Rather than taking a biochemistry approach to develop drugs that kill cancer cells, Provectus Biopharmaceuticals (NYSE MKT:PVCT) is using physical chemistry by harnessing the unique properties of Rose Bengal, a first-in-class halogenated xanthene.
“We are taking a different type of molecule and a different basis for the mechanism of action than has been used in the industry,” Peter Culpepper, CFO and COO, says in an interview with BioTuesdays.com.
“Our PV-10 drug candidate has the potential to be employed in the treatment of all solid tumor cancers like melanoma, liver and breast, without the typical safety issues, as demonstrated thus far in clinical testing,” he contends. “Those are the cancers we’re focusing on.”
In addition, he says PV-10, which recently entered Phase 3 testing for the treatment of melanoma, has the potential to be used before, during and after surgery, and in combination with other therapeutic agents and therapies, and after all else fails. The technology is protected by some 60 U.S. and international patents.
PV-10 is a new category of ablative immunotherapy made from an active ingredient, Rose Bengal, which has a long history of clinical use and an established FDA safety profile in liver and ophthalmic diagnostics, Mr. Culpepper points out. “We are the first company to use Rose Bengal as a therapeutic.”
Mr. Culpepper explains that PV-10 is injected directly into a solid tumor to generate tumor ablation in one-to-two hours and with minimal side effects. The treatment causes antigens to be released, leading to a systemic, tumor-specific immune response, including T-cell activation, in one-to-two weeks.
“That’s why we call it a two-pronged approach,” he adds. “A patient’s tumor burden is rapidly reduced after injection of PV-10 into cancerous lesions. Then a tumor-specific immune response causes certain regression of unrelated tumors in the body. As a result, the drug has the potential to prolong progression-free survival.”
Mr. Culpepper also suggests that the possible combination of PV-10 with immunotherapy drugs and other systemic therapies has the potential to be used in lesions that are inaccessible to a direct injection of PV-10.
Last month, Pfizer and Provectus received a notice of allowance from the U.S. patent office for a patent application that will protect the use of PV-10 in combination with certain other types of drugs in the treatment of melanoma and cancers of the liver. Provectus’ preclinical testing of PV-10 along with systemic inhibitors and enhancers of the immune system demonstrated their potential importance for treatment of advanced cancers.
In an earlier Phase 2 clinical trial with 80 patients with refractory cutaneous melanoma, lesions were treated up to four times each over a 16-week period with PV-10, and followed for one year.
Mr. Culpepper says PV-10 achieved a 50% complete response in patients where all disease was treated. In addition, median progression free survival was not reached in the study, he adds, noting that the mean PFS was more than 9.7 months for Stage 3 patients.
The Phase 2 melanoma study data was published in the peer-reviewed journal, Annals of Surgical Oncology, last October and presented at a number of medical conferences. Provectus also presented at poster at the American Society of Clinical Oncology last year about a feasibility study to determine the drug’s mechanism of action in treating melanoma.
Last month, Provectus began a Phase 3 study to enroll 225 patients with unresectable locally-advanced melanoma with disease confined to cutaneous or subcutaneous sites. Patients will be randomized so that 150 will be treated with PV-10 and 75 with systemic chemotherapy.
Mr. Culpepper says there will be an interim data read-out when 50% of events are reached, likely in the first half of 2016. The study is expected to conclude in the third or fourth quarter of 2017. The company is targeting 25 clinical sites in the U.S., 10 in Australia, and possibly one-or-two in San Paulo and Beijing.
The primary endpoint for the Phase 3 study is progression free survival, with complete response and overall survival as secondary endpoints. Patients who fail chemotherapy will be eligible to crossover for treatment with PV-10.
According to Mr. Culpepper, Provectus hopes to begin in the current quarter a clinical study of PV-10 in combination with immune checkpoint inhibitors. “We have identified the investigators who will lead this work, the agent to be used in conjunction with PV-10, the patient population, the dosing schedule for both agents and the study endpoints,” he adds.
To assess potential benefit of PV-10 for patients with advanced melanoma, he figures the Phase 1b/2 study will incorporate a modest sized single-arm Phase 1b component, with expedited safety and efficacy endpoints supporting expansion to a larger randomized Phase 2 component. “This is an important second development path for PV-10 in melanoma,” he contends.
Endpoints for Phase 1b include safety of the combination regimen and objective response rate at three-to-four months. For the Phase 2 component, endpoints will be progression free survival and overall survival. Since the checkpoint inhibitor to be used is licensed in the U.S., the company can commence the study with or without assistance of a partner, he adds.
Mr. Culpepper says that patient enrollment was completed during the first quarter on a study of PV-10’s immunologic mechanism of action at the Moffitt Cancer Center. Following up on interim data reported in 2014, Provectus expects further study data to be reported later this year or in early 2016.
“Since the initial findings reported last year from this study showed that the immunologic effects of tumor ablation with PV-10 are complementary to immune checkpoint inhibition, this study has been instrumental in devising our combination strategy,” he adds.
Provectus also is continuing to develop PV-10 for patients with liver and breast cancer, where further clinical development is being planned.
“Our liver cancer program will be more front-and-center this year because of our interaction with potential development partners in Asia,” Mr. Culpepper suggests.
During the first quarter, Provectus received a notice of allowance from the Chinese Patent Office for a patent application protecting the synthetic process used to produce the small molecule Rose Bengal, the active pharmaceutical ingredient in PV-10.
An expanded Phase 1 study of PV-10 for liver tumors continues to accrue patients at clinical sites in the U.S., especially those with tumors metastatic to the liver. Provectus expects to report initial data from this study at the ESMO Congress on Gastrointestinal Cancer in early July, with additional data presentations possible during the second half of the year, he adds.
In addition, Mr. Culpepper points out that planning is underway for a Phase 1b/2 study of PV-10 plus standard of care for hepatocellular carcinoma of the liver.
Meanwhile, Provectus continues to make PV-10 available for compassionate use at about eight hospitals in the U.S. and Australia. More than 100 patients have received PV-10 since the program began in 2009.
Mr. Culpepper says Provectus is pursuing regional partnerships for PV-10 in China, India and Brazil as a way to validate the technology platform and make the drug available in countries that only have systemic chemotherapy for their patients.
“With interim data for PV-10, we hope to sign a global agreement for the drug to provide the greatest return for our shareholders,” he adds.
Beyond oncology, Provectus is developing PH-10 as a treatment for psoriasis and eczema, with plans to develop the drug candidate for all inflammatory dermatoses. The company has completed Phase 2 studies in both indications and submitted data to the FDA in 2014.
PH-10 is a gel formulation of Rose Bengal for direct application to the skin. Mr. Culpepper says PH-10 has little or no systemic uptake and negligible side effects, as demonstrated in clinical studies thus far. In addition, the drug candidate has no substantial rebound after four weeks, unlike steroids, and no immuno-suppressant characteristics. Some 226 patients have already been treated with PH-10.
During the first quarter, Provectus opened recruitment for a Phase 2 mechanism of action trial of PH-10 for the treatment of mild-to-moderate psoriasis. The company expects the study to enroll up to 30 patients at three study centers in the U.S., with enrollment and data collection to be completed in December 2015.
“Data from the study is expected to aid in further development of PH-10, with the objective to co-develop or license PH-10 with a dermatological partner at an appropriate valuation,” Mr. Culpepper says.