Differences of Opinion

Craig and Eric? Image source

Over time, there have been a series of differences of opinion, perhaps sedimentary layers of differences (if you will), within Provectus and the management team — and without — in regards to combining PV-10 and other drug compounds, notwithstanding the joint combination therapy patent with Pfizer, Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer.

The patent process itself for this portion of Provectus' intellecual property could represent the rings of this "tree:" a notion conceived of in 2010/2011 [e/n 1], a patent application made in 2012, and an award achieved in 2015.

A. PV-10/Rose Bengal has a compelling clinical value proposition (use, safety, local efficacy, tissue sparing, systemic efficacy, and multi-indication viability).

But while management proposed a two-prong approach for treating cancer — local delivery via direct tumor injection of powerful, agnostic ablation (destruction) of cancer tumors that leads to systemic (anti-tumor) immune responses — at their core resides the firmly held position that cancer must be treated earlier (when tumor burden is low) to have a stronger effect and more certain outcome. Not only was earlier treatment right and proper, it represented the vast majority of the addressable market for cancer.

Despite being successful in eventually convincing the FDA of Provectus' pivotal melanoma Phase 3 trial design and potential label for Stage III patients, time elapsed.

B. In that time, the industry began to shift from single therapeutics/agents and single therapies to treat late-stage disease to combinations of them (e.g., drug-drug, drug-therapy). In addition to the combination therapy patent, Provectus began shifting too (if not in their treatment idealogy, then in their realization of drivers of company valuation):

• Dees et al., SITC 2012 regarding co-administration of PV-10 and other systemic therapy (i.e., systemic chemotherapy),

• Wachter et al., AACR 2013 regarding PV-10 plus anti-CTLA-4 antibody therapy, and

• Moffitt Cancer Center, SITC 2014 regarding PV-10 plus co-inhibitory blockade (anti-CTLA-4, -PD1 and PD-L1)

I observed this perspective at the time too, among them:

• December 28, 2011, com·bi·na·tion,

• September 21, 2012, The $PVCT.OB-$PFE Relationship Grows,

• July 26, 2014, Combinations & Permutations, Sequencing, and

• October 14, 2014, The Immune Checkpoint Inhibitor Global 4 (or 5).

Deals began materializing between partners of combination therapy pairs in 2014. See Combinations (July 24, 2014) on the Archived News II page.

Click to enlarge.

Click to enlarge.

C. As there has been an ebb and flow in regards to FDA support of local/intralesional agents for cancer (melanoma), there has been an ebb and flow in deal talks with Provectus regarding the pairing of PV-10 with another agent:

• June 1, 2013, Amgen Presents Positive Results From Talimogene Laherparepvec Phase 3 Study In Patients With Metastatic Melanoma,

• January 24, 2014, Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes,

• May 23, 2014, Provectus Biopharmaceuticals Inc. Reaffirms Its Commitment to Bringing PV-10 to Market Notwithstanding FDA Decision on Breakthrough Therapy Designation,

• October 8, 2014, Prescription Drug User Fee Act Patient-Focused Drug Development; Request for Comments,

• April 29, 2015, FDA Panels Support Approval of T-VEC in Melanoma, and

• October 27, 2015, FDA approves first-of-its-kind product for the treatment of melanoma.

Amgen struck deals and/or created clinical development programs (CDPs) to combine T-Vec (for metastatic melanoma) with Bristol-Myers' anti-CTLA4 drug ipilimumab in 2012/2013 and Merck's anti-PD-1 drug pembrolizumab in February 2014. When did the window open for intralesional agents?

Provectus' discussions, lack there of, stops and starts, etc. appear to mirror the above as well. But, no deal or collaboration has materialized.

D. Provectus' September 23, 2015 press release Announces Initiation of Phase 1b/2 Clinical Trial to Study PV-10 in Combination with Immune Check Point Inhibitor Pembrolizumab oddly spells out management's hand-strengthening steps for negotiating a co-development deal/CDP:

"This study is both scientifically and commercially important to Provectus. Scientifically, combination therapy in cancer treatment is a rapidly maturing area, where rational combination of agents is replacing the empirical approaches of the past. Commercially, this is the second of three steps that we hope will significantly strengthen our hand in negotiating a co-development transaction with an immunotherapy-focused partner. Our joint patent with Pfizer was the first; this study is the second; and the third is our immune mechanism of action clinical study, which is underway at the Moffitt Cancer Center and which has completed recruitment."

Steps:

1. Award (with Pfizer) of the combination therapy patent,
2. The Phase 1b/2 CDP, and more specifically data from the Phase 1b portion, and
3. Moffitt's complete elucidation of PV-10's immune mechanism of action (SITC 2015's poster was an appetizer; the main course, using this analogy, should be the publication of the work in a peer-reviewed journal).

Step #1 is complete (i.e., the patent has been awarded [e/n 2]). Step #3 would be complete when the manuscript is accepted and then published. Step #2 is generating data. Why has no deal materialized? Scenarios include:

• No one is interested in pairing PV-10 with their drug or compound,

• There is not enough data for a deal/relationship to materialize, 

• There is interest but the terms of a co-development (collaboration) are not acceptable to Provectus management, and

• There is not enough data for a deal/relationship acceptable to management to be consummated.

E. There were disagreements within Provectus' management team about whether to undertake a Phase 1b/2 trial program combining PV-10 with an immune checkpoint inhibitor. On one side there was the company's CTO Dr. Eric Wachter, PhD as a proponent for carrying out an early-stage trial. On the other side there was Provectus' Chairman and CEO Dr. Craig Dees, PhD, who was in opposition of such a move.

Craig's opposition comprised clinical as well as business/corporate development reservations. Clinically speaking, he primarily was worried much more about safety — could/would the combination of PV-10 (itself an immunomodulatory agent) with an immune checkpoint inhibitor create unforeseen or foreseen, immune-oriented adverse effects and events. In regards to the efficacy aspect of a combination CDP, his cynical "worry" was upstaging and making appear less relevant the checkpoint inhibitor.

Business-wise, Craig was worried about moving ahead with Step No. 2 and yielding no value to Provectus. How could no value be garnered from such work?

• PV-10 + pembrolizumab is a zero (you know, "drop that zero and get with the hero:" hero = pembro, zero = PV-10), 

• PV-10 + pembro = T-Vec + pembro. PV-10 is more than a zero, but in reality just noise, like most combination partners in the immuno-oncology space, or

• PV-10 + pembro is a hero, but no deal/CDP/relationship with Big Pharma materializes.

F. I don't think Step #3 generates a co-development deal (acceptable to management) by itself, or together with the Provectus-Pfizer patent (Step #1). Moffitt's elucidation in the open (i.e., peer review) of PV-10's immune mechanism of action critically answers (or at least helps market) why PV-10 does what it does.

A trial program that delineates a pathway to approval, together with a well-designed trial protocol and, critically, data demonstrating the path can be successfully traversed, should; that is, Step #2.

G. A Phase 1b/2 program of pembro + PV-10 vs. pembro permits a baseline, which is pembro, and the potential to demonstrate additional benefit (attributed to PV-10). This approach also permits approval of PV-10 as a single agent for metastatic melanoma.

H. A potential baseline for evaluating the PV-10/pembro combination comes from the results of the T-Vec/ipi combination. The ASCO 2014 abstract of T-Vec/ipi observed or concluded the following:

"In consideration with published reports, these data, although preliminary, suggest higher CR and OR rates than either agent alone and earlier responses after ipi initiation during T-VEC+ipi than with ipi alone."

Repeating: Higher (better) responses, earlier responses. [e/n 3]

Click to enlarge.

Median time to response (TTR) in T-Vec's Phase 3 trial was 4.1 months. Median TTR for pembro is 12-13 weeks. Mean TTR for ipilimumab in its pivotal Phase 3 trial (alone) was 3.2 months. Median TTR for T-Vec/ipi was first reported as 2.9 months.

Endnotes:
[E/n 1] See below.

Click to enlarge.

 [E/n 2] Continuations thus far are below

Click to enlarge.

 [E/n 3] Sources:

• http://meetinglibrary.asco.org/content/128142-144
• http://meetinglibrary.asco.org/content/92099?media=vm&poster=1
• http://meetinglibrary.asco.org/content/151884-156
• http://www.medpagetoday.com/upload/2010/6/7/NEJMoa1003466v1.pdf
• http://jco.ascopubs.org/content/early/2015/05/22/JCO.2014.58.3377.full
• http://www.onclive.com/conference-coverage/ecc-2015/t-vec-pembrolizumab-combination-demonstrates-safety-in-melanoma
• http://www.europeancancercongress.org/Scientific-Programme/Abstract-search#