Combinations & Permutations, Sequencing

Provectus' upcoming, presumably pivotal, Phase 3 trial for unresectable, locally advanced cutaneous melanoma is a potential pathway to approval for PV-10. Management noted in their July 8th annual CEO letter that: "Our development plans for PV-10 stem from the results of our phase 2 study. In that trial, tumors were no longer detectable in 50% of patients with locally advanced cutaneous melanoma who had all of their existing lesions injected. Results from these patients support the potential of PV-10 as a single agent, and provide rationale for a phase 3 randomized controlled trial in patients with unresectable, locally advanced cutaneous melanoma."

Management went on to write: "Provectus is not alone in advocating for an intralesional approach in the treatment of cancer. For melanoma patients with recurrent or in-transit disease confined to their skin this approach has been used to treat patients for many years, as evidenced by guidelines published by the National Comprehensive Cancer Network (NCCN Guidelines®) defining the standard of care for cancer treatment in the United States. Intralesional injection with BCG and certain immunomodulatory agents, local ablation, topical therapy for superficial lesions and regional radiotherapy are consensus interventions for these patients, while systemic therapy remains an option and participation in a clinical trial is the preferred option. We believe that, in this context, PV-10 is well positioned to show superiority in phase 3 testing as a single agent."

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Percent of Cases by Stage at Diagnosis: Melanoma of the Skin

According to the Melanoma Research Foundation, "[m]elanoma that occurs on the skin, called cutaneous melanoma, is the most common type of melanoma." The Phase 3 trial should enroll primarily or exclusively Stage IIIB and IIIC melanoma patients, where the goal, for this patient population, is to clearly demonstrate PV-10's superiority to consensus and other interventions. PV-10, however, is applicable to localized and regional melanoma (i.e., earlier stages), where in due course the drug should demonstrate superiority to surgery and other appropriately suggested interventions. PV-10's sparing of tissue -- injected tumors (i.e., diseased tissue) go away, but healthy tissue is spared -- together with its efficacy should provide a compelling value proposition and alternative to surgery. Localized and regional melanoma, according to the National Cancer Institute, represents 90-95% of melanoma of the skin cases by stage. First and foremost, however, the contemplated Phase 3 trial must be run and the initial pathway to approval achieved.

Beneficial options for patients with distant or metastasized cancer -- in this case, metastatic melanoma -- have dramatically increased in number (and thus choice) and improved in efficacy; however, there obviously still remains a sizable unmet need because the narrative has changed over the last several years from monotherapeutic approaches to treatment (particularly, after each one fails, is to pursue another approach) to combining treatments (whether two treatments are delivered concurrently, or treatments are knowingly delivered sequentially). The goals of combination therapy is to delivery more efficacy and to overcome resistance. I suppose the goal of any cancer therapy is to delivery better efficacy than what came before it, and to overcome resistance (or recurrence), and thus prolong survival.

And that's where the industry's thinking has evolved, by embracing the cancer immunity cycle to progress towards harnessing the body's immune system to fight cancer and thus better deliver on the promise of better efficacy and overcoming resistance. In this case, sequencing the delivery of a permutation of treatments (drugs, therapies) is what constitutes combination.

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Eggermont (2012) writes: "The immune system can be leveraged to fight cancer via four broad, overlapping strategies, comprising priming/boosting of the immune system, T-cell modulation, reducing immunosuppression in the tumour microenvironment and enhancing adaptive immunity." As the author further write: "As immunotherapies function by distinct mechanisms, it is possible that their combination with other treatment modalities may be synergistic."

What does Moffitt Cancer Center's Dr. Jeffrey Weber think? At a minimum he thinks:

• Injectable therapies are making a comeback, where one would use an intralesional agent to prime the immune system of a patient with late stage and/or visceral disease, and then boost it with a checkpoint protein inhibitors (or combination of inhibitors). Unfortunately, he sees Amgen's T-Vec as limited ("I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipilimumab, or a combination of those."). See 'Pretty Darn Impressive' PD-1 Data in Melanoma, Ribas and Weber, June 12, 2014.

• Moffitt's Phase 1 feasibility study of PV-10 provided "...more and more evidence that you are altering both local and systemic immunity in a positive way. It also provides a rationale for combination trials of PV-10 with check point protein inhibitors, such as ipilimumab, pembrolizumab and nivolumab. PV-10 might offer the perfect way to prime the immune system."

• In response to my question of how to assess the utility or value of an agent or compound as an immune system primer: "Simply its ability to synergize with the immune agent in question in terms of clinical effect when given prior to the second agent...the priming agent would simply add to the effect of the immune agent, when used at the same dose and schedule."

The priming agent above would be PV-10 (or T-Vec), while the immune agent would be one of the checkpoint inhibitors.

Weber previously said he is hard pressed to see a systemic role for IL therapies like T-Vec in patients with significant disease burden and visceral M1c disease. Stages IIIB-C and IV M1a patients could be treated with IL therapy. To expect, however, significant clinical and biologic systemic benefit (affect) with any IL therapy -- as we now know them -- in patients with significant disease burden and visceral M1c disease is very low. For now, for him and those he seeks to help, he sees PV-10's role, it would appear, as a potentially powerful (dare I say perfect) immune system primer to help patients with significant disease burden and visceral M1c disease. In addition to its role as a monotherapy for cutaneous melanoma, management wrote in its annual CEO letter about PV-10's role as part of a sequenced combination therapy for metastatic melanoma: "And for those patients who do not have all disease accessible to injection, medical oncologists have stated that using an agent like PV-10 to prime the immune system could be synergistic in combination with a systemic agent."

Management previously recognized of the benefit and value of combining PV-10 with other treatments and therapies:

• 2006 patent and Foote et al., 2010 regarding PV-10 plus radiotherapy;
• Dees et al., SITC 2012 regarding co-administration of PV-10 and other systemic therapy (i.e., systemic chemotherapy);
• 2012 patent regarding PV-10 plus systemic immunomodulative therapy; and,
• Wachter et al., AACR 2013 regarding PV-10 plus anti-CTLA-4 antibody therapy.

Moffitt previously concluded for AACR 2014 that "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma," and the same for ASCO 2014. Moffitt and Weber would seem to be key clinical players (i.e., site, lead/sole principal investigator) in any combination study.

Management, however, historically has been reticent to pursue combination therapy on their own dime (or spend significantly on it), aside from providing the drug for study, unless someone else (i.e., another company) stepped up to the plate. The situation appears to have changed, per their comments on recent conference calls regarding potential combination studies and related relationships. Experience would suggest (because of the aforementioned comments they made "now") the phone rang, Provectus picked it up, and management listened to what the party(ies) on the other end had to say. The company typically has not talked publicly about things until there is sufficient activity (with of course no certainty of closure or timing thereof) to warrant comment.

Utilizing the table I prepared in my July 24th Combinations news item (see below),...

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...Weber's support and contemplated use of PV-10 (and his industry associations and relationships), and other due diligence, likely, potential or possible interest (or lack thereof) is:

• Anti-CTLA-4: Bristol-Myers, obviously, but unlikely. Although an approved drug, it would appear anti-PD-1 agent nivolumab ultimately will supersede it (together with other PD-1 and PD-L1 agents), and PV-10 is potentially a more powerful priming and activation agent vis a vis steps in the cancer immunity cycle in order to combine with a PD-1 or PD-L1 agent.

• Anti-PD-1: Bristol-Myers and/or Merck.

• Anti-PD-L1: AstraZeneca, potentially. Roche is more likely to engage in combination studies utilizing investigational agents in its own pipeline that represent the distinct cycle steps, and thus not look to outside parties yet for combinations.

Grading any so-called co-development deal should Provectus be able to enter into one, more so than merely the design of the clinical studies, would be based on (among other things):

• Who pays for the trial (aside from, and above and beyond Provectus contributing drug product),
• Who conducts, operates (and sponsors) the trial,
• Whether Provectus, like Celldex, would receive an upfront payment, and if so how much,
• What exclusivity might constrain PV-10 to combine with other agents, and
• What right of first something(s) might accompany a co-development deal.