April 1, 2014

In Support of the Initial Label

Today's press release about Provectus' poster presentation at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO"), Provectus Biopharmaceuticals' PV-10 Data to Be Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, provided several items of useful information,

More detailed subset data to come. As the company has said in the past, it is relying on a 28-patient subset of its metastatic melanoma Phase 2 trial to seek breakthrough therapy designation ("BTD") and an initial pathway to approval. More information about the presentation should be forthcoming on May 14th when abstracts are released by ASCO; however, the title is informative: "Efficacy of intralesional Rose Bengal in patients receiving injection of all existing melanoma in phase II study PV-10-MM-02."

Data from the 28-patient subset of Phase 2 enrollees where all disease was treated was first highlighted at the 2013 European Cancer Congress in September (Exploratory Data Analyses of Intralesional PV-10 Clinical Phase 2 Study Results Presented at ECC 2013 Demonstrate Effective Locoregional Disease Control and Support Systemic Immunologic Activity in Refractory Metastatic Melanoma): "Results showed that for all subjects, BORR was 51% (26% CR, 25% PR) with the amount of tumor burden accessible to PV-10 injection prognostic for outcome. In the majority of subjects (68%) the lesions treated with PV-10, together with the up to two untreated bystander lesions, constituted all disease present, and these subjects achieved a BORR of 63%. In subjects where all disease was treated (35% of subjects) BORR further increased to 71% (with 50% achieving CR)." {Bold emphasis is mine}
Click the table to enlarge it. Poster source is here.
Following Provectus' December 16th meeting with the FDA, the company further discussed this 28-patient subset in its January 24th PR Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes.

First: "The meeting and official meeting minutes provided valuable guidance on a number of issues surrounding the approval path of PV-10:...In reference to discussions on the potential for breakthrough therapy designation, 'FDA advised Provectus to provide objective response rates with adequate information to evaluate the symptomatic treatment effects (e.g. pain, infection, bleeding) in patients presenting with locally advanced cutaneous melanoma who received PV-10 to all lesions.'" {Bold emphasis is mine}

Second: "The Phase 2 study of PV-10 showed:...In the subgroup of melanoma patients that received PV-10 injection into all known disease (28 of the 80 ITT patients), 50% achieved a complete response (71% ORR, CI 51-87%)."

Third, on a per-tumor basis for an expanded subset (all or ostensibly all disease treated): "In the subgroup of melanoma patients with locally advanced cutaneous melanoma that received PV-10 injection into all known disease or only had 1 or 2 designated bystander tumors untreated (54 of the 80 ITT patients), a complete response was achieved in 232 of 363 injected tumors (64% of lesions) with the vast majority of these tumors requiring only 1 or 2 injections." {Bold and underlined emphasis is mine}

Finally, fourth: "Dees continued, 'Measurement of tumor shrinkage via objective response criteria has been considered direct clinical benefit in drug approvals for other skin cancers and we believe a similar case can be made for PV-10 in locally advanced cutaneous melanoma. As advised by the Agency, we will submit data from the 28 patients in our Phase 2 study who had all existing disease treated in a formal BTD request this quarter, and should receive a decision within 60 days of receipt of that request.'" {Bold emphasis is mine}

The company continued to consistently communicate the narrative of PV-10 injected into all disease as the basis for its initial approval pathway in its March 24th PR Provectus Biopharmaceuticals Inc. Submits Application to FDA to Receive Breakthrough Therapy Designation for PV-10 for Treatment of Melanoma.

First: "Craig Dees, PhD, CEO of Provectus said, 'The decision to apply for BTD stems from our Type C meeting held with the FDA's Division of Oncology Products 2 in December 2013. At the meeting FDA expressed willingness to work with Provectus toward initial approval for the novel investigational oncology drug PV-10 in locally advanced cutaneous melanoma. This included a statement in the minutes that data in a cohort of patients that received PV-10 to all existing lesions should be submitted in a formal BTD application.'" {Bold emphasis is mine}

Second: "Dees continued, 'I want to make clear to our shareholders, the media and the market as a whole that BTD is not guaranteed and if the designation is conferred on PV-10 for melanoma, it does not bypass the need for a new drug application (NDA) and review, as both are required for commercialization of any drug. As I have stated previously, the Agency may yet recommend and it may be in the best interest of Provectus to undertake a small, short bridging study in patients where all tumor burden can be injected. This could occur either before or after we have approval to sell PV-10. Provectus has over $16 million in cash reserves and would not require additional capital or the resources of a partner to conduct such a study. If such a study is conducted, it also fits with needs for an international study supportive of licensure in Australia, Europe, China and India.'" {Bold emphasis is mine}

And third: "Dees concluded, 'We are confident that the studies done thus far illustrate the effectiveness and safety of PV-10: if you inject PV-10 into melanoma tumors, the tumors go away. For recurrent, aggressive skin cancers this unique mechanism confers tangible benefit to patients.'" {Bold emphasis is mine}

I imagine Provectus' ASCO poster (as well as their 2-5 slides that would be included in their poster highlight session) will provide more detailed per tumor data, and make clear the rationale the FDA appears to have embraced regarding treating all disease for locally advanced melanoma.

Poster Highlights Session selection. As noted in today's PR, the company's abstract was selected for this session, which should take place from 8 am to 12:45 pm CST on Monday, June 2nd. Dr. Agarwala (the probable discussant) likely will present a few slides during the session.

Breakthrough Therapy Designation. Selection to the poster highlight session must only have happened because the data underlying Provectus' abstract, the 28-patient "cohort," is being used to support BTD. While ASCO acceptance and highlighting certainly doesn't influence whether the company will secure the designation from the FDA, I think it is another measure of growing industry acceptance of the drug, the local nature of its use, and the initial indication for which it should (will) be applied. The "friendly reminder" in the PR that the company recently submitted a BTD application for melanoma may reflect management's supremely confident belief regarding successfully attaining the designation, Craig's "I want to make clear to our shareholders, the media and the market as a whole that BTD is not guaranteed..." notwithstanding.

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