October 6, 2013

$PVCT Going For The Deep Ball

My post entitled Counting Down elicited several inquiries from blog readers exclusively focused on whether or not Provectus had submitted a breakthrough therapy designation application ("BTD") to the FDA. The collection of opinions I sought over the last few days varied from "no" to "yes." Dot 1: I lean towards "yes."

On Friday, I was trying to verify a rumor that Peter was in China. He previously had been in Europe (Amsterdam) attending ECCO 2013, followed up by various investor and shareholder meetings (from what I gathered listening to several people). Dot 2: Follow-up suggested it was not likely he in China, but was he somewhere with the Chinese (i.e., Eddingpharm and/or Hisun-Pfizer)?

Speaking of ECCO 2013, on Friday, two more articles emerged from the conference about Provectus' poster presentation: FirstWord Pharma's Intralesional PV-10 Shows High Response Rate in Advanced Melanoma, Evidence of Systemic Effects and ecancer News' PV-10 in Metastatic Melanoma: blistering predicts good outcomes. The latter was written by the same author who penned Wednesday's PharmiWeb.com's Metastatic Melanoma: blistering in PV-10 treatment predicts good outcome. Like with the first article, there were some interesting content and quotes, by Dr Agarwala and, this time, Eric.

"“The principle is that this agent has a local chemoablative effect, one where we believe it enters into lysosomes causing local necrosis, and sometimes blistering of the lesion -- and then, in some patients, a systemic effect that we believe is immunologically mediated,” Dr. Agarwala explained. Further evidence of systemic effects, he noted, comes from a 54% complete plus partial response rate in uninjected “bystander” lesions." FirstWord article. Bold emphasis mine.

"Dr. Agarwala proposed 3 possible scenarios for PV-10 use -- for if and when it receives approval. First, it might be used in patients who are refractory to all other therapies and who have injectable disease. Second, it might be used in patients who have injectable lesions but who are not eligible for systemic therapy (e.g., the elderly or those with comorbidities). Third, it might be used in combination with other therapies (e.g., ipilimumab or nivolumab or both). “Of course, all of these need to be tested in clinical trials,” he said. A further option for PV-10 use, Dr. Agarwala added, would be in an attempt to turn unresectable lesions into resectable ones. “Beyond this, many of my surgical colleagues are interested in the idea of using PV-10 to stimulate the immune system before surgery to potentially lower the odds of recurrence,” he commented." FirstWord article. Bold emphasis mine.

"“Now we have the mechanistic explanation for our bystander effect, that we’re inducing a highly-specific T cell mediated response,” said Wachter. Data on the immunological mechanism of action, he added, suggested that PV-10 might be particularly relevant for patients with inhomogeneous clonal populations." ecancer article. Bold emphasis mine. As clarification, according to Eric, "inhomogeneous" and "heterogeneous" have equivalent meanings in this context.

You may recall my posts on tumor heterogeneity, such as $PVCT: #Tumor Heterogeneity. I’ve previously written that to understand PV-10 is to understand the relationship between chemoablation and immune-mediated signaling. It's what Craig means when he says the immune system responds in direct proportion to the degree of insult. Think of PV-10 chemoablation as the proxy for the degree of insult, which is rapid, complete and durable in the case of PV-10. But when Craig describes his approach in this way, what is he really getting at? How did he approach tackling or solving tumor heterogeneity?

Tumor heterogeneity is a critical problem. In any given cell there are, say, 15,000 unique mRNAs at any given second. A few seconds later, illustratively, 15,000 new ones. There are, for example, at least 15,000 to 20,000 unique proteins on a membrane surface at any one time. These change continuously. Does picking one of them to form the basis of a cancer treatment make sense? Does targeting a specific antigen as a holistic solution make sense? Heterogeneity is so wide, trying to target a specific antigen might be tough if not hopeless task. A needle in a haystack? Maybe a needle in an entire whole galaxy. Treating as many tumors as you can with PV-10 intratumorally achieves two significant positive outcomes. First, you lower the patient's overall tumor burden so as to allow the immune system to work better. Second, you allow more of the heterogeneous antigens (from the injected heterogeneous tumor) to be seen by the immune system. The more tumors treated by PV-10 the better.

Consider a 2012 article by Zhang and Austin, Physics of Cancer: The Impact of Heterogeneity (Annual Review of Condensed Matter Physics): "It is a common mistake to view cancer as a single disease with a single possible cure which we have just not found yet. In reality cancer takes on many forms that share a common symptom: uncontrolled cell growth and successful invasion of cancer colonies to remote regions of the body. The key reason why we may never be able to defeat cancer may lie in the extreme heterogeneity of the population of the cells in a tumor: there is no one magic bullet." This link, if you click on it, automatically will download a copy of the article.

Friday's statements dovetail with Wednesday's article's final sentence: "Provectus Pharmaceuticals believe they now have sufficient data to seek regulatory approval for PV-10." I've written about this before, and it seems even more clear. Management is seeking approval for the use of PV-10 in patients (metastatic melanoma Stage IIIb and IIIc) who are refractory to all other therapies and who have injectable disease because the data showed results: "...[f]or all subjects, BORR was 51% (26% complete response, 25% partial response) with the amount of tumour burden accessible to PV-10 injection prognostic for outcome." Furthermore, Provectus demonstrated clinical response predicted outcome in another way: "“If blistering occurs you can reassure patients that they’re likely to achieve a good response. It provides further evidence for an immunological basis for the mechanism of action.”" Dot 3: Management is seeking approval of PV-10 for this "narrow" label or claim, something that has become more obvious, at least to me, only over the last few months.

But how does Dot 3 relate to BTD? It's here where and about this I am fuzzy. Is Provectus seeking outright approval of PV-10, for the narrow claim above, under the BTD umbrella or separate from and in addition it? Did management simply move beyond the SPA, obfuscating its non-pursuit pursuit, to focus on what they've been trying to do since 2010, which is/was to convince the FDA to approve PV-10 for the narrow label of patients who are refractory to all other therapies and who have injectable disease.

I don't think just asking or focusing on whether the company submitted the/a BTD application alone or in a vacuum is productive or fulfilling. What else would be necessary to gain approval? Completing certain key elements of a new drug application ("NDA") filing? It's a topic I've queried management about for several months.

If Peter continues to speak with the Chinese (and the Indians), what then would be the ramifications on regional deal valuations and payment components of outright approval of PV-10? Again, it gets a little fuzzy here for me. Provectus is seeking outright approval of PV-10 for patients who are refractory to all other therapies and who have injectable metastatic melanoma, the company's lead indication. Yet, the lead indication for discussions with the Chinese and Indians is liver cancer ("HCC," or hepatocellular carcinoma). What then are the ramifications of an approval for melanoma, and/or BTD for it, on discussions related to HCC?

You'll recall Peter's slip of the pen, so to speak. In my post entitled And Now For Something Completely Different: $PVCT I wrote: Peter's TWST transcript revision is interesting. It was changed from "So our goals are to be in a Phase III trial in melanoma or submitting for FDA approval, and to be in Phase II in liver cancer, potentially with breakthrough therapy designation, because we have also filed the application for breakthrough therapy designation in both the melanoma and liver indications" to "So our goals are to be in a Phase III trial in melanoma or submitting for  FDA approval, and to be in Phase II in liver cancer, potentially with breakthrough therapy designation, which means an application for breakthrough therapy designation in both the melanoma and liver indications." Dot 4: How can regional license discussions advance on the basis of the sparse liver information made available by Provectus thus far?

I'm not saying the company has submitted BTD applications for melanoma and liver cancer. Still, what happened to progress towards the expanded Phase 1 HCC trial comparing sorafenib and sorafenib plus PV-10? Haven't one or a couple of patients (?) or more (?) been enrolled and treated? Haven't more sites (?) been added to the existing ones in San Diego (Sharp Memorial Hospital) and Florida (The Southeastern Center for Digestive Disorders & Pancreatic Cancer)?

In my investment letter posted on Seeking Alhpa, I wrote in regards to if I am wrong what would that scenario look like, management could be unable to monetize Provectus at a valuation commensurate with their innovation. In his TWST interview, Peter said management believes they "…could potentially do something along the lines of a Celgene-Abraxis type transaction, where Celgene acquired Abraxis for $2.9 billion upfront…" Bridging the valuation gap between Friday's $113 million market capitalization and a multi-billion payout will require definitive regulatory clarity, sizable commercial validation, and a copious amount of stock market exuberance. Dot 5: What exactly are the terms of a China deal (and/or of an Indian one, which I think mirrors the Chinese deal, or vice versa) in light of a focus on liver as the lead indication rather than melanoma?

I presume management is striving to protect the economics, particularly for HCC, which is the third leading cause of deaths related to cancer in the world. I had heard, albeit not verified by any stretch, that regional value components were in the range of $10 million upfront and $40-50 million upon some indeterminate regulatory clarity. That seems light to me, which makes me wonder just exactly what is management negotiating (and seeking) and how much money gets unlocked when regulatory clarity arrives.

A Hail Mary pass, "a very long forward pass in American football, made in desperation with only a small chance of success," by definition, is a deep ball (in U.S. football parlance). A deep ball is not a Hail Mary pass. A deep ball is a pass attempt over 20 yards in distance, and can be a key aspect part of a successful offensive strategy. With good to great X and Z wide receivers, defenses can't necessarily stack the box to stop the run, or overly focus on the slot receivers or tight ends running routes in the middle of the field. Of course, you have to have a good running game to which you commit, and capable slot receivers/tight ends. But well schemed offenses thoughtfully employing deep balls catch defenses napping and often lead to touchdowns when well executed.

No comments:

Post a Comment