On July 7, 2015 CureVac, a clinical-stage biopharmaceutical company pioneering the field of mRNA-based technology, reported that a Phase I/IIa study of the company’s mRNA cancer immunotherapy (CV9103) in advanced castration-resistant prostate cancer was published in the peer-reviewed Journal for ImmunoTherapy of Cancer ((Press release, CureVac, JUL 7, 2015, View Source [SID1234518778]). CV9103 is a self-adjuvanted, sequence-optimized, chemically unmodified mRNA immunotherapy targeting four antigens: prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), and six- transmembrane epithelial antigen of the prostate 1 (STEAP1). The research article, titled "Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study," describes CureVac’s clinical study of CV9103 in 44 patients with advanced castration-resistant prostate cancer. The related data signify the first Phase IIa clinical study in which an mRNA therapy has demonstrated antigen- specific immune responses in the majority of patients. Based on the favorable data, CureVac is currently conducting a randomized, placebo-controlled Phase IIb study in 197 prostate cancer patients with the follower vaccine CV9104 targeting six antigens. Ingmar Hoerr, CEO of CureVac, commented, "We are very pleased that the results of this Phase I/IIa clinical study of our RNActive technology were published in such an esteemed peer-reviewed journal as it validates our leadership position in mRNA therapeutics and highlights the continued advancement of our clinical pipeline. Prostate cancer remains our most advanced program, with the Phase IIb clinical trial progressing as planned, but CureVac also possesses a deep and diverse mRNA-driven pipeline spanning six clinical trials with more than 300 individuals treated so far and about 15 programs targeting multiple treatment opportunities and disease indications." As described in the article, the Phase I part of the study was designed to investigate the safety and recommended dosage of CV9103, with 12 patients up to five intradermal injections of 256 (n = 3), 640 (n = 3), or 1280 μg (n = 6) mRNA. In the Phase IIa part, 32 patients were enrolled to receive the recommended dose of 1280 μg mRNA defined in Phase I. The primary endpoint of the study was safety and tolerability, and the secondary endpoint was induction of antigen specific immune responses monitored at baseline and at weeks 5, 9 and 17. Data indicated that CV9103 was well tolerated, with the majority of related adverse events being of mild to moderate intensity. The most frequent treatment-related side effects were injection site erythema and injection site reaction in 27 (61%) and 21 (48%) patients, respectively. A quantitative analysis of ELISpot, ICS, and tetramer staining assays revealed that CV9103 was able to induce both CD4 and CD8 T cell responses. Of the 33 evaluable patients treated at 1280 μg, a cellular immune response could be detected in 25 (76%). Importantly immune responses against all four antigens could be induced indicating the versatility of the platform. Arnulf Stenzl, Medical Director of the Department of Urology, University of Tübingen Medical School, and senior author of the paper, stated, "The data generated by this Phase I/IIa clinical study demonstrate that CV9103 mRNA was well tolerated and immunogenic. Furthermore a trend towards longer survival time was also observed in immune responders that was strongest in patients responding to multiple antigens CV9103. Based on these results, it is evident that this mRNA technology warrants further clinical investigation." Just recently, CureVac published promising data of its RNArt technology platform in Molecular Therapy that demonstrated for the first time that sequence-optimized, chemically unmodified mRNAs raised relevant protein levels in non-human primates, indicating that mRNA achieves meaningful biological effects in large animals with body weight close to humans.

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On July 7, 2015 Navidea Biopharmaceuticals and its subsidiary, Macrophage Therapeutics reported they will hold a post-International Workshop on Kaposi’s Sarcoma Herpesvirus (KSHV) and Related Agents conference webcast to provide investors with a more detailed look at the recently presented Manocept platform clinical and pre-clinical data and results disclosed in today’s press releases (Press release, Navidea Biopharmaceuticals, JUL 7, 2015, View Source;p=RssLanding&cat=news&id=2065126 [SID:1234506179]). The webcast will take place on July 7, 2015 at 1:00 pm EDT. Rick Gonzalez, Navidea’s CEO and Michael Goldberg, M.D., Macrophage Therapeutics’ CEO will host the call along with Michael S. McGrath, M.D., Ph.D., Professor, Departments of Laboratory Medicine, Pathology, and Medicine at the University of California, San Francisco who will discuss the data presented.

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On July 7, 2015 Progenics Pharmaceuticals reported details of its planned Phase 3 clinical trial for 1404, a developmental stage small molecule designed to help visualize prostate cancer by targeting prostate specific membrane antigen (PSMA) (Press release, Progenics Pharmaceuticals, JUL 7, 2015, View Source [SID:1234506180]). Following recent End-of-Phase 2 interactions with the U.S. Food and Drug Administration (FDA), the design and key elements of a Phase 3 clinical trial for 1404 have been finalized.

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"The successful completion of our End-of-Phase 2 discussions with the FDA represents a milestone in our 1404 program," stated Mark Baker, CEO of Progenics. "Our Phase 3 study builds on our positive Phase 2 data, which established the broad potential of 1404 to detect local and metastatic prostate cancer in a wide range of patients, from low to high grade disease. Our Phase 3 program is designed to support commercialization in our initial target market for the 1404 imaging agent in the U.S. — patients with early disease who may be candidates for active surveillance."

The Phase 3 clinical trial is expected to enroll approximately 450 patients with biopsy-proven low-grade prostate cancer who are candidates for active surveillance but have planned to undergo radical prostatectomy (RP). The multicenter, multi-reader, open-label study will evaluate the specificity and sensitivity of 1404 to identify clinically significant prostate cancer. Histopathology of the tumor tissue will be used as the truth standard. An interim analysis will be performed after approximately one-third of the subjects have been treated and will include an analysis for futility and also evaluate the need for a sample size re-estimation.

Progenics expects the Phase 3 trial to commence by the end of this year.

About 1404, an Imaging Compound Targeting Prostate Specific Membrane Antigen

Progenics’ molecular imaging radiopharmaceutical product candidate 1404 targets the extracellular domain of prostate specific membrane antigen (PSMA), a protein amplified on the surface of > 95% of prostate cancer cells and a validated target for the detection of primary and metastatic prostate cancer. 1404 is labeled with technetium-99m, a gamma-emitting isotope that is widely available, is easy to prepare, and is attractive for nuclear medicine imaging applications. The image created provides the opportunity to visualize cancer, potentially allowing for improved detection and staging, more precise biopsies, and a targeted treatment plan including active surveillance as a disease management tool.

About Prostate Cancer

Prostate cancer is the second most common form of cancer affecting men in the United States: an estimated one in seven men will be diagnosed with prostate cancer in his lifetime. The American Cancer Society estimates that approximately 220,800 new cases of prostate cancer will be diagnosed and about 27,540 men will die of the disease and that approximately 2.9 million men in the U.S. currently count themselves among prostate cancer survivors.

On July 7, 2015 Provectus Pharmaceuticals reported two patients – one with hepatocellular carcinoma (HCC) and one with colorectal cancer (CRC) metastatic to the liver – had non-existent liver cancer at more than 40 months follow-up after a single injection of PV-10 to the liver (Press release, Provectus Pharmaceuticals, JUL 7, 2015, View Source [SID:1234506181]).

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The study, presented at the ESMO (Free ESMO Whitepaper) 17th World Congress on Gastrointestinal Cancer, 1-4 July, Barcelona, Spain, represents the first report of a chemoablative effect for PV-10 outside melanoma.

For HCC, the sixth most common cancer in the world and the third leading cause of cancer-related deaths globally (WHO, 2008), there is a clear unmet need for more effective therapies.

Treatment of HCC with chemotherapy, surgical resection, transplantation and other approaches (such as cryoablation, radiofrequency ablation, and chemoablation) have increased overall survival, but remain suboptimal.

The recent GIDEON study showed sorafenib, currently the only approved first line treatment in HCC, delivers a median overall survival of 10 months in patients under 70 years, and 20 months in patients older than 70 years.

PV-10, a 10% solution of rose bengal originally used as a textile dye and later as an agent to stain necrotic tissue in the cornea, has demonstrated high rates of complete response and durable response in metastatic melanoma.

In phase 2 data, presented last October at ESMO (Free ESMO Whitepaper), 50% of a subgroup of 28 patients with stage III melanoma who had all their cutaneous lesions injected with PV-10 achieved a compete response (where tumours totally disappeared) and 71% achieved an overall response (complete and partial response).

In animal models the investigators have successfully ablated liver, renal, breast and pancreatic tumours with PV-10.

"We had particularly high hopes of PV-10 working in liver cancer because these tumours are encapsulated with the result injected drugs should stay put longer," says Eric Wachter, the author of the abstract who co-developed PV-10.

For the current study two cohorts of patients, one with non-resectable HCC (n=6 patients overall, 7 tumours injected) and the second with other forms of cancer metastatic to the liver (n=7, 3 colorectal tumours, 2 non-small cell lung, 2 melanoma and 1 ovarian) underwent a single percutaneous injection of PV-10 guided by CT to one target lesion in the liver at least 1 cm in diameter.

The administered dose was 0.25 to 0.50 mL per cm³ lesion volume.

Patients could receive injection to a second tumour after initial follow-up of at least 28 days.

For the first analysis of five patients (six tumours) who had longer-term assessment, two patients showed no evidence of disease at more than 40 months follow-up according to RECIST and EASL criteria.

• The first patient was a 68 year old male with HCC (hepatitis B cirrhosis) alive at 54 months follow-up with no evidence of disease.
• The second patient was a 61 year old male with metastatic CRC alive at 42 months follow-up with no evidence of disease.

Furthermore, at up to 54 months follow-up 10 out of the initial 13 patients were alive, with one death due to cardiac comorbidity, one to serious adverse events and one to HCC progression.

Adverse events were generally limited to injection site reactions and photosensitivity and resolved without sequelae, with elevated liver enzymes observed during the first week after treatment.

"Having liver cancer patients alive at up to 54 months of follow-up with no evidence of disease is remarkable. This is even more extraordinary when you consider these patients received just one or two intralesional injections.

The study suggests that PV-10 has moved beyond just melanoma and may be agnostic to tumour type," says Wachter.

As with melanoma, the mechanism of PV-10 in HCC and metastatic liver disease is believed to be due to local chemoablative effects where the agent enters lysosomes causing tumour necrosis that can stimulate immunological effects.

In melanoma, patients injected with PV-10 have shown increased T cells in peripheral blood following injection including CD8 , CD4 , CD3 and NKT.

On the basis of these results Provectus Biopharmaceuticals, Inc. announced the signing of a Letter of Intent (LoI) with Boehringer Ingelheim China on July 2 to collaborate in bringing PV-10 to market in mainland China.

Together the two companies are planning phase 1b/2 studies of PV-10 in combination with standard of care (SOC) in liver cancer.

Provectus is also planning to expand the current cohort to 24 subjects with HCC and liver metastases, and also to HCC patients on sorafenib.
"We are confident that Boehringer Ingelheim’s expertise in navigating the regulatory requirements in China will prove beneficial to us," says Peter Culpepper, CFO and COO of Provectus.

With an estimated 400,000 new cases of HCC in China each year and 372,000 deaths, he adds, there is an urgent need for new treatments.

"The reason for the huge number of HCC cases in China is driven by population, hepatitis infection and aflatoxin, a fungal contaminant in maize that acts as a liver carcinogen."

Currently a phase 3 study of PV-10 versus dacarbazine or temozolomide is ongoing in patients with cutaneous and subcutaneous stage IIIB or IIIC melanoma.

On July 6, 2015 Provectus Biopharmaceutical reported that it is partnering with a global pharmaceutical company to help bring to market its investigative drug for cancer, PV-10, in mainland China, Hong Kong and Taiwan (Press release, Provectus Pharmaceuticals, JUL 7, 2015, View Source [SID:1234506182]).

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The letter of intent with Boehringer Ingelheim comes weeks after the Knoxville clinical-stage oncology and dermatology biopharmaceutical company announced a partnership with Pfizer, which jointly filed a patent application allowing for the use of PV-10 in combination with other types of drugs.

"We finally have the beginnings of serious validation by global pharma entities," said Peter Culpepper, the company’s chief financial and operating officer. "We’re starting to feel good and momentum is moving."

Provectus is in the midst of a Phase 3 clinical trial for PV-10, designed for injection into solid tumors to selectively target and destroy cancer cells in liver and melanoma.

The company, which is traded on the New York Stock Exchange, recently raised $13.1 million in a public offering of common stock and warrants, nearly doubling the company’s cash. An over-allotment option allowing for the purchase of additional shares may generate additional revenue.

Provectus intends to use the net proceeds of the offering for clinical development, working capital and general corporate purposes.

"We’re on the right track," Culpepper said. "We have the right people we’re talking to, but we legitimately need data."

The company is finally in a position to generate that data, he added.

It has in place a supply chain to manufacture the drug, intellectual property in various locations, a mechanism for data through Moffitt Cancer Center and the University of Illinois at Chicago, and now collaborations with big pharma companies that "agree with us and want to help."