"Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes"

December 18^th Press Release: Provectus Type C Meeting With FDA Oncology Division Held December 16, 2013

Byline: OFFICIAL MINUTES EXPECTED BY JANUARY 15, 2014 (stop shouting)

Balance sheet cash: $8.3 million, as reported in Provectus' 3Q13 10-K and as at 9/30/13

Key statements:

• “The purpose of the meeting was to determine which of the available paths that Provectus' novel oncology drug PV-10 will take in pursuit of FDA approval and commercialization.”
• “The minutes will clarify the available regulatory paths and, therefore, allow the Company to better estimate a time-line to commercialization of PV-10.”
• “There are different possible routes to approval of PV-10 such as a breakthrough therapy designation or accelerated approval, and each of these has different requirements and time lines” (Craig’s quote).

January 24^th Press Release: Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes

Bylines: Treatment of "Locally Advanced Cutaneous Melanoma" to be Path to Initial Licensure, Phase 2 Data to be Submitted in Formal BTD Request This Quarter with FDA Response Expected Within 60 Days of Receipt

Balance sheet cash: ~$18 million, as noted in the 1/24/14 PR, and resulting from warrant exercises to date; see the Blog's News tab entry Strong. Getting Stronger. (December 31, 2013)

Key statements:

1. “As a result of this meeting, Provectus will submit data from its Phase 2 study in a formal breakthrough therapy designation (BTD) request this quarter, and should receive a decision within 60 days of receipt of that request.”
2. “This meeting with the FDA is another significant step forward in streamlining the pathway to initial U.S. approval of PV-10 as the first local agent for recurrent locoregionally advanced melanoma” (Craig’s quote).
3. “We are very pleased that the path to initial approval in the U.S. is now clear and PV-10 can be available to help patients in a more condensed time frame than if the Agency required an overall survival endpoint in a large randomized Phase 3 study” (Craig’s quote).

Further thoughts: (1) Provectus will submit a BTD application. Should management submit it by or before March 31st, we should hear by or before May 30th (60 days thereafter). The FDA (CDER) currently is running at 100% performance for action taken within 60 days of receipt of a BTD request for fiscal year 2014 (97% for FY 2013). FY13 BTD acceptance was ~37%, and ~27% FY14 year-to-date.

While the success of the company's eventual BTD application is neither predestined nor guaranteed, I would be very surprised if it was not accepted (n.b. Provectus' January 24th PR: "As Provectus has previously reported, based on rapid tumor destruction in a positive Phase 2 trial in melanoma patients receiving PV-10 (protocol PV-10-MM-02), input from the Agency regarding the current development plan was sought. Agency guidance (Frequently Asked Questions: Breakthrough Therapies) encourages sponsors to seek such advice prior to formal request for designation;" FDA BTD website: 11) Does a sponsor have to request breakthrough therapy designation? Yes, a request to be considered for designation is required. However, the FDA may suggest that the sponsor consider submitting a request for breakthrough therapy designation if: (1) after reviewing submitted data and information (including preliminary clinical evidence), the Agency thinks the drug development program may meet the criteria for breakthrough therapy designation and (2) the remaining drug development program can benefit from the designation.)

(2) The “label” has changed from metastatic melanoma (i.e., patients with advanced melanoma) to locally advanced cutaneous melanoma (specifically, recurrent locoregionally advanced melanoma). The latter is a different disease than the former, and much larger addressable market.

In my post A Paradigm Shift vs. Obsolescence I referenced the same subset of patients the company first presented at its September 30th ECC 2013 poster and subsequently mentioned in its Janaury 24th PR: At a patient or subject level, focusing specifically on the subset of patients for whom all lesions were treated (i.e., all disease burden), ORR was 71%; 50% CR and 21% PR. Local-regional disease control was 82%. These figures derive from a patient subset, and not the entire patient population, which included Stage IIIB-C and Stage IV M1a-c patients refractory to treatment. I think it's reasonable, however, to focus on the above patient subset only in the context of the regulatory pathway to approval being sought by Provectus: local-regional control of recurrent melanoma.

The PR further elaborated on this subset at a tumor level (which the ECC 2013 did not, as it only discussed response for all target tumors: At a tumor level, the ECC 2013 poster provided insight into PV-10's effectiveness killing, shrinking and arresting tumors. Among 491 target lesions -- that is, injected lesions -- CR was 53%.): "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."

It seems management is basing its BTD application on this subset (subgroup). The PR elaborated by noting: "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."" I imagine the company has continued to work with the Agency since December 16th (presumably when "FDA advised Provectus...," which it appears were final meeting minute comments by virtue of the PR's use of quotations), the date of the Type C meeting, to provide this information to them.

(3) It does not appear like a Phase 3 trial will be required. It also appears if an additional trial is necessary, it would be run following receipt of BTD: "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 would allow more frequent dosing than was permitted in the Phase 2 study, presumably akin to the dosing schedule currently used to treat nearly 100 patients under our expanded access protocol, and allow symptomatic endpoints to be prospectively correlated with objective response criteria. Provectus has $18 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" (Craig's quote). Underlined emphasis is mine. One might assume the Phase 2 tumor-level patient subset/subgroup data is enough/was enough/will be enough to assert the correlation between the new endpoint and objective response "OR") in the BTD application. Perhaps the Agency may desire the additional data to be collected as part of or akin to a confirmatory study of sorts.

It now would appear PV-10 may finally has an initial path to approval in the U.S. as the first local agent for recurrent locoregionally advanced melanoma.