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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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).

Bristol-Myers vs. The Field (ex-Provectus)

Last week Bristol-Myers filed a lawsuit against Merck over [anti-]PD-1 agent pembrolizumab (trade name Keytruda), which was approved last week by the FDA for late-stage or metastatic melanoma.

Specifically, Bristol-Myers claims that Merck is violating the patent on its Opdivo mediation for tackling melanoma, which was recently approved in Japan and became the first so-called PD-1 inhibitor to win regulatory backing anywhere. A PD-1 inhibitor blocks a protein that acts as a brake on certain immune system cells and prevents them from attacking healthy tissue. (Bristol-Myers Sues Merck Over a Patent on its new Cancer Drug, The Wall Street Journal, September 8, 2014)

Merck disclosed PD-1 antibody patent oppositions and litigation, at the time in Europe, in its 10-Q filing for the period ending June 30, 2014 (see page 22):

As previously disclosed, Ono Pharmaceutical Co. (“Ono”) has a European patent (EP 1 537 878) (“’878”) that broadly claims the use of an anti-PD-1 antibody, such as the Company’s immunotherapy, pembrolizumab (MK-3475), for the treatment of cancer. Ono has previously licensed its commercial rights to an anti-PD-1 antibody to Bristol-Myers Squibb (“BMS”) in certain markets. The Company believes that the ‘878 patent is invalid and filed an opposition in the European Patent Office (the “EPO”) seeking its revocation. In June 2014, the Opposition Division of the EPO found the claims in the ‘878 patent are valid. The Company expects to receive the Opposition Division’s written opinion in the third quarter of 2014, after which it will begin the appeal process. {Underlined emphasis is mine}

As FiercePharma's Tracy Staton writes: "The lawsuit asks for damages, but more importantly, asks the court to declare that Merck infringes that PD-1 patent. Such a decision would bolster Bristol-Myers and Ono's argument that they are owed royalties on sales of rival PD-1 drugs."

As I wrote in my Why Keytruda's approval is a good thing for PV-10 (September 8, 2014) news item under the blog's News tab:

KOLs see PD-1s as treating the bulk of late stage cancer. Key opinion leaders ("KOLs") see PD-1s, which fall under the category of checkpoint protein inhibitors that also include CTLA-4 and PD-L-1 agents, as an improvement over CTLA-4 agents like approved ipilimumab (trade name Yervoy) and tremelimumab. KOLs will use PD-1s to treat as many indications as they can scientifically support. Abstracts of Merck oncology-sponsored pembrolizumab studies being presented at ESMO 2014 in late-September, for example, include bladder and gastric cancer, advanced melanoma, non-small cell lung cancer ("NSCLC"), and head and neck cancer.

Bristol-Myers and Merck's PD-1s are projected to play key roles in the supposed several tens of billions of dollars equity research analysts estimate will be derived from the immuno-oncology addressable market.

But KOLs believe the more dominant use of PD-1s will come from combining them with other drugs to treat late-stage cancer, rather than strictly using them as monotherapies. I summarized 14 previously announced and/or conducted combination studies below, and first in my Combinations (July 24, 2014) news items under the blog's News tab.

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Bristol-Myers, however, has its bases covered with a combination therapy patent that covers PD-1s and other therapeutic compounds and compound categories. Again, Merck challenged it, noting such in the above mentioned quarterly filing:

On April 30, 2014, the Company, and three other companies, opposed another European patent (EP 2 161 336) (“’336”) owned by BMS and Ono that it believes is invalid. The ‘336 patent, if valid, broadly claims anti-PD-1 antibodies that could include pembrolizumab. {Underlined emphasis is mine.}

Bristol-Myers and Ono Pharmaceutical's '878 patent covers PD-1s as monotherapies.

Bristol-Myers and Ono's '336 patent covers PD-1s in combination with other agents, and appears to include a number of companies' products including Amgen's oncolytic virus and intralesional agent talimogene laherparepvec ("T-Vec"). T-Vec had been combined with Bristol-Myer's approved [anti-]CTLA-4 agent ipilimumab (trade name Yervoy), the results of which were presented at ASCO 2014. Amgen and Merck plan to combine T-Vec with Keytruda in a trial slated to start later this year.

A Big Pharma (BMS) with a market capitalization of about $85 billion (per Yahoo! Finance as of yesterday's close) battling one (MRK) with a market cap of about $176 billion. Afterall, in 2013, Citi analyst Andrew Baum estimated potential annual immuno-oncology-related sales to be $35 billion by 2023 (cough). Titans battling...

It does not appear PV-10 is covered by Bristol-Myers and Ono Pharmaceutical's '336 combination therapy patent. PD-1s in combination with PV-10 apparently are, however, covered by Provectus' combination therapy patent application (20120263677 ["'677"]) that it jointly filed with Pfizer (through an expansion, or continuation in part, of Claim #1) in 2012. Pfizer and Provectus would share CTLA-4-related combination therapy sales revenue via the '667 patent application if/when issued, but the former has no claim in the patent app on economics derived from PD-1-related combination therapy sales.

Whether the '878 monotherapy patent ultimately prevails -- that is, whether Merck is violating the patent for tackling cancer (see paragraph 047) -- is Merck's problem, and the Big Pharma eventually may elect to direct royalties Bristol-Myers and Ono's way(s).

Merck could, however, circumvent paying the other parties by meaningfully combining pembrolizumab/Keytruda with PV-10. Directionally speaking, immuno oncology is trending towards combination therapies for late-stage cancer treatment. Strategically, PV-10 should permit Merck's PD-1 to achieve greater tumor destruction and immunological signaling, and be the perfect front end for an immunologic back-end like Keytruda for the ultimate and better benefit of patients than what the PD-1 alone could achieve as a monotherapy. This combination proposition of course would require a sound scientific and medical data-based foundation, which one hopes Moffitt Cancer Center will present and convey at the Society for the Immunotherapy of Cancer's annual meeting in early-November. Tactically, an effective Keytruda/PV-10 combination with a compelling clinical value proposition should obviate the need for royalty payments to Bristol-Myers/Ono because the '336 combination patent would not be infringed. Increasing anti-PD-1 antibody patent opposition and litigation could tip Merck's decision-making scales in favor of embarking on a near-term combination study of Keytruda and PV-10, with perhaps an eye to a longer-term combination.

Potential Catalysts

Potential catalysts through 1Q15 could include:

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Commencing enrollment of its pivotal late-stage trial for melanoma (locally advanced unresectable/unresected cutaneous melanoma) is a key milestone and important catalyst for Provectus because the eventual outcome should provide clarity about the prospects for PV-10's regulatory validation (i.e., the drug's initial pathway to approval).

Securing a good-to-great regional transaction or two, in these cases for the world's two most populous countries, among other things (i) validates the drug's commercial prospects, (ii) more than bolsters Provectus' balance sheet with non-dilutive monies, (iii) brings partners to the fore that can facilitate late-stage trials in their respective geographies for primary liver cancer (and potentially breast cancer), further strengthening PV-10's multi-indication viability, and (iv) establishes a viable non-U.S. centric go-to-market strategy.

Moffitt Cancer Center's presentation of pre-clinical work underscoring their contention (initially conveyed at the 2014 annual meeting of the American Society of Clinical Oncology, and later at the 4th European Post-Chicago Melanoma & Skin Cancer Meeting) -- intralesional PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma, and PV-10 would be a good candidate to evaluate in conjunction with available systemic therapies and new agents in development (respectively) -- could be the catalyst for a drug combination study of PV-10 and an anti-PD-1 agent like nivolumab or pembrolizumab. I think a study only materializes if (because) the data is sufficiently compelling to encourage one of the Big Pharmas to accede to more favorable non-clinical-related terms and conditions than to what other combo study partners have agreed. This data should be presented by Moffitt at the 2014 annual meeting of the Society for Immunotherapy of Cancer in early-November.

MD Anderson, More Cash, Checkpoint Protein Inhibitor Combinations

MD Anderson surgical oncologist and Provectus principal investigator Dr. Merrick Ross' paper Intralesional therapy with PV-10 (Rose Bengal) for in-transit melanoma, published in peer-reviewed Journal of Surgical Oncology, was made broadly available by the company today.

Abstract: Rose Bengal is a novel injectable agent that has been evaluated as a rational treatment strategy for melanoma patients with recurrent unresectable local/regional metastases accessible for intralesional injection. PV-10 (10% Rose Bengal) has completed phase 1 and phase 2 multi-center clinical trials demonstrating significant local/regional disease control and also responses in non-injected regional bystander lesions and distant metastases. The published results of studies that have assessed PV-10 are presented, and the rationale for combining its use with recently approved immunotherapeutic agents is discussed.

See the link to the paper here. The digital version provided by Provectus on its website reached the maximum number of users/views allowed (i.e., too many views), however. The company will have to up this number for more folks to read it. I discussed the paper when it was first published online; see blog news item Journal Publication (February 11, 2014) under the Archived News tab.

A blog reader further highlighted his takeaways from Ross' paper:

• "In addition to an excellent safety profile, encouraging results were observed, including effective local tumor ablation, bystander responses in un‐injected lesions, and unexpectedly prolonged delays in disease progression, particularly in patients who were observed to have local tumor destruction. These latter observations suggested an induced systemic immune response elicited by the tumor ablation."

• "These observations suggest that tumor necrosis may lead to a robust specific anti‐tumor host immune response. The effects of released tumor antigens on nearby antigen presenting cells may facilitate the presentation of specific antigenic targets to circulating T and B cells. The potential for chemokine release and local inflammation in response to granulocyte destruction may enhance the host response. Interestingly, spontaneous involution of untreated tumors was observed in a mouse hepatocellular homograft model and closely correlated with effective ablation of injected target tumors. These observations support the induction of a tumor‐specific host immune response."

• "Furthermore, unexpected long‐term survival was observed in the patients achieving a response compared to similarly staged patients receiving other therapeutic modalities. These observations strongly support the concept that effective tumor ablation can elicit an effective anti‐tumor systemic response."

• "Because of easy access to the local/regional disease, intralesional agents have been studied, but only recently with the rigor of formal prospective trials. IL PV‐10, is well tolerated, easy to administer, and based on Phase 1 and 2 data has an established and excellent safety profile, and results in meaningful responses in injected lesions and untreated bystander lesions. IL PV‐10 compares favorably with the published experience with the vast majority of other injectable agents in terms of side effects and local disease control."

I also add:

Further study of PV‐10 is certainly warranted either in the context of a phase 3 trial, or as a phase 1/2 study in combination with the checkpoint blocking agents or vaccines. The goal of these phase1/2 trials would be to document the safety of these novel combinations and demonstrate enhanced local/regional response and disease control as well as an augmentation of the systemic anti‐tumor responses. The success of such trials would further advance the melanoma treatment landscape.

Dr. Ross has been involved with the company for several years, and MD Anderson has been a compassionate use program ("CUP") site on and off since about 2009. Interestingly, it only was since March 2014 (around the time Provectus announced it had submitted its breakthrough therapy designation application ["BTD"]) that the cancer center was named a CUP site on clinicaltrials.gov. See my blog post Provectus Submits Application to FDA for Breakthrough Therapy Designation. As I noted in blog news item Various (July 30, 2014), MD Anderson noted Provectus' CUP in its August 2014 Melanoma Horizons newsletter, following ASCO 2014 and BTD denial.

Per my blog news item Provectus increases cash balance (July 31, 2014) it would appear the company has increased the amount of cash on its balance sheet, by virtue [I believe] of management writing "Cash on hand supports planned operations until 2016" (rather than its previous comment as late as July 28th of "Cash on hand supports planned operations until 2015"). In my blog post 2014 Annual CEO Letter (pt. 1) I wrote:

Without consideration of the melanoma Phase 3 trial, the projected cash balance should look something like the below. At a projected $2.5 million average quarterly burn, Provectus would approach its accounting firm BDO LLC's minimum cash threshold figure of about $4 million in the 4Q15 timeframe (potential fund raising would occur before that so the threshold is not met of course).

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We should find out the source of the additional cash (I assume quarterly burn rate guidance has not changed of course) during the company's quarterly earnings conference call on August 7th. I speculate it originates from executive compensation repayment; however, the question is whether ~$4.5 million or $9 million was repaid. A lower projected burn rate (ex-pivotal melanoma Phase 3 trial expenses) than the $2.5 million quarterly figure [in order to compare apples-to-apples above] also could allow for the change in the corporate website presentation cash burn message (i.e., until 2015) without an increase in cash on hand. In blog news item Revisiting Cash On Hand (July 15, 2014) I wrote:

Provectus' June 12th 8-K detailing the settlement of the shareholder derivative lawsuit noted a date of July 24th for a hearing on the terms of the proposed settlement. Depending on how much is paid back by management (i.e., ~$4.5 million or ~$9 million), the additional cash should provide further runway for the company to reach the trial's interim readout and make its case to the Agency for filing the NDA. Below, for example, I assume these monies are paid back in 3Q14. Without consideration of the melanoma Phase 3 trial, the projected cash balance would look something like the below. At a projected $2.5 million average quarterly burn, Provectus would approach its accounting firm BDO LLC's minimum cash threshold figure of about $4 million in the 1Q16 timeframe, assuming repayment of the lower amount (the higher payment obviously provides at least an additional quarter of runway).

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With combining oncology drugs all the rage in 2014, FierceBiotech's John Caroll wrote this week in his article Immuno-oncology partnering-palooza continues with Genentech, AstraZeneca deals:

"AstraZeneca has managed to be included in the pioneering group of players working on immune checkpoint inhibitors, which prominently features competing teams from Bristol-Myers Squibb ($BMS) (nivolumab), Merck ($MRK) (pembrolizumab) and Roche ($RHHBY) (the rival PD-L1 drug MPDL3280A.) Merck has been the leader in the partnering arena, executing a long lineup of collaborations. But all the players see combo treatments as the big second wave in R&D, with immuno-oncology treatments dismantling the protective screen cancer cells use to hide from the immune system and other drugs spurring an attack."

Where is Provectus and PV-10 in this partnering-palooza? Management's plan A was and still is to pursue a monotherapy path for PV-10, which finally appears to be unresectable locally advanced cutaneous melanoma for which I think the Phase 3 trial should commence enrollment at the end of September.

The plan B path to approval, albeit a very reticent one in the past, was to allow PV-10 to be combined with checkpoint inhibitors, initially anti-CTLA-4 agents (early on tremelimumab before it was out-licensed by Pfizer to AstraZeneca/MedImmune in 2011, later following approval ipilimumab) but now anti-PD-1 agents (at the moment both Bristol-Myers' nivolumab and Merck's pembrolizumab). Moffitt Cancer Center as recently as ASCO 2014 said/wrote in/on their PV-10-related abstract/poster: "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma." Moffitt later repeated the statement at a presentation during the 4th European Post-Chicago Melanoma Meeting: Interdisciplinary Global Conference on News in Melanoma. One of management's reservations has been paying for or materially contributing to the expense of such a combination study. The checkpoint inhibitors range in cost from $100,000 to over $200,000; see my blog news item % CR per thousand dollars of treatment cost (February 6, 2014) under the blog's Archived News tab. The total cost of treatment for several treatment courses over whatever prescribed time period for a combination study would be much more (the above costs are for a single course). There also are investigator, site and other customary costs of running a trial. If management were to agree to combine PV-10 with, say, nivolumab or pembrolizumab, they presumably would require (unless their current stance is materially different from their historical one) the partner to pay for most if not all of the study's cost save for Provectus' contribution of PV-10 drug product.

Moffitt's Dr. Jeffrey Weber, M.D., Ph.D. is a notable proponent of combination therapy (quotes below are from a December 2013 interview/article):

• "If you use [BRAF drugs] sequentially, it isn’t as good as using them in combination. The way to deal with metastatic melanoma is to hit it hard upfront rather than treat them, wait for resistance, then try to overcome resistance. So the best way to approach treatment is to hit them hard, hit them quick, and hit them often. Melanoma is a difficult disease, and backing off is a sure-fire way to not benefit the patient."

• "I think community oncologists should also consider patients for combination BRAF inhibitor trials—not just treat them on vemurafenib, but consider them for a trial of combination therapy. The combination therapies are all investigational, of course. You can always treat someone with vemurafenib, but they are almost always going to progress. So why not try to do something where they may not progress? And I would send patients for combination ipilimumab/PD-1 trials, because it turns out that the combination, despite a fair amount of toxicity, has a very impressive response rate. Many patients become complete responders, which is very encouraging. I think there are many good combination therapy trials under way, as well as trials with adoptive cell therapy, that look very promising to me."

• "If you combine blocking of CTLA-4 in the mouse with some sort of vaccine strategy, tumors could be cured. In fact this was seen in some tumors that otherwise were very difficult to treat in the mouse model. This was studied around 2001, and initial studies were at the National Institutes of Health and in Los Angeles, where I was at the time."

I think the "tough" part of any combination study is to finalize the sequencing of PV-10 and the partnered checkpoint inhibitor. I wrote about likely combinations in my blog post Combinations & Permutations, Sequencing. Weber's important Big Pharma relationships include Bristol Myers and Merck. For combination study relationships to be struck with Provectus for PV-10, I would presume Moffitt's pre-clinical work on combining the drug with checkpoint protein inhibitors will have to be front and center, Dr. Weber and Moffitt will have to play a key (primary) role in carrying the work out, there would have to be strong interest on the part of prospective partners, and small or little expense would have to be incurred by Provectus.

Combinations & Permutations, Sequencing

Provectus' upcoming, presumably pivotal, Phase 3 trial for unresectable, locally advanced cutaneous melanoma is a potential pathway to approval for PV-10. Management noted in their July 8th annual CEO letter that: "Our development plans for PV-10 stem from the results of our phase 2 study. In that trial, tumors were no longer detectable in 50% of patients with locally advanced cutaneous melanoma who had all of their existing lesions injected. Results from these patients support the potential of PV-10 as a single agent, and provide rationale for a phase 3 randomized controlled trial in patients with unresectable, locally advanced cutaneous melanoma."

Management went on to write: "Provectus is not alone in advocating for an intralesional approach in the treatment of cancer. For melanoma patients with recurrent or in-transit disease confined to their skin this approach has been used to treat patients for many years, as evidenced by guidelines published by the National Comprehensive Cancer Network (NCCN Guidelines®) defining the standard of care for cancer treatment in the United States. Intralesional injection with BCG and certain immunomodulatory agents, local ablation, topical therapy for superficial lesions and regional radiotherapy are consensus interventions for these patients, while systemic therapy remains an option and participation in a clinical trial is the preferred option. We believe that, in this context, PV-10 is well positioned to show superiority in phase 3 testing as a single agent."

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Percent of Cases by Stage at Diagnosis: Melanoma of the Skin

According to the Melanoma Research Foundation, "[m]elanoma that occurs on the skin, called cutaneous melanoma, is the most common type of melanoma." The Phase 3 trial should enroll primarily or exclusively Stage IIIB and IIIC melanoma patients, where the goal, for this patient population, is to clearly demonstrate PV-10's superiority to consensus and other interventions. PV-10, however, is applicable to localized and regional melanoma (i.e., earlier stages), where in due course the drug should demonstrate superiority to surgery and other appropriately suggested interventions. PV-10's sparing of tissue -- injected tumors (i.e., diseased tissue) go away, but healthy tissue is spared -- together with its efficacy should provide a compelling value proposition and alternative to surgery. Localized and regional melanoma, according to the National Cancer Institute, represents 90-95% of melanoma of the skin cases by stage. First and foremost, however, the contemplated Phase 3 trial must be run and the initial pathway to approval achieved.

Beneficial options for patients with distant or metastasized cancer -- in this case, metastatic melanoma -- have dramatically increased in number (and thus choice) and improved in efficacy; however, there obviously still remains a sizable unmet need because the narrative has changed over the last several years from monotherapeutic approaches to treatment (particularly, after each one fails, is to pursue another approach) to combining treatments (whether two treatments are delivered concurrently, or treatments are knowingly delivered sequentially). The goals of combination therapy is to delivery more efficacy and to overcome resistance. I suppose the goal of any cancer therapy is to delivery better efficacy than what came before it, and to overcome resistance (or recurrence), and thus prolong survival.

And that's where the industry's thinking has evolved, by embracing the cancer immunity cycle to progress towards harnessing the body's immune system to fight cancer and thus better deliver on the promise of better efficacy and overcoming resistance. In this case, sequencing the delivery of a permutation of treatments (drugs, therapies) is what constitutes combination.

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Eggermont (2012) writes: "The immune system can be leveraged to fight cancer via four broad, overlapping strategies, comprising priming/boosting of the immune system, T-cell modulation, reducing immunosuppression in the tumour microenvironment and enhancing adaptive immunity." As the author further write: "As immunotherapies function by distinct mechanisms, it is possible that their combination with other treatment modalities may be synergistic."

What does Moffitt Cancer Center's Dr. Jeffrey Weber think? At a minimum he thinks:

• Injectable therapies are making a comeback, where one would use an intralesional agent to prime the immune system of a patient with late stage and/or visceral disease, and then boost it with a checkpoint protein inhibitors (or combination of inhibitors). Unfortunately, he sees Amgen's T-Vec as limited ("I see this as 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."). See 'Pretty Darn Impressive' PD-1 Data in Melanoma, Ribas and Weber, June 12, 2014.

• Moffitt's Phase 1 feasibility study of PV-10 provided "...more and more evidence that you are altering both local and systemic immunity in a positive way. It also provides a rationale for combination trials of PV-10 with check point protein inhibitors, such as ipilimumab, pembrolizumab and nivolumab. PV-10 might offer the perfect way to prime the immune system."

• In response to my question of how to assess the utility or value of an agent or compound as an immune system primer: "Simply its ability to synergize with the immune agent in question in terms of clinical effect when given prior to the second agent...the priming agent would simply add to the effect of the immune agent, when used at the same dose and schedule."

The priming agent above would be PV-10 (or T-Vec), while the immune agent would be one of the checkpoint inhibitors.

Weber previously said he is hard pressed to see a systemic role for IL therapies like T-Vec in patients with significant disease burden and visceral M1c disease. Stages IIIB-C and IV M1a patients could be treated with IL therapy. To expect, however, significant clinical and biologic systemic benefit (affect) with any IL therapy -- as we now know them -- in patients with significant disease burden and visceral M1c disease is very low. For now, for him and those he seeks to help, he sees PV-10's role, it would appear, as a potentially powerful (dare I say perfect) immune system primer to help patients with significant disease burden and visceral M1c disease. In addition to its role as a monotherapy for cutaneous melanoma, management wrote in its annual CEO letter about PV-10's role as part of a sequenced combination therapy for metastatic melanoma: "And for those patients who do not have all disease accessible to injection, medical oncologists have stated that using an agent like PV-10 to prime the immune system could be synergistic in combination with a systemic agent."

Management previously recognized of the benefit and value of combining PV-10 with other treatments and therapies:

• 2006 patent and Foote et al., 2010 regarding PV-10 plus radiotherapy;
• Dees et al., SITC 2012 regarding co-administration of PV-10 and other systemic therapy (i.e., systemic chemotherapy);
• 2012 patent regarding PV-10 plus systemic immunomodulative therapy; and,
• Wachter et al., AACR 2013 regarding PV-10 plus anti-CTLA-4 antibody therapy.

Moffitt previously concluded for AACR 2014 that "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma," and the same for ASCO 2014. Moffitt and Weber would seem to be key clinical players (i.e., site, lead/sole principal investigator) in any combination study.

Management, however, historically has been reticent to pursue combination therapy on their own dime (or spend significantly on it), aside from providing the drug for study, unless someone else (i.e., another company) stepped up to the plate. The situation appears to have changed, per their comments on recent conference calls regarding potential combination studies and related relationships. Experience would suggest (because of the aforementioned comments they made "now") the phone rang, Provectus picked it up, and management listened to what the party(ies) on the other end had to say. The company typically has not talked publicly about things until there is sufficient activity (with of course no certainty of closure or timing thereof) to warrant comment.

Utilizing the table I prepared in my July 24th Combinations news item (see below),...

Click to enlarge.

Click to enlarge.

...Weber's support and contemplated use of PV-10 (and his industry associations and relationships), and other due diligence, likely, potential or possible interest (or lack thereof) is:

• Anti-CTLA-4: Bristol-Myers, obviously, but unlikely. Although an approved drug, it would appear anti-PD-1 agent nivolumab ultimately will supersede it (together with other PD-1 and PD-L1 agents), and PV-10 is potentially a more powerful priming and activation agent vis a vis steps in the cancer immunity cycle in order to combine with a PD-1 or PD-L1 agent.

• Anti-PD-1: Bristol-Myers and/or Merck.

• Anti-PD-L1: AstraZeneca, potentially. Roche is more likely to engage in combination studies utilizing investigational agents in its own pipeline that represent the distinct cycle steps, and thus not look to outside parties yet for combinations.

Grading any so-called co-development deal should Provectus be able to enter into one, more so than merely the design of the clinical studies, would be based on (among other things):

• Who pays for the trial (aside from, and above and beyond Provectus contributing drug product),
• Who conducts, operates (and sponsors) the trial,
• Whether Provectus, like Celldex, would receive an upfront payment, and if so how much,
• What exclusivity might constrain PV-10 to combine with other agents, and
• What right of first something(s) might accompany a co-development deal.

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.

Click on the figure to enlarge it.

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.

Click on the figure to enlarge it.

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..."

Click on the figure to enlarge it.

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).

Click on the figure to enlarge it.

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.

Click on the figure to enlarge it. The table source is here.

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.

A Dark Horse For $PVCT: $MRK

As global Big Pharma interest in the company accelerates, Merck is a dark horse for Provectus.

Article link here.

Article link here.

Article link here.

$PVCT: Merck Anti-PD-1 Agent MK-3475 (lambrolizumab) and Breakthrough Therapy Designation

Last week, Merck announced the FDA had designated lambrolizumab (MK-3475) as a Breakthrough Therapy for the treatment of patients with advanced melanoma.

On MK-3475 & BTD: "Wendy Selig, president and chief executive of the Melanoma Research Alliance, an advocacy organization based in Washington, DC, welcomes the new designation for lambrolizumab. “We view it as a really important step in the process of creating this ‘all hands on deck’ mentality, where you have a serious unmet medical need and where there are big gaps in terms of what’s available,” she says."

In November 2012, Merck presented early-stage interim data for MK-3475 of a single-arm, open-label Phase IB study. "Patients were administered MK-3475 in one of three regimens: low dose every 3 weeks, high dose every 3 weeks and high dose every 2 weeks. Following an initial disease evaluation, patients received one of the three regimens of MK-3475. After 12 weeks, disease status was evaluated by the investigator and compared to baseline using immune-related response criteria (irRC). Those patients demonstrating stable disease or response at the 12-week evaluation time point continued to receive MK-3475 and follow-up monitoring."

"Data has so far been obtained for 85 of the 132 patients enrolled in the study. Of those patients, a total of 43 patients (51 percent) showed an objective anti-tumor response, and of those, 8 patients (9 percent) showed a complete response at or after the 12-week assessment. Notably, of the 27 patients who had previously been treated with ipilimumab monotherapy, the current standard of care for late-stage melanoma, 11 patients (41 percent) showed an objective anti-tumor response to MK-3475 monotherapy; none of those patients showed a complete response."

PV-10's final MM Phase 2 data from ESMO 2012:

• An Objective Response Rate (OR) of 51% in subjects' target lesions (25% Complete Response and 26% Partial Response),
• 69% disease control in these lesions (combined Complete, Partial and Stable Response subjects);
• 33% of subjects having an untreated bystander melanoma lesion achieved an OR in their bystander lesions while 50% achieved disease control in these lesions,
• Response of bystander lesions was highly correlated with outcome in treated target lesions, with a bystander lesion OR of 61% in subjects achieving complete or partial response in their target lesions versus 18% bystander lesion OR in subjects that did not achieve this level or response in their target lesions, and 
• Stage III subjects experienced a substantially higher target lesion response rate (60% OR and 79% disease control) versus Stage IV subjects (22% and 33%, respectively).