Overall Survival

Overall survival (OS) is the so-called gold standard for trial endpoint. Several years back, the FDA issued an oncology guidance document stating that overall survival is usually preferred, but progression free survival (PFS) may be appropriate in some cases (link). Other gold standards include improving “quality of life” measures, reducing toxicity of treatment, and reducing the cost of treatment.

The company has underreported OS; there are snippets of information about OS from the MM Phase 1 trial and the first cohort of the MM Phase 2 trial. Full MM Phase 2 trial data related to OS, however, only will be available when the peer-reviewed article on this trial is published in the globally recognized periodical management says may come out later this year or early next year.

Quite some time back, I wanted to compare what OS data was available for PV-10 (see here and here) to other studies. Korn et al. (2008) performed a meta-analysis of 42 MM phase 2 metastatic melanoma studies (70 arms) that included 2,100 patients.

I did compare. Fully understanding the caveats of comparing trials and comparisons themselves -- comparisons provide useful information, but of course one does not digest them in a vacuum -- I gained robust knowledge.

In Figure 3 of their paper (below), the authors present "event rates for each trial arm versus the sample size in the trial arm: (A) overall survival (OS) rates at 1 year, (B) progression-free survival (PFS) rates at 6 months. The solid lines are 95% confidence bounds. The dotted line is the overall 1-year survival rate (25%) or the overall 6-month PFS rate (15%). (A small number of plotted points have been slightly jittered to avoid complete overlap.)‏"

I added the OS data available for the first cohort of 40 patients of PV-10's MM Phase 2 trial. Note where PV-10 sits on the two graphs for 1-year OS and 6-month PFS.

As a comparison, a couple of years ago, OncoVEX(GM-CSF)'s 50-patient MM Phase 2 trial achieved a 0.58 (58%) 1-year survival figure and compared (positioned) OncoVEX on Korn et al.'s graph.

Amgen acquired BioVex, the maker of OncoVEX, announcing the signing of the deal in January 2011, for an upfront payment of $425 million upfront and [likely up to] $575 million in additional development and sales milestones. At the time, Michael Yee, an analyst with RBC Capital markets, told Bloomberg: "It's a call option on a late-stage, potential blockbuster drug for Amgen." BioVex commenced OncoVEX's pivotal MM Phase 3 trial in April 2009.

Now, it is quite possible that, when the full Phase 2 data is published, the orange dots of PV-10 move upward (better 1-year OS, better 6-month PFS) and to the right (more patients; i.e., n=80). The conservative nature of the principal investigators and, thus, their initial data analyses and presentations could differ (be lower) from the results generated by a suitably conducted, appropriate and extensive data validation process, one that I imagine would or will have been undertaken before the Phase 2 data would have been or will be released for publication.

BioVex heralded OncoVEX's position on Korn et al.'s graph by noting that no study fell outside the 95% confidence intervals denoted by the solid lines.

What would be your perspective of Provectus and PV-10, given the positioning of the orange dots for the first cohort and the entire trial?

• A higher 1-year OS than OncoVEX (upward), and
• A larger trial-arm sample size than OncoVEX (to the right).

CEO Letter Thoughts

PV-10
Metastatic Melanoma


During 2011 we held our second and third meetings with the FDA to discuss the design of a pivotal Phase 3 randomized controlled trial ("RCT") suitable for Special Protocol Assessment ("SPA"). In December the FDA provided us further guidance regarding the submission of our Phase 3 protocol for review, notifying us that they did not require an additional end-of-Phase 2 meeting. Using the recommendations that we received from senior FDA officials regarding patient population and primary endpoint, we are requesting SPA review of our protocol. While the review process could occur in as little as 45 days from the date of submission, we expect it will be an iterative process, and thus, more time may be required to work with the FDA on a study design agreement. This, we believe, represents a major step for our company, probably the most significant achievement yet, in our pathway to approval for PV-10.


⬆ I will address this in a separate post.


As you may recall, too, the Australian Therapeutic Goods Administration ("TGA") has agreed in November 2010 to the same primary endpoint of progression free survival that has been proposed to the FDA. In our meetings with TGA we discussed the use of interim data from the first half of Phase 3 study subjects, in conjunction with safety data collected in earlier studies of PV-10 for melanoma, to allow early evaluation for marketing approval in Australia for metastatic melanoma. TGA agreed that these data should be sufficient for this review if the analysis confirmed efficacy.

⬆ This appears to be just a recap.


In addition, nonclinical studies, designed to characterize the immunologic response to PV-10 chemoablation, have been conducted by researchers at the Moffitt Cancer Center in Tampa, Florida, with initial results reported in March 2012 at the Society of Surgical Oncology Annual Meeting. Paul Toomey, M.D., presented his work and that of his colleagues, confirming that PV-10 chemoablation of melanoma lesions leads to induction of systemic, tumor-specific anti-tumor immunity. Additional nonclinical studies are underway with confirmatory clinical studies planned. This work is fundamental for full characterization of PV-10's systemic benefit and may provide pivotal support for accelerated approval in the U.S.

⬆ I previously posted that the full scope of Moffitt's work -- completed, in-process and in the near future -- makes accelerated approval a real possibility.


Liver Metastasis


In April 2011 we received orphan drug designation from the FDA for Rose Bengal, the active ingredient in PV-10, for the treatment of hepatocellular carcinoma ("HCC"), the most common form of primary liver cancer. This designation entitles Provectus to exclusive marketing rights for PV-10 for HCC in the U.S. for up to seven years if we are the first company to receive marketing approval for this therapeutic drug product. We are also eligible to apply for a waiver from the FDA of certain user fees required by the Prescription Drug User Fee Act ("PDUFA"). In other words, once regulatory approval is received, orphan drug designation provides assurance for the value of our company's proprietary property, grants us market exclusivity, thereby affording us both financial and regulatory benefits. This orphan drug designation for HCC is in addition to that received for metastatic melanoma in December 2006.

⬆ This appears to simply highlight what management has been doing to move PV-10 for HCC along.


We are conducting nonclinical drug-drug interaction studies to verify safety of combining PV-10 with sorafenib, the standard of care for nonresectable locally advanced primary liver cancer. This supports advanced development of PV-10 for HCC in clinical studies comparing PV-10 with the standard of care versus the standard of care alone, to demonstrate an overall survival benefit of treating HCC with PV-10. We expect to provide further guidance on this important indication when we are closer to commencing a Phase 2 or Phase 2/3 clinical study.

⬆ I find it interesting to read that non-clinical drug-drug interaction studies to verify safety of combining PV-10 with sorafenib are ongoing (i.e., confirming the orthogonality of PV-10 and sorafenib). I do not have an expectation of the potential timing of a Phase 2 or Phase 2/3 trial yet.


Breast Cancer and Other Oncology Indications


One of our many objectives during 2011 was to demonstrate that PV-10 has multi-indication potential, and we intend to continue that quest in 2012. We are now in a position for a Phase 2 study in recurrent breast carcinoma, following the completion of our Phase 1 study several years ago. We look forward to being able to report further progress on this indication as well. Furthermore, we have shown success with PV-10 in treating pancreatic cancer in nonclinical studies and are considering a proof of concept clinical study in this equally important indication.

⬆ I take two things away from this. First, the company can start a Phase 2 trial, and second, they appear to me to be assessing whether to start such a trial. I also find it interesting to read about the success in treating pancreatic cancer in non-clinical studies. If you recall, Craig mentioned this in talks late last year.

Compassionate Use Program


I am also pleased to report that our Compassionate Use Program for PV-10 for patients with non-visceral cancers continues, with over 70 patients enrolled in six centers across the U.S. and Australia. The protocol for this program enables subjects to undergo more frequent and extensive treatments with PV-10 over a longer period of time than was allowed under the protocols used for the Phase 1 and 2 trials. We believe this dose regimen serves as a blueprint for our planned Phase 3 clinical trial for metastatic melanoma.

⬆ I previously posted that the utility of Provectus' compassionate use program, outside of the great benefit it has had and continues to have for patients accepted into it, is not fully appreciated.

PH-10
Psoriasis


Our largest clinical trial to date was completed in 2011. The data from this Phase 2C RCT, which enrolled ninety-nine subjects with mild-to-moderate plaque psoriasis, corroborated the potential effectiveness of PH-10 observed in these patients in our earlier clinical study.

⬆ This appears to be just a recap.


Reaching this milestone has also triggered increased efforts for our company to seek a licensure of PH-10 for the treatment of serious dermatological diseases, which would include psoriasis and atopic dermatitis, another indication for which PH-10 has completed Phase 2 clinical trials. We remain on track to secure a term sheet from a potential partner that would lead to a proposed licensing agreement and the engagement of a financial advisor to effect this transaction.

⬆ This also appears to be just a recap.


We have also successfully completed various dermatological toxicity studies which are appropriate at this stage of development of PH-10. We will work with the FDA to design the remaining toxicity studies necessary to support a New Drug Approval (NDA) filing. Because of the well-tolerated safety profile of Rose Bengal, we are enthusiastic about the potential for widespread acceptance of PH-10 upon eventual expected approval.

⬆ Again, another recap. I think management also is sharing their perspective about the licensing process and prospective partner feedback on PH-10.


PRESENTATIONS AT SCIENTIFIC CONFERENCES


PV-10 was the subject of several scientific presentations this year. Of particular note, Dr. Sanjiv Agarwala, Principal Investigator for the Phase 2 melanoma study, presented data at the European Association of Dermato-Oncology ("EADO") Conference in Nantes, France, in June 2011. This audience of prospective European investigators who specialize in dermato-oncology had a special interest in injectable therapies, and we were encouraged by the level of interest this group had in PV-10, particularly as we prepare for a global Phase 3 trial.

⬆ This appears to be just a recap.


In November 2011, Professor Merrick Ross, M.D., a Principal Investigator for our Phase 2 Melanoma trial, delivered a presentation at the 2011 International Melanoma Congress during the 5th Meeting of Interdisciplinary Melanoma/Skin Cancer Centres meeting in Tampa, Florida. His presentation included a discussion on the role of intralesional therapies for controlling both local disease and their possible effect on systemic disease, such as that which has been shown in Phase 2 testing of PV-10.

⬆ At the HemOnc Today conference in NYC earlier this month, Dr. Ross publicly said PV-10 should be approved. I have much more blog post material on PV-10 and the HemOnc Today conference.


We expect additional presentations at scientific conferences this year that will be announced when appropriate, as well as various peer-reviewed publications either this year or next.

⬆ Management is trying to push for the publication of the MM Phase 2 and/or HCC Phase 1 trial results in globally recognized peer-reviewed periodicals in 2012. Only time will tell if they are successful.

CORPORATE DEVELOPMENTS


Prominent leaders joined our Board of Directors and Corporate Advisory Board this year. Alfred E. Smith IV, Senior Advisor for the Marwood Group, joined our Board of Directors. Mr. Smith has extensive financial and healthcare experience. His knowledge of business and medicine has already helped provide our company with guidance on several drug development and corporate strategies.

⬆ This appears to be just a recap.

Dr. Craig Eagle, MD, Vice President of Strategic Alliances and Partnerships for the Oncology unit at Pfizer, and Stuart Fuchs, Chairman and CEO of CognoSPECTi, joined our Corporate Advisory Board. Dr. Eagle's experience in drug development, and Mr. Fuchs's venture capital and investment banking experience in the biotech industry, are great assets to our company as we further our path towards commercialization. Mr. Fuchs joined the Corporate Advisory Board after having served eight years on our Board of Directors. We expect to appoint others to our respective Boards this year and next.

⬆ Comments related to Eagle and Fuchs also appear to be just a recap. I think the comment related to the potential future appointments to the Corporate Advisory Board and the Board of Directors is very interesting to read.

Our balance sheet remains strong, with $7.7 million in cash and cash equivalents, providing us ample cash to fund our operations through 2013. Since we seek to spin-off our non-core subsidiaries, and concentrate our efforts on our drug development activities, in December 2011 we completed an unregistered offering of Units. Each Unit, which included shares of common stock in Pure-ific and a warrant to purchase ¾ share of the Company's common stock, were sold to accredited investors. The net proceeds of this transaction are expected to be used to spin-off Pure-ific as a new publicly traded company. We plan to fund and spin-off the remaining four non-core subsidiaries as well.

⬆ This also appears to be just a recap.

Also, we are in the process of implementing a new executive bonus plan that is expected to be based upon certain additional performance-based criteria, such as stock price and the signing of partnership agreements. This plan will replace the prior one which had been based on the attainment of certain scientific, medical and clinical milestones. We will disclose the details of the new plan once it is finalized.

⬆ I think the comments related to a new bonus compensation plan are interesting to read. I plan to follow-up with more due diligence, analysis and commentary on this topic.

Triggers

Repeatability vs. Reproducibility vs. Publication

The Nature article provides an opportunity for me to expand upon repeatability and reproducibility, and why these dimensions of Provectus' work underscore my investment thesis.

Repeatability has long been there.

Reproducibility has been as well, but not as much, until now: the results of Moffitt's immunology-related work presented at SSO, and the results of work already done but not yet presented and the results of work to be done.

Publications don't necessarily lead to good products and businesses, or, by themselves, are [clearly] not predictors of good or great outcomes. Repeated and reproduced results generally do and are.

FierceBiotech's take:

"Many Cancer Studies Are Actually Unreliable?"

Littlebits, on the Silicon Investor chat room for Provectus, recently linked to a blog post entitled Many Cancer Studies Are Actually Unreliable? at Pharmalot by Ed Silverman.

Silverman, summarizes a Nature article (the Nature editorial makes a good read, too) as centered around the work of two cancer researchers who reviewed "landmark papers" that were published in leading journals and emanated from reputable laboratories. They observed (a) an overall poor quality of published preclinical data and (b) that the vast majority of this work -- nearly all of it -- could not be replicated.

Bradpalm1 subsequently followed up Littlebits' entry with a link to Derek Lowe's weblog column at Corante on the Nature article entitled Sloppy Science. Lowe's comments are direct, including "I think that this problem has been with us for quite a while, and that there are a few factors making it more noticeable: more journals to publish in, for one thing, and increased publication pressure, for another...But there's no doubt that a lot of putatively interesting results in the literature are not real."

Lowe also links to a Reuters article that provides a damning anecdote:

Part way through his project to reproduce promising studies, Begley met for breakfast at a cancer conference with the lead scientist of one of the problematic studies. 

"We went through the paper line by line, figure by figure," said Begley. "I explained that we re-did their experiment 50 times and never got their result. He said they'd done it six times and got this result once, but put it in the paper because it made the best story. It's very disillusioning." 

Such selective publication is just one reason the scientific literature is peppered with incorrect results.

Publications don't necessarily lead to good products and businesses, or, by themselves, are [clearly] not predictors of good or great outcomes. Repeated and reproduced results generally do and are.