August 10, 2014


Provectus held its second quarter conference call on Thursday. A transcript is here. Some of my initial takeaways are below. I open, however, with a brief aside about at least two indications on which management thinks it may commence trials in 2H14.

Locally advanced, unresectable (unresected) cutaneous melanoma, the subject of a Phase 3 trial, does not kill you. Its spread, however, eventually does. Putting it perhaps too simplistically, the tumor on your skin may not immediately kill you; however, its unchecked or unsuccessfully treated spread should at some point. It is the nature of the indication, melanoma's virulence and subsequent metastasis, that presumably has created seemingly idealogical differences and skepticisms over using local agents and therapies to treat what otherwise is considered a systemic disease.

On the other hand, locally advanced unresectable (unresected) liver cancer, the subject of what should be a Phase 2 randomized control trial ("RCT"), can kill you. Simplistically, the tumor on your liver may or probably will kill you before its spread does. Perhaps also too simplistically, the spread of a primary (non-hepatocellular carcinoma, or non-HCC) cancer to the liver (i.e., a cancer metastatic to the liver) probably kills you faster than the primary cancer in its non-liver location. Using local agents and therapies (i.e., ablation therapies) is much more easily accepted.

PV-10's initial pathway to approval, using it to treat locally advanced, unresectable cutaneous melanoma, recognizes an alternative way, with this particular compound, to treat melanoma: stop its spread. A subsequent pathway would be to explore PV-10's role in combination with a checkpoint protein inhibitor (as an immune system primer and activator) to, after melanoma has spread, defeat its metastasis. It would seem that as much as PV-10's rapid local ablative properties are of interest to certain parts of the medical community, its potentially robust immunological properties are of greater interest to other parts.

Expanding PV-10's opportunities for approval, this time using it to treat locally advanced, unresectable liver cancer is more straightforward, more acceptable, and more understandable in its benefit. Injecting PV-10 into a tumor on the liver to make it go away would seem much more of a victory to some than injecting the drug into a melanoma tumor on the skin to make it also go away. As a result, PV-10's immunologic benefit would seem to some (and I make a very thin straw-man argument here) greater or more important for melanoma than for liver cancer, even if PV-10 injection in a tumor on the liver metastasized from another primary cancer demonstrates regression or remission of this cancer from whence it came.

Process similarities between the two indications (and hoped for/sought after labels) of locally advanced, unresectable cutaneous melanoma and locally advanced, unresectable liver cancer include working with the FDA's Division of Oncology Products 2 ("DOP2") and, as Eric noted:
Any combination studies in the liver are likely to follow similar development strategies to those outlined earlier for melanoma and rely on much of the same foundational science.
A. Melanoma Phase 3 Trial (PV-10)

When will the trial protocol be filed, and when could the trial start? On the conference call Eric said:
We've indicated previously that we plan to commence the study this year and this work is allowing us to put the finishing touches on the protocol before it undergoes final review in the next few weeks by key melanoma investigators and consultants in clinical operations and regulatory affairs. 
And: As I outlined in my earlier comments, we're working to address both long-term and recent guidance from the agency, and particularly the recent guidance provided via our interactions with the agency since December concerning the relevance of symptom assessment in our patient population, those patients with locally advanced cutaneous melanoma. We're working with leading partners in this area to finalize this aspect of our study design and expect to send our protocol out for review by our team of CROs, regulatory consultants and investigators in coming weeks. 
And: So to reiterate, we expect to commence the Phase 3 melanoma study by the end of the year, including filing the protocol with the agency and starting patient enrollment at sites already using PV-10 under our expanded access protocol.
I previously initially assumed (projected) a September start to the trial and a partial quarter of recruitment, enrollment and treatment ("accrual"), with a full 4Q14 quarter of accrual in my July 10th 2014 Annual CEO Letter (pt. 1) blog post. Later I revised this to an end of September start, and thus assumed a full 4Q14 quarter of accrual in my July 31st MD Anderson, More Cash, Checkpoint Protein Inhibitor Combinations blog post. There is the risk of "trial start creep," perhaps similar or analogous to the creep in the company's pursuit of a special protocol assessment ("SPA") for a pivotal melanoma Phase 3 trial. Is it different this time, or is it the same?

I think it's different because with the SPA Eric said, finally and beginning with the May 23rd conference call, he did not have (i.e., was not in agreement with the FDA on) the right patient population for the trial (i.e., the right indication), the right endpoints, and the right drug supply. "Right" means high likelihood of trial success:
Click to enlarge. June 19th conference call
Whereas, presumably now, he does have it right: the right patient population (no uninjectable disease; i.e., akin to the all lesions treated sub-group of the Phase 2 trial), the right endpoints, and sufficient modernized drug supply.

Eric still is finalizing the Phase 3 protocol because he hasn't completed one piece of it (or is putting "the finishing touches" on it): the third secondary endpoint of Patient Reported Outcomes ("PROs") to assess impact on lesion pain and other skin symptoms:
Furthermore, our endpoints with complete response rate should allow us to highlight one of the key features of PV-10, and we'll measure patient reported outcomes to better characterize the relationship between complete response and symptoms of locally advanced cutaneous melanoma, such as pain and bleeding. 
We're working with several leading CROs with specialized expertise in the assessment of patient reported outcomes to show that our planned assessments are rock-solid. This is an important but complex topic and the experience of these expert groups is allowing us to put into place the final missing pieces of our protocol. 
And: So to summarize so far, we are finalizing the process of combining our expertise gained from years of clinical testing of PV-10, inputs from meetings with our scientific advisors, investigators and advocates in the field, and design input from multiple CROs having specialized expertise in key areas such as assessment of patient reported outcomes, radiologic and clinical image management, bio-statistics, clinical data management, and so on, to ensure that we have a robust protocol that can address the needs of licensure. 
We are also adopting, to the extent possible, important design elements from successful pivotal trials of other drugs recently approved in melanoma and other cancers that address issues pertinent to pivotal testing in PV-10. These include details on scheduling of response assessments, handling of issues pertinent to our comparative drugs, and the collection and interpretation of patient reported outcome. {Bold and/or underlined emphasis is mine}
It's clear (at least to me) Eric feels he can adequately predict the outcome of the Phase 3 trial for the primary and first two secondary endpoints of progression free survival ("PFS"), complete response [rate] ("CR") and overall survival ("OR").
I can't really speculate on what effect size we anticipate seeing in Phase 3. Classically, there is a phenomena of effect size compression and the effect of the drug is smaller progressing from Phase 1 to Phase 2 and then again from Phase 2 to Phase 3. We've seen the opposite so far going from Phase 1 to Phase 2. I don't know if that is necessarily going to be a continuing trend, but it certainly is directionally favorable. We will be using fully conforming RECIST assessments in the Phase 3 study versus modified RECIST assessment. So, really it's not directly comparable. 
Having said, we do expect to see a very high rate of complete response consistent with the patients in the Phase 3 study where we treated all in existing disease, we'll be treating all existing disease in our Phase 3 patients and so we can use that group from Phase 2 as a model. {Underlined emphasis is mine.}
Company and investigator medical conference presentations over time periodically present and discuss various response and survival results: objective response (and components: CR, partial response, stable disease), PFS, OS, disease specific survival ("DSS"), etc. (although the presented data should be a fraction of the total, frustrating, secretive, and most assuredly intellectually inconsistent in the founders' thinking as it is). This means, in my view, that Eric believes he can adequately predict the trial's outcome, and more than reasonably project or "guess" the mean/median and confidence intervals of the primary endpoint PFS and secondary endpoints CR and OS of patients in the PV-10 arm should beat statistically significantly/not overlap those of the patients in the comparator (systemic chemotherapy dacarbazine) arm.

What remains, or what may have recently been completed, could be assuring the approach to PRO assessments are "rock-solid." Eric's comment of "We are also adopting, to the extent possible, important design elements from successful pivotal trials of other drugs recently approved in melanoma and other cancers that address issues pertinent to pivotal testing in PV-10" likely refers to, for example, the use of the Skindex survey Genentech used in vismodegib trials and approval for locally advanced or metastatic basal cell carcinoma.

The timing of the filing of the Phase 3 protocol, and thus the commencement of the trial itself, may be as early as after its "final review in the next few weeks by key melanoma investigators and consultants in clinical operations and regulatory affairs," or having observed Eric's process over time, meticulous, deliberate and seemingly lacking in urgency as it may appear, filing and enrollment could occur later than I previously assumed (e.g., September, end-of-September). For now, I'll stick with the end of September until such time as I have to revise my viewpoint.

When the trial starts v. How the trial ends. Loosely speaking (writing), I don't think Eric cares as much about when the trial starts as he does about whether he can adequately predict the outcome of the trial, and thus how (and when) the trial ends or could end.

B. Liver Phase 2 trial (PV-10)

Getting to a deal in China (or India), let alone closing one, should be a function of or tied to finalizing, and thus filing, a Phase 2 trial protocol for a presumably pivotal RCT:
Peter: This is a gray topic and we are actively discussing with potential partners in both India and China in particular when to enter into a transaction, but I think conservatively it does make sense for a protocol for both melanoma and liver that's appropriate for those respective countries to be in place prior to at least a transaction be consummated. It's possible that MoU could be signed in advance, but conservatively I think it makes sense for say you as an investor, Dr. Gollum, or any to see that protocol filed on and then you could make a logical assumption from there, once the Phase 3 melanoma study or the Phase 2 liver that Eric touched on has been filed, that that makes sense for potential global partner or geographic partners. Eric can comment.
Like the final piece of getting to a final melanoma Phase 3 protocol is addressing possibly the last piece of PRO assessment, the final piece of getting to a final liver Phase 2 protocol probably is addressing the respective liver cancer needs of geographic populations:
Eric: Follow-up of our initial patients at one or more conferences and in the literature in coming months, and we're assessing strategies to accelerate transition to Phase 2 testing in a randomized controlled trail, either alone or in combination with systemic therapy. Any combination studies in the liver are likely to follow similar development strategies to those outlined earlier for melanoma and rely on much of the same foundational science.
And: As the CTO, I cover both clinical development and intellectual property portfolio of the Company and I'll point out that in those sorts of scenarios, it's almost certain any protocol that we entered into in Asia would be an international protocol because there are certain implications of a single country of protocol and intellectual property rights. So, you can expect that that would be one of the aspects of such protocol.
For example, the final piece needed to fall in place might be deciding, in advance consultation with key liver cancer investigators and consultants in clinical operations and regulatory affairs (prior to his trip) as well as with prospective geographic partners (during it), whether to (i) compare sorafenib and sorafenib + PV-10 with separate American/Western European and Asian cohorts because of different etiologies, or (ii) undertake a "Western" study of PV-10 in combination with systemic therapy (sorafenib) and an "Eastern" study of PV-10 versus an ablation therapy (like percutaneous ethanol injection). I imagine Eric should return from his trip next week to China with, I hope, sufficient and final perspective on how to complete and file the design of the Phase 2 trial upon his return and after reviewing it with his team of investigators and consultants.

I'll address the PH-10 mechanism of action study and a potential melanoma combination therapy Phase 1 (or 1b)/2 trial involving PV-10 and a checkpoint inhibitor in a subsequent blog post or news item.

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