycle, which may or should comprise multiple injections and several vials of PV-10 (i.e., a treatment cycle) [Updated: I erred. Moffitt meant a single injection. Multiple injections are required when the initial one is applied incorrectly, or when the target tumor requires more PV-10 because of tumor volume and thus additional injections of drug],
• "Revolutionize:" 1. change (something) radically or fundamentally, "this fabulous new theory will revolutionize the whole of science," synonyms: transform, alter dramatically, shake up, turn upside down, restructure, reorganize, transmute, metamorphose, and
• The mention of boosting the immune response in the blood stream, which I believe is a focus area of Moffitt (but more on that item in a subsequent post).

It will take time for the PR to circulate on social media and elsewhere, and requires follow-up from Moffitt to further broaden and deepen the story, message and narrative. There is no mention of Provectus, as there should not be from an institution focused on translational research.

This story only has begun. There is much more Moffitt has done by way of pre-clinical and clinical studies (e.g., on PV-10, on combinations of PV-10 with other agents, on other indications, etc.). While some of these results no doubt have been provided to the FDA, Moffitt will, in its self-interest, present and promote their findings and the implications and ramifications of such, over time.

As a result, I do not think there will be any immediate impact on share price. The market primarily is focused on regulatory clarity.

But, one could well think PV-10's, and thus Provectus', legitimacy has been established. The FDA, then, follows. From there the share price naturally will react.

Awareness of $PVCT is clearly growing

Provectus' media/communications profile has resulted in this blog being more closely associated with the company, PV-10 and their digital brand. Google "Provectus Pharmaceuticals" and the blog shows up in the top 10 search results returned. Most searches with Provectus + [another word related to oncology or dermatology] may well result in a list that includes one or more blog posts. Thus, tracking unique visitors to the blog, I think, might be a decent proxy for tracking awareness of the company.

At the blog's first anniversary, readership statistics were:

After only 6 months following that date (November 16) -- that is, November 17, 2012 to May 16, 2013 -- readership statistics like unique visitors are nearly the same. Blog readership over the last 6 months has nearly matched readership over the blog's first 12 months.

The point I wish to make here is that while the share price has lagged, awareness of Provectus and PV-10 (measured through unique visitors to this blog) has steadily grown.

An Inflection Point in $PVCT Data

We finally may have reached the long-awaited inflection point in Rose Bengal data (PV-10 & PH-10).

Management thinks 2013 marks a turning-point in how Provectus is regarded by the FDA, Big Pharma and medical community key opinion leaders (KOLs) vis a vis "the data:" MM Phase 1 & 2, Breast Phase 1, HCC/liver Phase 1, inflammatory skin disorder Phase 1/2, Moffitt murine model immunology, Provectus murine model combination therapy, and the compassionate use program.

That's not to say more data is not very desirable: MM Phase 3 (if necessary), breast Phase 2, pancreas Phase 1, skunk works success by Craig with another key indication, Moffitt human immunology, and Moffitt-like immunology (and also toxicity) investigational work into PH-10 by a world-renowned university whose laboratory head has a world-class reputation with the FDA.

Video -- Matastasectomy: Does it make sense in the setting of effective systemic therapy?

I found this video presentation from Dr. Argarwala's 2013 HemOnc Today Melanoma Conference this past March in New York interesting: Matastasectomy: Does it make sense in the setting of effective systemic therapy? by Moffitt Cancer Center's Dr. Vernon Sondak. Provectus some time back had initially facilitated my ability to communicate and interact with Dr. Sondak.

In the presentation, he contrasts and compares surgery PFS and survival times and their respective percentages (PFS6, OS12) to results of various systemic treatment therapies.

Intralesional therapy like PV-10 is the best treatment option for patients who are not amenable to surgery. There undoubtedly will be interest in the pre-operative use of intralesional therapy, but traditional thinking suggests such interest would be on a research basis for the foreseeable future. 

Surgical oncologists, however, including several key opinion leaders, think intralesional therapy PV-10 already is viable for pre-operative use, whether the patient is or is not amenable to surgery.

$PVCT #Horse #Race (updated)

Last updated here.

A $PVCT #China #Travel Vignette

Peter is traveling to China with a small team of people, the composition/functional role/number of whom in situations with him would depend on place/venue/nature of an in-country meeting.

$PVCT: #Godzilla ($PFE) Vs. #Mothra

A blog reader and frequent e-mailer sent me this article: Is AstraZeneca getting ready to buy a pipeline? by FierceBiotech's John Carroll. Thank you.

The story comes from Reuter's Ben Hirschler's article New AstraZeneca CEO plans to invest through tough year. A notable quote:

After reading both of the articles, I could not help but think of Craig's comments and related presentation slide at the Noble conference.

Godzilla versus Mothra?

Let's get it on!

$PVCT: Refractory scalp #Sarcoma

I wanted to dig deeper into Tan and Nehaus’ letter to the editor about the “Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcoma.”

Refractory means “resistant to treatment or cure.” So, refractory scalp sarcoma means a sarcoma already shown to be resistant to other treatments. “A sarcoma is is a cancer that arises from transformed cells of mesenchymal origin. Sarcomas are quite rare. Common malignancies, such as breast, colon, and lung cancer, are almost always carcinoma.”

The article in ANZ Journal of Surgery is just another example of PV-10 have a positive effect on tumors.

The first patient previously underwent surgery, which was followed by radiotherapy to combat his sarcoma. Nodules, however, appeared afterwards in the area to which radiotherapy was applied. Rose Bengal (PV-10) was used, and a complete clinical response was attained.

The second patient also underwent, first, surgery and, second, radiotherapy. Rose Bengal was used with good clinical effect; however, he subsequently developed pulmonary metastases, which is being combated with a systemic chemotherapy. It does not appear from reading the letter that the pulmonary mets was challenged with PV-10.

Some would say, quickly: one success and one failure. More substantively and intellectually honestly: one complete success and one near success. After all, only two patients were treated, with limited frequency (once per patient) and amount of Rose Bengal treatment, with stunning success given sarcomas are rare. I doubt much successful clinical work has been done on patients with fibrous histiocytoma. Yet, here Rose Bengal is with near complete success (both patientdespite limited application.

Both patients were treated with PV-10 after first being treated with surgery and then with radiotherapy, an immunosuppressive therapy.

What happened with the second patient? Maybe surgery removed a certain antigenic type, and the pulmonary mets are another type that does not match. Tumor heterogeneity might be interfering (a topic of a blog entry that I will post in a bit). Maybe all of the high-affinity monoclonal antibodies capable of killing the tumor were killed by the radiotherapy treatment. How the patient was first treated (i.e., surgery, radiotherapy) might precipitate the failure of immune system to ultimately help in the removal of the tumor.

Maybe the patients’ parents didn’t give their now elderly son the proper genes for his immune system to respond. There are a number of these folks in any population, and saving them with any kind of treatment is a near impossibility.

As Craig has long said, and I expect Moffitt to confirm, using PV-10 first, followed if necessary by other treatments is the way to go. In the two cases highlighted by the authors, the approach was backwards. Yet, the “backwards” approach yielded good results on refractory sarcoma. Why backwards? Recall Foote et al.’s past and current work: PV-10 first, followed by radiotherapy. That appears to be the right treatment order.

Still, and to be intellectually honest, we’re talking about only two patients. There is much more to do and much more to learn.

$PVCT: Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcoma (update)

Source here. (Updated 1/31/13: Link updated.)

Click to enlarge figure.

$PVCT: Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcoma

$PVCT: Horse Race (updated)

Last updated here. For the moment, I returned the first group of horses to all being equally close to the finish line. In the second group, India, since my last update, has pulled ahead of Japan.

$PVCT: Horse Race (updated)

Last updated here. The horse race above is a snapshot in time. Horses surge ahead, they fall behind, they come out of nowhere. Sometimes, we don't know the outcome until they cross the wire. I adjusted some of the positions slightly to reflect more nuance and opinion.

$PVCT: China Process

Previously having written about the possible make-up of a potential deal here, below are thoughts about what the process might entail.

Click figure to enlarge it.

$PVCT: The Challenge. The Opportunity. The Total Addressable Market.

Source material: "Black swan theory," Wikipedia. "The black swan theory or theory of black swan events is a metaphor that describes an event that is a surprise (to the observer), has a major effect, and after the fact is often inappropriately rationalized with the benefit of hindsight. The theory was developed by Nassim Nicholas Taleb to explain:

• The disproportionate role of high-profile, hard-to-predict, and rare events that are beyond the realm of normal expectations in history, science, finance, and technology
• The non-computability of the probability of the consequential rare events using scientific methods (owing to the very nature of small probabilities)
• The psychological biases that make people individually and collectively blind to uncertainty and unaware of the massive role of the rare event in historical affairs."

"Taleb regards almost all major scientific discoveries, historical events, and artistic accomplishments as "black swans"—undirected and unpredicted." Taleb introduced black swan events in his 2004 book Fooled By Randomness.

I think the pervasive use of PV-10 -- first, second, last and everywhere in between during the treatment of cancer patients -- as a potential black swan event.

Click figure to enlarge it. Source map here.

Assume:

• A PV-10 treatment price (for the necessary cycles of RB to treat a particular indication), using a number of injections per vial, a number of vials per cycle, a number of cycles per treatment (the number of cycles will vary from indication to indication), the price per vial of PV-10, etc.,
• The treatment of a percentage of annual, global, new incidences of cancer,
• An average annual royalty rate,
• Initial penetration rates that grow to their respective equilibrium levels, and
• Perhaps some fine tuning on a per indication basis (although I am fan of a McKinsey'ish 8-20 to garner a perspective of the size of the potential black swan event.

The result is a very large total addressable market.

My point is this: A dispassionate and objective case can be made for a good return on investment outcome for Provectus shareholders, including myself. My investment, while founded on this outcome, is, however, more focused and a play on the potential of a PV-10 black swan.

$PVCT: Horse Race (updated)

Last updated here. The horse race above is a snapshot in time. Horses surge ahead, they fall behind and, sometimes, they come out of nowhere.

$PVCT: More Data Is Necessary Until It Isn't

On the one hand, Provectus has a $64MM market capitalization (as at Wednesday's closing price). On the other, Moffitt might say PV-10 is the nearest thing they have seen as a cure for cancer, or Pfizer might consider PV-10 the holy grail*. There's a lot of space between those two hands. Cures and grails obviously have not yet translated into a commensurate company valuation. And therein lies the answer, I think. You see it separately with PV-10 and PH-10.

PV-10: Big Pharma clearly recognizes a group of drug compounds have local and distant effects on lesions, substantiating the hypothesis injections of these drugs in local tumor lesions result in systemic effects. PV-10 works more easily and effectively. It took Moffitt time, effort and work to begin to wrap their heads around this "phenomena." In the process, they could confirm the first, second and last solution PV-10 may well be (e.g., a pre-surgery treatment).

PH-10: If the premise is that PH-10 has no toxicity, and that the "normal rules" of treatment do not apply, what then? Even though Provectus likely has sufficient directionally positive clinical data for a dermatology transaction, immunologic MOA characterization work, as I previously wrote about, would be helpful with the FDA in designing toxicity studies appropriate for an approved drug. This work should make dermatology companies more desirous of PH-10. The immunologic MOA characterization work came to the forefront when management was working on the remaining toxicity studies for the FDA. When they had difficulty finding any dose limiting toxicity (DLT) or maximum tolerable dose (MTD), they sought to better understand PH-10's unique lack of toxicity.

The answer? Big Pharma just might need more data than otherwise would have been necessary before pulling the trigger(s).

* "The holy grail for cancer would be to trigger the body’s own immune system to fight off the cancer, so that you somehow stimulate the antibodies in a way that that happens." Fareed Zakaria, Fareed Zakaria GPS

Possible $PVCT Publications In 2013

2012 produced the following investigator & researcher and sponsor abstracts/poster presentations and presentations:

• 2012 Society of Surgical Oncology Annual Meeting (Subject: Immunologic MOA Characterization, Author: Moffitt [several authors], Medium: Abstract/Poster presentation),
• HemOnc Today - Melanoma and Cutaneous Malignancies Conference (MM Phase 2 data, Dr. Merrick Ross, Presentation),
• 2nd European Post-Chicago Melanoma Meeting 2012, Interdisciplinary Global Conference on Developing New Treatments for Melanoma (Final MM Phase 2 Data, Dr. Sanjiv Agarwala, Presentation),
• European Society for Medical Oncology) 2012 Congress (Final MM Phase 2 Data, Dr. Sanjiv Agarwala et al., Poster Presentation), and
• Society for Immunotherapy of Cancer (SITC) 27th Annual Meeting (Immunologic MOA Characterization, Craig et al., Abstract/Poster Presentation).

Expectations for 2013 are:

• Subject: Final MM Phase 2 Data, Authors: Investigators (Agarwala, etc.) & Sponsor (Eric), Medium & Venue: Global Medical Journal
• Immunologic MOA Characterization, Moffitt [several authors], Journals and/or conferences
• HCC Phase 1 Data, Dr. Goldfarb-? & Eric, ?
• Psoriasis Phase 2c Data, Dr. Lebwohl-? & Eric, ?
• Compendium of the Use of Rose Bengal, Eric et al., ?
• PV-10 Compassionate Use Program, Site doctors-? & Eric et al., ?

$PVCT: Horse Race (updated)

The geographies Provectus identified above probably represent the limit of the company's potential oncology end-game partners' disinterest. There likely is no appetite to geographically segment the licensure of PH-10.

$PVCT: Will Management Get A Deal Done In China?

I previously wrote a blog post entitled Can Management Get A Deal Done In China? I used "can" because I thought management could be able to secure a deal; that is, there is the ability to get or the possibility of getting a deal in China done.

Time passes. More dots connect.

I think the question, for over the next few weeks to the next couple of months, now is: Will management get a deal done in China? I use "will" to query management's intention to do this deal, or another.

Existing shareholders and prospective investors, in my view (through discussions with a variety of them), thought or think of "can" as management's ability -- their skill set -- or PV-10's (or PH-10's) ability -- the facets and features of the drug(s). I have never thought that way. Rather, I have examined and focused on the whether management has the process and pieces of sufficient quality and quantity to get a deal or deals done.

Management has been approached and continues to be approached to do deals. Frankly, anyone can do a deal. The real question -- the real perspective -- is whether the deal is a good or great one. Lots of people can and do do bad deals all of the time. Provectus understands better than most, and now better than ever, the value of the company's portfolio of drug compounds.

It seems we are drawing closer and closer to a seminal event, or more.

There have been previous discussions across and around the table about licensing PH-10 and PV-10. I do not doubt those discussions involved numbers, terms and conditions; however, in my experience, such discussions become "more real" or advance when a term sheet materializes.

From what I can gather (and it may well be a rumor), a term sheet has materialized in China. The parameters probably are not too dissimilar from what I wrote here. There is of course lots we do not know.

Who is the prospective Chinese big pharma partner? For example, is the partner on the list below?

Click figure to enlarge it. Source: China's Pharmaceutical Industry - Poised For The Giant Leap. KPMG, 2011.

Is Pfizer involved in some way? Pfizer's presence in China, from sales to R&D to manufacturing, is notable.

Click figure to enlarge it. Source: China's Pharmaceutical Industry - Poised For The Giant Leap. KPMG, 2011.

I previously wrote that regulatory and governmental agency backing in China was crucial. What kind of backing does Provectus and its prospective Chinese pharma partner have? I had the good fortune of participating in a trade delegation to China several years ago (what a treat!), and met a senior member of the Premier's staff. For pharmaceuticals, I would assume the State Food and Drug Administration and the Ministry of Health are germane regulatory and governmental bodies, among others.

If management elects not to do a deal in China yet, what else is there to take its place?