Rose Bengal (PV-10) at ASCO 2016

[Colored emphasis below is mine.]

A phase 2 study of intralesional PV-10 followed by radiotherapy for localized in transit or recurrent metastatic melanoma.

Author(s): Matthew C Foote, Bryan H Burmeister, Janine Thomas, Tavis Read, Bernard Mark Smithers; Princess Alexandra Hospital and University of Queensland, Brisbane, Australia; Princess Alexandra Hospital, Brisbane, Australia

Background: Intralesional rose bengal (IL PV-10) can elicit ablation of injected tumors and a T-cell mediated abscopal effect in untreated lesions. Phase 2 testing in patients with Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. Three patients who progressed received external beam radiotherapy (XRT) to their recurrent lesions with an impressive response without an increased radiation reaction. Methods: An open-label, single-arm phase 2 study was performed to assess efficacy and safety of IL PV-10 followed by XRT. Eligibility included recurrent localized dermal, subcutaneous, in-transit or metastatic malignant melanoma (stage IIIb / IIIc) suitable for intralesional therapy and XRT. Patients received a single course of PV-10 into lesions treatable within a localized radiotherapy field. If CR was not achieved patients received 30 Gy (6 fractions of 5 Gy twice weekly over 3 weeks) 3D conformal radiotherapy (photons or electrons) commencing 6-10 weeks after PV-10. Outcome assessments included ORR and clinical benefit (CR+PR+SD) of in-field target lesions by RECIST criteria, toxicity using CTCAE V3.0, and progression free survival (PFS). Results: There were 15 patients enrolled with 13 completing the radiotherapy component. Two patients had rapidly progressive distant disease following PV-10 injection. The mean age of patients was 69 years. With a median follow up duration of 19.3 months the overall response rate was 87% (CR 33%, PR 53%) with 93% clinical benefit on an intent-to-treat basis. The mean time to best response was 3.8 months, mean duration of complete response (PFS) 12.2 months, overall loco regional progression rate 80% and melanoma specific survival 65.5 months. Size of metastases ( < 10mm) predicted potential for lesion complete response. Treatments were well tolerated with no treatment associated grade 4 or 5 adverse events. Conclusions: The combination of IL PV-10 and radiotherapy resulted in lesion specific, normal tissue sparing, ablation of melanoma tumors with minimal local or systemic adverse effects. The study results justify expanded evaluation in a randomized trial.

Intralesional rose bengal for treatment of melanoma.

Author(s): Sanjiv S. Agarwala, Robert Hans Ingemar Andtbacka, Kristen N. Rice, Merrick I. Ross, Charles Raben Scoggins, Bernard Mark Smithers, Eric D. Whitman, Eric Andrew Wachter; St. Luke's Hospital and Health Network and Temple University, Bethlehem, PA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Medcl Onc Assoc of San Diego, San Diego, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Louisville, Louisville, KY; Princess Alexandra Hospital and University of Queensland, Brisbane, Australia; Atlantic Melanoma Ctr, Morristown, NJ; Provectus Biopharmaceuticals, Inc, Knoxville, TN

Background: Intralesional rose bengal (PV-10) is an investigational small molecule ablative immunotherapy that can elicit primary ablation of injected tumors and secondary T-cell activation. Phase 2 testing in Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. PV-10 is currently undergoing phase 3 testing as a single agent in patients with locally advanced cutaneous melanoma and phase 1b testing in combination with immune checkpoint inhibition for more advanced disease. Methods: Study PV-10-MM-31 (NCT02288897) is an international multicenter, open-label, randomized controlled trial of PV-10 versus investigator’s choice of chemotherapy (dacarbazine or temozolomide) or oncolytic viral therapy (talimogene laherparepvec). A total of 225 subjects with locally advanced cutaneous melanoma (Stage IIIB or Stage IIIC recurrent, satellite or in-transit melanoma) randomized 2:1 will be assessed for progression free survival (PFS) by RECIST 1.1 (using blinded Independent Review Committee assessment of study photography and radiology data). Comprehensive disease assessments, including review of photography and radiology data, are performed at 12 week intervals; clinical assessments of progression status are performed at 28-day intervals. Study PV-10-MM-1201 (NCT02557321) is an international multicenter, open-label, sequential phase study of PV-10 in combination with pembrolizumab. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab are eligible. In the current phase 1b portion of the study, up to 24 subjects will receive the combination of PV-10 and pembrolizumab (PV-10 + standard of care). In phase 2 an estimated 120 participants will be randomized 1:1 to receive either PV-10 and pembrolizumab or pembrolizumab alone. The primary endpoint for phase 1b is safety and tolerability with PFS a key secondary endpoint; PFS is the primary endpoint for phase 2. Clinical trial information: NCT02288897

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 "...it 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, http://www.cell.com/immunity/abstract/S1074-7613(13)00296-3

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.

Disfigurement, Discomfort, Death

+273% 1-year stock performance, January 7, 2013 to January 7, 2014, no insider sales

+135% 1-month (roughly) performance, December 9, 2013 to January 7, 2014, no insider sales

-3% 1-week performance, December 31, 2013 to January 7, 2014, no insider sales

There are no sale-related Form 4 filings on the SEC website for Provectus filings through Tuesday, January 7th. For the previously provided link, check the “include” circle under “Ownership?” to bring up stock ownership-related filings. Another way is here, where I searched for filings using "4." I note Tuesday because filings must be made within two business days. It is theoretically possible management sold shares Wednesday or Thursday, with reporting of these transactions made via filings Friday and Monday, respectively. While I cannot write with certainty management have not sold shares, I’m going to go out on a limb and suggest they have not.

Historically, there have been no insider sales by Provectus officers and directors.* There only have been purchases.

You may recall Provectus' stock’s value proposition from my September 22^nd investment letter (the closing share price: “The Company’s stock value proposition is very compelling at the current share price. Provectus appears close to achieving regulatory clarity for its lead indication, appears close to consummating regional license transactions for PV-10 in China and India, appears to have as least the interest of Pfizer as well as the attention of other global pharmaceutical companies, has no historical insider selling and plenty of historical insider buying, and has low institutional ownership. The Company, on the other hand, has a stock that until this year was mired in a multi-year downward trend, a capital structure that historically has weighed on the share price, trades on a minor U.S. stock exchange, is led by first-time public company leadership with no prior experience bringing an oncology drug to market and of which Wall Street is very skeptical, and has no institutional or Wall Street sponsor (the lack of playing Wall Street’s game in a highly regulated and capital-intensive industry like biotechnology, together with some shortcomings, has restrained the share price heretofore).”

Buy/sell transactions by directors/ex-directors (chronologically, I believe, Fuchs, McMasters, Koe and Smith) provide information and sometimes knowledge. I believe I am correct in writing only Koe purchased stock as a director (part of the September announced private placements), already having considerable ownership prior to his election as a member of Provectus' board of directors. Fuchs’ ownership, I believe, derived from his early funding involvement with the company, with warrants and possibly stock that also may have come with it. All directors have been awarded stock options over time for their roles.

* With Fuchs' departure from the board in July 2011, thus becoming an ex-director, he may have sold some or all of his shares thereafter.

A tweet from Thursday

I’m more interested, however, in management transactions. More specifically, and more to the point, there have been no sales ever by Craig Dees, Tim Scott, Eric Wachter and Peter Culepper.

Management has told us they await FDA guidance, per their December 18th Provectus Type C Meeting With FDAOncology Division Held December 16, 2013 press release. Presume management knew what went on in the meeting by being and participating in the meeting. Then:

• If the meeting went “bad,” would they not have sold shares by now? By not selling, are they, along with shareholders, planning to go down with the ship and stock? That's, um, noble...

• If the meeting (and, potentially, any follow-up**), however, was good or great, would it not make sense to continue to own stock, given now their view into FDA guidance that also might inform their view of PV-10's commercialization timeline. The founding principals and principal no. 4 are playing for tens and tens and tens and … of dollars, having historically eschewed a Wall Street or investment sponsor, and desirous of leading and controlling the company and the solving of a problem of global importance. Management is not playing for tens and tens of cents.

** It's clear from the thousands of pages of administrative and correspondence documents readily available on the Internet for drug approvals that sponsors (applicants) and the FDA routinely and regularly communicate and interact through the drug approval process.

From my investment letter: "PV-10, a novel oncology compound being developed by Knoxville, Tennessee-based Provectus Biopharmaceuticals, Inc., exemplifies innovation over incrementalism, meaningful over marginal, productized technology over hypothetical, and changing the world over accepting the status quo, with not an insignificant amount of serendipity over contrivance. In sum, these form the quintessential essence of a paradigm shift in the treatment of cancer.

This is where my investment thesis begins and ends: a novel drug compound with a pristine safety profile, a treatment well tolerated by and easily administered to patients, a ready made product inexpensively produced at scale, and a vast addressable market of unmet need that should be fully and very profitably met over time." Bold emphasis is mine. No one can call PV-10 a cure (or the Holy Grail), for now. I focus on the drug's ability, it's vast potential, to shift how doctors think about and subsequently act on treating cancer once found.

Cancer causes disfigurement through surgery, often the first solution considered by physicians (for those patients where surgery is a viable option) for many solid tumor cancers once discovered and diagnosed. PV-10’s tissue sparing ability, together with its safety and efficacy, eventually should eliminate the consideration of surgery first.

Cancer causes discomfort of varying degrees, typically adverse to toxic, when chemotherapy, radiotherapy, and many immunotherapies with actual or likely black box warnings or detrimental short- and long-term effects are used. PV-10’s 30-minute “half-life” means the drug is in the patient’s bloodstream for 30 minutes before it is excreted in the bile. Much more effective than other therapies, PV-10’s pristine safety profile and paucity of side effects eventually should eliminate the need for considering chemotherapy, radiotherapy or immunotherapy before first using PV-10.

Cancer causes death, often because the patient’s tumor burden is too great for the immune system to effectively fight back. Cancer wins because it’s discovered too late. It wins because the immune system is overwhelmed by toxic therapies like chemotherapy, radiotherapy and many immunotherapies, rendering it unable to effectively fight back. Can PV-10 mitigate or eliminate death caused by cancer? Time, more study and research, etc. only will tell. In the case of heavily diseased or tumor burdened patients, PV-10 eventually might be injected into as many accessible tumors as possible with the drug, increasing the likelihood of as many antigens as possible being presented to T cells and other immune system components for the immune system to eradicate as many or all vestiges of cancer from the body. For those previously with no hope, patients with very heavily diseased burden and severely compromised immune systems, PV-10 still could be used in combination (to be further examined, strategized, optimized and ultimately decided) with other systemic therapies like chemotherapy, radiotherapy and other immunotherapies to reduce tumor burden sufficiently for PV-10 to then help stimulate the immune system to finish off the cancer.

A paradigm shift in the treatment of cancer

Indeed.

$PVCT: PV-10 + Radiotherapy by Foote et al.

Recall the combination of PV-10 + radiotherapy: Foote et al.'s initial and ongoing work combining PV-10 and radiotherapy are showing dramatic improvement for patients with much later stage disease (Stage IV) and heavy tumor burden.

A recent article on Princess Alexandra Hospital (Australia) radiation oncologist Dr. Matthew Foote, MD highlighted stereotactic body radiation therapy, where radiation is delivered at sub-millimeter precision (1 millimeter is equal to about 4 hundredths of an inch) to treat cancerous tumors while minimizing harm to normal tissue. By beng precise in its direction, Dr. Foote is able to "...crank up the dose of radiation." Craig historically has held the view that other drugs killed cancers through toxicity rather than tumor tissue specificity, and thus had poor efficacy and problematic side effects. The drugs killed normal tissue, leaked out and systemically poisoned patients, preventing the proper and effective stimulation of the immune system. It is interesting to note "targeted radiotherapy" is better than less precisely delivered radiotherapy.

In the article, Dr. Foote is quoted as saying "There’s evidence that the body’s immune system can fight melanoma so a high radiation dose can actually help stimulate the patient’s immune system to then fight off the melanoma."

Also recall the work by Tan and Nehaus: "Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcoma." In the two cases highlighted by the authors, the approach was backwards. Yet, the “backwards” approach yielded good results on refractory sarcoma. Why backwards? Recall Foote et al.’s past and current work: PV-10 first, followed by radiotherapy. That appears to be the right treatment order.

Perhaps Dr. Foote will try PV-10 first, followed by targeted radiotherapy.

When Provectus provided an update about Dr. Foote's PV-10 + radiotherapy trial in October 2012, 7 subjects were enrolled.

Around January 2013, it appeared at least 10 patients have been treated, a follow-up to the success of their initial work on 3 patients.

I gather [but not from the company] half of the contemplated 30-patient trial has been enrolled.

$PVCT.OB: The Orthogonality Paradigm

Yesterday's PR of Craig et al.'s poster at SITC highlighted additional data that demonstrated the use of PV-10 in combination with systemic chemotherapy. The combination cancer treatments, whether chemotherapy, radiotherapy or immunotherapy, is a growing theme within the medical community. In the case of the work presented at SITC, PV-10, the immuno-chemoablative therapeutic agent, was combined with a systemic chemotherapeutic.

Pre-clinical and clinical data has shown PV-10 generates immunity even in patients afflicted with very late stage cancer. The immune system, however, can be overwhelmed by cancer (and infections). Management thinks the key, for very late stage disease, is to use a chemotherapeutic or another systemic immunotherapeutic agent (like Yervoy/Ipilimumab) to wound the cancer (the infection) just enough so the PV-10-generated immunity can finish it off. Like antibiotics, PV-10 and the application of other therapeutic agents in this manner (i.e., to wound cancer, before PV-10 finishes it off) would not cure anyone. Rather, they hold or bound the infection until the body's natural immune mechanisms can do the job of curing it.

Next up should be the results of combining PV-10 and anti-CTLA-4 system immunotherapeutic agents like Yervoy/Ipilimumab.

Note the importance of Provectus joint patent application with Pfizer for combining local and systemic therapies for enhanced treatment of cancer. More questions arise: How good were the pre-clinical results from combining PV-10 and Yervoy/Ipilimumab? What would the beneficial impact be on very late stage metastatic melanoma cancer patients from this combination? What would the implications be for Bristol-Myers Squibb, and for Pfizer (which retained the right to certain combinations of therapies with tremelimumab?

This Provectus work foreshadows Moffitt's subsequent murine results, having initially reproduced Craig and the team's work and identified the quintessential immune response: a more complete assessment of PV-10's immune-mediated response, demonstration on multiple cancers and in combination with other therapies, and the durability of the immune response (through various challenge studies).

Ultimately, the “orthogonality paradigm” demonstrates PV-10 is orthogonal to (neither impacted by nor having an impact on) other therapeutic agents. This is important because PV-10 would be used first, second and at all times during patient treatment.