October 18, 2014

"PV-10 delivers greatest effects when all lesions are injected"

The title of an article published this week by medical writer Janet Fricker, who has written several times about PV-10, provided a cogent description of the drug's value proposition for its patient population afflicted with melanoma, and, eventually, I believe, for all solid tumor cancers: PV-10 delivers greatest effects when all lesions are injected, which discussed Provectus' completed Phase 2 trial data presented at ESMO 2014.

Because PV-10 is very safe, the more you give, the more you get. No dose limiting toxicity.

The article frames what might be expected from the upcoming pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma, in large part because of the trial's design whereby all lesions will be injected:
"The latest analysis reported at ESMO reveals that the subgroup of 28 patients who had all their lesions injected achieved a progression free survival of 9.8 months compared to 6.0 months for the seven patients who had a median of five untreated lesions. “The progression free survival of 9.8 months compares favourably with historical progression free survivals of less than 2.5 months for DTIC/TMZ,” commented Sanjiv Agarwala, the first author from St. Luke’s Hospital and Health Network, Bethlehem, Pennsylvania." {Underlined emphasis is mine}
The more lesions into which PV-10 is injected ("the more you give"), the more antigens are created and released, the more antigens then are presented, the more the immune system then is primed and activated, the more T-cells then are trafficked to tumors, the more T-cells then infiltrate tumors, the more cancer cells then are recognized by T-cells, and the more cancer cells finally are killed ("the more you get").

No dose limiting toxicity. PV-10 can deliver its greatest effect because it can be injected into all lesions until they (and occult cancer cells) go away.

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Provectus made a Form D filing on October 15th related to a possible financing of up to $15 million through Network 1 Financial Securities. I previously wrote about this two weeks ago. See Fundraising (October 3, 2014) and Fundraising -- Updated (October 4, 2014) on the blog's News page. The filing noted: "Sales in the offering will be staged incrementally at the sole discretion of the Company."

It has been said the company could require additional cash to meet requested or demanded requirements of the New York Stock Exchange and/or Provectus' accounting firm BDO. Be that as it may, Provectus concurrently is trying to close a regional license transaction with Chinese pharmaceutical distributor Sinopharm and garner sufficient payment at the signing of a definitive agreement in order to obviate the need to raise money via Network 1.

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A deal structure that potentially may provide insight into Provectus' discussions with Sinopharm is Celsion's 2013 license deal, ultimately not consummated, with Zhejiang Hisun Pharmaceutical Company ("Hisun) for China. This deal was constructed as:
  • $25 million at signing of a definitive agreement (Celsion previously received $10 million from two payments, which then were credited against the signing amount),
  • $55 million in upfront milestone and regulatory milestone payments over 18 months,
  • $45 million in sales target milestone payments, and 
  • Escalating double-digit sales royalties over ten years.
Because no further or amended Form D filing has been made as of this writing (to disclose Provectus took in money from the above mentioned offering), I assume Peter is able to "hold off" the NYSE and/or BDO for a period of time until he can ascertain what cash he would receive from Sinopharm upon signing of a definitive agreement (should such a license transaction be completed).

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St. Luke's Cancer Center's Dr. Sanjiv Agarwala, M.D. is presenting at 5:30 pm local time (5:30 am EST) on October 18th (today) at the 2014 Beijing International Melanoma Congress. See 2014 Beijing International Melanoma Congress (October 7, 2014) on the blog's News page. An interview with Peter conducted by BioMedReports, which discussed the Provectus-Sinopharm memorandum of understanding, was published on October 16th. I very much dislike Provectus raising this topic beyond the initial press release of August 18th (much like they repetitively mentioned their breakthrough therapy application earlier this year). Nevertheless, the interview, likely conducted this week, and proximate to Dr. Agarwala's presentation, at which I imagine Provectus principals and/or advisors should be in attendance, contained some noteworthy items, among them:

"We will be able to assign the license agreement and will control the supply chain unless we agree to do otherwise." Being able to assign the license to an end-game acquirer is an important Provectus-Sinopharm contract item. Under what circumstances would Provectus agree to relinquishing supply chain control? I would think Provectus would consider this only in the context of Big Pharma discussions about a transaction for the company, and only in conjunction with a global partner that has an existing (e.g., Pfizer's 2012 national retail strategic cooperation framework agreement) or planned partnership with Sinopharm.

"Also, PV-10 as an anti-tumor agent that is injected is very appealing to the China and India patient population and their caregivers."

Peter also replied, in answer to the question of what is the object PVCT has in doing business in Asia: "For our signature drug, PV-10 to treat liver cancer, most of the liver patients are in Asia versus the US or Western Europe." I think it's obvious the Chinese, in this case Sinopharm, are more interested in seeing or confirming the final and/or filed liver protocol for a Provectus Phase 2 liver trial than they would be in a filed protocol for the Phase 3 melanoma trial.

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Returning to the Celsion deal structure, it seems to me the nature of the discussions and negotiations between Provectus and Sinopharm probably now revolve around how much of near-term money is available (from Sinopharm) to be paid (to Provectus) at (i) signing of a definitive agreement and (ii) upon checking of whatever box(es) to be deemed an upfront payment. This matters for both substantive and cosmetic reasons. For example, more money sooner is better than the same money later...duh. More money sooner makes a bigger splash. All of this assumes the other compoents of the deal structure are sufficiently good.

Ultimately, Provectus shareholders want management to close a good deal that is well structured, and not contrived. Management has not reached for nor agreed to [very likely informal] deal offers in the past that poorly valued their innovation. I do not expect them to start settling now.

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On October 15th the company issued another press release about Moffitt's presentation at the annual meeting of SITC in early-November, and filed an associated 8-K. Of note was the comment Moffitt's poster will be available and presented at two sessions, during the regular poster viewing one and at an evening Presidential reception. In addition, Craig's obligatory quote contained a couple of potentially notable words and phrases, which I hope ultimately are indeed notable.
“Dr. Pilon-Thomas and her team at Moffitt have been doing very interesting work assessing the potential combinations of PV-10 with immune checkpoint inhibitors for melanoma. Their work may be an important step forward as part of our corporate strategy for addressing unmet need in late stage melanoma patients and in other uses of PV-10.” {Underlined emphasis is mine}
I suppose “very interesting” means unprecedented and unique in scientific parlance? Does “other uses” means other indications (like breast cancer, which was included in Moffitt's AACR 2013 poster: Intralesional Injection with PV-10 Induces a Systemic Anti-tumor Immune Response in Murine Models of Breast Cancer and Melanoma)?

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Finally, in a press release and associated 8-K filing on October 16th Provectus confirmed Dr. Agarwala's presentation of PV-10 clinical data and value proposition (as a monotherapy and in combination) as part of a satellite session sponsored by Amgen and titled “Oncolytic immunotherapy – engaging the immune system to target melanoma” on November 15th at the 11th International Congress of the Society for Melanoma Research in Zurich, Switzerland. See Melanoma Congress 2014 (October 15, 2014) on the blog's News page.

Dr. Agarwala's continues his three-month world tour of Spain (September 28th), Russia (October 12th), China (October 18th) and, now, Switzerland (November 15th). Medical oncologist Agarwala may see the potential opportunity to enhance his position as a global key opinion leader with the success of PV-10 as a monotherapy for earlier stages of disease.

Medical oncologist and Moffitt Cancer Center's Dr. Jeffrey Weber probably sees the potential opportunity to further enhance his position as a global key opinion leader responsible for translating investigational compounds into approved drugs with the success of PV-10 in combination with immune checkpoint blockade (inhibitors) for late stage disease. That, however, is for a later discussion and debate once we learn more about Moffitt's presentation and data at SITC 2014 on November 8th.

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