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.

Why? [Now] You Know Why.

Sometimes, it's what isn't said that may be as important or more so than what's said. Sometimes, it's not just how you say what you say, but how you say what you don't say.

We don't talk at all about serious adverse events ("SAEs") related to PV-10 trials and the compassionate use program ("CUP"). We rarely talk about AEs in general, aside from the mild to moderate ones experienced thus far in the trials and CUP.

Sometime between last year, sometime, and this year, sometime, Provectus arrived at an agreement with the FDA on a special protocol assessment ("SPA") for its pivotal metastatic melanoma ("MM") Phase 3 trial. How do I know? I don't. Do I know for sure? No. If one presumes or contends management is feckless or incompetent, then they're still working to convince the FDA that the local agent PV-10 has some sort of value, and wasting value cash in a pointless task. The SPA still is M.I.A.

I don't presume anything of the sort, even though there have been breadcrumbs of the SPA scattered among company communications and medical conference presentations, that tantalize us about parameters, timing, enrollment, etc. With each of these crumbs we thought the SPA and trial commencement are upon us, or within our grasp.

I think the breakthrough therapy designation ("BTD") arrived essentially in the middle of the process of management working towards the SPA with the Agency, "upsetting" the old SPA path and setting the company onto a new BTD one (whether in parallel, or as an extension). I'm guessing the supposed agreement was verbal in nature, proffered to Eric and his regulatory team, but set it aside in pursuit of an accelerated path to approval.

But, not everyone sang from the same hymn book. In hindsight, those "off key" notes were prescient.

It's not a bad thing the SPA up and vanished like a fart in the wind. It's the "good" option. It always has been. Interim Phase 3 results would provide Big Pharma with the traditional data they required to consider a worldwide license or acquisition of the company.

It might feel to some like we've been down this road before. High expectations: 2010. Accelerated approval. 2012. SPA. Today, nothing...yet.

Is this time different? Everyone seems to be singing from the same hymnal. Finally.

The current regulatory affairs narrative seems to have several facets to it:

• The company has filed its BTD application. Previously, there'd been, at times, an almost absurd did-they-file, did-they-not-file charade to the process.

• The company filed for BTD around October 1st, starting the/a so-called 60-day clock. Adding about 15 days because of the recent partial federal government shutdown (precisely, October 1-16), an expectation for communication from the FDA on this conceivably could come around or before mid-December. Since you never know about federal government mailrooms, and with business time inevitably slowing after Thanksgiving, it's conceivable Provectus, and thus we, don't hear until the end-of-December or January.

• The BTD process to date [sort of] works like this: Work with the FDA and their process, such as it is, get "pre-qualified," and you get BTD. 100% of the companies [purportedly] that worked with the Agency in such a fashion received the designation. Don't work with the FDA, don't follow their process, don't get pre-qualified, and you don't get BTD. 100% of the companies [purportedly] that did not work with the Agency in the required fashion did not receive the designation. Provectus worked with the FDA. So, they'll get BTD, right? BTD was the "better" option.

• They asked for a meeting with the FDA to discuss BTD, and how (how best?) to request accelerated approval ("AA") or outright approval ("OA") in this context. I don't believe management has any doubt, and if one of them has it's small or de minimis, that they've successfully demonstrated PV-10's clinical value proposition for MM Stage IIIb-IIIc patients refractory to prior treatments. AA/OA was the "best" option.

I said I wouldn't discuss the details of my call with Dr. Weber, but here's a small perspective of how he said what he said, and how he said what he didn't. I have no doubt he is very experienced talking to "outsiders" like me. Dr. Weber was generous with his time, and thoughtful in his answers. "Methought the professor dost protested too much."

The commercial validation narrative appears singular: Regional deals and the Big Pharma end-game follow regulatory clarity.

[Now] you know why.

Tipper: You know what? I can get a couple of my brother's loser ass friends to go over to Mason's apartment, knock on the door and when he opens it wham! They'll junk-punch him all up in his man business and he'll fall to the floor whaling and crying "why?" and then we'll say "you know why!" (What Happens In Vegas)

$PVCT CEO Letter: PV-10 Compassionate Use Data To Come

When I heard 75% of compassionate use program (CUP) patients were cancer-free (but without any specifics regarding longevity), I wanted context/more information with which to compare this PV-10 success rate. I found some expanded access program data for ipilimumab:

Whether adjusting for patients receiving ipilimumab who were lost to follow-up or not (>20% or more), a "rough" comparison with PV-10 (75%) is notable to say the least.

It's "Very Easy" To Buy $PVCT

In reading the short theses Adam Feuerstein provided by a short seller (an MD I believe) for Ziopharm Oncology (ZIOP) (palifosfamide), Clovis Oncology (CLVS) (CO-101) and Celsion (CLSN) (Thermodox), I was struck by what appeared to be the common thread of data mining from results of a previous trial (e.g., Phase 2) leading to trial design of the subsequent one (e.g., Phase 3). While some could be argued all of these drugs provided incremental benefit, many believed prior trial success would lead to successful subsequent trial outcomes, which did not generate near the benefit expected.

PV-10's success utilizing a constrained treatment protocol in its MM Phase 2 trial -- an initial injection into each of up to 20 lesions, followed by up to 3 re-treatments (weeks 8, 12 and 16) -- was fundamentally better on an absolute basis and when compared to other "leading" (at the time) intralesionally injected compounds like T-Vec and Allovectin-7.

The contemplated MM Phase 3 trial for which Provectus is seeking an SPA from the FDA -- an initial injection into any and all lesions, followed by additional re-treatment as necessary -- looks to build upon the success of the compassionate use program ("CUP") where patients were treated with PV-10 more freely and frequently. PV-10 would appear fundamentally better than its intended comparator, DTIC/TMZ.

Lesion > Patient > Cohort > Trial Population.

In the Phase 2 trial, there was an 80% treatment success rate of individual lesions with an associated complete response ("CR") of more than 50%. Think of a set of data comprising all lesions treated, irrespective of patient. Success was achieved in 80% of these datapoints.

80% success was achieved despite limited treatment (i.e., 1 initial injection and up to 3 additional injections), physician error while injecting lesions (i.e., some lesions were improperly injected), patients and their lesions left the trial, and patients with compromised immune systems and ravaged bodies from failed prior treatments had their lesions injected.

Does 20% lack of success of all lesions treated fully or completely comprise limited, improper, incomplete and immuno-challenged treatment? Perhaps not completely, but probably pretty close.

I don't know if Craig's innovated the cure or a cure, but dots connect to a near-100% success rate with freely and frequently treated lesions of, say, Stage III patients.

Now imagine if the lesions of Stage IV or heavily tumor-burdened patients are freely and frequently treated. Oh wait, that's the CUP, where well over a majority of treated patients are now cancer-free.

$PVCT CUP: Against The Odds

I imagine Compassionate Use Program ("CUP") patients are on the worse end of the suitable Gaussian or other distribution curve of disease stage. If the x-axis, from left to right, denotes early to later and later disease stage or amount of tumor burden, I would think CUP patients are 2 sigma'ish or worse (i.e., to the far right of the curve). They're likely to be suffering from compromised immune systems with bodies ravaged by failed prior treatments and therapies (e.g., chemotherapies, other immunotherapies, radiation, etc.).

Yet, a supermajority of more than 75 CUP patients -- very compromised, afflicted and ravaged patients with heretofore little to no good treatment options save for PV-10 -- are now cancer-free thanks to the drug?

Hmmm...