More of Better > More or Less of Worse

In a February 2013 Cancer Watch article entitled Back to Phase 1: Understanding Systemic Effects of PV-10, Moffitt Cancer Center's Dr. Amod Sarnaik, M.D. said of the cancer center's Phase 1 feasibility study, result of which later were presented at AACR 2014 and ASCO 2014:

“A further impetus toward teasing out the precise mechanism of how PV-10 can exert a systemic immune response in patients is to allow us to rationally combine PV-10 treatment with some of the exciting emerging immunotherapies for metastatic melanoma”... 

...The focus at Moffitt, Dr. Sarnaik continued, is on discerning the presence of immune cell infiltrate in untreated tumors after PV-10 injections into other lesions. “We are really interested in harnessing immune cell infiltrate as a form of treatment,” he said, noting also that while creating cancer vaccines has been thought of traditionally as one of the Holy Grails of cancer research, cancer vaccines have turned out to be not strong enough to generate an adequate immune response... 

...“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... {Underlined emphasis is mine}

A potent, long-lived systemic immune response to solid tumor cancers should:

(i) Originate at the tumor sites themselves, 

(ii) Require a broader array of tumor antigens to be released and presented, 

(iii) Require this array to be comprised of pristine, un- or non-denatured antigens (i.e., whole tumor antigens, not antigen fragments,), and 

(iv) Result from the subsequent, more comprehensive, T-cell response.

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MD Anderson Cancer Center surgical oncologist and Provectus principal investigator Dr. Merrick Ross, M.D., noted in a recent video, below, while speaking at the setting of ASCO 2014:

"The rapid lysis of the tumor and when the tumor is lysed it does not denature the antigen. So the antigens are expressed in a way where an inflammatory response can occur and therefore antigen presentation probably is up-regulated and enhanced, which could lead to a systemic host response." {My transcription, and underlined emphasis is mine}

The idea is to present as many un-denatured or pristine antigens as possible to dendritic cells ("DCs") and antigen presenting cells ("APCs"). Showing fewer pristine antigens or more denatured ones cannot generate a sustainable, systemic, specific, anti-tumor response. Showing more pristine ones should have the opposite and a much better effect.

Said another way, by a shareholder, blog reader and internist whose patients include those afflicted with cancer:

"Rapid lysosomal-mediated tumor lysis following IL injection of PV-10 uniquely produces pristine, un-denatured antigens that up-regulates antigen presentation to DCs and APCs with a resultant systemic immune response (to paraphrase Merrick Ross). The fidelity of these un-denatured tumor antigens (akin to injecting whole tumor antigens, not antigen fragments, into a patient) is what provokes a very accurate and specific immunological T-cell response that bystander tumors are vulnerable to (presuming they don’t possess too many mutated antigens due to selection pressure from previously therapies)." {My transcription, and underlined emphasis is mine}

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Roche's Genentech's Drs. Daniel Chen, M.D, Ph.D. and Ira Mellman, Ph.D.'s Oncology Meets Immunology: The Cancer-Immunity Cycle provides the opportunity to illustrate the interplay between (a) immune checkpoint blockade [Step #7] and (b) the creation, release and presentation of antigens [Steps #1 and 2], and the subsequent priming and activation of the immune system [Step #3]. I write interplay of these steps because they appear to be what industry thus far is focusing on when it considers combination therapies for late stage diseases, and permutations of treatments and therapeutics from each of these steps in an eventual combination.

The illustration below builds on (is revised by me of) Chen & Mellman's Figure 1:

The generation of immunity to cancer is a cyclic process that can be self propagating, leading to an accumulation of immune-stimulatory factors that in principle should amplify and broaden T cell responses. The cycle is also characterized by inhibitory factors that lead to immune regulatory feedback mechanisms, which can halt the development or limit the immunity. This cycle can be divided into seven major steps, starting with the release of antigens from the cancer cell and ending with the killing of cancer cells. Each step is described above, with the primary cell types involved and the anatomic location of the activity listed. Abbreviations are as follows: APCs, antigen presenting cells; CTLs, cytotoxic T lymphocytes.

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Various types of treatments and/or therapeutics in Steps #1, #2 and #3 may create and release antigens ("Antigen Release"), present them to DCs and APCs ("Antigen Presentation"), and prime the body's T-cells ("T-Cell Priming).

See Chen & Mellman's section entitled Initiating Anticancer Immunity: Antigen Release.

Attempts to activate or introduce cancer antigen-specific T cells, as well as stimulate the proliferation of these cells over the last 20 years, have led to mostly no, minimal or modest appreciable anticancer immune responses. The majority of these efforts involved the use of therapeutic vaccines because vaccines can be easy to deploy and have historically represented an approach that has brought enormous medical benefit (reviewed by Palucka and Banchereau, 2013). Yet, cancer vaccines were limited on two accounts. First, until recently, there was a general lack of understanding of how to immunize human patients to achieve potent cytotoxic T cell responses. This limitation reflects continued uncertainties concerning the identities of antigens to use, their mode of delivery, the types of adjuvants required, and the proximal characteristics of the desired T cell response (Palucka and Banchereau, 2013). Second, the presence of the immunostat in the tumor microenvironment may dampen or disable antitumor immune responses before clinically relevant tumor kill can occur. Thus, as long as these negative signals are in place, the prospects for vaccine-based approaches used alone are likely to be limited. {Underlined emphasis is mine}

Therapeutic vaccination is not the only approach to accelerating and expanding the production of T cell immunity. Because anticancer T cells can be produced spontaneously, there is a growing appreciation that the tumor itself represents a type of endogenous vaccine. Accessing the naturally occurring source of cancer-associated antigens avoids problems associated with selection and delivery (Heo et al., 2013, van den Boorn and Hartmann, 2013). This approach is also convenient, but achieving it requires detailed knowledge around whether standard of care chemotherapy or targeted therapies are compatible with immunotherapies. Some therapies are thought to cause tumor cell death in a fashion that promotes immunity (reviewed in Zitvogel et al., 2013). However, it is unclear whether this effect can be accurately predicted and will, in any event, require empirical study. Chemotherapy, radiation therapy, and targeted therapies must also be evaluated for their effects on the immune system. Although it is assumed that many might be antagonistic, there are some reports that others might promote T cell activity (Demaria et al., 2005, Duraiswamy et al., 2013, Hiniker et al., 2012, Ott et al., 2013, Postow et al., 2012, Stagg et al., 2011, Zitvogel et al., 2013). {Underlined emphasis is mine}

See Chen & Mellman's section entitled Presentation, and T Cell Priming.

Another exciting development is that the initial demonstrations that genetically modified autologous T cells could be reinfused into patients to yield substantial clinical benefit, at least in certain B cell malignancies (Grupp et al., 2013; reviewed in Kalos and June, 2013). The most well developed of these is the use of “CARs,” or chimeric antigen receptors, in which a patient’s T cells are transfected with a construct encoding an antibody against a tumor surface antigen (typically CD19) fused to T cell signaling domains (Kochenderfer and Rosenberg, 2013). Similar approaches are under investigation with recombinant T cell receptors (reviewed in Kalos and June, 2013). The procedure avoids the need for immunization and may even overcome mechanisms of immune suppression by overwhelming the system through infusion of large quantities of the modified T cells. This can force the revolution of the Cancer-Immunity Cycle, enhancing the accumulation of stimulatory immune factors, and potentially promotes eventual self-propagation of the cycle. The potential limitations here, which are yet to be fully determined, include whether the approach can be extended to cancers beyond hematologic malignancies, whether the delivery of large numbers of monospecific T cells will cause resistance due to antigenic drift, and whether the toxicity issues already identified can be safely managed. {Underlined emphasis is mine}

See Chen & Mellman's section entitled T Cell Priming and Activation.

Whether tumor antigens are delivered exogenously or are captured and presented by DCs endogenously, another strategy for intervening in the Cancer-Immunity Cycle involves the control of T cell activation. This is the presumed primary mechanism of action of anti-CTLA4 antibodies, such as ipilimumab, which blocks the interaction of the major negative regulator of T cells (CTLA4) with its ligands B7.1 and B7.2 (CD80 and CD86; Qureshi et al., 2011). Thus, during antigen presentation in lymphoid organs (or in the periphery), the expansion of T cell responses is disinhibited, thereby promoting the production of autoreactive T cells, including tumor-specific T cells. The lack of selectivity in T cell expansion combined with the fundamental importance of CTLA4 as a checkpoint may underlie the significant immune-related toxicities seen in patients treated with ipilimumab (Hodi et al., 2010). {Underlined emphasis is mine}

This second illustration below builds on (is revised by me of) Chen & Mellman's Figure 2:

The numerous factors that come into play in the Cancer-Immunity Cycle provide a wide range of potential therapeutic targets. This figure highlights examples of some of the therapies currently under preclinical or clinical evaluation. Key highlights include that vaccines can primarily promote cycle step 2, anti-CTLA4 can primarily promote cycle step 3, and anti-PD-L1 or anti-PD-1 antibodies can primarily promote cycle step 7. Although not developed as immunotherapies, chemotherapy, radiation therapy, and targeted therapies can primarily promote cycle step 1, and inhibitors of VEGF can potentially promote T cell infiltration into tumors—cycle step 5. Abbreviations are as follows: GM-CSF, granulocyte macrophage colony-stimulating factor; CARs, chimeric antigen receptors. {Underlined emphasis is mine}

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In the cancer immunity cycle, where certain drugs (based on known and yet to be known factors, notably stimulatory and inhibitory) promote a step (or potentially more than one step), who owns what "real estate" (i.e., who owns what drugs) should be key to understanding the competitive landscape, and where it eventually leads. As the researchers, industry and the FDA combine therapies to address the still unmet needs of late-stage cancer patients, ownership of cancer assets used in whatever combinations may and do work (and thus eventually are approved) translates into sales, profit and return on investment (in R&D).

Step #1: Chemotherapies and radiation therapies likely produce more antigen fragments than whole antigens, but antigens nevertheless. Chemotherapies are commoditized (read: inexpensive, not so profitable, and growing obsolete). Radiation therapy is owned and delivered by physicians. There are numerous targeted therapies owned by various pharmaceutical companies. They may or may not generate whole and/or fragmented antigens, but it seems their owners are worried about the dismantlement of their franchises, as some rush to combine and partner with PD-1 and PD-L1 agents.

Step #2: These agents presumably facilitate the presentation of the antigens released in Step #1, and include failed (or as yet ineffectively utilized) vaccines, CD40 agent owners (like Genentech-Roche, among others), and not-so-valuable-properties-because-of-widespread-use (read: un-patentable, like INF alpha).

Step #3: There potentially is more real estate here. Already owned includes, notably, Bristol-Myers' approved CTLA-4 agent (ipilimumab), and CD137, OX40 and CD27 agents by Pfizer and Roche, among others.

Step #7: The PD-1 owners include Bristol-Myers (Opdivo) and Merck (Keytruda). The PD-L1 owners include Roche and AstraZeneca. IDO owners include, among others, Incyte (non-exclusive combination study relationships/agreements with AstraZeneca, Bristol-Myers, Merck, and Roche) and NewLink (exclusive, now, to Roche)

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Celgene's expansion of its license relationship with Sutro today (building on 2012's initial arrangement), provides Celgene with real estate, and potentially special ones at that. In terms of real estate, while the Big Biotech can access CTLA4, PD-1 and PD-L1 via Sutro, it notably also gets LAG-3 and TIM-3 (the next generation of immune checkpoint inhibitors?).

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The illustration below builds on (is revised by me of) Chen & Mellman's Figure 3 (note LAG-3 and TIM-3 inhibitors, alongside PD-1 and PD-L-1):

Each step of the Cancer-Immunity Cycle requires the coordination of numerous factors, both stimulatory and inhibitory in nature. Stimulatory factors shown in green promote immunity, whereas inhibitors shown in red help keep the process in check and reduce immune activity and/or prevent autoimmunity. Immune checkpoint proteins, such as CTLA4, can inhibit the development of an active immune response by acting primarily at the level of T cell development and proliferation (step 3). We distinguish these from immune rheostat (“immunostat”) factors, such as PD-L1, can have an inhibitory function that primarily acts to modulate active immune responses in the tumor bed (step 7). Examples of such factors and the primary steps at which they can act are shown. Abbreviations are as follows: IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high-mobility group protein B1; TLR, Toll-like receptor; HVEM, herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T-lympocyte antigen-4; PD-L1, programmed death-ligand 1; CXCL/CCL, chemokine motif ligands; LFA1, lymphocyte function-associated antigen-1; ICAM1, intracellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indoleamine 2,3-dioxygenase; TGF, transforming growth factor; BTLA, B- and T-lymphocyte attenuator; VISTA, V-domain Ig suppressor of T cell activation; LAG-3, lymphocyte-activation gene 3 protein; MIC, MHC class I polypeptide-related sequence protein; TIM-3, T cell immunoglobulin domain and mucin domain-3. Although not illustrated, it is important to note that intratumoral T regulatory cells, macrophages, and myeloid-derived suppressor cells are key sources of many of these inhibitory factors.

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Additionally, according to FierceBiotech, the real estate is special:

"Sutro's team believes it has devised a much better way to build ADCs--those precise cancer cell-killing constructs made up of a targeting antibody, linker and payload--and bispecifics, teeing up potentially best-in-class products that promise to be more efficiently and consistently manufactured. Using biochemical synthesis, they've hatched a technology that can bypass the current approach to biologics by genetically engineering drugs that are much simpler to make, more akin to small molecules." {Underlined and bold emphasis is mine}

PV-10's effectiveness is attributed to its physical chemistry and small molecule nature.

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Moffitt presents pre-clinical (murine model) data about PV-10 in combination with co-inhibitory blockade at SITC 2014 (Provectus' press release on the topic is here). Chen and Mellman note "inhibitors shown in red [in their Figure 3] help keep the process in check and reduce immune activity and/or prevent autoimmunity distinguish between checkpoint," but distinguish between CTLA-4, and PD-1 and PD-L-1:

"Immune checkpoint proteins, such as CTLA4, can inhibit the development of an active immune response by acting primarily at the level of T cell development and proliferation (step 3). We distinguish these from immune rheostat (“immunostat”) factors, such as PD-L1, can have an inhibitory function that primarily acts to modulate active immune responses in the tumor bed (step 7). "

The presentation could explain Moffitt's Dr. Jeff Weber, M.D., Ph.D.'s contention PV-10 may be the perfect immune system primer. What does being the perfect primer mean, and entail?

Provectus recently revised its Fact Sheet to note more work by Moffitt, this time on biomarkers:

What happened to the next cohort of the Phase 1 feasibility study? Of the total enrollment of 15 patients, 8 were reported on at AACR/ASCO 2014. April 2014 article PV-10 decreases melanoma cells in tumours, which followed AACR 2014, noted:

Studies are now underway in an additional seven patients to take biopsies and blood samples at more frequent time intervals after PV-10 injection to elucidate the pathways more clearly.

Moffitt's presentation could discuss whether or not PV-10 promotes steps #4, #5 and/or #6 of the cancer immunity cycle. If so, why and how?

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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.

$PVCT is Going for BTD. BTD is Tantamount to Approval.

In pursuit of accelerated approval

In April 2010, in response to Provectus' routine request for accelerated approval ("AA"), the Agency request proof of PV-10's systemic properties and benefit. Of note, Craig said "While we believe the Phase 3 with an SPA represents an industry standard path to approval, we believe the door may still be open for accelerated approval."

It would have seemed that, at the time, for a "mere" local-regional drug, showing PV-10 worked and worked well was insufficient to attain AA. Provectus learned it also had to show systemic benefit.

So, later in 2010, Provectus engaged Moffitt Cancer Center about conducting the necessary work to explain PV-10's mechanism of action ("MOA") and prove the compound's systemic benefit. MD Andersen Cancer Center also was considered as a potential partner for work.

By early 2011, Moffitt had begun conducting murine model work at its own expense, demonstrating [even back then] how excited the cancer center was to explore PV-10's MOA. Such work boded well for the eventual full-scale study work and publication of the data.

Into mid-2011, Moffitt was generating success from its work, such as demonstrating the so-called bystander effect in a very harsh lung metastases mouse model.

On January 17, 2012, Provectus issued a PR about the beginning of Moffitt's work, which was presented at the Society of Surgical Oncology Annual Meeting in March 2012.

Just recently, Moffitt presented more results of its work at AACR in April 2013: clear, unambiguous, unequivocal proof of PV-10's systemic properties and benefit. The FDA's request, it would seem, had been answered.

A parallel pursuit of a special protocol assessment

At the same April 2010 meeting with the FDA, the first end-of-Phase 2 ("EOP2") meeting, the journey towards a Phase 3 trial under a Special Protocol Assessment ("SPA") for metastatic melanoma began.

A second EOP2 meeting was held in March 2011.

A third meeting was held in November 2011.

On January 18, 2012, the FDA provided guidance to (told) Provectus no further end-of-Phase 2 meetings were required, and to submit the company's Phase 3 protocol for review, either via standard review or a request for Special Protocol Assessment ("SPA").

It seemed the first half of 2012 was spent finalizing the protocol for the trial, which was first noted in June 2012 (and discussed in more detail in October)

The second half of the year seemed to encompass, among other things, getting supportive programmatic elements into place, which was first noted in October 2012.

By March 2013, it appeared the Phase 3 trial was on track to commence enrollment by mid-2013.

In 2013 I have been left unsatisfied by management's explanation for the time taken in attaining the SPA. Their description of the process has been lacking, most recently in the annual CEO letter circulated in May 2013: "While preparation for submission of our SPA has taken longer than expected, it is crucial to remember that oncology presents a moving playing field."

By early June 2013, there seemed to be clear feedback the SPA had not yet been submitted.

The arrival of the breakthrough therapy designation

The Food and Drug Administration Safety and Innovation Act ("FDASIA") was signed into law in July 2012. Through FDASIA, the breakthrough therapy designation ("BTD") was offered.

Intended to expedite the development and review of drugs for serious or life-threatening conditions, the pharmaceutical industry now believes BTD is tantamount to approval.

Having been stalled in their circa 2010 and previous efforts to attain AA, opportunity in the form of BTD fell into management's lap.

By, I think, February 2013, management has begun to explore BTD as yet a third path to regulatory clarity, the first being AA and the second being the SPA.

As early as March 2013, management said they would submit a BTD application.

There was more than speculation earlier this year that the FDA asked Provectus to submit a BTD application. This "speculation" was confirmed in early June 2013.

Moffitt's upcoming peer-reviewed publication was thought to have been a fundamental component of the company's BTD application.

The criteria for breakthrough therapy designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. NCCN guidelines for patients with Stage III melanoma indicate the primary (main) treatment as systemic therapy, such as chemotherapy, which is dacarbazine (DTIC) or temozolomide (TMZ). Progression free survival ("PFS") for these drugs is about 2-3 months.

PFS for PV-10's Stage III patients in the company's Phase 2 trial, reported at ESMO in October 2012, was about 10 months, a substantial improvement over the available therapies of DTIC and TMZ. PFS is the primary endpoint of the contemplated MM Phase 3 trial for which the SPA is being sought.

A collaborative and supportive FDA

Provectus has described its relationship with the FDA as a collaborative and supportive one.

At the time, summer 2011, the new Division of Oncology Products 2 ("DOP2") took over review responsibility of PV-10 for melanoma after an extensive reorganization of the FDA. DOP2 personnel would review both the SPA and BTD submissions (and, I suppose, an AA request or submission).

It seems odd that DOP2 would evaluate three concurrent, parallel but different requests. It would seem there would or has to be some prioritization of these paths in the eyes of or by the FDA.

Moffitt, its already published work, work yet to be published and the results of ongoing work (e.g., the Phase 1 feasibility study, much more murine model work) seems to have dramatically changed for the positive the perception or view of PV-10 and Provectus in the eyes of the Agency.

There is preliminary clinical evidence that demonstrates PV-10 has substantial improvement on PFS over available therapy.

Is a collaborative and supportive FDA being proactive, guiding the company towards a BTD application submission (rather than an SPA one) that would translate into either a safety/truncated trial (less likely) or AA (more likely)? Better and best.

Better = a truncated trial. Best = AA. No need for good anymore.

I think the FDA is being proactive with Provectus and PV-10

PV-10 is a paradigm shift in the treatment of cancer. "In the eyes of Richard Pazdur, a breakthrough cancer drug should be "transformative." "It's really for transformative therapies that are a marked improvement, where there is no therapy, or a drug has a significant advance over what is out there," based on preliminary evidence, Dr. Pazdur said in an interview."

Management, it would seem, clearly is going for BTD.

BTD, according to the industry, is tantamount to approval.

For PV-10 and Provectus, the outcome is clear: approval.