When Provectus Biopharmaceuticals Inc. (OTC:PVCT) announced at the end of May that the FDA had denied it Breakthrough Therapy Designation (BTD)
it caused a sharp drop in the stock price. The extreme move in the stock market obscured the significant and steady progress forward that the company has been making in the development of its premiere product: PV-10 (Rose Bengal) as a treatment for various types of cancer. PVCT is not just a stock that can be shorted and traded, pumped and dumped, but it is also a biotech company that is developing a product that has a rich and interesting story that is worth telling.
The way traders have beaten down the stock, it may seem as if there is nothing behind the stock symbol. However the company has an advisory board composed of 2 senior executives of Pfizer (NYSE:PFE), a senior executive of Sanofi (NYSE:SNY), a senior executive of Bayer (OTCPK:BAYRY), a senior executive with Boehringer Ingelheim (a private $17billion drug company) and a senior executive of the Livestrong anticancer organization. These are busy business people who would not give their names and their time to a company unless they were sure that it has a promising technology.
Rose Bengal is a dye that was first prepared in 1884. It has been used safely in the human body for more than 70 years. Currently it is used as an eye stain to identify damage to the eye. It has also been used as a diagnostic agent in the human liver. For our purposes, this shows that Rose Bengal, the active ingredient of PV-10, has a well-established record of safe usage in the human body. It has been injected into the human body for more than 70 years.
For more than a decade, Provectus has been working to establish that its formulation of Rose Bengal solution, called PV-10, is an effective agent against various forms of cancer. To date it has completed the following studies: Phase 2 study for the treatment of melanoma that was completed, a Phase 1 study for Liver Metastasis that was expanded and is still ongoing and a Phase 1 study for Breast Cancer that was completed.
Although it continues to work on Liver Metastasis, Provectus has focused its efforts on working towards approval of PV-10 as a drug to treat melanoma, cancer of the skin.
The Phase 2 study for Melanoma was a considerable success. The fact that it was a Phase 2 study meant that various treatment methods were tried, many of which were not optimal, but the results were encouraging and raise high expectations for success in the more focused Phase 3 that has been announced and is expected to begin in 2014.
As reported at the prestigious ASCO conference this past June, altogether 80 patients were treated in that Phase 2 study. Because of the fluid nature of the Phase 2 study, they were at various stages of the disease. Nonetheless, from the group of patients that were most similar to what would be found in a clinical treatment setting, meaning that all of their known cancerous lesions were treated, there was a 71% objective response rate which included 50% were there was a complete response, meaning that all the lesions simply went away after being treated one or more times with PV-10. Investigators could no longer detect any cancer at the site of the previous tumor. This result supports the potential of PV-10 as a single agent for treatment of cancerous lesions and provides a rationale for the PV-10 phase 3 randomized controlled trial in locally advanced melanoma patients. (See PV-10 Data Presented at the American Society of Clinical Oncology (OTC:ASCO) Annual Meeting Defines Path Forward for Provectus Biopharmaceuticals, Inc.)
Here is photographic documentation of the effect of PV-10 on a 57-year-old male whose melanoma had reappeared after being surgically removed three times prior to this treatment with PV-10.
And here is the photographic documentation of the effect of PV-10 on an 86-year-old male who had a large lesion on his cheek.
Both of these patients were melanoma stage III and are of the general type that will be treated in the announced Phase 3 Randomized Control Trial (RCT) study for PV-10 that is due to begin some time in this quarter of 2014.
These pictures cannot be from any other drug, since there is no other known drug that produces an effect like this.
The denial of BTD status by the FDA is not a significant setback in developing PV-10 as a recognized cancer treatment. BTD is a special status that has been conferred on only a handful of the thousands of new drugs under development, and it is no shame not to receive it. Most drugs that are approved never receive it. The denial letter of the FDA actually contained positive statements about the effectiveness of PV-10: "The preliminary clinical data provided in your request for Breakthrough Therapy designation are indicative of drug activity in the treatment of local, satellite or in-transit recurrence of malignant melanoma..."
Provectus noted in the ASCO poster referenced above that the FDA guidance in their denial of BTD helped them to design the Phase 3 Randomized Control Trial (RCT) that they are undertaking. This was further discussed in a Conference Call on June 19. They will enroll 210 patients altogether. At the conference call they announced that they had 7 centers lined up to participate in this enrollment, and that they may eventually have more. They have also hired a specialist firm to manage the study.
How Does PV-10 Work Inside Tumors?
The environment in most cancerous tumors is acidic. This is because the cancerous cells reproduce so rapidly. Since they crowd each other, they do not get enough oxygen and cannot eliminate acidic waste well. The result is that the tumor environment is acidic, much more acidic than the environment of normal cells.
More than a decade ago, the Provectus researchers decided to try targeting this difference in acidity to attack the cancerous cells. They found that Rose Bengal is attracted to acidic cells. Also, it does not enter normal cells, but it does enter cancerous cells. This behavior is well documented, but the reason is not yet fully understood. Rose Bengal passes through the cell wall of cancerous cells, but not of healthy cells.
PV-10 treatment for melanoma is by direct injection into the cancerous lesion. The PV-10 molecules released in the tumor pass through the walls of cancerous cells and enter into them. Once inside the cancerous cells the PV-10 molecules are further attracted to the most acidic parts of the cells: the lysosomes. These are little organelles in the cells that usually digest the nutrients. The PV-10 molecules enter the lysosomes and eventually cause them to burst. The bursting lysosomes release their very acidic contents into the cell which causes the entire cancer cell to burst apart.
Whatever Rose Bengal does not enter the cancer cells is broken down by the body and eliminated very quickly. It has a half-life of thirty minutes, meaning that half of any PV-10 that is in the patient's bloodstream and not attacking cancerous cells will be excreted in the bile within half an hour.
There is a cute animation of this method of operation available at this link:
Since PV-10 relies on basic chemistry, the strength of the effect does not decline with use. The PV-10 is always able to pass through the cell walls of cancerous cells. Similarly, normal tissue cells will not allow the PV-10 through. Thus no resistance is ever built up to the operation of PV-10.
Similarly, since PV-10 specially targets cancerous cells, no damage is done to normal cells. Many treatments for cancer are harmful to normal cells as well - but they are more harmful to cancer cells. PV-10 has no effect on normal cells. This means that it can be used to treat patients who may be too weak to survive the damage done by some other treatments.
The Immunological Effect
The activity and effect of PV-10 is not complete after it bursts all of the cancerous cells. PV-10 causes a documented effect also on tumors elsewhere in the body, in which it was not injected!
Investigators had noticed in the Phase 1 and Phase 2 studies that tumors that were not treated with PV-10 also showed a therapeutic effect in that they shrank and/or disappeared. It was certainly a surprise to find that tumors that had not been injected, and even tumors at far away places in the body, were somehow affected by PV-10 that was injected into specific cancerous tumors.
At first the only formal documentation for this effect was in mice. In studies undertaken at the Moffitt Cancer Center in Florida, a large, independent cancer research and treatment center, an unmistakable effect was seen in mice. Moffitt performed this research in fulfillment of its commitment to translational research, meaning research "aimed at the rapid translation of scientific discoveries to benefit patient care." (From the Moffitt website)
What Moffitt scientists did was to inject cancer cells in the flanks of hamsters to produce a tumor there, and at the same time they injected the same cancerous cells into the bloodstream to induce metastases on the lungs. Eight days after making them sick, the hamsters were injected with a single injection of PV-10 into the flank tumor. A control group was injected with a salt solution which obviously had no effect on the tumor. Eleven days later, the effect of the injection on the flank tumor was measured and also the lungs of all the animals were examined for the presence of cancerous tumors. (Full details presented professionally are available on the AACR poster)
The results were dramatic:
Up until the treatment, the blue lines representing untreated hamsters, and the red lines representing hamsters treated with PV-10, follow the same path. At the time of treatment, the flank tumors were about 13 mm square. After treatment, the divergence becomes very evident. At the end of 11 days, the tumors injected with only a salt solution are an average of 194 mm squared. The thick blue line shows the average, and the thin blue lines show individual animals. The flank tumors of the hamsters injected with PV-10 were completely destroyed in a few days and were not measurable any more after 11 days.
The effects on the uninjected tumors in the lungs were also pretty striking:
The hamsters treated with PV-10 had from 0 to 6 lung metastases, with an average of only 3.2.
The hamsters treated with the saline solution had a minimum of 37 metastases with most having more than 100. The average was 84.
The results were published in an article in a peer-reviewed journal PLOS One last year.
The researchers at Moffitt and at Provectus tried several combinations to see what would happen. For one thing, they saw that several measures of immune system activity registered very high on the PV-10 treated animals. Then they tried transferring T cells (a kind of white blood cell that are a central part of the immune system) taken from mice who had tumors and were treated with PV-10 to other mice who had the same kind of tumor. They could see a clear effect on the tumors of those mice. They also tried injecting the PV-10 into a flank which had no tumor, and there was no effect at all (as I would expect). Finally, they tried injecting T cells into animals whose immune system was crippled and nothing happened.
Most medically naive observers (like the current author) were convinced by these results. But not medical professionals. "It's only mouse data," they said. "It is interesting, but you cannot be sure what will happen when it is tried in human bodies."
Research professionals knew that you cannot be sure what you have until it was actually tried in human patients.
The researchers at Moffitt did just that and they just reported the results at the recent ASCO convention in a poster entitled, "Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions."
The results showed that PV-10 primed the immune system to make it particularly effective at fighting the kind of tumor it was injected into. As the abstract says in its conclusion, "IL PV-10 treatment can lead to systemic anti-melanoma immunity and pCR in injected and uninjected lesions including treatment-refractory tumors."
So far, no one knows fully how PV-10 accomplishes this stimulation of the immunological system. The most informed speculation is that the mass destruction of the cells caused by the injection of PV-10 into the tumor causes a massive release of antigens to which the immune system is exposed, leading it to ramp up its ability to fight the cells with those antigens. The presence of the immunological effect is now documented as noted above in the study by the Moffitt Cancer Center and presented at ASCO. However how it works is not yet fully understood.
The current state of knowledge was summed up by Dr. Jeffrey Weber, the senior author of the presentation by the Moffitt Cancer Center: "This data provides more and more evidence that you are altering both local and systemic immunity in a positive way. It also provides a rationale for combination trials of PV-10 with check point protein inhibitors, such as ipilimumab, pembrolizumab and nivolumab."
The main product in the development pipeline of Provectus Biopharmaceuticals Inc., PV-10, shows a lot of promise. Although it must be remembered that it is still in a research and development stage, the results so far suggest that it may do well enough in the Phase 3 study to achieve approval by the FDA for treatment of melanoma. It also shows promise for use in combination with other drugs that use the immune system to fight cancer.
PVCT: The Stock
After the denial of Breakthrough Therapy Designation for PV-10 for melanoma, the price of the stock crashed, reaching as low as 30 cents in the middle of a trading day. Recently it has drifted between $0.88 and about $1.10 on very low volume of only a few hundred thousand shares. Major moves are unlikely until/unless there is some significant news, such as the filing and approval of the Phase 3 study for PV-10 for melanoma, or a licensing agreement with a foreign pharmaceutical company, something that Provectus management has been talking about for a long time. But it is worth nothing that for the first five months of this year the price was over $2 and there has been progress on the product since then.
The stock has been under attack at least twice this year from shorts who assessed (correctly it seems) that it was vulnerable to attack.
As with many speculative biopharmaceuticals, if the drug trials are successful it is like to be worth a very lot more than the current price of about a dollar. However, despite the considerable success the lead drug PV-10 has enjoyed so far, an investment in PVCT must be looked at as a very speculative investment.
Disclosure: The author is long PVCT. The author wrote this article themselves, and it expresses their own opinions. The author is not receiving compensation for it. The author has no business relationship with any company whose stock is mentioned in this article.
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