100 year old chemical could be the future of cancer treatment
Published on 23/12/15 at 10:24am
melanoma cell
Provectus' PV-10 has shown the most promise as a treatment for melanoma (Credit: National Institutes of Health)
Peter Culpepper, chief operating officer at Provectus Biopharmaceuticals, explains the secrets of Rose Bengal, which has impressed in clinical trials for various cancers and attracted big-name partnerships.
With a 135-year-old chemical, Provectus says it is advancing a new front in the war against cancer, and big pharma seems to agree. That chemical is Rose Bengal, a stain originally discovered in 1882, and for more than half a century used as a dye in cancer diagnosis, but now taking the fight directly to tumours as a therapeutic.
Rose Bengal, in a 10% solution known as PV-10, has displayed greatest promise in the treatment of melanoma, where it was shown in an 80-patient Phase II trial to achieve a complete response rate in 50% of patients’ tumours and an overall response in 71%. A bystander effect was also seen in untreated lesions, suggesting a positive immune response, although it was more effective when all lesions were injected with PV-10.
The success of this trial attracted the attention of some of the world’s largest pharma companies. Pfizer signed a joint patent agreement with Provectus earlier this year, followed by Boehringer Ingelheim’s deal to develop the drug in the Chinese, Hong Kong, and Taiwanese markets.
Personal journey
It has been a long road to the results seen in recent Phase II and now Phase III clinical trials, but for Provectus’ chief operating officer Peter Culpepper, a former telecom executive, it has also been an extremely personal journey that brought him to the forefront of pharmaceutical research.
In the late 1990s, his daughter was diagnosed with a very rare form of brain cancer. By coincidence, this shocking discovery was made just after Culpepper had returned to the US from life as an expat working in Austria, and found himself in the midst of the country’s top medical professionals, and with a new interest in pharma.
“I was in a situation where I was confronted with this disease, which I had never encountered before, so it became a personal, traumatic situation,” he explains. “Thankfully my daughter survived, but I understand how tough the disease and the side effects of treatment can be.
“I was determined to find some investigators and developers who were trying to do something different. I told a headhunter to find me some crazy people who were doing cancer research—and she did. The biggest problem in medical innovation is finding the true trailblazers, and I found that with the founders of Provectus.”
Those founders are Craig Dees, Tim Scott and Eric Wachter, who have worked together for more than 15 years. Rose Bengal may only now be realising its full potential in cancer therapy, but German scientists were already studying chemical dyes for biologic applications in the late 1800s.
With the advent of World War One, this research was halted, only to be revived some 85 years later by scientists at Oak Ridge National Laboratory. This included Provectus’ founders, who were searching for light-sensitive compounds. This is when the PV-10 aspect of Rose Bengal and other agents came to their attention as a potential therapeutic, thanks to its photosensitivity characteristics.
“In the early 2000s, they actually determined that Rose Bengal is an ideal agent, in the right concentration, it will not just stain the disease, but actually kill the disease,” Culpepper explains.
Upcoming trials
A key aspect of the aforementioned Phase II trial—which began in 2007—was that it was built both to study how PV-10 treats the disease when injected directly into lesions, and also indirectly, the bystander effect.
But it was the 50% direct complete response rate that really got the FDA’s attention, and which led the Agency to assist with the design of the in-progress Phase III study for Stage III melanoma. This randomised international trial began enrolling patients in April 2015, and will compare PV-10 to systemic chemotherapies.
PV-10 is also being investigated in late Stage IV melanoma. In September 2015, Provectus initiated a Phase Ib/II trial of PV-10 in this indication in combination with Merck’s Keytruda (pembrolizumab).
Culpepper comments: “In this indication, the industry is making progress, but we are not yet where we want to be with progression-free survival, and we need rational combination studies to improve patient outcomes. Amgen is doing this brilliantly with T-Vec and systemic immunotherapy combinations, and we using the same type of trial design here.”
“Phase II helped us understand that there is a rationale for PV-10, just like Amgen’s rationale for T-Vec, as both are delivered intralesionally. We applaud the FDA’s approval of T-Vec, and we believe it is very important for patients to have an option. We believe that PV-10 would be another option, should we be successful in the Phase III and Ib/II trials.”
Other cancers
While Rose Bengal’s strongest results to date have been observed in melanoma, its mechanism of action is applicable to any other tumour-based cancer, as it responds equally to all lesions. Culpepper believes liver cancer represents an even better global opportunity than melanoma, and is the next targeted indication for PV-10.
“In Asia, PV-10 is seen as the ideal intralesional agent for liver cancer, and it comes back to the bystander effect. What we are seeing so far is that when we ablate the lesion in the liver—and it’s not just primary liver cancer, but any cancer metastatic to the liver—we can ablate the tumour directly, and are seeing evidence of immunologic signalling. We are tracking that now, with biomarkers in the current liver study, and will be tracking that in the Ib/II.”
It is this that makes PV-10 a particularly exciting prospect in cancer therapy. Provectus is studying this mechanism of action in combination with the Moffitt Cancer Centre and Research Institute, and recently-presented data showing that tumour-specific T cells were increased in the blood after tumour ablation with PV-10.
Culpepper comments: “That is particularly encouraging, because in Asia, they use local ablation as the primary standard of care. They see PV-10 as a local ablation that would make particularly good sense, with the notion that it actually has an immunologic introduction of anti-tumour immunity through the ablation.”
“That particularly captivates the local liver specialists, because you can see the bystander effect for treating liver tumours directly with the untreated tumours. We will continue in our studies to better understand that; it is very important, because we are still not where we would like to be in treating primary liver cancer.”
“We haven’t really arrived yet in any of these late-stage indications, and we need to figure out as an industry how to better harness the immune system to completely ablate the tumour, and that is where we come in. The question is how to optimise that for patients in any indication, depending on the stage, and that is what we are going to try.”
2016 and beyond
In these efforts, 2016 is set to be a busy year for Provectus. Culpepper highlights the Phase III melanoma study as a key priority, and expects interim data to demonstrate PV-10’s superiority to the comparators. As for the Keytruda combination study, the company wants to see meaningful interim data not only in Phase Ib, but also out of Phase II.
In support of these studies, Provectus also anticipates additional mechanism of action data in peer-reviewed publications that will have significant resonance with global oncologists.
Culpepper adds: “We will also have data out on the other therapeutic area we are in—inflammatory dermatoses—we are doing an advanced clinical study also on that, and the data should be coming out throughout next year as well. We want the industry to understand how Rose Bengal, in our formulations, is doing what we are saying it’s doing.”
Just how important PV-10 can be to the future of cancer therapy remains to be seen, but the existing data are certainly encouraging, and the body of evidence for its safety and efficacy are growing all the time.
“Really, what the investigators and the people who use our drugs say is that PV-10 is the ideal, global, intralesional agent, because it can be stored at room temperature, it is very straightforward to manufacture. It’s a small molecule, and not a biologic, so you don’t need any fancy equipment or handling methods. It is delivered in a very straightforward way and it is globally applicable with regulatory bodies.”
“A surgeon always wants to remove a solid tumour, but when they can’t do this to their satisfaction, they inject it, and see how fast the patient’s tumour responds. PV-10 primes the immune system across tumour types, so it is the ideal agent, because you can envision treating tumours earlier.
"Why wait for late-stage patients with this kind of treatment when you can get tumours killed earlier and get the immune system primed? This is where Provectus comes in; we think PV-10 has a real global opportunity, and the Boehringer and Pfizer interest speaks to that.”
What is clear from our discussion is the enthusiasm the COO has for PV-10 and his belief in its abilities. As for Provectus’ future, Culpepper pointed to Celgene’s deal with Abraxis for its lead candidate Abraxane as the ideal transaction, when the company’s goals are achieved. “We do want to have an exit,” he comments. But for now, the highly promising work and the PV-10 trials continue.
Joel Levy
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Mission Statement
Published on 23/12/15 at 10:24am
melanoma cell
Provectus' PV-10 has shown the most promise as a treatment for melanoma (Credit: National Institutes of Health)
Peter Culpepper, chief operating officer at Provectus Biopharmaceuticals, explains the secrets of Rose Bengal, which has impressed in clinical trials for various cancers and attracted big-name partnerships.
With a 135-year-old chemical, Provectus says it is advancing a new front in the war against cancer, and big pharma seems to agree. That chemical is Rose Bengal, a stain originally discovered in 1882, and for more than half a century used as a dye in cancer diagnosis, but now taking the fight directly to tumours as a therapeutic.
Rose Bengal, in a 10% solution known as PV-10, has displayed greatest promise in the treatment of melanoma, where it was shown in an 80-patient Phase II trial to achieve a complete response rate in 50% of patients’ tumours and an overall response in 71%. A bystander effect was also seen in untreated lesions, suggesting a positive immune response, although it was more effective when all lesions were injected with PV-10.
The success of this trial attracted the attention of some of the world’s largest pharma companies. Pfizer signed a joint patent agreement with Provectus earlier this year, followed by Boehringer Ingelheim’s deal to develop the drug in the Chinese, Hong Kong, and Taiwanese markets.
Personal journey
It has been a long road to the results seen in recent Phase II and now Phase III clinical trials, but for Provectus’ chief operating officer Peter Culpepper, a former telecom executive, it has also been an extremely personal journey that brought him to the forefront of pharmaceutical research.
In the late 1990s, his daughter was diagnosed with a very rare form of brain cancer. By coincidence, this shocking discovery was made just after Culpepper had returned to the US from life as an expat working in Austria, and found himself in the midst of the country’s top medical professionals, and with a new interest in pharma.
“I was in a situation where I was confronted with this disease, which I had never encountered before, so it became a personal, traumatic situation,” he explains. “Thankfully my daughter survived, but I understand how tough the disease and the side effects of treatment can be.
“I was determined to find some investigators and developers who were trying to do something different. I told a headhunter to find me some crazy people who were doing cancer research—and she did. The biggest problem in medical innovation is finding the true trailblazers, and I found that with the founders of Provectus.”
Those founders are Craig Dees, Tim Scott and Eric Wachter, who have worked together for more than 15 years. Rose Bengal may only now be realising its full potential in cancer therapy, but German scientists were already studying chemical dyes for biologic applications in the late 1800s.
With the advent of World War One, this research was halted, only to be revived some 85 years later by scientists at Oak Ridge National Laboratory. This included Provectus’ founders, who were searching for light-sensitive compounds. This is when the PV-10 aspect of Rose Bengal and other agents came to their attention as a potential therapeutic, thanks to its photosensitivity characteristics.
“In the early 2000s, they actually determined that Rose Bengal is an ideal agent, in the right concentration, it will not just stain the disease, but actually kill the disease,” Culpepper explains.
Upcoming trials
A key aspect of the aforementioned Phase II trial—which began in 2007—was that it was built both to study how PV-10 treats the disease when injected directly into lesions, and also indirectly, the bystander effect.
But it was the 50% direct complete response rate that really got the FDA’s attention, and which led the Agency to assist with the design of the in-progress Phase III study for Stage III melanoma. This randomised international trial began enrolling patients in April 2015, and will compare PV-10 to systemic chemotherapies.
PV-10 is also being investigated in late Stage IV melanoma. In September 2015, Provectus initiated a Phase Ib/II trial of PV-10 in this indication in combination with Merck’s Keytruda (pembrolizumab).
Culpepper comments: “In this indication, the industry is making progress, but we are not yet where we want to be with progression-free survival, and we need rational combination studies to improve patient outcomes. Amgen is doing this brilliantly with T-Vec and systemic immunotherapy combinations, and we using the same type of trial design here.”
“Phase II helped us understand that there is a rationale for PV-10, just like Amgen’s rationale for T-Vec, as both are delivered intralesionally. We applaud the FDA’s approval of T-Vec, and we believe it is very important for patients to have an option. We believe that PV-10 would be another option, should we be successful in the Phase III and Ib/II trials.”
Other cancers
While Rose Bengal’s strongest results to date have been observed in melanoma, its mechanism of action is applicable to any other tumour-based cancer, as it responds equally to all lesions. Culpepper believes liver cancer represents an even better global opportunity than melanoma, and is the next targeted indication for PV-10.
“In Asia, PV-10 is seen as the ideal intralesional agent for liver cancer, and it comes back to the bystander effect. What we are seeing so far is that when we ablate the lesion in the liver—and it’s not just primary liver cancer, but any cancer metastatic to the liver—we can ablate the tumour directly, and are seeing evidence of immunologic signalling. We are tracking that now, with biomarkers in the current liver study, and will be tracking that in the Ib/II.”
It is this that makes PV-10 a particularly exciting prospect in cancer therapy. Provectus is studying this mechanism of action in combination with the Moffitt Cancer Centre and Research Institute, and recently-presented data showing that tumour-specific T cells were increased in the blood after tumour ablation with PV-10.
Culpepper comments: “That is particularly encouraging, because in Asia, they use local ablation as the primary standard of care. They see PV-10 as a local ablation that would make particularly good sense, with the notion that it actually has an immunologic introduction of anti-tumour immunity through the ablation.”
“That particularly captivates the local liver specialists, because you can see the bystander effect for treating liver tumours directly with the untreated tumours. We will continue in our studies to better understand that; it is very important, because we are still not where we would like to be in treating primary liver cancer.”
“We haven’t really arrived yet in any of these late-stage indications, and we need to figure out as an industry how to better harness the immune system to completely ablate the tumour, and that is where we come in. The question is how to optimise that for patients in any indication, depending on the stage, and that is what we are going to try.”
2016 and beyond
In these efforts, 2016 is set to be a busy year for Provectus. Culpepper highlights the Phase III melanoma study as a key priority, and expects interim data to demonstrate PV-10’s superiority to the comparators. As for the Keytruda combination study, the company wants to see meaningful interim data not only in Phase Ib, but also out of Phase II.
In support of these studies, Provectus also anticipates additional mechanism of action data in peer-reviewed publications that will have significant resonance with global oncologists.
Culpepper adds: “We will also have data out on the other therapeutic area we are in—inflammatory dermatoses—we are doing an advanced clinical study also on that, and the data should be coming out throughout next year as well. We want the industry to understand how Rose Bengal, in our formulations, is doing what we are saying it’s doing.”
Just how important PV-10 can be to the future of cancer therapy remains to be seen, but the existing data are certainly encouraging, and the body of evidence for its safety and efficacy are growing all the time.
“Really, what the investigators and the people who use our drugs say is that PV-10 is the ideal, global, intralesional agent, because it can be stored at room temperature, it is very straightforward to manufacture. It’s a small molecule, and not a biologic, so you don’t need any fancy equipment or handling methods. It is delivered in a very straightforward way and it is globally applicable with regulatory bodies.”
“A surgeon always wants to remove a solid tumour, but when they can’t do this to their satisfaction, they inject it, and see how fast the patient’s tumour responds. PV-10 primes the immune system across tumour types, so it is the ideal agent, because you can envision treating tumours earlier.
"Why wait for late-stage patients with this kind of treatment when you can get tumours killed earlier and get the immune system primed? This is where Provectus comes in; we think PV-10 has a real global opportunity, and the Boehringer and Pfizer interest speaks to that.”
What is clear from our discussion is the enthusiasm the COO has for PV-10 and his belief in its abilities. As for Provectus’ future, Culpepper pointed to Celgene’s deal with Abraxis for its lead candidate Abraxane as the ideal transaction, when the company’s goals are achieved. “We do want to have an exit,” he comments. But for now, the highly promising work and the PV-10 trials continue.
Joel Levy
Login or register to post comments Printer-friendly version
Mission Statement
I'm in it to win it!
NASDAQ DIP and RIP
Here is the best word that describes what i do here.
Intuitive;
means having the ability to understand or know something without any direct evidence or reasoning process.
I was born with it, I'm truly blessed!
Alway's searching for winners'
NASDAQ DIP and RIP
Here is the best word that describes what i do here.
Intuitive;
means having the ability to understand or know something without any direct evidence or reasoning process.
I was born with it, I'm truly blessed!
Alway's searching for winners'
