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[In no particular (including chronological) order:]

September 2, 2015 / The undifferentiation of immune checkpoint inhibitors? Incyte Corporation (Nasdaq: INCY), a nearly $21 billion biopharmaceutical company as of a 9/4/15 share price close, announced a global license and collaboration agreement with China's Jiangsu Hengrui Medicine to develop and commercialize the latter's investigational anti-PD-1 agent (SHR-1210). Under the agreement, Incyte would have exclusive worldwide rights to SHR-1210 except for mainland China, Hong Kong, Macau and Taiwan.

Possible or potential item takeaway: For the deal structured and money paid by Incyte, it didn't want or couldn't get from Jiangsu Hengrui Medicine China and SARs.

According to the Incyte press release "SHR-1210 is expected to enter proof-of-concept studies for the treatment of patients with advanced solid tumors in the coming months." {Italicized emphasis is mine}

As backdrop, as FierceBiotech's John Carroll writes, "[a] little more than a year ago Incyte swiftly lined up combination deals that matched its IDO1 inhibitor, epacadostat (INCB24360), with PD-1 and PD-L1 drugs from Bristol-Myers Squibb ($BMY), Merck ($MRK), Roche ($RHHBY) and AstraZeneca ($AZN). INCB24360 is an immunotherapy designed to amp up an immune system attack on cancer, while the checkpoint programs are designed to dismantle cancer cells' cloaking mechanism that prevents an assault from happening." The idea of the combination therapy approach above is/was the use of an immune system amper upper — Incyte's IDO1 inhibitor epacadostat (INCB24360) — to help/assist/partner with the back-end — immune checkpoint inhibitors or co-inhibitory blockade agents like anti-PD-1 and anti-PD-L1 agents from the above mentioned companies.

Last year, for example, Roche partnered up with NewLink and its IDO inhibitor (NLG919). Later, in 2015, Roche partnered with India's Curadev Pharma and its IDO inhibitor.

According to Chen and Mellman's 2010's Oncology Meets Immunology: The Cancer-Immunity Cycle, IDO inhibitors do not appear to be front-ends or immune system accelerators or amper uppers or stimulatory factors or agonists or co-stims but rather back-ends or inhibitors or antagonists.

Click to enlarge. Image source (Figure 2)

Possible or potential item takeaway: Incyte brought an immune checkpoint inhibitor in-house because...

• Combination therapies [of some sort] will become standard of care for advanced-stage cancer (eschewing [making obsolete] monotherapeutic use of immune checkpoint inhibitors)?

• It is better to own both parts of the pairing for various clinical and/or business reasons?

• If it is better to own both parts, differentiation of co-inhibitory blockade is more business (or marketing) than clinical?

• Win or lose, Bristol-Myers PD-1-related lawsuit against Merck is irrelevant (or its outcome de minimis)? "Every" biopharmaceutical company, including Chinese companies for their own domestic (as well as for international collaboration purposes), has or will have an immune checkpoint inhibitor?

September 1 / A new class of immunotherapy.

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If/when PV-10 stands on the cusp of approval (in T-Vec's case, while not certain, probable approval would occur by or before the drug's October 27, 2015 PDUFA date), it would be a new class of immunotherapy. And St. Luke’s University Health Network's Dr. Sanjiv Agarwala would be PV-10's Dr. Howard Kaufman, MD. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part I (July 13, 2015) on the blog's Current News page.

Possible or potential item takeaway: What is PV-10? An ablative immunotherapy? An autologous vaccine? An oncolytic immunotherapy? PV-10 has no specific target, receptor or pathway; however, this item cannot be properly discussed at the current time because knowledge and discussion presumably definitively relies on the presentation/publications of the results of Moffitt Cancer Center's mechanism(s) of action study due later this year. See August 29, 2015 blog post PV-10 has much better gas mileage.

September 1, 3 and 4, 2015 / Tinkering with Mother Nature. The official blog of AACR posted a 9/1 entry by Dr. Srivani Ravoori, PhD entitled Advances in Immunotherapy: Fine-tuning CAR T Cells. On 9/3 FierceBiotech's Carroll wrote an article entitled Novartis team tracks remissions of 4-plus years in a pioneering CAR-T study. In The Pipeline's Dr. Derek Lowe, PhD blogged CAR-T Follow Up on 9/4.

Ravoori wrote about scientists from the University of Pennsylvania and The University of Texas MD Anderson Cancer Center tinkering with the target-binding end of CAR T cells to make them safe for patients with solid tumors:

"CAR T cells designed to target CD19 in B-cell cancers are not selective. They cannot distinguish cancerous B cells that have high levels of CD19 from normal B cells that have physiological (lower) levels of the same protein. But this does not severely impede treating B-cell malignancies because a patient’s immune system can function even when normal B cells are depleted. This form of immunotherapy, however, is not readily adaptable to solid tumors because targetable proteins present on the cancer cells of solid tumors, such as ErbB2 and EGFR, are also present on normal cells that form the vital organs of the body. While losing normal B cells when treated with CD19 CAR T-cell therapy poses manageable side effects in a patient, loss of normal cells that are part of vital organs when treating solid tumors with CAR T-cell therapy can damage these vital organs, which has serious consequences. In fact, in a case report, CAR T cells designed to target ErbB2 present in metastatic colon cancer cells also attacked cells in the patient’s lungs that had low levels of ErbB2, resulting in severe toxicity and death. So, it became evident that if CAR T-cell therapy were to work for solid tumors, engineering T cells that can selectively target cancer cells and spare normal cells is inevitable." {Underlined emphasis is mine}

But, according to Ravoori:

Enter scientists from the University of Pennsylvania and The University of Texas MD Anderson Cancer Center, two teams that used different approaches to answer the same question: Will lowering the affinity of CAR T cells to the target protein make them selective to cancer cells that have high levels of the protein and spare normal cells that have low levels of the same protein? Based on the data the two teams published independently in the AACR’s journal Cancer Research, it appears the answer is “Yes.”

Carroll wrote:

Five years after the University of Pennsylvania began recruiting a small group of 14 patients with hard-to-treat chronic lymphocytic leukemia, researchers are still tracking three of them who are still alive with no signs of their cancer returning after being treated with a first-generation CAR-T therapy...Out of the 14, four experienced complete remissions, meaning their cancer was no longer detectable. One of those four later died of other causes. Four patients had partial responses, with two of them dying after 10 months and 27 months of therapy. One of the partial-response patients died from a pulmonary embolism, and the other was switched to a different therapy after 13 months and died after three years.

But, according to Carroll:

All of the patients who responded to the therapy experienced a potentially life-threatening case of cytokine release syndrome, sometimes called a cytokine storm, with the drug triggering high fevers and in several cases difficulty with breathing and low blood pressure. Doctors responded with the antibody drug tocilizumab and steroids, and all of the patients survived...In a small study like this, investigators can learn as much from failure as they can from success. Testing the 6 patients who did not respond, the scientists said that their customized T cell populations did not expand as aggressively as in the patients who were first flattened by a cytokine storm in their first response to the solo treatment. 

Finally, Lower wrote (about the Novartis study):

"So there’s definitely something major here, and definitely room to improve it. That’s what Novartis, and Juno, and Kite (and who knows who else) are frantically working to do right now. The biggest prizes are to extend this idea to more tumor classes, and to make it scalable to larger numbers of patients. The second one is a big challenge, and the first is even bigger. People have been antigen-hunting for quite a while now, looking for something that’s fit to turn the immune system on in other types of tumors, and it’s slow going. But you have to be sure, because if the immune system can strip a couple of pounds of aberrant white blood cells out of your system, so vigorously that it nearly overloads your kidneys, then it can do the same with lots of other tissues, too, some of which you might prefer to keep. Ripping out a couple of pounds of motor neurons or Kupffer cells would be suboptimal, to say the least."

Possible or potential item takeaway: Safety, specificity, durability? Questions UPenn/Novartis and MD Anderson are a long, long way from fully answering.

September 4, 2015 / A Rumsfeldian Perspective. Lowe, in his 9/4 blog post, wrote "People have been antigen-hunting for quite a while now, looking for something that’s fit to turn the immune system on in other types of tumors, and it’s slow going."

US Secretary of Defense Donald Rumsfeld was once quoted as saying"...because as we know, there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns – the ones we don't know we don't know."

As Provectus' Chairman and CEO Dr. Craig Dees, PhD has discussed with me almost from the beginning of my due diligence and share ownership (paraphrasing in Rumsfeldian), there antigens we know, antigens we don't know, and antigens we don't know we don't know.

And this knowledge or lack of knowledge (crucially relevant in the treatment of cancer because antigens equal targets) is but one aspect of Dees, President Dr. Tim Scott, PhD and CTO Dr. Eric Wachter's belief that killing cancer tumors in the correct way held the key to successful medical treatment because a proper approach could enable the immune system to stimulate cancer-killing cells throughout the body.

Properly destroying cancer tumors means killing only tumors and doing so completely, quickly and, very importantly, safely (that is, leaving healthy tissue unharmed). They believe this approach is the only effective way of sustainably stimulating a person’s natural anti-cancer defenses. Instead of bathing the entire body or even parts of it with radiation, or filling the bloodstream with oral or intravenous chemotherapies or present-day immunotherapies, Dees et al. firmly hold the position that stimulating the immune system is best achieved through treating tumor tissue by injecting into it a drug capable of destroying the entire tumor as quickly as possible without damaging surrounding healthy cells. Completely also means everything from visible tumor tissue to occult or hidden cells in and immediately around the injection site. Quickly means having the drug processed through and excreted from the body in short order. Antigens generated from the tumor destruction caused by drug injection then can be presented to the body’s cells responsible for selecting the best and most relevant antigens in order to encourage cancer-killing cells to replicate themselves throughout the body. Importantly, tumor antigens have to be viewed in context; physical tumor destruction techniques such as heating or freezing tissue destroyed fragile antigens and disrupted their relevant contextual structures. Disruption of cell membranes and removal of lipids, proteins, and complex carbohydrates destroy the antigens’ context, which is to what immune system cells respond. Thermal destruction denatures potential antigens, changing their chemical structure so that they were no longer representative of the tumor cell. In order to work rapid destruction of tumors has to preserve both antigenic structure and biological context. (Paragraph source, with slight edits by me for verb tense: MicroCap Review, pp. 6-8, September 2015)

Possible or potential item takeaway: For Craig et al. to have PV-10, and themselves, more fully recognized, all constituents of the biopharmaceutical ecosystem are going to have to embrace the above.

With PV-10: One shot, one kill

The University of Illinois at Chicago's College of Medicine's Department of Surgical Oncology's Ajay Maker Laboratory's PV-10 (rose bengal)-related preclinical colorectal cancer work in 2014/2015 employed a single injection of intralesional PV-10.

"Treatment of subcutaneous tumors with a single injection of intralesional PV-10 led to near complete responses in all animals within days of exposure and significant regression of the injected lesions compared to controls (n=6 per group, p=0.027)." See my blog post Intralesional Injection of Rose Bengal Induces an Anti-tumor Immune Response and Potent Tumor Regressions in a Murine Model of Colon Cancer.

Moffitt Cancer Center's preclinical and clinical multi-indication work from 2011 to date also employed a single injection of Provectus' lead oncology agent:

"Treatment of the subcutaneous lesion with a single injection of IL PV-10 led to regression of the injected lesion as well as the distant B16 melanoma lung metastases." See Moffitt's publication Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer.

Single injections of PV-10 were used in Moffitt's clinical feasibility study at AACR and ASCO 2014, and their combining of PV-10 with immune checkpoint inhibitors at SITC 2014. You may even recall Moffitt's rather sensational August 2013 press release: Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows.

These single injections more often than not completely destroy the tumors into which they are injected. At ESMO 2014 (and ASCO 2014) Provectus' presented exploratory analysis work of the company's melanoma Phase 2 trial that showed most lesions required 1-2 injections of PV-10 for complete destruction (i.e., complete response). Provectus' primary and secondary liver cancer Phase 1 and expanded Phase 1 liver trials sees tumors injected once, too. The company's recurrent breast cancer Phase 1 trial of several years ago also saw patients have their lesions injected once.

A single injection of PV-10 matter...so what?

First, few injections or one injection per lesion bodes very well for patient compliance with PV-10.

Second, one injection achieving complete response should mean PV-10 is absolutely and relatively more effective than other approved and investigational agents also trying hard to destroy tumors. More with less might lead to much more with more.

Third, more robust efficacy at the so-called local level of lesion injection that leads to complete response (complete destruction) might mean greater immunological signalling of the immune system and thus a better result for destroying cancer elsewhere in the body.

Big Pharma admits that while they are pretty good at shrinking tumors, they are not good at getting rid of them. See my February 2014 blog post Big Pharma has a Shrinkage Problem.

Oddly, at ASCO 2015 Dr. James Allison, PhD said ignore the tumor and just work on the immune system, while attempting to patent the treatment combination of an oncolytic virus and immune checkpoint inhibition. See the blog's news page's ASCO Day #3, sampling (May 31, 2015).

"Up-and-coming" oncolytic virus company Viralytics' lead investigational drug based on Coxsackievirus A21 requires a multi-day, multi-injection per lesion approach (i.e., 10 series of injections).

Amgen's talimogene laherparepvec, as part of their collaboration with Bristol-Myers to combine T-Vec and ipi, was administered by intratumoral injection on day 1 of week 1, day 1 of week 4, and then every two weeks thereafter.

Amgen's preclinical work of T-Vec presented at AACR 2015 exploring the efficacy of the combination of T-Vec and immune checkpoint blockade required multiple injections of the intralesional/intratumoral agent.

Idera's recent "strategic clinical research alliance" with MD Anderson Cancer Center to combine the company's intratumoral toll receptor with ipilimumab in patients with advanced melanoma is the logical combination of a co-stim agent (Idera's IMO-2125) with a co-inhibitory agent (CTLA-4 ipi). Interestingly, or perhaps not so interestingly, IMO-2125 requires injections over multiple days (i.e., 4-5) and achieves less efficacy than PV-10.

The first guy through the wall

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Today's joint meeting of the Cellular, Tissue and Gene Therapies Advisory Committee ("CTGTAC") and Oncologic Drugs Advisory Committee ("ODAC") voted by an overwhelming 22-to-1 margin in favor (i.e., yes to the question) of talimogene laherparepvec ("T-Vec") having an overall favorable benefit-risk profile for the treatment of injectable regionally or distantly metastatic melanoma, and thus supporting traditional approval of the drug.

The meeting's positive outcome for T-Vec and Amgen also is a positive for PV-10 and Provectus. Both T-Vec and PV-10 are investigational intralesional ("IL") therapies, often referenced together, and share existing and potential clinical trial investigators and/or paid consultants such as MD Anderson Cancer Center's Dr. Merrick Ross, MD, St. Luke's Cancer Center's Dr. Sanjiv Agarwala, MD, Hunstman Cancer Institute's Dr. Robert Andtbacka, MD, and Moffitt Cancer Center's Dr. Vernon Sondak, MD and Dr. Jonathan Zager, MD.

Two great sources of meeting coverage, with both insightful and observational tweet comments and commentary, were Jamie Singer (@JSwatercooler) and SAC Tracker (@FDAadcomm). Jamie is a consultant to Provectus. Tarius SAC Tracker provides global regulatory intelligence to the healthcare industry, and later wrote a summary of the meeting entitled US FDA Advisory Committee Supports Amgen’s T-Vec to Treat Metastatic Melanoma.

Amgen is seeking approval of T-Vec for the treatment of injectable regionally or distantly metastatic melanoma (side note: unresected or unresectable was not included in Big Biotech's proposed indication). FierceBiotech's John Carroll noted in his article about today's meeting: "The final decision is being left in the hands of the FDA, though today's vote would make T-Vec an odds-on favorite for approval." T-Vec's PDUFA date is October 27th (it previously was July 28th, and pushed back for Amgen to submit additional information.

My takeaways about the meeting's outcome as it relates to PV-10 include:

1. Today's decision was a very big win for IL agents for cancer.

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It bears repeating. The panel concluded that the reduction of injected tumors equates to/is clinical benefit.

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Hwu is MD Anderson Cancer Center's Dr. Patrick, MD (medical oncology), chair of Melanoma Medical Oncology and Sarcoma Medical Oncology, and recently named division head of Cancer Medicine.

Fierce further observed "[a] number of the experts noted that the more "arrows" they had in their therapeutic quiver, the better off patients would be," although Jamie tweeted:

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2. There is more work to do for IL agents to better clarify and demonstrate their role in treating late-stage cancer and patients with heavy disease burden and visceral disease — i.e., an IL agent like T-Vec or PV-10 (a stimulatory agent, co-stimulatory, start the engine, step on the gas pedal) plus an immune checkpoint inhibitor (an inhibitory agent, co-inhibitory, release the brakes).

Nevertheless, today's decision, assuming it is accompanied by FDA approval of T-Vec later this year, first opens the door for IL agents to metastatic or advanced melanoma. Approval would place T-Vec in the same group of approved agents for advanced melanoma that includes ipilimumab (approved in 2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), trametinib (2013), pembrolizumab (2014) and nivolumab (2014). All of the nibs and mabs are systemic agents. Peginterferon is systemically administered.

More than likely, use of IL agents for advanced melanoma as monotherapies will be limited to Stage IV M1a.

Click to enlarge. Amgen CTGTAC / ODAC Meeting Briefing Document, page 53. Purple emphasis is mine.

Click to enlarge. FDA CTGTAC / ODAC Meeting Briefing Document, page 14. Purple emphasis is mine.

Even more likely is the treatment of Stage IV M1a to M1c (especially) with the combination therapy of an IL agent and immune checkpoint blockade. Amgen currently has T-Vec in trials with ipilimumab and pembrolizumab for advanced melanoma (i.e., Stage IIIb to IVM1c Melanoma).

3. Today's decision reaffirmed the value of good IL agents for the treatment of earlier stages of disease (i.e., Stage 3), when all of the disease is accessible for injection, and for use first or second before other treatment options are considered, when the immune system is not overwhelmed by tumor burden and spread (as it is for most Stage 4 patients).

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PV-10's upcoming pivotal Phase 3 trial is for locally advanced cutaneous melanoma, and will be exclusively comprised of Stage IIIb-c patients (although it would appear 50% of the patients in the treatment arm must have failed at least one systemic immunotherapy or not be a candidate for them).

While members of the panel wanted to distinguish T-Vec's use between non-visceral (e.g., Stage IIIb-c and IVM1a) and visceral (IVM1b-c), rather than an overly broad distinction between Stage 3 and 4, one of hypotheses of PV-10's Phase 3 trial is that if the drug make lesions go away it will forestall progression of the patient's disease (which would be shown via the trial's progression free survival primary endpoint.)

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Amgen is pushing further to the left (i.e., earlier use) with T-Vec, comparing T-Vec and surgery to surgery alone in completely resectable Stage 3b-c and IVM1a melanoma: Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Melanoma.

4. PV-10 is of course a competitor to T-Vec.

From a 2012 presentation by Huntsman Cancer Center and lead T-Vec Phase 3 trial investigator Dr. Robert Andtbacka, MD (and now paid Provectus consultant and likely PV-10 Phase 3 trial investigator):

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Andtbacka recently said of T-Vec: “Our patients are living longer, and we’re able for the first time in melanoma to potentially talk about a cure, which is something we have not been able to talk about before,” said Dr. Robert Andtbacka, who is a surgical oncologist. Andtbacka said the new treatment teaches the body to heal itself. See Familiarity (April 7, 2015) on the blog's News Page.

Johns Hopkins University's Dr. Suzanne Topalian, MD referred to the drug as an autologous tumor vaccine (along with T-Vec and Allovectin-7). See Keep talking (and keep doing) (January 29, 2015) on the News Page.

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5. PV-10 is a much better IL agent than T-Vec.

Moffitt's Dr. Sondak (again, a paid consultant to both Amgen and Provectus) noted last year at the 4th European Post-Chicago Melanoma Meeting:

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Hunstman's Dr. Andtbacka historically has compared Phase 2 trial results of T-Vec and PV-10, the version below from 2012:

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My comparison (a sampling):

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Click to enlarge. Footnote 6 of above table.
T cells in the peripheral blood mononuclear cell ("PBMC") of melanoma patients

They ARE out to get me...

My reading of Frank David's March 2nd Forbes article entitled Only The Paranoid Biotechs Will Survive converged interestingly with Peter's presentation at the 8th Annual European Life Science CEO Forum & Exhibition. David wrote:

"The drug industry is surely at a similar “strategic inflection point”. Sales forces are less effective, prices are under constant and increasing assault, and physicians and patients alike are raising the bar for how they define clinical value. (My prior takes here, here, here and here.) High prices and huge sales forces used to prop up even minimally differentiated drugs, especially in big markets like hypercholesterolemia and depression. But today, something is changing: commercial muscle no longer guarantees success unless you also have a compelling clinical benefit. 

But I’d argue we’re in the midst of a “strategic inflection point” that threatens many biotechs’ ability to secure Pharma deals. Whereas the biggest hazard to biotechs in the past was moving too slowly or running out of funds, it’s hard to deny that today, the risk of not demonstrating clinical differentiation is far greater." {Underlined emphasis is mine}

Pembrolizumab. In his presentation Peter noted Merck & Co.'s approved anti-PD-1 therapeutic pembrolizumab (Keytruda) as the control in a planned Phase 1b/2 combination study of PV-10 + immune checkpoint blockade — see Updated presentation slides (March 3, 2015) on the blog's News page.

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Peter has a somewhat "annoying" (because I have to regularly and carefully read, search and sometimes parse them) but mostly helpful (because there often are relevant or germane regulatory, clinical development and commercial bits and bobs in them) habit of placing Easter Eggs of a sort in Provectus' corporate website/investor presentations.

This particular egg referenced Merck's PD-1 drug as the other drug and control in a pairing with PV-10. The "trial" title then would be Pembrolizumab With or Without PV-10 in Unresected Melanoma.

For comparison, Amgen and Merck announced their collaboration and combining of T-Vec and pembrolizumab (MK-3475 at the time) in February 2014 — Amgen's press release is here. The trial protocol of this pairing was filed on ClinicalTrials. gov in September. Recruitment began in December.

If one assumes this egg is not spurious, then Peter's placement was purposefully communicative. While I'm not in a position to opine on whether or not Bristol-Myers will prevail in its lawsuit against Merck U.S. over each other's anti-PD-1 agent, I imagine Craig et al. would not consider doing a trial — with Merck, or by themselves (since the trial size of oncology Phase 1bs can range from 20-25 patients — in a potential future scenario where Bristol-Myers prevails over Merck.

First-in-class. I chuckled when I saw the cover slide of Peter's presentation read "first-in-class halogenated xanthene dye." Before I explain my snorting, it would appear first-in-class means to the FDA (or is defined by the Agency) "...drugs which...use a new and unique mechanism of action for treating a medical condition." Is this another Easter Egg? I believe it is, presumably emanating from further discussions with the FDA.

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Can Drug A be called first-in-class [with its associated mechanism of action ("MOA")] if it is approved for Indication X? If Drug B is approved second for X, is it second-in-class? Or, if A is approved before B, is A then just first-in-class [with MOA]. By this fragile, inexperienced logic, pembrolizumab is a first-in-class PD-1 inhibitor or anti-PD-1 antibody. Is nivolumab second-in-class?

I laughed at the non-FDA contextual use of the entire phrase — first-in-class halogenated xanthene dye — because while pembrolizumab is owned by Merck US, and nivolumab is owned by Bristol-Myers, and Pfizer has a PD-1 inhibitor, and AstraZeneca's for now is labelled MEDI0680, etc., Provectus owns Rose Bengal and related xanthenes (e.g., first-in-class, second-in-class, etc.).

Competition? Amgen will have its FDA PDUFA completion date for T-Vec in October 2015, but the Agency will meet to hold an AdComm meeting in April. In this instance T-Vec is being considered as a monotherapy for advanced melanoma (i.e., the the treatment of patients with injectable regionally or distantly metastatic melanoma).

Interestingly, Amgen filed a trial protocol on ClinicalTrials.gov in November 2014 entitled Phase 2, Open-Label, Single-arm Trial to Evaluate the Correlation Between ORR and Baseline Intratumoral CD8+ Cell Density in Subjects With Unresected Stage IIIB to IVM1c Melanoma With Talimogene Laherparepvec. The trial appears to be taking place in Spain, and may soon begin recruiting. The purpose of the study is to evaluate the correlation between CD8+ cell density and response rate. Cell density (the number of cells per unit volume, such as cells per microliter) presumably plays an important role in immunotherapy effectiveness (i.e., the higher the density, the better the effectiveness). I do wonder whether this density figure, which measures quantity or concentration, also includes a measure of quality too.

In a February 2013 Cancer Watch article entitled Back to Phase 1: Understanding Systemic Effects of PV-10, it was written:

While adoptive cell transfer offers the advantage that enough T cells can be obtained for infusion in all patients, the T-cell receptors transfected into the T cells have a limited antigen-specificity. The strategy works, Dr. Sarnaik said, only about half the time. “We generate large numbers of T-lymphocytes, but we don’t have control over their quality. We think one of the limitations is that the T cells you get out of the tumor just aren’t good enough.” PV-10, however, does cause an immune response, suggesting that a combination treatment may improve the quality of the T-lymphocytes and have a greater impact on the disease. 

When Shari Pilon-Thomas, PhD, also a Moffitt researcher, demonstrated that T-lymphocytes recovered from mice treated with PV-10 do appear to be of a higher quality, as evidenced by stronger tumor reactivity, the stage was set for Dr. Sarnaik’s current 15-patient pilot study. In it, one of two resectable melanoma tumors is injected with PV-10. Both are removed several weeks later. Serum is assessed before and after treatment to look for changes in the infiltration of immune cells. In patients with an immune response, PV-10 therapy can be continued. 

“This is a straightforward study that will give a yes or no answer,” Dr. Sarnaik said. 

Bristol-Myers/Amgen's combination trial that paired ipilimumab and T-Vec. Ipi with or without T-Vec) provided germane information on immunologic signaling (see below, on the right), where PBMC stands for peripheral blood mononuclear cell. PBMCs "...are the populations of immune cells that remain at the less dense, upper interface of the Ficoll layer...PBMCs include lymphocytes (T cells, B cells, and NK cells), monocytes, and dendritic cells."

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My takeaway for this blog post, by returning to David's article, is, again, risk-reward. The potentially vast reward opportunity for Provectus is to effectively demonstrate and communicate that compelling clinical benefit and differentiation.

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:

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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.

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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.

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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).

The company PV-10 keeps

There is a saying "you are the company you keep," or perhaps "you're only as good as the company you keep." PV-10's company? MPDL3280A (Roche),  Yervoy and nivolumab (Bristol Myers), MK-3475 (Merck), T-Vec (Amgen), Abraxane (Celgene), etc.

Over the next three months, April to June, PV-10 data will be presented and/or discussed in at least 6 presentations at five medical conferences. Never in Provectus' history has data been presented at so many venues in such a short period of time.

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First, on April 6th, Moffitt Cancer Center presents a poster at the 2014 annual meeting of the American Academy of Cancer Research ("AACR") entitled Induction of anti-melanoma immunity after intralesional ablative therapy. The focus likely should be on the second step of PV-10's two-step mechanism of action ("MOA"), and perhaps further explanation of the drug's viability for multiple indications like breast cancer, on which I think Moffitt and Provectus may further collaborate.

Second, on April 11th, "PV-10 will be an integral part of..." the HemOnc Today - Melanoma and Cutaneous Malignancies Conference's Session 4: Local and Regional Therapy. The session will include Amgen's T-Vec, Vical's failed Allovectin-7, other intralesional therapies, and a debate about the role of systemic intralesional therapy.

Third, on May 7th, St. Luke's University Health Network's and Provectus principal investigator Dr. Sanjiv Agarwala will participate in a plenary session at the 10th European Association of Dermato-Oncology ("EADO") congress entitled New Drugs and new trials. Other drugs on the agenda include:

• Amgen's T-Vec,
• Bristol-Myer's Yervoy (ipilimumab, an anti-CTLA4 agent),
• Roche's MPDL3280A (an anti-PD-L1 agent),
• BMS' nivolumab (an anti-PD-1 agent),
• BMS' combination of Yervoy and nivolumab,
• Merck's MK-3475 (an anti-PD-1 agent), and
• OncoSec's ImmunoPulse.

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Amgen, Bristol-Myers, Roche, Merck and...Provectus.

Fourth, on June 2nd, Dr. Agarwala will present a poster at the 2014 annual meeting of the American Society of Clinical Oncology ("ASCO") during the day's Poster Highlight Session (in addition to the regular poster presentation day and time) entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions. The focus likely should be on the 28-patient data subset of Provectus' metastatic melanoma Phase 2 trial that formed the basis of the company's breakthrough therapy designation ("BTD") application.

You know, the BTD submission stated or commented on publicly by management [at least] 11 times thus far --five press releases, three Provectus News items (to be fair, BTD submission was picked up by third parties),  two 8-Ks, one 10-K, and a partridge in a pear tree -- and on the website.

I'm obviously poking fun at management. For a company with a history of being somewhat opaque or obtuse in communications regarding clinical data, regulatory interaction, and other matters, it's not unreasonable for the casual observer to think Provectus currently is promotional in regards to their BTD submission. The change in stride certainly is notable. Once or twice, in an SEC filing, I get. But, more than ten times? The same casual observer might think it strange; however, long-time investors who have done their due diligence on Eric's historical interactions with the FDA along the company's regulatory approval journey understand, and I think the company has said as much in its PRs: the Agency appears to have (has) agreed tumor-based endpoints (i.e., complete response: "...if you inject PV-10 into melanoma tumors, the tumors go away...") and not survival-based endpoints (e.g., overall survival, progression free survival, etc.) are appropriate for approving this drug. If you assume this Agency embracing of PV-10 and hurdle-clearing of endpoints, and I cannot fault folks if they don't, one could understand management's confidence in securing BTD, and then (and only then) these many BTD submission mentions.

BTD, in some respects, marks the beginning of a potentially speedy pathway to approval. The decision tree might be one of the FDA either (a) requiring the company to conduct a bridging study in order to file a new drug application ("NDA") for PV-10 -- "...before...we have approval to sell PV-10..." -- or (b) permitting the study to be a post-marketing requirement/commitment -- "...after we have approval to sell PV-10..."

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Managing our investment in Provectus of course requires me to manage risk. Even as a presumably well-informed investor, it's still very hard for me to assume a BTD award is in the bag. Probable, yes. Certain, no. The FDA may say no, and the company (like others turned down before them) very likely would have been told by the Agency to obtain more clinical data. But, as I wrote in my post Provectus Submits Application to FDA for Breakthrough Therapy Designation, the FDA doesn't want nor does it encourage companies to submit BTD applications that are more likely to be turned down than accepted. One would imagine the boldness with which management speaks of BTD suggests they very strongly believe they'll attain it (because of interactions with the Agency that suggest so) on, before or well before May 23rd.

Fifth, also on June 2nd, Moffitt will present a poster at ASCO, also during the day's Poster Highlight Session (again, in addition to the regular poster presentation day and time) entitled Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions. This presentation should elaborate on both the clinical (MOA step #1, ablation/destruction of injected lesions) and immune (MOA step #2, immune response/destruction of non-injected lesions) efficacy observed in patients enrolled in the cancer center's feasibility study, where Moffitt essentially experimented on them.

Sixth, on June 27th, Moffitt's Dr. Vernon Sondak will participate in a symposium session at the 4th European Post-Chicago Melanoma/Skin Cancer Meeting entitled New drugs and trials: An update on immunotherapy and chemotherapy. Other drugs on the agenda include:

• Bristol-Myer's Yervoy (ipilimumab),
• BMS' nivolumab,
• Merck's MK-3475,
• GlaxoSmithKline's failed MAGE-A3 (a cancer vaccine),
• Amgen's T-Vec,
• OncoSec's ImmunoPulse, and
• Celgene's Abraxane (chemotherapy nab-paclitaxel).

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Bristol-Myers, Merck, GlaxoSmithKline, Amgen, Celgene and...Provectus.

This month and over the next two, we can expect a lot of pre-clinical and clinical PV-10 data, and potentially a positive BTD decision. More data and MOA elucidation is good (and I am very much looking forward to reading them). Regulatory clarity and steps (i.e., BTD and what comes with it) is better, and very, very necessary for this company.

But how now China? And/or other regional transactions? And/or the endgame?

If management believes it will get BTD for PV-10 for locally advanced melanoma, thinks they might have to conduct a bridging study prior to filing the NDA (i.e., in this case de facto approval) "at worst," has about $16 million of cash on the balance sheet (see the company's March 24th PR), and possibly estimates the cost of a bridging study at $5-$10 million or thereabouts (comparable or less if the trial is terminated early, and some patient number overlap is acceptable to the various geographical regulatory agencies), why consummate a deal with a Chinese partner or any partner for that matter until after a BTD decision and clarity is achieved as to the step(s) toward and after approval?

I'm particularly interested in Dr. Agarwala's ASCO presentation, which will focus on the 28-patient subset that formed the basis for Provectus' BTD application and in all likelihood its awarding. This data was first broken out at the 2013 European Cancer Congress in September: Exploratory Data Analyses of Intralesional PV-10 Clinical Phase 2 Study Results Presented at ECC 2013 Demonstrate Effective Locoregional Disease Control and Support Systemic Immunologic Activity in Refractory Metastatic Melanoma:

Click the table to enlarge it. Poster source is here.

If one were to not consider the non-evaluable subjects (NEV above), loco-regional control of the disease -- the value proposition underscoring approval of PV-10 for locally advanced melanoma: the drug forestalls or defeats the spread of the disease to a metastatic stage, or alternatively "...if you inject PV-10 into melanoma tumors, the tumors go away..." -- increases to 88%.

Craig would tell you the residual percentage, 12% w/o NEV (or 18% as presented at ECC 2013 for the full subset), is more than likely due to physicians not injecting the lesions properly and thus not getting the expected result. The results PV-10 and PH-10 generate appear to be startlingly consistent from properly injected lesion (volume of drug per unit volume of tumor, proper administration) to properly injected lesion.

88% loco-regional control, and you want to do a deal now? Wouldn't it make sense to wait or seriously contemplate waiting until after a decision (unless a counter party aggressively bids for a deal, which doesn't appear to be the case at the moment)? There is of course risk in doing so; however, if you're supremely confident based on clinical data and regulatory interaction heretofore, you wait. Wait for the bigger regional check as milestone payments turn into upfront payments based on what transpires regulatory-wise. Wait to submit a BTD application or two for your liver program (e.g., in combination with maintenance sorafenib, cancers metastatic to the liver). Wait until impatient Big Pharma with drugs and compounds that are not sufficiently efficacious or safe, and very expensive, see their respective Kodak moment coming and decide to deal. By Kodak moment, I specifically mean technology disruption that could end in a near-zero sum game in the case of PV-10. If you own it you survive, and flourish. If you don't...

As folks line up to associate themselves with Provectus, and/or deal with the company, Pfizer might lose first mover advantage. Provectus has three executives from two Top 15 ranked (by pharmaceutical sales) companies on its strategic advisory board. It may add executives from up to three more Top 15 firms.

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There is much for the company to accomplish before thoughts of the end-game can and should percolate. And although I've written often on this blog that I think Pfizer will be the end-game acquirer, and a topic for another post, it's not a given the company with the biggest checkbook (and the nose under the tent for the longest time) wins. Vision, strategic rationale, ambitiousness and, ultimately, verve, together with a not inconsequential balance sheet should win the M&A day.