Dominic Rodrigues

Dominic Rodrigues
Contributor since: 2013
I do not think this presents an issue for PV-10. Yes, the generation of too much necrotic tissue (i.e., the rapid creation of dying cancer cells) may lead to tumor lysis syndrome ( for some cancer treatments. From what I understand, this has not been encountered by Provectus ( The rapid ablation of tumors, from where these fragments are created, leads to the presenting of many antigens to T-cells and other immune system components, which leads to the stimulation of the immune system and generation of tumor specific immunity.
petethepanzer raises several worthwhile points to further explore and discuss.
1. Tumor regression and elimination
When I began conducting due diligence on this investment opportunity, I initially was struck by Rose Bengal’s pristine safety profile. Rose Bengal (RB), the active pharmaceutical ingredient in both PV-10 and PH-10 (Provectus’ lead compound for inflammatory skin disorders), has an established safety profile with the FDA for prior human use as IV hepatic diagnostic Robengatope, approved by the Agency prior to 1982 (new drug application number 016224), and topical ophthalmic diagnostics Rosettes and Minims®. RB has been used in liver function studies for more than 90 years.
It would seem the safer a drug is, assuming some efficacy, the more one might give of it in hopes of improving a patient’s outcome, at least before resistance kicks-in (if it does at all).
Speaking to petethepanzer’s primary point, I then was further struck, at the time, by the amount of tumor regression and more importantly tumor elimination RB (PV-10) displayed in pre-clinical work on mice, dogs and horses and early clinical studies on humans. Historical information thus far, through management comments and summary results of their own research and work, published pre-clinical and clinical study results by third parties like principal investigators (e.g., Thompson, Agarwala, Ross, etc.) and Moffitt Cancer Center; and compassionate use program (CUP) outcomes, where purportedly 75-80% of patients are cancer free, point to a very high degree of tumor elimination or destruction.
PV-10 has to be injected into tumors for chemoablation, the first step in the drug’s two-part mechanism of action (MOA), to occur and the immunologic benefit, the MOA's second part, to be triggered. The metastatic melanoma (MM) Phase 2 protocol limited the amount and frequency of PV-10 injections, unlike within the CUP where patients receive more PV-10 and more frequent injections of it until their cancers recede or go away (or it is determined they simply cannot be helped because they unfortunately are too compromised).
The affects of PV-10’s chemoablation are to unmask the antigenic material of the injected tumors, which oncologists refer to as the drug’s antigenization or antigen storm phenomena (an “internal vaccine”). Although PV-10 is not a vaccine, the affects are vaccine-like because chemoablation produces the antigenic material in context sufficient for robust responses by T cells and other immune system components.
Provectus published preliminary MM Phase 2 results in November 2010 ( a complete response (CR) of PV-10 injected lesions as 24% of subjects, a 25% partial response (PR, requiring at least a 30% reduction in tumor volume) and an objective response ("OR") of 49% (24% + 25%). In October 2012 the Company published final MM Phase 2 results ( an OR of 51% in subjects' target lesions (25% CR, 26% PR).
In BioVex’s March 2010 presentation of MM Phase 2 results entitled "OPTiM Trial in Stage IIIb/c and IV Advanced Melanoma," a tabular comparison of OncoVEX to state-of-the-art at the time – DTIC, IL-2, MDX010 (Ipilimumab/Yervoy), tremelimumab, Genasense/DTIC, and Elesclomol+Paclitaxel – was made for OR, CR and 6-month durable response rate (see the presentation’s slide number 7). For the purpose of discussing tumor regression and elimination, compare CRs and ORs included in BioVex’s presentation and those of Allovectin-7 and PV-10's Phase 2 trials:
DTIC, 2-3%, 7-12%
IL-2, 6%, c. 10%
MDX010, 3-4%, 5-15%
tremelimumab, >5%, 8-11%
Genasense/DTIC, 3%, 12%
Elesclomol+Paclitaxel, 2%, 15%
OncoVEX/T-Vec, 20%, 28%
Allovectin-7: 3%, 12%
PV-10, 25%, 51%
OncoVex, now Talimogene laherparepvec or T-Vec following Amgen’s 2011 acquisition of BioVex, eventually produced moderate Phase 3 results, which were released before and at ASCO 2013. Vical’s Allovectin-7 recently failed its Phase 3 trial.
Such comparisons cannot be undertaken without caution because they are not apples-to-apples. Response rates also do not necessarily translate into nor predict overall survival (for which Provectus also has displayed impressive progression free survival results for Stage IIIb and IIIc patients). Nevertheless, there is knowledge to be gleaned, particularly as it relates tumor regression (PR) and elimination (CR). What jumps out, at a minimum to me, is the divergence in tumor elimination between the various therapies.
Robert Langreth wrote in May 2013 ( about anti-PD-1 agents, "Building on the success of Bristol-Myers’ Yervoy drug for melanoma that reached the market in 2011, drugmakers are devising more potent immune therapies or combining treatments for maximum effectiveness. They are also testing the new medicines in more types of cancers, including lung and breast," and "If the new generation of immune therapies lives up to its promise, “this is going to be a paradigm shift for treating cancer,” said Merck senior vice president Gary Gilliland in an interview. “We are pretty good at shrinking tumors, but not good at getting rid of them. Immune therapy is a way to begin to approach that.”"
“Second generation” anti-PD-1 agents CRs are higher and growing higher than their “first generation” counterpart ipilimumab, an anti-CTLA-4 agent.
Provectus may publish further information from its MM Phase 2 trial regarding response rates (as well as response durability) such as CR and OR for individual tumors were about or greater than 50% and 70-80%, respectively. PV-10 results, whether for patients or individual tumors, are materially better than other approved or potential treatments. Take into consideration PV-10’s pristine safety profile, and PV-10’s “risk-adjusted benefit” is even higher.
2. 2010 Japanese paper
The y-axis of Figures 3 to 6 indicates lower, or closer to the origin, is better. One minus the y coordinate should yield “efficacy" (the lower the unstained amount, the greater the sonodynamically induced cell damage). The y-axis also is represented on a log scale.
Whether RB or RBD (Rose Bengal derivative), the unstained fraction is substantially lower than US (ultrasound) alone. While cells, tumors or lesions, and patients represent different scales, the paper’s results appear to be consistent with the pre-clinical and clinical efficacy success RB has achieved thus far.
3. Rose Bengal’s discovery
RB’s discovery by Provectus principals is described in "Rose Bengal: From a Wool Dye to a Cancer Therapy", Pharmacy and Therapeutics, Vol. 35, No. 8:469-469, August 2010. I suppose history is written or re-written by the victors as the case may be (assuming of course the victors indeed are or become the victors).
“How did Dr. Wachter’s team stumble onto Dr. Ito’s three-line sentence on improved survival in his 1986 journal article? The Provectus co-founders, including Dr. Wachter, a laser specialist; Craig Dees, PhD, a molecular virologist; and Tim Scott, PhD, a chemical engineer, had met while working at the Oak Ridge National Laboratory. They became interested in photodynamic therapy, and in the late 1990s they were looking for a candidate agent with antineoplastic activity. Known agents posed some problems: they were either uncontrollably toxic throughout the body, or they failed to penetrate the disease site sufficiently. A commercial data search service identified several hundred potential agents. Then, through their own internal screening process, which quickly narrowed the candidates to only those agents with powerful effects, the Provectus researchers turned to rose bengal. Preclinical tests with bacterial and cancer cell lines quickly showed rose bengal to have impressive cytotoxic activity and to be worthy of deeper study. Intensive review of the literature uncovered Ito’s work with the nearly hidden three-line report of a striking survival advantage.
The next hurdle lay in the fact that Dr. Wachter, a true laser aficionado, was absolutely certain that rose bengal had to be activated by laser energy.
“I was a laser expert, and I was very psyched about finding this perfect molecule to go with our exciting laser techniques,” he said.
Drs. Scott and Dees, however, were worried that the technology was too sophisticated for routine use in the clinic and that the severe phototoxicity reported in prior experience with photodynamic therapy, which required patients to stay not only out of direct sunlight but also away from intense indoor lighting for up to several weeks, would hamper wide acceptance despite the agent’s efficacy. They reformulated rose bengal for use without laser activation and came back to Dr. Wachter with results from tests of injected (and laser-less) rose bengal showing the same antineoplastic efficacy as had been achieved with laser activation. Their subsequent animal, and then human, studies confirmed that when rose bengal was delivered within lesions, it was a potent and selective agent for ablating cancers. Thus, PV-10 was born.”
4. Snake oil & Skepticism
It is always healthy to be skeptical, particularly of things that smell and feel like snake oil. Provectus management readily admits PV-10 was considered snake oil around the times when MM Phase 1 and 2 trial results were first disseminated because how good they appeared to be. In my view, Moffitt Cancer Center provided the third party validation of Craig’s historical results and work (and, to some degree, the clinical trials to date) through repeatability and reproducibility. Since then, Moffitt has gone on to verify and validate the broadening and deepening of PV-10’s clinical value proposition as a monotherapy, in multiple indications and in combination with multiple agents. Reduction or elimination of broader skepticism only will come with the FDA’s decision on regulatory clarity for PV-10 and MM, and further publication of Moffitt’s pre-clinical and clinical work.
Have you thought to expand your table above to include PV-10 (and Provectus Pharmaceuticals)?
T-Vec (formerly OncoVEX), Allovectin-7 and PV-10 have been compared (on the basis of their respective Phase 2 trials) as intralesional therapies, along with IL-2 and BCG. Dr. Robert Andtbacka has utilized a slide at medical conferences where he compares response rates of these therapies for injected lesions, non-injected lesions and non-injected systemic lesions (understanding, of course, that response rate and survival measurements are different and not completely related):
He most recently displayed this slide and comparison at the 8th World Melanoma Congress; however, the slide in the above link is from March 2013's HemOnc Today Melanoma and Cutaneous Malignancies Conference.
The local response figures above for T-Vec (26%) and A-7 (19%) compare to IL-2 (70-97%), BCG (45-91%) and PV-10 (49%). For non-injected systemic lesions, IL-2 and BCG produced a 0% response, compared to responses produced by T-Vec, A-7 and PV-10.
T-Vec, A-7 and PV-10 routinely are compared, on the basis of their respective Phase 2 trials, as a group of intralesional therapies (together with IL-2 and BCG). For example, Dr. Robert Andtbacka's utilizes a comparison slide, which he most recently showed at the 8th World Melanoma Congress (the link that follows is from his slide presentation at HemOnc Today in March of this year), to compare response rates of these therapies for injected lesions, non-injected lesions and non-injected systemic lesions (understanding that response rates and survival are two different and not completely related measures): You wrote about PV-10 (and Provectus) about 15 months ago, as you did about AMGN and ONCS ( Might the competition also include PV-10?
Thank you for the kind words.
More than 200 people have been treated with the company's oncology and inflammatory skin disorder (dermatology) compounds (PV-10 and PH-10, respectively) in metastatic melanoma (Phase 2), breast cancer (Phase 1), liver cancer (Phase 1), atopic dermatitis (Phase 2) and psoriasis trials (Phase 2). There also is a oncology compassionate use (expanded access) program where patients also have been treated. You can find more information under the R&D tab on Provectus' website.
Currently, we await the outcome of management's efforts to seek regulatory clarity; specifically, whether the company can agree with the FDA on the design of a metastatic melanoma Phase 3 trial under special protocol assessment (SPA). An expectation is this will be achieved in Q2 2013. The company hopes to complete an expanded liver cancer (HCC) Phase 1 trial by the end of the 2013.
The share price decline over the last month has not changed my investment thesis. $0.59 reflects market uncertainty caused by management's exploration of a preferred stock offering to list on the NASDAQ.
Pfizer will wait as long as it has to wait; however, I do not think the wait will be the 30-month trial period. The waiting should end shortly after the interim analysis of half the contemplated patient population of the trial (or ~90 people).
I have not sold any shares.
The conjecture was from industry constituents; as such, I thought you might have been aware of such "inside baseball" speculation. The essence of my initial comment only was to gain your insight on endpoint design. The Cowen analyst, on the Q2 earnings call, summed up the situation of the delay and determination of the outcome well.
Thank you for your response. I did not ask about interim analysis. I sought, among other things, your thoughts about the design of the primary endpoint. Vical's Phase 3 trial is not really "relatively small" compared to first Ipi trial; that is a 20-25% difference, depending on the denominator (I grant you the comparative difference of the other two trials). Nevertheless, endpoints and trial design dictate study size. Most studies have large or larger patient numbers because their effect size is lower, which means very incremental improvement. Vical probably did not design an interim analysis or efficacy read into their design (and thus did not provide patients in the control arm with a cross-over benefit) because such a design, as you point out, would have put a greater burden on the efficacy outcome. If Vical were supremely confident about the significance of the drug's results, management would have included an interim look and used an even smaller patient study size.
This VICL article is informative and well written, in keeping with your previous ones.
What credence do you give to the conjecture VICL did not meet the primary endpoint in its pivotal MM Phase 3 study?
Mr. Samant commented: "Our Phase 3 trial was designed with no interim analyses for efficacy to keep it as small and cost-effective as possible. Because there were no interim looks at efficacy, there would be no basis to allow crossovers from the control group to the treatment group. The lack of crossovers also prevents compromise of the survival data."
Do you think the trial's primary endpoint was not as well designed as it should have been?
Mr. Samant's rationale of keeping it as small and cost effective as possible would be at odds with the large number of patients enrolled. The lack of a trial design feature to permit crossovers seems sub-optimal, despite his explanation of the potential for comprising survival data.
Nice article. You are comparing OncoSec Phase 1 trial results to Provectus' Phase 2 trial results. Amgen shut down BioVex's other phase 3 trial, a head and neck cancer, for OncoVex. Good comment: "In order for biotech investors to make a decision on efficacy comparisons, the data set needs to be broken down for Provectus to determine how the patients responded as a whole in terms of complete response rate." That is why Dr. Sanjiv Agarwala's presentation of MM Phase 2 trial final data at the 2nd European PostASCO Melanoma Meeting 2012 in Munich on June 22 bears very close watching.