A new article, a new clinical trial

Last week Reuters' Bill Berkrot wrote an article on Provectus, its drug PV-10 and the drug's active pharmaceutical ingredient Rose Bengal entitled Old red dye shows promise as new cancer foe. Provectus also initiated a new clinical trial last week entitled A Phase 1 Study of PV-10 Chemoablation of Neuroendocrine Tumours (NET) Metastatic to the Liver. Some thoughts of mine regarding my takeaways from and questions about them are below.

Article. (1) By far the biggest takeaway for me from Berkrot's article was the association, finally, between PV-10/Rose Bengal and an immune system response.

Click to enlarge. Purple emphasis is mine.
Screenshot of Old red dye shows promise as new cancer foe

The article effectively labeled or categorized PV-10 as an immunotherapy (at least a potential one), like Bristol-Myers' ipilimumab (Yervoy) and nivolumab (Opdivo), Merck & Co.'s pembrolizumab (Keytruda) and Amgen's talimogene laherparepvec (Imylgic), among others.

PV-10's consideration as an immunotherapy, or potential one, is nothing new given Moffitt Cancer Center's long-time work (presented and published since 2012; first pre-clinical, then clinical) and the University of Illinois at Chicago's more recent work (presented and published since 2015; pre-clinical to date). But, PV-10 hasn't been readily recognized as an immunotherapy or a potential one, despite both pre-clinical and clinical, company and third party work that should have at least encouraged such thinking. I believe this is changing, such as PV-10 and Rose Bengal's treatment in Garbe et al.'s 2016 review paper Intralesional immunotherapy as a strategy to treat melanoma. See T cells (February 24, 2016) on the blog's Current News page for more information.

(2) Another major takeaway for me was the presentation of the article's content, which was came across as a down-the-middle-of-the-fairway, opening journalistic piece, delivering facts and perspective with little or no opinion, and providing information about Rose Bengal's long, unique history.

Rose Bengal is an industrial chemical that has been around for well over a century. It's been used as a dye. It's been used as food coloring. It's been used as a diagnostic. It's inexpensive to manufacture. Berkrot and/or his editors could have colored some of that perspective, but I think wisely elected not to. In doing so, the article can be a foundational piece of information for those new to or unaware of Rose Bengal, PV-10 and Provectus' stories.

For example, the author wrote:

"While some doctors are encouraged by the research, government approval is years off and not guaranteed. The company must replicate its early results on a bigger scale, and a U.S. Food and Drug Administration decision is not expected before 2019."

Factually true. Provectus' pivotal melanoma Phase 3 trial, per its ClinicalTrials.gov webpage, has an estimated study completion date of October 2017. Add to this some time for preparation of a new drug application (NDA), a 60-day NDA filing review period and normally a 10-month period for the FDA to review new drugs, and one can easily understand Berkrot's 2019 timeframe. Nowhere in a down-the-middle-of-the-fairway article could there be room for, say, management's guidance of a mid-year interim assessment of efficacy and safety or pursuing accelerated approval on the basis of such data.

In another example, Berkrot wrote:

"In a study of 80 people with advanced melanoma, half of the patients who had all of their lesions injected appeared cancer free after an average of two months. A year later, 11 percent continued to show no signs of cancer, according to a report published the Annals of Surgical Oncology. The lesions were destroyed from the inside with no apparent harm to healthy tissue, researchers said. Reported side effects included injection site pain and blistering."

Again, factually true. PV-10 treatment is safe and potentially effective.

The author does not broach the detail that patients who had all of their lesions injected in the above Phase 2 trial received a second injection of PV-10 into all of their melanoma tumors two months after the first injection. In Provectus' ongoing Phase 3 trial, patients will have all of their lesions injected once a month until their lesions go away.

In a third example Berkrot factually and crisply summarizes the goal of this Phase 3 trial, which is to demonstrate PV-10 can prevent or forestall the progression of Stage III melanoma to Stage IV (underlined emphasis below is mine):

"Final results from an ongoing 225-patient melanoma trial of the experimental drug compared to chemotherapy are expected in early 2018. The hope is that the drug, known as PV-10, will prevent melanoma from progressing beyond Stage III, in which the disease has spread but not yet to other organs, and allow patients with more advanced cancer to live longer."

(3) Another minor takeaway would be Berkrot's take on the discovery of Rose Bengal's therapeutic benefit: an accident, but what was the real accident?

That Japanese researchers investigating Rose Bengal's food dye version in the 1980s first observed its therapeutic benefit (i.e., dose-dependent survival) but did nothing, or that Big Pharma researchers in their global, decades-long attempts to boil the oceans in search of new drug compounds did not find this work?

(4) A final and minor takeaway is the author not mentioning anything or making a "big deal" about the local agent's administration (i.e., no specific mention of intralesional (IL) delivery by name; rather, simply the observation PV-10 is injected).

Trial. Takeaways for and questions from me about the initiation of this new clinical trial include:

(1) It's a liver trial.

Specifically, it's a cancer metastatic to the liver or secondary liver cancer trial, rather than a hepatocellular carcinoma (HCC) or primary liver cancer trial.

The company currently is running a Phase 1 liver trial, A Study to Assess PV-10 Chemoablation of Cancer of the Liver, which has explored and is exploring HCC and cancer metastatic to the liver. Preliminary results from this work noted the treatment of several different types or kids of liver mets including colorectal, non-small cell lung, melanoma, and ovarian. I also previously noted a NET metastatic to the liver had been treated with PV-10.  See New clinical study (February 26, 2016) on the blog's Current News page for more information.

(2) Where is the previously management-guided progression of the original Phase 1 liver trial?

In July 2015 presentations of Provectus' preliminary liver cancer data, both HCC and metastatic, the company's CTO Dr. Eric Wachter, PhD indicated the next step in this clinical program would be an Asia-Pacific Phase 1b/2 combination study of HCC (i.e., a single arm trial of regional standard of care + PV-10, followed by a randomized control trial of regional standard of care + PV-10).

Why was a NET metastatic liver Phase 1 trial initiated before the Asia-Pacific Phase 1b trial? What is the significance of NET mets?

(3) Dosing and the number of lesions that can be treated have increased.

The original Phase 1 liver trial permitted treatment of a single lesion up to a maximum PV-10 dose of 7.5 mL. As the trial expanded, an expansion cohort (Expansion Cohort 1, or EC1) was established where a single lesion was treated with up to a maximum PV-10 dose of 15 mL.

In addition, the same two-step dosing approach (two cohorts, low and high PV-10 doses: Expansion Cohort 2.1 or EC2.1 and Expansion Cohort 2.1 or EC2.1, respectively) was provided to patients already receiving sorafenib.

The new Phase 1 liver trial will permit treatment of, first, a single lesion up to a maximum PV-10 dose of 15 mL, and second, if safety is established, all amenable lesions to a maximum dose of 15 mL.

(4) The new liver trial will collect biomarker, symptom and quality of life data.

The original trial collected changes in markers of hepatic function, pharmacokinetics of PV-10 in the bloodstream following IL injection, and pharmacokinetics of sorafenib in the bloodstream following IL injection.

The full title of the new trial is A Phase 1 Study to Assess the Safety, Tolerability and Effectiveness of PV-10 Chemoablation of Neuroendocrine Tumours (NET) Metastatic to the Liver in the Reduction of Biochemical Markers and Symptoms Caused by Secretory Products. Information to be collected includes:

• Change in NET biomarkers (chromogranin A or CgA, and/or 5-Hydroxyindole Acetic Acid or 5-HIAA),
• Reduction in major symptoms (diarrhea and flushing) using EORTC QLQ-C30 and GI.NET21 symptom scores vs. baseline values,
• Reduction in other symptoms (including bronchoconstriction and abdominal cramping) using the same approach immediately above, and 
• Change in peripheral blood mononuclear cells (PBMC), which was measured by Moffitt Cancer Center's Phase 1 feasibility study.

See NET symptoms below:

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(5) Initial efficacy data to be collected in the new liver trial will be objective response rates.

On February 26th the FDA approved Novartis' everolimus (Afinitor) for the treatment of adult patients with progressive, well-differentiated non-functional, NET of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.

From Novartis' pivotal trial "...overall response rates were 2% in the everolimus arm and 1% in the placebo arm. At the planned interim analysis, there was no statistically significant difference in overall survival between arms...Everolimus was discontinued for adverse reactions in 29% of patients and dose reduction or delay was required in 70% of everolimus-treated patients. Serious adverse reactions occurred in 42% of everolimus-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock)." {Underlined emphasis is mine}

Click to enlarge. Image source

One obviously cannot compare the following for many reasons, but I believe it is worthwhile to note that in Provectus' preliminary liver cancer data, a tumor-specific objective response rate of 50% was achieved -- in 4 patients, however.

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(6) I imagine Provectus will press release more information about the new liver trial this coming week.

"Going to be a leading player in 2nd wave of combos."

Blog post title attribution: From a tweet by @lisamjarvis below:

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Provectus issued a press release yesterday, Confirms First Patients Dosed in Trials of PV-10 for Melanoma, which also included the sub-headline "Phase 1b/2 Trial of PV-10 In Combination with Keytruda® for Stage IV Metastatic Melanoma." See my initial comments under "FPFV" (January 12, 2016) on the blog's Current News page.

As I noted in January 10th's blog post Generating Clinical Data, I believe the ideology behind Provectus' pivotal melanoma Phase 3 trial (that is, management's consequential ideas and ideals) is a clear and present focus on the earlier treatment of cancer patients — in the pivotal study's case, the treatment of patients with locally advanced cutaneous melanoma, otherwise mostly known as Stage III (specifically, Stage IIIB-C recurrent, satellite or in-transit cutaneous or subcutaneous melanoma). The ideology is evidenced if and only if/when and only when the trial's hypotheses are proven: (i) complete response of injected tumors is tantamount to elimination of disease symptoms, and (ii) PV-10 can forestall or prevent the spread of the disease from Stage III to Stage IV if all of it is treated.

Provectus management, however, acknowledges that while the greater unmet need in melanoma is the silent masses of earlier stage patients with no real good treatment options, therapy or therapeutic, a potentially much greater driver of value for this indication for a company like Provectus (and thus valuation or market capitalization) lies in combining PV-10 with an immune checkpoint inhibitor like pembrolizumab (Keytruda) in patients with advanced melanoma (Stage IV disease), which comprises a fraction of the total population of people afflicted with this cancer.

The company's CTO Dr. Eric Wachter, PhD's first quote in the PR is interesting:

"With patients starting treatment in both of these studies, the clock is ticking to interim results and ultimately the completion of these studies. Our recruitment activities are moving ahead and we are hopeful that these studies will play critical roles in demonstrating effectiveness and safety of PV-10 in melanoma." {Underlined emphasis is mine}

Eric has the tendency to be [very] precise, on occasion, I believe, at the detriment of accuracy, in context. Nevertheless, "the clock is ticking," at least for me, is sort of odd in its usage in that sentence. Or is it? "clock is ticking, the:" The time (for something to be done) is passing quickly.

Later, in the PR, in regards to the Phase 1b/2 combination study, the release (Eric) notes:

"Up to 24 subjects will be enrolled in the Phase 1b portion of the study. Each subject in this cohort will receive the combination of IL PV-10 and pembrolizumab. The expected completion date is in 2016 for the Phase 1b portion of the study." {Underlined emphasis is mine}

When would be an interim data readout be undertaken; sometime in 2016 (if the completion date is planned for this year as well), but when exactly?

Eric's second quote in the PR says:

"Current research suggests that using anti-cancer drugs in combination can have additive or synergistic effects that can improve the outcomes patients experience. KEYTRUDA® and PV-10 together may prove more effective than either agent alone in treating certain cases of melanoma. We believe that our current Phase 3 study that tests PV-10 on its own for Stage III patients is designed to prove its effectiveness, but we also believe that we should examine combination therapies to maximize potential benefit to patients, especially those with advanced disease." {Bolded and underlined emphasis is mine}

As I also noted in Generating Clinical Data, the crux of the Phase 1b/2 study is showing PV-10 can work in combination with another drug or drug compound, proving orthogonality from both safety and efficacy perspectives. This study's hypothesis in my view is PV-10, together with a checkpoint inhibitor, can benefit patients (Stage IV melanoma) with disease inaccessible to PV-10 injection, with a management ideology of demonstrating a PV-10 solution for late-stage patients with heavy tumor burdens and visceral disease.

An interim data readout of the Phase 1b study might be based on about half of the target number of patients (it might not be, but my baseline guess is half), or about 12 (i.e., half of "up to 24 subjects"). In 4Q15 I heard speculation 5 to 6 patients had been treated (by that time). If PV-10 plus Keytruda makes for a potent combination, how many cycles would a patient require to show meaningful response [rates] and progression-free survival? Provectus' completed Phase 2 Study of Intralesional PV-10 for Metastatic Melanoma saw complete responses mostly require 1-2 injections of Rose Bengal, but in some cases up to 4 treatments. Patients in the Phase 1b study will have up to 5 treatments of both therapies.

Could the trial have recruited enough patients for an interim data readout, and could those patients have received 1-2 cycles of PV-10 and Keytruda?

Click to enlarge.

Takeaway: In saying the clock is ticking to interim results, is Eric actually saying the Phase 1b study in particular is nearly there?

As for the title of this blog post, Pfizer is a part-owner of Provectus' intellectual property regarding combination therapy: Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer (including continuation #1, continuation #2).

Potential Catalysts & "Catalysts"

Caveat: I have been hilariously off-base in the past. See, for example, my August 31, 2014 blog post Potential Catalysts.

Updated (8/9/15): To reflect a longer period of pivotal melanoma Phase 3 site activation, and to include as a catalyst the potential approval of Amgen's intralesional agent for metastatic melanoma talimogene laherparepvec (T-Vec).

Updated (8/9/15): To reflect a year-end start to a Phase 1b trial combining PV-10 and an immune checkpoint inhibitor in patients with advanced melanoma.

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"Provectus Biopharmaceuticals' Novel Synthesis Patent Application Allowed by Chinese Patent Office"

Image source

Provectus issued press release Provectus Biopharmaceuticals' Novel Synthesis Patent Application Allowed by Chinese Patent Office on Monday, noting the company "...received notification of allowance from the Chinese Patent Office for its patent application protecting the synthetic process used to produce the small molecule Rose Bengal, the active pharmaceutical ingredient (API) in PV-10, the Company's lead oncology drug candidate."

The synthesis patent, according to Provectus, "...covers the process under which pharmaceutical grade Rose Bengal and related xanthenes are produced, reducing the formation of certain previously unknown transhalogenated impurities that currently exist in commercial grade Rose Bengal in uncontrolled amounts. The requirement to identify and control related substances is in accordance with International Conference on Harmonisation (ICH) guidelines for manufacture of API suitable for clinical trial material and commercial pharmaceutical use."

A screenshot of the allowance is below:

Image source

The joint Provectus-Pfizer combination patent application filed in China also is below and, according to Provectus, "...covers a method of treatment of cancer that comprises administering a therapeutically effective amount of an intralesional chemoablative pharmaceutical composition in combination with a therapeutically effective amount of a systemic immunomodulatory anticancer agent. The systemic immunomodulatory anticancer agent comprises anti-CTLA-4 antibodies including ipilimumab and tremelimumab." Claims not yet made public purportedly include anti-PD-1 and anti-PD-L1 antibodies.

Image source

Both patent applications were submitted at the same time to their respective geographic regulatory agencies. That is, the synthesis patent was filed on September 17, 2010 with both the U.S. and Chinese patent offices, and the combination patent was filed with both agencies on March 9, 2012. According to Eric (paraphrasing), Provectus files Patent Cooperation Treaty ("PCT") versions of the company's PTO patent applications simultaneously in designated jurisdictions within their respective PCT deadlines. Such filings may be made months after the U.S. case is filed. This allows management to obtain initial input from U.S. examination before the process commences in earnest in other jurisdictions, and to fine tune claims before international prosecution starts. Additionally, Provectus also typically elects to file first in certain key jurisdictions the company has learned are both important and rigorous, which allows management to further refine their international claims before proceeding with other jurisdictions. See IP & China (December 26, 2014) on the blog's Archived News II page.

Protecting intellectual property around the world is good process, and a valuation driver for Provectus. An important component of the company's upcoming pivotal Phase 3 trial for locally advanced cutaneous melanoma would be clinical sites in international locations, such as Australia (a given based on prior participation in Provectus' metastatic melanoma Phase 1 and 2 trials), Western Europe, and so-called emerging market/developing countries.

A China site, and its associated investigator, should be on the roster when the trial starts, or shortly thereafter. The site, at least one of them in the country, should be the Peking University Cancer Hospital (also known as, or having the other titles of, the Beijing Cancer Hospital, the Beijing Institute for Cancer Research, and Peking University School of Oncology). Clinical studies registered on ClinicalTrials.gov for the Beijing Cancer Hospital may be found here (there are 3 that are recruiting).

The investigator should be  Professor and Dr. Jun Guo, M.D., Ph.D (Vice President of Clinical Oncology, Peking University; Deputy Director, Beijing Institute for Cancer Research; Director of Department of Melanoma & Renal Cancer, Peking University School of Oncology). Clinical studies registered on ClinicalTrials.gov for Dr. Gou may be found here (there are 102 of them of various statuses). See also The Asia Melanoma Group (November 26, 2014) on the blog's Archived News II page.

St. Luke's University Health Network's and Provectus' lead melanoma Phase 2 trial investigator Dr. Sanjiv Agarwala spoke at Dr. Guo's October 17th-19th Beijing melanoma conference (2014 Beijing International Melanoma Congress), which was co-chaired by Dana-Farber/Harvard Cancer Center's Professor and Dr. Keith Flaherty, M.D. See 2014 Beijing International Melanoma Congress (October 7, 2014) on the blog's Archived News II page.

Dr. Guo is the head of the Asia Melanoma Group, the establishment of which was announced at above mentioned Beijing conference. See China Daily article New group offers hope to melanoma sufferers:

"The new group consists of 17 leading melanoma experts from countries including China, Singapore, Korea and Hong Kong. "Given Asian patients' differences in genetic background and disease types to Europeans, it is high time Asian experts stand together to form a group that will break down barriers in research on melanoma," said Guo Jun, deputy director of the Beijing Cancer Hospital and head of the newly-established group. The incidence of melanoma is higher among white people than Asians but Asian people have a much higher probability of mucous melanoma than Caucasians, which usually has a poorer prognosis than melanoma on the skin, Guo explained."

Dr. Guo also is a member of Melanoma International Foundation's Scientific Advisory Board, which is co-chaired by Dr. Flaherty.

Amgen's pivotal metastatic melanoma Phase 3 trial for T-Vec did not include any clinical trial sites in China. International locations included sites in Canada, South Africa, and the United Kingdom

Dr. Weber

An interview of Moffitt Cancer Center's Dr. Jeffrey Weber, M.D., Ph.D. by OncLive's Andrew Roth, Expert Discusses Integration of PD-1 Inhibitors Into Clinical Practice, was published last week. I found several of Weber's answers to Roth's questions separately notable by themselves and germane to PV-10 (when viewed in the context of his involvement with the drug).

Dr. Weber's public positions on intralesional therapies and PV-10 are interesting, as has been his work with Provectus' drug when one considers his other clinical work. I have not been able to find disclosure statements for him that included Provectus—if you find any, let me know. Into November 2014 sample Weber disclosures included:

Click to enlarge. ESMO 2014-related (i.e., September)

Click to enlarge. November 6, 2014

Moffitt and Dr. Weber's work with PD-1s pembrolizumab and nivolumab are:

• Moffitt Cancer Center Plays Pivotal Role in FDA Approval of New Anti-PD-1 Inhibitor Keytruda for Metastatic Melanoma (Moffitt press release, September 2014): "Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at Moffitt Cancer Center, was one of the lead investigators of the PD-1 clinical trial which led to the drug receiving breakthrough status from the FDA. “Pembrolizumab is the first PD-1 drug to be approved by the FDA, and it is a clearly effective drug that will prolong survival for many patients with metastatic melanoma.  This approval is a real advance, and a major milestone in the treatment of the disease,” Weber said."

• Bristol-Myers Squibb Receives Accelerated Approval of Opdivo (nivolumab) from the U.S. Food and Drug Administration (Bristol-Myers press release, December 2014): "“The approval of Opdivo gives patients and physicians an important new treatment option for a population where they were once very limited,” said Jeffrey S. Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center. “For the first time, a PD-1 blocking antibody has shown a response rate of 32% in a Phase 3 randomized clinical trial of patients with unresectable or metastatic melanoma, who have progressed following first line therapy.”"

Click to enlarge. Source link

Moffitt and Dr. Weber also have been involved in three other melanoma approvals, ipilimumab, vemurafenib, and the combination of dabrafenib and trametinib:

• (2011) "Researchers at several NCI-designated cancer centers were lead investigators in the pivotal phase III clinical trial that ultimately led to FDA approval in March 2011of ipilimumab as a treatment for advanced melanoma. These researchers included Dr. F. Stephen Hodi Exit Disclaimer of the Dana-Farber/Harvard Cancer Center, Dr. Jeffrey A. Sosman Exit Disclaimer of the Vanderbilt-Ingram Cancer Center, Dr. Jedd D. Wolchok Exit Disclaimer of the Memorial Sloan-Kettering Cancer Center, and Dr. Jeffrey S. Weber Exit Disclaimer of the Moffitt Cancer Center and Research Institute."

• FDA Approves Personalized Medicine Drug For Melanoma (Moffitt press release, August 2011): From Moffitt's website, "Jeffrey S. Weber, M.D., Ph.D., and others at Moffitt contributed significantly to the approval and testing of the melanoma drug Vemurafenib, including important laboratory work in developing an inhibitor to overcome resistance to the drug that has led to improved outcomes."

• Moffitt Cancer Center Instrumental in FDA Approval of Revolutionary Two-Drug Combo to Treat Advanced Melanoma (Moffitt press release, January 2014): "“Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin disease,” said Jeffrey S. Weber, M.D., Ph.D., director of Moffitt’s Melanoma Research Center of Excellence. “This new combination therapy is a huge step in the right direction for the treatment of melanoma, and our researchers played a large role in bringing this treatment option to patients.”"

Of seven drugs the FDA has approved for melanoma since 2011, according to Moffitt and Dr. Weber, they have been instrumental or significantly participated in six approvals.

To date Dr. Weber has publicly associated himself (so to speak) with PV-10 two times, both around ASCO 2014 (June).

• He was senior author of Moffitt's ASCO abstract and poster entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions, which discussed some of the cancer center's clinical work. Moffitt's Dr. Amod Sarnaik, M.D., however, stood next to the poster and presumably spoke about it during relevant sessions, and

• Immediately following ASCO, Weber said "PV-10 might offer the perfect way to prime the immune system."

To add context to the above, however, he:

• Does not believe intralesional ("IL") therapies have a singular role in treating late-stage melanoma with heavy tumor burden and spread of the disease to visceral organs. See Debating Systemic Intralesional Therapies (April 16, 2014) on the blog's Archived News I, and

• Also described Amgen's IL agent tamilogene laherparepvec ("T-Vec") as (November 2014) "...a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipilimumab, or a combination of those."

In the moment, as it relates to Provectus' upcoming pivotal Phase 3 trial for locally cutaneous advanced melanoma, the company has an initial pathway to licensure. When they finally start their trial, management finally would have advanced their drug candidate to the final clinical stage prior to approval (pending of course a positive outcome for the trial). A "fully FDA-approved" and fully operational Phase 3 protocol should be tantamount to a prospective drug label; that is, who to treat and how to treat them.

Returning to Dr. Weber's OncLive interview:

OncLive interview, Figure 1

Takeaway: He notes three approved drugs (ipi, pembro and nivo), and the IL agent (T-Vec) that has begun testing in combination with ipi and will be combined with pembro. Anti-CTLA-4 and PD-1 drugs do not sufficiently work singularly for late-stage patients. Combinations now are the order of the day for this patient population where drug permutations would be graded based on a combination of safety ("keep toxicity down") and efficacy ("boost the response rate). Combining two checkpoint inhibitors, or drugs that release the brakes of the immune system, does not make sense (you're further releasing the brake?) from safety, efficacy and cost perspectives. Combining a stimulatory agent (starting the engine) with an inhibitory one (i.e., a checkpoint blockade agent) makes more sense in order to garner a better grade.

OncLive interview, Figure 2

Takeaway: The role of chemotherapy is being diminished and presumably eventually eliminated as drugs are approved for different melanoma patient populations as safer and more effective alternatives to chemo. He notes three approved immunotherapies (ipi, pembro and nivo). IL-2, also an immunotherapy, was approved in 1998. If and when T-Vec is approved (for metastatic melanoma), it would be an alternative for certain patients. If and when PV-10 is approved (for locally advanced cutaneous melanoma), it would be an option for another segment of melanoma patients.

OncLive interview, Figure 3

Takeaway: I found this answer interesting because Provectus principal investigator and St. Luke's University Health Network medical oncologist Dr. Sanjiv Agarwala said at ECC 2013, "[d]iscussing the interest in the use of PV-10 by his surgical colleagues, Dr. Agarwala added other potential benefits of pre-surgical intralesional injection—turning unresectable lesions into resectable ones and stimulating the immune system to lower the odds of recurrence." Neoadjuvant therapy refers to treatment given prior to the primary one (i.e., in this context, surgery—turn an unresectable lesion into a resectable one so it may be removed with surgery or excision). PV-10 achieved a 71% objective response and 50% complete response in the subgroup of 28 patients from Provectus' melanoma Phase 2 trial who received PV-10 into all existing melanoma lesions (i.e., no un-injected lesions).

OncLive interview, Figure 4

Takeaway: I don't believe Moffitt has commented on progress it may have made in determining a biomarker for PV-10. At this year's J.P. Morgan Health Care Conference, Roche's Chief Financial Officer Dr. Alan Hippe, Ph.D. said 70% of the company's projects in development have a biomarker hypothesis, which underscores Roche's deal with Foundation Medicine. Provectus's upcoming pivotal Phase 3 trial would include patients with "indolent, low-burden, low bulk with normal LDH."

Should Dr. Weber lend his voice—appropriately and in context—to the process of approving PV-10, his could be an important one to the FDA, and one that could help frame the drug's initial and potential eventual roles in treating advanced melanoma in particular and melanoma in general.

Let Me Tell You A Story About Pfizer

Provectus issued a press release and filed an associated 8-K this past week regarding the addition of a third Pfizer executive to its strategic advisory board ("SAB"), Deanna Angello, Director, Commercial Strategy and New Business Planning of Pfizer's Global Established Pharma business. As an aside, there are two other businesses in the reorganized company: Global Innovative Pharma and Global Vaccines, Oncology and Consumer Healthcare.

It would seem reasonable to say there Pfizer's interest in Provectus has existed since at least 2011 (and likely before, probably starting in 2010) and continues to exist, led by Pfizer's Dr. Craig Eagle, M.D. Eagle's last reported position at the firm was Vice President of Strategic Alliances and Partnerships for the Oncology unit. His professional background includes patient care (he was a hematologist-oncologist), and both managerial and participatory experiences in pharmaceutical research, drug development, regulatory affairs, pricing, reimbursement, and post-merger integration. Until I believe relatively recently, it hasn't included profit/loss ("P&L") experience.

Dr. Eagle also appears to be a forward-thinker about oncology, and the role and opportunity of the immune system to restrain, if not defeat, cancer. Consider, for example, a snippet of an Oncology Business Dynamics interview of Eagle following ASCO 2007:

"Oncology Business Dynamics: And the other investigational agent we seemed to hear a lot about was CP675,206. What’s new with this one? 

Craig Eagle: This is a very interesting compound which essentially releases the brakes on the immune system. CTLA-4 is a molecule which normally puts the brakes on the immune system and stops it from attacking tumors. CP-675,206 is an antibody which works on CTLA-4 and renders it inactive so that the immune system can attack the tumor. We presented results from a phase 2 study with 89 patients in which we saw survival times 10.3 to 11 months, which is longer than historical data. While this is preliminary data it was also encouraging enough that we are going to further our investment in the development of The CP-675,206 Phase 3 study in metastatic melanoma has completed enrollment and we are awaiting the data In this study CP-675,206 was used as a single agent administered once every three weeks." {Underlined emphasis is mine.}

CP-675,206 was Pfizer's initial label for its monoclonal antibody and immunotherapy tremelimumab, which is related to Bristol-Myers' approved immunotherapy ipilimumab (trade name Yervoy). Pfizer out-licensed tremelimumab to AstranZeneca's MedImmune in 2011.

Eagle's longstanding interest in PV-10 is a second example; a local drug that is very safe and kills cancer locally, and has demonstrated the ability to systemically kill cancer. A third example would be his contribution to and involvement in Provectus' patent application Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer, which covers and protects the combination of PV-10 and other therapeutic agents, particularly all checkpoint blockade categories (i.e., anti-CTLA-4, anti-PD-1 and anti-PD-L1), and of which he is a co-author (Pfizer is a co-assignee). He probably saw much earlier than most the eventual trend of the FDA and pharmaceutical industry towards the use of combinations of drugs to treat late-stage cancer.

His interest and, by extension, Pfizer's, however, has not translated into an increase in Provectus' share price. The stock price on the date of the first public Pfizer touchpoint, Eagle's addition as the first Pfizer executive on the SAB on August 30, 2011, was $0.92. The price on the date of the fourth public touchpoint, Angello's addition on December 17, 2014, was $0.88. The stock market has placed no premium on a Pfizer-Provectus relationship or association.

The historical touch points between Pfizer and Provectus, starting in 2011 -- three Pfizer executives on Provectus' SAB, and the companies as co-assignees of a combination therapy patent application that includes the pairing of PV-10 and different categories of checkpoint inhibitors -- might encourage one to ask: "Given Pfizer's interest in Provectus, why hasn't it invested in and/or acquired the company yet?"

One answer, it would seem, is not for lack of "trying." I believe Pfizer (Eagle) has tried three times. For two of those times, Provectus management would not have found the valuation proposition sufficiently compelling and thus worthwhile to pursue. In the third instance, Craig et al. likely concurred with valuation but fell short in their efforts to reciprocate Pfizer's interest to formalize the relationship/association.

Transactions, whether venture capital, private equity or portfolio management, typically stem from an underlying value proposition and, more often than not, require a catalyst. PV-10's clinical value proposition, together with the drug's ease of administration and low cost to manufacture, ship and store, is both very clear and attractive. See, for example, my blog post PV-10 (Rose Bengal) Clinical Value Proposition. The historical record of fact and "fiction" paints a picture of potential catalysts that may have provided context for either an acquisition of Provectus or an equity investment in the company by Pfizer. The facts are the addition of three Pfizer executives to Provectus' SAB, and the joint oncology combination therapy patent application the two companies made. The "fiction" includes:

• A rumored 2011 bid for the company for the same $1 billion valuation as and around the same time when Amgen acquired Boston (Woburn), Massachusetts-based, privately held, intralesional oncology company Biovex,

• A rumored equity investment that may have led or co-led Provectus' preferred stock "IPO (using the NASDAQ ticker symbol PVCTP) in 2012, which was to have been predicated on or catalyzed by a special protocol assessment ("SPA") for a melanoma Phase 3 trial. The "IPO" might have been contemplated at a $1 billion pre-money valuation that, while yielding a minority ownership in Provectus for Pfizer, could have provide the impetus and opportunity for Provectus to grow its market capitalization much higher, and

• The rumored 2014 bid for the company for a valuation of more than $2 billion prior to the company's submission of its breakthrough therapy application ("BTD").

2010-2011

Provectus presented preliminary, full, melanoma Phase 2 results at the Society for Melanoma Research's Melanoma 2010 Congress (see Provectus' press release Provectus Reports Full Phase 2 Study Data on PV-10 for Metastatic Melanoma). Prior to that, competing intralesional oncology therapy company Biovex, venture-backed and Boston-based, began enrolling patients in its pivotal melanoma Phase 3 trial for OncoVEX GM-CSF in 2009 (the press release is here, and clinical trial information is here). In 2011 Amgen acquired BioVex for a top-line amount of $1 billion, and renamed the drug talimogene laherparepvec ("T-Vec").

Without reference to a specific timeframe but sometime in 2011 it is possible Dr. Eagle had a casual conversation with Provectus about their interest to be acquired. He may have understood PV-10's value proposition, and Amgen's acquisition of BioVex could have been a direct or indirect catalyst. In M&A parlance the acquisition would have been a precedent transaction used to provide a datapoint establishing price. Provectus management, believing they knew what PV-10 and thus the company were worth, then may have rebuffed Eagle's informal overture.

Given his work with tremelimumab, his interest in PV-10 and its potential in combination with other drugs, and/or possibly a positive opinion of Provectus' early-stage trial effectiveness and capital efficiency, all underscoring a desire to continue working with the company if he could not acquire them, it is possible Eagle tried to out-license Pfizer's anti-CTLA-4 agent to Provectus.

Eagle joined the SAB in August 2011. Pfizer out-licensed tremelimumab to MedImmune (AstraZeneca) in October.

Figure 1. Click to enlarge.

2011-2012

It has been said biotechnology companies typically are acquired when they are in Phase 3 trials. BioVex was acquired by Amgen after beginning its pivotal melanoma Phase 3 trial for intralesional oncology agent T-Vec (formerly OncoVEX) but before an interim analysis was read out.

In 2011 Provectus seemed like it would commence a pivotal melanoma Phase 3 trial. The company had held a meeting with the FDA in October 2011. In January 2012 management issued press release Provectus Receives Guidance From FDA On Pathway to Approval for Phase 3 Trial of PV-10 For Metastatic Melanoma noting they would seek an SPA for the trial. In July Peter filed a $100 million mixed securities shelf of both common and preferred stock; he filed the prospectus for the "IPO," an offering of preferred shares with warrants, in September (the related SEC filings are here and here, respectively). The fundraising round was to have totaled $30 million, if I recall properly, with a "fictional" pre-money valuation of somewhere around or between $800 million and $1 billion.

The situation made sense. While Provectus management may not have been willing to sell the company (i.e., give up all ownership) for a BioVex-like amount of a $1 billion, they might have been prepared to give up a percentage to Pfizer and the round's other investors to cement a relationship with the Big Pharma company. In return, however, Pfizer likely would have required Provectus to be on a firm pathway towards the commencement of a Phase 3 trial. Unfortunately, as we finally learned on the company's May 23rd conference call in the wake of the FDA's denial of Provectus' BTD application, Eric had been unable to agree upon a trial design (endpoints and patient population) with the Agency. There ended up being no investment by Pfizer because there ended up being no catalyst (i.e., no Phase 3 trial design, no Phase 3 trial).

The "IPO" was cancelled in October 2012 amid monstrous volatility in the share price.

Figure 2. Click to enlarge.

2013-2014

Finally, during Provectus' December 16, 2013 Type C meeting with the FDA, Provectus appeared to establish its initial pathway to the licensure of PV-10 with the Agency. See, for example, January 2014 press release Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes, which was locally advanced cutaneous melanoma. The day after the meeting the company issued press release Provectus Announces Name Change to Provectus Biopharmaceuticals, Inc. and Reincorporates in Delaware in which they seemingly buried the addition of the second Pfizer executive to Provectus' SAB, Bob Miglani. Miglani appeared to have substantive international pharmaceutical business experience, and a corporate functional role (as opposed to Dr. Eagle's operational and oncology-focused role). In the same January press release above management noted they also would apply for BTD.

Sometime before Provectus submitted its BTD application it is possible Dr. Eagle had a casual conversation with Provectus about their interest to be acquired this time for $2 billion or thereabouts. He may have been more comfortable with PV-10's regulatory pathway -- albeit not completely certain about it -- and the company's BTD application could have been a direct catalyst (a successful application would have made Provectus much more expensive to buy in his mind). Provectus management, believing PV-10 and the company were worth more, would have rebuffed Eagle's second presumably informal overture.

Provectus' BTD application was denied in May 2014.

Figure 3. Click to enlarge.

2014 And Beyond

In early-November 2014 Moffitt Cancer Center presented preclinical combination therapy work at SITC 2014. Around mid-November Pfizer seemingly jumped into the middle of the immuno-oncology pool with their own anti-PD-1 agent in one hand and Merck KGaA's anti-PD-L1 agent in the other. According to the immediately linked Pfizer press release, Albert Bourla, Group President of Pfizer's [Global] Vaccines, Oncology and Consumer Healthcare business said "Immuno-oncology is a top priority for Pfizer."

Last week, on December 17, Provectus issued press release Provectus Biopharmaceuticals To Sponsor American Association of Physicians of Indian Origin in which they seemingly buried, yet again, the addition of a third Pfizer executive to Provectus' SAB, Deanna Angello. Angello appears to have substantive commercial strategy experience, which notably includes "...formulating robust business cases, and performing due diligence to thoroughly assess the commercial value and fit of in-licensing and acquisition opportunities," and an operational role in Pfizer's Global Established Pharma business, which presumably is not where the bulk of the Big Pharma company's oncology assets lie. Wouldn't they reside in Global Vaccines, Oncology and Consumer Healthcare?

Returning to the concept that many biotechnology companies or assets are acquired or licensed during their respective Phase 3 trials, Provectus soon should announce the company will begin enrolling patients in its own pivotal melanoma Phase 3 trial. Interestingly, Pfizer, but more likely Dr. Eagle, has added a colleague with experience constructing and making the business case to license a therapeutic or buy the company that owns it. It would appear, however, Angello is in a different Pfizer business than Eagle. Wouldn't his visible title put him in Global Vaccines, Oncology and Consumer Healthcare?

I speculate Eagle currently is tied (or has moved) to Pfizer Injectables, which is part of the Global Established Pharma, because he probably needs to add P&L responsibility to his resume to further his career prospects at Pfizer. The division's portfolio of products includes oncologics (PV-10 is an injectable compound of course). Additionally, if someone is going to be tapped to assess the commercial value of the drug, why would he or she come from an ostensibly different Pfizer business. Eagle may be augmenting his professional background while at the same time maintaining his running start on trying to acquire Provectus for Pfizer.

Figure 4. Click to enlarge.

The answer to the question "Given Pfizer's interest in Provectus, why hasn't it invested in and/or acquired the company yet?," if you believe my "fiction," might be that the stars -- valuation and catalyst -- have not yet aligned for both Pfizer and Provectus. It would seem to me Eagle has a reasonably long-standing belief in how to more effectively treat cancer, and a long-standing interest and belief in Provectus and their treatment approach. Craig et al. are and have been focused on protecting the economics of their fully owned cancer asset, and have not been nor currently appear inclined to give the company away. It would also appear Pfizer (Eagle) has been prepared in the past to offer a very healthy premium to the then market capitalization of the company.

While it is not a foregone conclusion Pfizer will acquire Provectus, it would appear the Big Pharma company may be in the pole position (also see my July 2012 Pole Position post). The better question to ask Provectus management, and a key question existing and prospective investors in the company should pose to themselves, might be "Can Provectus get its price?"

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.

The Immune Checkpoint Inhibitor Global 4 (or 5)

In 2013 Citi equity research analyst Andrew Baum projected cancer immunotherapies "...will generate sales of up to $35 billion (a year) over the next 10 years and be used in some way in the management of up to 60 percent of all cancers" (see Immune system cancer drugs tipped to be a $35 billion market, Ben Hirschler, Reuters, May 22, 2013). The analyst and others in the investment community refer to the next generations of immune checkpoint inhibitors, anti-PD-1 and anti-PD-L1 agents, having moved past approved anti-CTLA-4 agent ipilimumab (Yervoy).

Players (2013 ranking by oncology sales) in the checkpoint inhibitor space include:

• Bristol-Myers (#9): CTLA-4 (approved ipilimumab/Yervoy), and PD-1 (approved internationally nivolumab/Opdivo),

• Merck & Co. (#8): PD-1 (approved pembrolizumab/Keytruda),

• Roche (#1): PD-L1 (investigational MPDL3280A), and

• AstraZeneca (#7): PD-L1 (investigational MEDI4736).

Farther behind, it seems, is Novartis (#3): PD-1 (potential candidates via its CoStim acquisition). It could be late for Novartis to bring a checkpoint inhibitor to market. By the time it gets its version out, Novartis should have four competitors with similarly functioning drugs.

Even before Baum made his bold claim, it was clear the FDA, researchers and industry understood the combination of checkpoint inhibitors and other agents and therapies would be the eventual approach for treating late-stage disease. As result, companies established various combination study relationships, and continue to do so.

Checkpoint inhibitor companies do this because PD-1s and PD-L1s should work more effectively in combination depending on the setting (e.g., co-inhibitory/co-stimulatory). Companies with no checkpoint inhibitors (and no robust immune system primers) do this because a combination should provide them an advantage for their treatments that would be surpassed if they did not do these partnerships at all, and potentially permit much earlier market access for their non-checkpoint inhibitor agent.

For example:

• Pfizer (#11): Merck's PD-1 + targeted therapy (crizotinib/Xalkori),  + targeted therapy  axitinib/Inlyta), and + 4-1BB co-stimulatory agent (PF-05082566), 

• Amgen (#2): Bristol-Myers's CTLA-4 + intralesional (tamilogene laherparapvec or T-Vec), and Merck's PD-1 + intralesional (T-Vec),

• Celgene (#4): Bristol-Myers' PD-1 + targeted therapy (paclitaxel/Abraxane), and

• Novartis (#3): In addition to PD-1s and CAR (chimeric antigen receptor)-T cell therapy, Bristol-Myers' PD-1 + [separately] three targeted therapies (ceritinib/Zykadia, INC280, and EGF816).

SugarCone Biotech's Paul Rennert, in his September 2014 blog post Rational Immunotherapy Combinations: How’s That Work Again?, wrote about "...the question of how to parse the potential immunotherapy combinations that may soon become available, noting that different combinations may prove differentially useful across a wide range of oncology indications." His post is very informative. It is a not-so-simple process to understand and develop the appropriate rationale for why, what and how one combines different agents and therapies, as he clearly illustrates in a cursorily-populated table:

Click to enlarge.

Rennert goes on to write (where I look past his use of vaccines to the broader issue of how to generate many more antigens in order for PD-1s and PD-L1s to be more successful in their individual efforts towards the combination):

"There are other consequences in this new landscape. Nearly every oncology vaccine company claims that as soon as they run a combo trial with an anti-PD-1 or anti-CTLA4 antibody their particular vaccine approach will perform beautifully. There are a few problems with this, notably, very few of these companies have a chance in hell of getting an anti-PD-1 antibody via collaboration, and the rest will pay heavily for the privilege. Second we have no idea of how to rationally pair vaccines with immune checkpoint exposure in order to induce optimal responses. Third, there are not enough patients to go around, a simple fact in many indications."

As recent as the company's ESMO 2014 poster Provectus highlighted the combination study aspect of its business/corporate development strategy.

Click to enlarge.

The value proposition/rationale (but not necessarily the specific medical and scientific rationale and sequencing) for combining PV-10 with a checkpoint inhibitor seems straightforward:

• Immune checkpoint inhibitors have been and will be combined with intralesional agents. Thus far, Bristol-Myers & CTLA-4/ipilimumab/Yervoy and Amgen's T-Vec, Merck & PD-1/pembrolizumab/Keytruda and T-Vec. As expected, the combination of ipilimumab and T-Vec produced responses rates higher than the individual treatments themselves (ASCO 2014). That is, Response_A+B > Response_B > Response_A (A = ipilimumab, B = T-Vec).

• The combination produced notable immunologic signaling. This also was reported from the CTLA-4/ipilimumab and T-Vec combination study at ASCO 2014. The greater the immunologic signaling, the greater [one would imagine] the response and interaction of the immune system to fight and hopefully beat cancer. That is, perhaps, Signaling_A+B > Signaling_B > Signaling_A. The poster presented at ASCO of this work only conveyed the immunologic signaling of the combination.

• PV-10 kills tumors far better than T-Vec. PV-10 produce higher complete responses than T-Vec. The medical community has understood for a while the more antigens produced and presented as a result of tumor destruction (antigenization) the more likely the potential of a greater immune response by the body.

If T-Vec works, PV-10 should work better. But, how much better?

Dr. Agarwala noted in his October 12th presentation at the III Eurasian Melanoma and Skin Cancers Forum that intralesional therapies (PV-10 and T-Vec, since Allovectin-7 failed its metastatic melanoma Phase 3 trial) would form the backbone of combination therapies.

Click to enlarge.

The challenge for Big Pharma, perhaps for some of them more than others, is the lack of "hard data" about PV-10's strong immunologic properties. Presumably Moffitt Cancer Center's presentation on November 8th -- Coinhibition and Costimulation: Targets and Strategies session, Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma poster -- will provide it.

What makes Provectus think they can overcome Rennert's obstacles above?

First, does Provectus have a chance of collaborating with a PD-1 and/or PD-L1 owner? I think the company has a good chance, but the cost or benefit of doing so has yet to be determined (i.e., the details, considerations and concessions of a contractual relationship, and not so much the trial design itself). Obviously, the more a checkpoint inhibitor owner wants to combine with PV-10, the better for Provectus.

I think it's reasonable to believe the Global 5 are aware of PV-10's potential, and its possibilities in combination with immune checkpoint inhibitors. Due diligence begins with getting to know the compound, the available data and practitioners knowledgeable in its use, and then learning more about its combination potential. In regards to the former (i.e., getting to know PV-10), a Merck researcher purportedly attended Moffitt's Dr. Vernon Sondak's June 27th PV-10 presentation at the 4th European Post-Chicago Melanoma/Skin Cancer Meeting specifically to hear/learn more about the drug (a European-based Provectus shareholder routinely attends PV-10 data presentations at European medical conferences). Roche seems to be aware of PV-10, but questions the lack of "hard data" about the compound's immunologic signaling.

Second, how would Big Pharma and Provectus rationally pair immune checkpoint blockade with PV-10? Moffitt's upcoming SITC work presumably should begin to describe how to rationally pair, and dose and sequence PV-10 and a checkpoint inhibitor. It seems the immune system primer & activator/cancer antigen releaser should be given first, followed by the checkpoint inhibitor. In the ipilimumab + T-Vec trial noted above, the investigators sequenced the drugs in that way:

T-VEC was given intralesionally at week 1, week 4, and then every other week. Ipilimumab was given every third week starting at week 6. Treatment continued until dose limiting toxicity, intolerance, all injectable tumors disappeared or disease progression.

I think Rennert's larger question is the whys of rationally pairing drugs, before getting around to the hows. I liken it to understanding what step or steps of the cancer immunity cycle each drug partner in a combination promotes.

Third, are there enough patients to go around? According to Provectus there are sufficient patients available because investigators have asked to use PV-10 in combination with other agents in studies when they are established. This too remains to be seen.

Speaking of Dr. Agarwala, he probably will make a similar presentation to the one he made in Suzdal, Russia at the 2014 Society for Melanoma Research Congress in Zurich, Switzerland (a satellite symposium sponsored by Amgen and entitled Oncolytic immunotherapy – engaging the immune system to target melanoma).