Provectus Submits Application to FDA for Breakthrough Therapy Designation

The company issued press release Provectus Biopharmaceuticals Inc. Submits Application to FDA to Receive Breakthrough Therapy Designation for PV-10 for Treatment of Melanoma today, following their related 8-K filing Friday (about couriering the application to the Agency for receipt today). An 8-K filing associated with this press release also was filed.

Compelled by good SEC housekeeping practices to do so (see New SEC filing (March 21, 2014) under the blog's News tab), wholly confident they will attain breakthrough therapy designation ("BTD") (and thought a PR was a good idea) or some other rationale, the PR obviously establishes an event point for the market. 60 days or thereabouts from today (Friday, May 23rd) the company could announce in some form or fashion it received BTD from the FDA, or did not (consistency would require a PR too).

Adam Feuerstein asked on Twitter: "Other than $PVCT, how many drug cos. have spoken publicly about seeking BTD?" He notes Ariad Pharmaceuticals, which mentioned their rejection in an earnings call (2Q13):

Ariad: "One final note on 113. We filed for breakthrough therapy designation for 113 in ALK-positive non-small cell lung cancer. Which is a relatively short follow-up of many of the ALK-positive patients treated with 113 to date, and the small numbers, our request for breakthrough therapy designation was not granted by the FDA. We continue to move expeditiously in the development of 113 with a pivotal trial in ALK-positive lung cancer patients to begin as planned this quarter, and we believe this decision by the agency will have no impact on our ability to pursue our ambitious development plans and timeline. 113 has shown impressive response rates in patients with ALK-positive non-small cell lung cancer, including in brain metastasis in these patients, and we are pursuing this opportunity with great focus."

Analyst: "And then on the breakthrough therapy destination, that's something that's new for all of us who are all trying to learn the process here. I guess, is this something that you could, in the future, refile for with more data? And then when you cited the reasons that they denied that, do they specify that to you specifically? Or do you -- is that just an assumption that you have as to why they rejected that?"

Ariad: "...So our understanding, yes, we can refile if we wish. And if we deem it appropriate, there's no restriction on that. And yes, that commentary is directly from them. They have -- it's a pretty open and communicative process and response, and those were the cited reasons." {Bold and underlined emphasis is mine}

In the subsequent thread, other folks replied: @JacobEPVantage with MolMed S.p.A., an Italian biotechnology company in a February 2014 press release (they had previously and initially mentioned it in late-2013 one): "As far as the Breakthrough Therapy submission is concerned, the U.S. Food and Drug Administration (FDA) has not - at this time - granted the designation for the cell therapy TK as adjunctive treatment in hematopoietic stem cell transplantation (HSCT) for adult patients affected by high risk acute leukaemia. However, the FDA indicates that the Company can submit a new request once new clinical evidence becomes available." {Underlined emphasis is mine}

@bradloncar noted Advaxis, which mentioned BTD submission and rejection in [at least] its FY 2013 10-K: "On October 7, 2013, we submitted a request for breakthrough therapy designation (BTD) to the IND for ADXS-HPV in the treatment of invasive cervical cancer. The FDA denied the request in December 2013, but stated that a new request may be submitted if we obtain new clinical evidence that supports BTD." {Underlined emphasis is mine}

In Provectus' PR today Craig says: "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 and underlined emphasis is mine}

Recall the company's January 24th PR: "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 and underlined emphasis is mine}

One could observe the FDA indicated the 28-patient cohort who had all existing disease treated was sufficient clinical evidence to support BTD. But, as Craig said in today's PR: "I want to make clear to our shareholders, the media and the market as a whole that BTD is not guaranteed..." Still, the decision to publicly mention BTD submission irrespective of one's confidence level can be criticized. I too wonder why Provectus 8-Ked and PRed BTD submission. I had wanted management not to publicly disclose this.

The press release also addressed several notable items.

A small, short bridging study. While almost identical to Craig's comments in the January 24th press release Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes, there appears to be a key sentence in today's PR:

January 24th: "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."

Today: "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." {Underlined emphasis is mine}

Today's PR appears to me to be much clearer than the January 24th one. Craig notes BTD is just that, a designation, and not itself a pathway to approval. By adding the underlined sentence above, it would seem to me the pathway to approval (i.e., approval established only after an NDA submission and review, and by the final process step of receipt of an action letter from the FDA) could be regular or accelerated approval ("AA"), where the bridging study is a post-marketing commitment ("PMC") or a post-marketing requirement ("PMR"), or the study is a "pre-marketing" study for approval. Some may debate whether a bridging study, technically or otherwise, still is a Phase 3 clinical trial.

If regular approval (outright or "OA") or AA, the process steps would include filing a new drug application (which Provectus may or may not PR), waiting 60 days after the aforementioned filing to conduct a preliminary review that would assess whether the NDA is "sufficiently complete to permit a substantive review" (the receipt of such notice the company would PR), and then working with the Agency for a time to complete the review, followed by Agency action. Presumably under the scenarios of OA or AA, the study would follow as a PMC by Provectus or a PMR of the FDA, respectively.

For Pharmacyclics' ibrutinib that received BTD and later received accelerated approval, the NDA filing was made June 28, 2013, the filing was accepted by the FDA on August 27, and approval was attained on November 13 (roughly four-and-a-half months from filing). The process of course can be longer.

If the bridging study is first required, the timeframe would be elongated presumably by the length of the study and subsequent data compilation, analysis and submission. With new tumor-based endpoints (primary as complete response, secondary as disease symptoms like pain, infection and/or significant bleeding) the per-patient time from enrollment to completion could be 2-3 months. The result of the first injection could take 1-2 weeks to assess if the tumor went away. Subsequent injections, if needed to make the tumor go away, would be administered every two weeks. Photographs likely would be taken during a one- to two-month period following injection to record confirmation of complete tumor destruction and disappearance. Multiple U.S. and international sites (e.g., Australia, Europe, China, India) might assist with rapid overall patient enrollment. The NDA review process then may (would) follow.

PV-10 makes tumors go away (a.k.a. a complete response). "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." {Bold and underlined emphasis is mine} Put enough water on the fire and it goes out.

Provectus' liver program. A cursory mention that deserves some follow-up. I'll address this item later.

M.D. Anderson added to the compassionate use program. The CUP on ClinicalTrial.gov only identifies 3 U.S. sites (Sharp Memorial, the University of Louisville, and St. Luke's Hospital). M.D. Anderson has been a CUP site on and off for quite a while. PV-10 supporter and key opinion leader Merrick Ross (a surgical oncologist) works here. See Journal Publication (February 11, 2014) under the blog's News tab. I believe there may be other unnamed sites.