November 18, 2014

Provectus notebook

Pilon-Thomas & Moffitt Cancer Center. Frequent medical writer of PV-10 Janet Fricker has an article out in Medical News Today today about Moffitt's poster presentations at SITC 2014 entitled Melanoma shows improved regression with combination of PV-10 and checkpoint inhibitor.

The article has an interesting quote from the cancer center's Dr. Shari Pilon-Thomas, Ph.D. about their work:
"The spirit of our study was to determine whether combining PV-10 with a checkpoint inhibitor would enhance the systematic immune responses of the initial injection of PV-10."
Phrased via slightly different editing: The spirit of the study was to determine whether combining ABC with XYZ would enhance the systematic immune responses of ABC. Not, whether combining XYZ with ABC would help XYZ.

Pfizer. Pfizer announced Monday it had (i) a PD-1 agent and (ii) licensed a PD-L1 agent from Merck KGaA (Germany), thus changing the competitive landscape to look more like the below:
Click to enlarge.
See blog post "Together, these studies support the induction of increased tumor-specific immunity after co-inhibitory blockade in combination with IL PV-10 therapy."
Interestingly and notably, Pfizer immediately guided 2014 and 2015 earnings downward as a result of the transaction and to recognize its upfront payment as a certain significant item.

Some preliminary opinions on the deal include:
Jacob Plieth, EP Vantage: "This disproves the notion that a handful of big names – Merck & Co, Bristol-Myers Squibb and  Roche – had already seized all the early promise in  PD-1/PD-L1 inhibition."
The Deal Pipeline: "Pfizer in May walked away from AstraZeneca after painting itself into a corner by describing a takeover proposal - one of a series - as "final..." The deal would have also given Pfizer access to AstraZeneca's own immuno-oncology treatment, which are known as anti-PD-L1 compounds...The New York company has now found a less contentious way to access the technology." 
Pfizer's view of its immuno-oncology pipeline now, in cancer-immunity cycle terms, is:
Click to enlarge. Pfizer presentation, November 17, 2014.
Merck & Co., (U.S.A.). Merck announced positive results from a Keytruda (PD-1) melanoma trial on Sunday. The comparator for late-stage patients in this trial was systemic chemotherapy, the co-primary endpoints were progression-free survival ("PFS") and overall survival ("OS"), a secondary endpoint was overall response rate ("ORR"), and additional data was collected on duration of OR, patient-reported outcomes (the EORTC QLQ-C30 questionnaire) and safety (adverse events).

Provectus' upcoming melanoma Phase 3 trial of earlier stage patients whose disease has not spread to distant sites (which is not late-stage disease, where the disease indeed has spread) has a comparator of systemic chemotherapy, a primary endpoint of PFS, and secondary endpoints of complete response rate ("CRR"), duration of CR, patient-reported outcomes (the Skindex-16 questionnaire), OS and safety (adverse events).

China. I thought the comments by Sinopharm A-THINK's CEO in Provectus' PR Provectus Biopharmaceuticals Extends Memorandum of Understanding with Sinopharm-China State Institute of Pharmaceutical Industry and Sinopharm A-THINK Pharmaceutical Co., Ltd that " is hopeful that a contract will be finalized in the coming weeks" were interesting. They become notable if and when a meaningful and material deal is consummated. I don't doubt part of the deal process is for both parties (Sinopharm and Provectus) to interact with the China Food and Drug Administration.

The Cancer-Immunity Cycle. The Medical News Today article about Moffitt, PV-10 and SITC also noted:
"The mechanism, [Dr. Pilon-Thomas] adds, is thought to be that injection of PV-10 into melanoma lesions results in tumor cells releasing antigens that induce T cell immunity, with the checkpoint inhibitors then "releasing the brakes" on the resulting T cells. Next, the team plans to investigate the types of immune cells released at the tumor site." {Underlined emphasis is mine}
"[T]he types of immune cells released at the tumor site" refers to cycle steps 5 and 6 in Chen & Mellman's (2013) Oncology Meets Immunology: The Cancer-Immunity Cycle:
"In the first step, neoantigens created by oncogenesis are released and captured by dendritic cells (DCs) for processing (step 1). In order for this step to yield an anticancer T cell response, it must be accompanied by signals that specify immunity lest peripheral tolerance to the tumor antigens be induced. Such immunogenic signals might include proinflammatory cytokines and factors released by dying tumor cells or by the gut microbiota (Figure 2, Table 1). Next, DCs present the captured antigens on MHCI and MHCII molecules to T cells (step 2), resulting in the priming and activation of effector T cell responses against the cancer-specific antigens (step 3) that are viewed as foreign or against which central tolerance has been incomplete. The nature of the immune response is determined at this stage, with a critical balance representing the ratio of T effector cells versus T regulatory cells being key to the final outcome. Finally, the activated effector T cells traffic to (step 4) and infiltrate the tumor bed (step 5), specifically recognize and bind to cancer cells through the interaction between its T cell receptor (TCR) and its cognate antigen bound to MHCI (step 6), and kill their target cancer cell (step 7). Killing of the cancer cell releases additional tumor-associated antigens (step 1 again) to increase the breadth and depth of the response in subsequent revolutions of the cycle." {Underlined emphasis is mine}
Click to enlarge. Chen & Mellman, Figure 1,
Australia. In November 2010 Provectus wrote in their press release Provectus Meets with the Therapeutic Goods Administration to Review Path for Approval of PV-10 in Australia:
"The recent meeting focused on manufacturing, characterization and specifications for PV-10, along with a review of clinical data and anticipated Phase 3 study design and endpoints. The proposed primary endpoint of progression free survival, which Provectus proposed to the U.S. Food and Drug Administration (FDA) earlier this year in its first end-of-Phase-2 meeting with FDA, was deemed appropriate for assessment of efficacy in light of established European Medicines Agency (EMEA) standards adopted by TGA. Use of interim data from the first half of Phase 3 study subjects, in conjunction with safety data collected in earlier studies of PV-10 for melanoma, was discussed to allow early evaluation for marketing approval for metastatic melanoma, and TGA agreed that these data should be sufficient for this review if the analysis confirmed efficacy."
I learned from folks in Australia that management will be there around the time of the annual scientific meeting of the Clinical Oncology Society of Australia (December 2nd to 4th). I would think visiting the TGA, Australia's FDA, would be on their trip itinerary.

In addition to sites in Australia for Provectus' melanoma Phase 1 and 2 clinical trials and the company's compassionate use program, and the work therein, investigator-initiated work was and is being done combining PV-10 with radiotherapy. Preliminary work (3 patients) was published in 2010 as A novel treatment for metastatic melanoma with intralesional rose bengal and radiotherapy: a case series in Melanoma Research. Follow-up investigator-initiated work by the same lead (Dr. Matthew Foote, M.D.) appears to be one patient short of full enrollment and treatment (25 patients).
Click to enlarge. Above screenshot taken from a presentation
by Dr. Sanjiv Agarwala, M.D. at the 2nd European Post-Chicago Melanoma Meeting (2010)
The average cost of drug R&D. A study by the Tufts Center for the Study of Drug Development out today said developing a new prescription medicine that gains marketing approval costs $2.6 billion. A related article on the study by FierceBiotech author John Carroll framed Tuft's estimate in the context of an estimate by Doctors Without Borders of $186 million.

Through September 30, 2014, Provectus has spent (balance sheet item Accumulated Deficit) $157 million for multi-indication viable PV-10.

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