December 8, 2014

PV-10 (Rose Bengal) Clinical Value Proposition

Updated 12/10/14: Bigger font (particularly for the footnotes)
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Original post below.
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December 1, 2014

November Blog Stats, and other bits and bobs

Bits and Bobs.
Blog readership mostly rose from October depending on the statistic. I wrote 22 blog posts (7) and news items (15) in November, versus 22 during the previous month (5 and 17, respectively). November month-over-month changes were:
  • +8% for the number of unique visitors (2,255 v. 2,085),
  • +4% for page views (18,851 v. 18,106),
  • +5% for visits (8,591 v. 8,173),
  • -10% for U.S. cities [from where visitors came] (584 v. 649),
  • -16% for world cities (137 v. 163), and
  • No change for countries (51 v. 51).
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 Roche's Genentech's Dr. Daniel Chen, M.D., Ph.D., PD-L1 Global Development Leader, noted in May 2014 that:
"One theory about immunotherapies is that they could work for everyone, with any type of cancer. The data to date show that this isn’t the case. Even though everyone has an immune system, not all patients will respond to the same medicine in the same way. 
Our immunotherapy program at Genentech has a large biomarker and diagnostic focus so we can find those who are most likely to experience a meaningful benefit. 
But what about those who do respond, but not well enough? 
Perhaps those people with a small to moderate response should be candidates for combination trials. Some immunotherapies may be more effective if they are combined with different types of medicines, including chemotherapies, personalized medicines and even other immunotherapies. 
In this way, biomarkers for cancer immunotherapy don’t just tell us who will or will not respond. Rather, they could help guide treatment strategies involving one or more medicines."
I recently asked Eric about this. He commented (paraphrasing):
Biomarker (i.e., targeted) therapies have proven quite successful in a number of cases, such as vemurafenib (trade name Zelboraf) and imatinib (trade name Gleevec). But these generally have limited time before escape* occurs since they target one or a few mutations, and cancer cells, which are generally highly adept at mutating, mutate to circumvent the therapy. 
Our understanding of immune targets relevant to cancer is still very primitive along with our ability to devise drugs specific to unique targets. Part of the problem is that "unique" targets are generally conserved**, just as molecular pathways are, in other kinds of cells and thus we get "off-target" effects (e.g., cholitis, secondary tumors, etc). 
Craig would say that PV-10 works by training our very sophisticated immune system to recognize complex patterns of targets that are expressed but sequestered by cancers. This is a bit like grabbing a very carefully selected handful of biomarkers and deploying them simultaneously.
* "Time before escape" is akin to survival time.
** "Conserved" means similar or identical.

 Peter updated Provectus' website to include information about the number and diversity of people and vendors working for the company. See About Us, Management, and scroll to the bottom of the page. It is a competent first step that provides some useful, basic insight into company operations.
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Of the 50 FTE figure in the bottom left hand corner, Eric's consultants and contract labor (see "consulting and contract labor" in Provectus' quarterly and annual SEC filings) comprise 36 FTEs (not including himself). The balance of 14 FTEs comprise Provectus' four principals and employees, and 10 FTEs that Peter characterizes as the full-time equivalents of the 134 people servicing and supporting his "corporate infrastructure."

 I recently asked Peter about the possible impact of a potential approval (i.e., a speculative PDUFA date of April 2015) of Amgen's intralesional oncology agent talimogene laherparepvec ("T-Vec") as a monotherapy for metastatic melanoma. He commented (paraphrasing):
People seem to like the idea of intralesional agents becoming appropriate to treat disease, and it is believed both T-Vec and PV-10 are helping to establish the relevancy of and build the intralesional agent category. People like having options as well, so two intralesional agents are better than one, in general. No matter what happens with T-Vec as a monotherapy, it is already believed T-Vec used in combination with ipilimumab is synergistic, and further builds the intralesional agent category.
 According to Neuroscience For Kids, the blood-brain barrier is semi-permeable, allowing some materials to cross, but preventing others from crossing. Further:
"More than 100 years ago it was discovered that if blue dye was injected into the bloodstream of an animal, that tissues of the whole body EXCEPT the brain and spinal cord would turn blue. To explain this, scientists thought that a "Blood-Brain-Barrier" (BBB) which prevents materials from the blood from entering the brain existed."
According to
"The brain is the only organ known to have its own security system, a network of blood vessels that allows the entry of essential nutrients while blocking other substances. Unfortunately, this barrier is so effective at protecting against the passage of foreign substances that it often prevents life-saving drugs from being able to repair the injured or diseased brain."
Very small amounts of rose bengal cross the blood-brain barrier. See, for example, Table 3 of Klaassen's Pharmacokinetics of rose bengal in the rat, rabbit, dog and guinea pig (October 1976).
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Some patients in Provectus' melanoma Phase 2 trial had visceral disease, including brain metastases. How many patients with brain mets is unclear. Provectus has publicly discussed one such patient at medical conferences (Subject 0907 with Stage IV M1c disease), noting "“Near complete resolution” of pulmonary nodules observed at Week 12" during an ASCO 2010 clinical development update presentation.

If the brain is on the other side of the blood-brain barrier (and the immune system is on the other, so to speak), and PV-10 is injected into visible lesions on the skin, how were these brain tumors (nodules) positively impacted?

Blood Brain Barrier, Margaret Reece, Ph.D. (November 2013):
"The blood brain barrier is designed to exclude both pathogens and the cells of the immune system. It also excludes large proteins including immune system antibodies. It is only after viruses and bacteria are able to trigger a breakdown of the blood brain barrier that immune system responders gain entrance. And, when it occurs, it seldom turns out well."
The small amounts of rose bengal that may permeate the barrier are very unlikely to be able to reduce or destroy tumors, and the drug was not systemically administered (just injected into the skin at the location of a cutaneous or subcutaneous lesion). As Craig would say, Mother Nature's immune system knows how to get to brain tumors without destroying the normal brain tissue. But how?
"The brain has often been considered an immunologically privileged organ. This was based on early studies that found few antigen-presenting cells in the central nervous system. In addition, there was a perceived lack of a lymphatic system within the brain to carry immunogenic material in the central nervous system to lymph nodes where a humoral immune response could be initiated. And finally, the presence of the blood-brain barrier (BBB) was thought to prevent the entry of immune cells from the peripheral circulation into the brain. However, there is increasing evidence to suggest that the brain is under immunological surveillance." (Miller, Immunobiology of the blood-brain barrier, December 1999)

November 28, 2014

Safely specific (a.k.a a diseased tissue-specific way of generating a systemic response)

An August 2014 Drug Discovery Today article entitled Loco-regional cancer drug therapy: present approaches and rapidly reversible hydrophobization (RRH) summarized the shortcoming of systemic chemotherapy:
"Insufficient drug uptake by solid tumors remains the major problem for systemic chemotherapy. Many studies have demonstrated anticancer drug effects to be dose-dependent, although dose-escalation studies have resulted in limited survival benefit with increased systemic toxicities."
A similar criticism -- that is, the cost-benefit of systemic toxicity and greater survival -- could be made of checkpoint inhibitors (e.g., anti-CTLA-4s, anti-PD-1s, anti-PD-L1s), although there presumably is greater drug intake of these immunotherapies than chemotherapies.

Craig has long said (paraphrasing) one of the keys to solving the problem of cancer -- to generating correct, sustainable and thus successful systemic responses -- was to solve the problem of specificity. Other contributors to this proper response included route of delivery, and how the therapeutic or therapy in question induced cells to die. Specificity, manner of cell death, and route of delivery all importantly contribute to the safety, robustness and durability of a therapeutic or therapy's correct and successful systemic response.

The Drug Discovery Today article above continues:
"One solution to this has been the idea of loco-regional drug treatments, which offer dramatically higher drug concentrations in tumor tissues while minimizing systemic toxicity." {Underlined emphasis is mine}
Once they knew rose bengal (PV-10) had the necessary kind of specificity (and thus solved this problem) -- destroying only diseased tissue while leaving healthy tissue untouched or unaffected -- Craig contends they knew the main problem mostly was solved.

Other agents induce autophagy (where cells eat themselves). Can those agents induce this action only in cancerous cells, and not normal ones too?

Other agents can be delivered intralesionally or intratumorally, with the goal of delivering more drug product into the tumor. Without specificity, however, would not both the tumor and its surrounding normal tissue be affected, leaving a confused immune system to try and sort out what it must and must not do?

Craig believed a loco-regional agent could generate the correct systemic response, but needed a diseased tissue-specific way of doing so to make it practically effective and sufficiently safe: PV-10 (rose bengal).

November 26, 2014

It's Eric's process

When Provectus issued its November 6th Provectus Biopharmaceuticals Submits PV-10 Phase 3 Melanoma Protocol to FDA press release, the action of merely submitting the protocol to the Agency felt incomplete because management noted in the PR "The FDA is expected to review the submission and comment on the proposed study population, clinical endpoints, and statistical analyses within 30 to 45 days."

If you've followed Provectus long enough, and gotten to know the principals and their ways, you develop a better understanding of their respective processes.

Eric's process in this instance may have required him to wait for the above mentioned review period to pass, so as to examine and evaluate what (if any) significant and/or general comments the FDA might have provided to him about the protocol, before Provectus would commence or move forward on actions and activity dependent upon an agreed to, uncommented on, essentially approved, etc. protocol (e.g., Phase 3 trial commencement, filing the protocol with country-specific versions of the Agency, regional license transaction consummation, etc.).

The website page for the melanoma Phase 3 trial notes the protocol was received November 4th. Assuming Eric submitted it to the Agency, say, either October 31st (Friday) or November 3rd (Monday) [leaving a day or two for it to make its way to the website], a 30 to 45-day period of time takes one anywhere from early- to mid-December (e.g., 1st, 3rd, 15th, 18th).

November 18, 2014

Provectus notebook

Pilon-Thomas & Moffitt Cancer Center. Frequent medical writer of PV-10 Janet Fricker has an article out in Medical News Today today about Moffitt's poster presentations at SITC 2014 entitled Melanoma shows improved regression with combination of PV-10 and checkpoint inhibitor.

The article has an interesting quote from the cancer center's Dr. Shari Pilon-Thomas, Ph.D. about their work:
"The spirit of our study was to determine whether combining PV-10 with a checkpoint inhibitor would enhance the systematic immune responses of the initial injection of PV-10."
Phrased via slightly different editing: The spirit of the study was to determine whether combining ABC with XYZ would enhance the systematic immune responses of ABC. Not, whether combining XYZ with ABC would help XYZ.

Pfizer. Pfizer announced Monday it had (i) a PD-1 agent and (ii) licensed a PD-L1 agent from Merck KGaA (Germany), thus changing the competitive landscape to look more like the below:
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See blog post "Together, these studies support the induction of increased tumor-specific immunity after co-inhibitory blockade in combination with IL PV-10 therapy."
Interestingly and notably, Pfizer immediately guided 2014 and 2015 earnings downward as a result of the transaction and to recognize its upfront payment as a certain significant item.

Some preliminary opinions on the deal include:
Jacob Plieth, EP Vantage: "This disproves the notion that a handful of big names – Merck & Co, Bristol-Myers Squibb and  Roche – had already seized all the early promise in  PD-1/PD-L1 inhibition."
The Deal Pipeline: "Pfizer in May walked away from AstraZeneca after painting itself into a corner by describing a takeover proposal - one of a series - as "final..." The deal would have also given Pfizer access to AstraZeneca's own immuno-oncology treatment, which are known as anti-PD-L1 compounds...The New York company has now found a less contentious way to access the technology." 
Pfizer's view of its immuno-oncology pipeline now, in cancer-immunity cycle terms, is:
Click to enlarge. Pfizer presentation, November 17, 2014.
Merck & Co., (U.S.A.). Merck announced positive results from a Keytruda (PD-1) melanoma trial on Sunday. The comparator for late-stage patients in this trial was systemic chemotherapy, the co-primary endpoints were progression-free survival ("PFS") and overall survival ("OS"), a secondary endpoint was overall response rate ("ORR"), and additional data was collected on duration of OR, patient-reported outcomes (the EORTC QLQ-C30 questionnaire) and safety (adverse events).

Provectus' upcoming melanoma Phase 3 trial of earlier stage patients whose disease has not spread to distant sites (which is not late-stage disease, where the disease indeed has spread) has a comparator of systemic chemotherapy, a primary endpoint of PFS, and secondary endpoints of complete response rate ("CRR"), duration of CR, patient-reported outcomes (the Skindex-16 questionnaire), OS and safety (adverse events).

China. I thought the comments by Sinopharm A-THINK's CEO in Provectus' PR Provectus Biopharmaceuticals Extends Memorandum of Understanding with Sinopharm-China State Institute of Pharmaceutical Industry and Sinopharm A-THINK Pharmaceutical Co., Ltd that " is hopeful that a contract will be finalized in the coming weeks" were interesting. They become notable if and when a meaningful and material deal is consummated. I don't doubt part of the deal process is for both parties (Sinopharm and Provectus) to interact with the China Food and Drug Administration.

The Cancer-Immunity Cycle. The Medical News Today article about Moffitt, PV-10 and SITC also noted:
"The mechanism, [Dr. Pilon-Thomas] adds, is thought to be that injection of PV-10 into melanoma lesions results in tumor cells releasing antigens that induce T cell immunity, with the checkpoint inhibitors then "releasing the brakes" on the resulting T cells. Next, the team plans to investigate the types of immune cells released at the tumor site." {Underlined emphasis is mine}
"[T]he types of immune cells released at the tumor site" refers to cycle steps 5 and 6 in Chen & Mellman's (2013) Oncology Meets Immunology: The Cancer-Immunity Cycle:
"In the first step, neoantigens created by oncogenesis are released and captured by dendritic cells (DCs) for processing (step 1). In order for this step to yield an anticancer T cell response, it must be accompanied by signals that specify immunity lest peripheral tolerance to the tumor antigens be induced. Such immunogenic signals might include proinflammatory cytokines and factors released by dying tumor cells or by the gut microbiota (Figure 2, Table 1). Next, DCs present the captured antigens on MHCI and MHCII molecules to T cells (step 2), resulting in the priming and activation of effector T cell responses against the cancer-specific antigens (step 3) that are viewed as foreign or against which central tolerance has been incomplete. The nature of the immune response is determined at this stage, with a critical balance representing the ratio of T effector cells versus T regulatory cells being key to the final outcome. Finally, the activated effector T cells traffic to (step 4) and infiltrate the tumor bed (step 5), specifically recognize and bind to cancer cells through the interaction between its T cell receptor (TCR) and its cognate antigen bound to MHCI (step 6), and kill their target cancer cell (step 7). Killing of the cancer cell releases additional tumor-associated antigens (step 1 again) to increase the breadth and depth of the response in subsequent revolutions of the cycle." {Underlined emphasis is mine}
Click to enlarge. Chen & Mellman, Figure 1,
Australia. In November 2010 Provectus wrote in their press release Provectus Meets with the Therapeutic Goods Administration to Review Path for Approval of PV-10 in Australia:
"The recent meeting focused on manufacturing, characterization and specifications for PV-10, along with a review of clinical data and anticipated Phase 3 study design and endpoints. The proposed primary endpoint of progression free survival, which Provectus proposed to the U.S. Food and Drug Administration (FDA) earlier this year in its first end-of-Phase-2 meeting with FDA, was deemed appropriate for assessment of efficacy in light of established European Medicines Agency (EMEA) standards adopted by TGA. Use of interim data from the first half of Phase 3 study subjects, in conjunction with safety data collected in earlier studies of PV-10 for melanoma, was discussed to allow early evaluation for marketing approval for metastatic melanoma, and TGA agreed that these data should be sufficient for this review if the analysis confirmed efficacy."
I learned from folks in Australia that management will be there around the time of the annual scientific meeting of the Clinical Oncology Society of Australia (December 2nd to 4th). I would think visiting the TGA, Australia's FDA, would be on their trip itinerary.

In addition to sites in Australia for Provectus' melanoma Phase 1 and 2 clinical trials and the company's compassionate use program, and the work therein, investigator-initiated work was and is being done combining PV-10 with radiotherapy. Preliminary work (3 patients) was published in 2010 as A novel treatment for metastatic melanoma with intralesional rose bengal and radiotherapy: a case series in Melanoma Research. Follow-up investigator-initiated work by the same lead (Dr. Matthew Foote, M.D.) appears to be one patient short of full enrollment and treatment (25 patients).
Click to enlarge. Above screenshot taken from a presentation
by Dr. Sanjiv Agarwala, M.D. at the 2nd European Post-Chicago Melanoma Meeting (2010)
The average cost of drug R&D. A study by the Tufts Center for the Study of Drug Development out today said developing a new prescription medicine that gains marketing approval costs $2.6 billion. A related article on the study by FierceBiotech author John Carroll framed Tuft's estimate in the context of an estimate by Doctors Without Borders of $186 million.

Through September 30, 2014, Provectus has spent (balance sheet item Accumulated Deficit) $157 million for multi-indication viable PV-10.

November 15, 2014

"This determination is based on the paucity of data..."

Updated 11/16/14: See A Bridging Study to an NDA (November 16, 2014) on the blog's News page.

Copyright of (presumably) the Knoxville News Sentinel.
January 24, 2014 (December 16, 2013). On January 24th, following their December 16th Type C meeting with the FDA, Provectus issued press release Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes in which the company highlighted the indication being sought (and patient population being targeted) as locally advanced cutaneous melanoma.

Provectus also discussed guidance from the FDA during the meeting:
  • The Agency agreed with Provectus that treatment of cutaneous and subcutaneous tumors in patients with locally advanced cutaneous melanoma (i.e., recurrent, in-transit or satellite melanoma that has not yet spread from the skin to distant sites) could provide clinical benefit to such patients, particularly if the measured objective responses in patients' disease correlated to a demonstrated treatment effect on one or more symptoms of their disease (e.g., pain, infection or significant bleeding), (1)
  • The Agency agreed to work with Provectus to quantify symptom control in this patient population, and
  • In reference to discussions on the potential for breakthrough therapy designation, "FDA advised Provectus to provide objective response rates with adequate information to evaluate the symptomatic treatment effects (e.g. pain, infection, bleeding) in patients presenting with locally advanced cutaneous melanoma who received PV-10 to all lesions."
Provectus wrote in the PR, constructing a quote for/from Craig:
  • "We are very pleased that the path to initial approval in the U.S. is now clear and PV-10 can be available to help patients in a more condensed time frame than if the Agency required an overall survival endpoint in a large randomized Phase 3 study." (2)
Finally, the company wrote, again via a quote from Craig:
  • "The Agency may yet recommend and it may be in the best interest of Provectus to undertake a small, short bridging study in patients where all tumor burden can be injected. This would allow more frequent dosing than was permitted in the Phase 2 study, presumably akin to the dosing schedule currently used to treat nearly 100 patients under our expanded access protocol, and allow symptomatic endpoints to be prospectively correlated with objective response criteria."
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  • Via a quote from the FDA's BTD denial letter: "We have reviewed your request and while we have determined that treatment of 'locally advanced cutaneous melanoma' meets the criteria for a serious or life-threatening disease or condition, the preliminary clinical evidence you submitted does not indicate that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints." 
  • Via a quote from Craig: "We are very happy that the Agency recognized that locally advanced cutaneous melanoma is a serious condition and consider that a win for melanoma patients. We believe that elimination of these patients' tumors is clinically relevant, but as we alluded to in our January 24, 2014 press release regarding our Type C meeting of December 16, 2013, a focused bridging study appears to be necessary to conclusively establish a link between complete response and symptom-based endpoints."
Additionally, the Agency letter also said:
  • This determination is based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding) and our inability to determine the clinical significance of the reduction in the size in one to 10 target lesions in patients with locally advanced melanoma, who may have additional untreated cutaneous, subcutaneous, or visceral sites of disease. (3) The information provided on durability of response is also of unclear clinical significance given the modifications to RECIST.
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May 23, 2014. On the conference call convened to discuss the company's go forward approach in the wake of BTD denial, Eric said (edited from the call's transcript to remove sos and uhs):
The longer version of my answer is that definitely we were very encouraged by the guidance that we received from the Agency in that meeting.
That being said, I described myself recently as being a professional worrier. Maybe that’s good for someone who is responsible for clinical development in a small company. But I was worried about being able to conclusively demonstrate a correlation between this high level of objective response, and I’ll use that loosely. What I mean by that is objectively observable response, uh, evidenced by complete responses in patients. 
All of their disease is gone after PV-10 injections in 50 percent of those patients versus what I knew was very thin data concerning the types of symptoms that the Agency was suggesting should be shown, uh, improvement in. 
And we did our best with that study. Looked at, as I mentioned earlier, pain data, and we were able to draw some supporting evidence to show that there is definitely a trend in pain data that matches the trend in objectively observed response of tumors. 
The Quality of Life EORTC-QL2-C30 instrument, this 30-question questionnaire that’s principally designed for patients with late stage systemic disease maybe that are taking toxic chemotherapy, I had great concerns that that was not going to be valuable because we had already shown in the full analysis for [unintelligible] patients in studies that there were no clear trends evident other that the patients didn’t get worse and that proved to be correct. 
There was nothing that we could extract from that particular instrument. It was a measured risk submitting the application. (4) But again as I mentioned earlier, our logic seemed clearer that if we were making the patients' tumors disappear in 50 percent of the patients that was a very large effect size, and that was tantamount to making any symptoms that they might have been suffering from the tumor burden disappear. (5)
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November 13, 2014. Provectus issued press release Provectus Biopharmaceuticals' Protocol for Phase 3 Study Of PV-10 As Treatment for Melanoma Now Available Online to highlight the publication of its trial protocol on The primary endpoint ("EP") is:
  • Progression-free survival ("PFS") -- a loco-regional disease-oriented EP.
The secondary EPs are:
  • Complete response rate ("CRR") -- a loco-regional disease-oriented EP,
  • Duration of complete response -- a loco-regional disease-oriented EP,
  • Change in total symptom score from baseline using the patient reported Skindex-16 instrument* -- a patient-reported outcome ("PRO"),
  • Overall survival ("OS") -- a distant disease-oriented EP, and
  • Number of participants with adverse events -- loco-regional & distant disease-oriented EP.
Among other aspects of the trial, there was the following cross-over provision:
  • Subjects in the comparator arm who have completed at least 1 cycle of dacarbazine or temozolomide and who meet the study protocol definition of disease progression but do not have evidence of distant cutaneous, subcutaneous, active nodal or visceral metastases will be eligible to enter the crossover portion of the study and receive PV-10.
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January. In January, and just prior to BTD denial, there would have been excitement at Provectus about the potential prospect of an expedited approval path for PV-10. Setting aside the speed of traveling along the path, the issue at hand would have been the path itself. There was agreement on the suitable patient population of PV-10: locally advanced cutaneous melanoma.

The January 24th PR's sentence above (2) implied no Phase 3 trial with OS as a primary EP. Locally advanced melanoma patients have a lengthy life expectancy that makes OS problematic as a primary EP. In addition, National Comprehensive Cancer Network ("NCCN") guidelines indicate "clinical trial" as the preferred treatment option for these patients.

But, the clinical significance of objective response (i.e., complete responders + partial responders) still was unclear to the FDA for these patients, stated in PR's sentence above (1). Since Provectus is attempting to establish new regulatory precedent in melanoma, the PR describes the Agency as advising the company to show them how to establish a link between observable response (such as objective response) and clinically significant change in patients (i.e., reduction of suffering, etc).

The BTD application would have attempted to link observable response metrics to clearly evident symptomatic benefit in sufficient patients to demonstrate preliminary evidence. These patients were the sub-group of 28 who had all of their disease treated in the Phase 2 trial (e.g., see PV-10 delivers greatest effects when all lesions are injected).

Although management thought their available data was compelling at the time, and hoped it also would prove compelling to the FDA as part of a BTD application, they understood further study (i.e., a so-called [but undefined] bridging study) may have been needed (i.e., collected at some point in the future) to provide sufficient evidence to support granting of BTD. Such a study would have served to support BTD, validate EPs to be used in any subsequent pivotal study, and provide crucial supportive safety and efficacy data for a new drug application ("NDA").

Management thus calculated their existing sub-group data may prove sufficiently compelling to the Agency to warrant granting BTD, which if achieved would have afforded Provectus the opportunity to comprehensively and quickly review the PV-10 melanoma development program with senior Agency staff to design efficient clinical demonstration of efficacy.

May. A partially skeptical FDA (from the seemingly multiple personalities of the BTD denial letter) said the subgroup data was not sufficiently compelling, and asked for more data.

Eric said on the conference call it was a measured risk. See May 23rd conference call transcript sentence above (4). His rationale was PV-10 making tumors disappear was tantamount to making patient suffering disappear. See May 23rd conference call transcript sentence above (4).

Shortly after the decision was communicated by Provectus, a shareholder with whom I regularly collaborate on this project conveyed feedback he had sought on the letter from folks who routinely interact with Agency staff on oncology matters. Their (these folks') view was not to read too much into the BTD denial letter, and that the FDA merely was asking for more information (data). The company had the right data, but not enough of it. See the May 16th BTD denial letter sentence above (3).

 Several aspects of the protocol suggest an interesting [to me] description of Provectus' pivotal Phase 3 trial. These are:
  • The use of systemic chemotherapy (intravenous dacarbazine or oral temozolomide) as the trial's comparator. As I noted above, NCCN guidelines indicate "clinical trial" as the preferred treatment option for patients with locally advanced cutaneous melanoma, and not systemic chemotherapy,
  • The above mentioned cross-over set-up that permits switching after only one 28-day (4-week) chemotherapy cycle (and study protocol definition of disease progression, as well as no evidence of distant disease). The first EP assessment period is 12 weeks (4 weeks for the adverse event EP),
  • The anticipation that many (perhaps all) patients in the chemotherapy control arm would not develop distant disease after one cycle, and
  • The confounding of the OS EP, the so-called gold standard of distant disease-oriented EPs, due to crossover. Crossover would have an impact on the measurement of OS, but not PFS, CRR, duration of CR, patient-reported outcomes or adverse events. I have no doubt Eric knows it is unlikely there would be a statistically significant difference in the two arms** given the study size, as the Phase 3 trial does not appear to be powered for survival because there is no way to estimate what any difference might be (in light of crossover). In addition, the trial's patient population comprises Stage III patients with expected lengthy OS.
The above might allow one to describe Provectus' upcoming pivotal Phase 3 randomized control trial for locally advanced cutaneous melanoma as a "single-arm study" collecting more of the right data about PV-10 for the FDA.

As such, I think the trial may be much shorter in duration than expected, and provide the necessary supportive safety and efficacy data for a PV-10 NDA filing.

* The Skindex-16 health-related quality of life questionnaire was utilized in clinical trial work for basal cell carcinoma-approved vismodegib.

** There should be marginal survival benefit between or no statistically difference in the two arms, because the control arm would start out as patients receiving chemotherapy and then transform into the arm of patients who started out on chemotherapy and then switched over to PV-10. Thus, there likely would not be much difference in survival of (i) patients initially receiving PV-10 and (ii) patients receiving, say, 1 cycle or month of chemotherapy and then PV-10. It may be possible, however, to analyze the data for OS by modelling the absence of crossover through rank-preserving structural failure time (see Pfizer, sunitinib, gastrointestinal stromal tumours).

November 12, 2014

"These murine studies support combination therapy with IL PV-10 and co-inhibitory blockade."

Provectus issued a press release, filed an associated 8-K and made available Moffitt Cancer Center's PV-10-related poster from the 29th annual meeting of the Society for Immunotherapy of Cancer ("SITC") Monday. Of the conclusions provided by Moffitt, it struck me the key one was the first:
Moffitt affirmed there is a clinical rationale and value proposition, based on pre-clinical murine model work, to undertake a study (studies) combining PV-10 and each/any of the anti-PD-L1, -PD1 and -CTLA4 therapeutic agents.

❐ Moffitt's initial murine model work investigating PV-10 as a monotherapy -- "Intralesional Injection of Melanoma with Rose Bengal Induces Regression of Untreated Synchronous Melanoma In a Murine Model," Society of Surgical Oncology Annual Meeting, March 2012, and "Intralesional Injection with PV-10 Induces a Systemic Anti-tumor Immune Response in Murine Models of Breast Cancer and Melanoma," American Association for Cancer Research Annual Meeting, April 2013 -- demonstrated:
  • Regression in both injected and un-injected melanoma tumors,
  • Anti-tumor immunity (T-cell generation & activity), and
  • Increased survival (in mice).
❐ Moffitt followed up their mousie work with a human feasibility study of PV-10 as a monotherapy -- "Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions," American Society of Clinical Oncology Annual Meeting, June 2014 -- that demonstrated:
  • Regression in both injected and un-injected melanoma tumors, and
  • Anti-tumor immunity (T-cell generation & activity).
❐ Moffitt continued their murine model work investigating PV-10 in combination with each of three categories of checkpoint inhibitors (anti-PD-L1, -PD1, -CTLA4) -- "Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma," Society for Immunotherapy of Cancer Annual Meeting, November 2014 -- that demonstrated:
  • Regression in both injected and un-injected melanoma tumors,
  • Anti-tumor immunity (T-cell generation & activity), and
  • Increased survival (in mice).
All of Moffitt's work, murine and human, involved a single intralesional injection of PV-10 per injected lesion. It would appear what Moffitt is doing with PV-10 the way they are doing it is procedural, meaning the cancer center is trying to better understand PV-10's tumor-specific immunity with scientific experimental methods, rather than with specific clinical or clinically translational approaches at this time. Ultimately, it seems Moffitt wanted to know if PV-10 worked, found out it did, then wanted to know how well it worked, and then found out how much it did -- as a single agent, and in combination with other agents.

All Moffitt posters -- SSO 2012, AACR 2013, ASCO 2014, SITC 2014 -- have been exclusively co-authored by Moffitt researchers/employees. It is interesting to note Provectus, it appears, freely allowed the cancer center to undertake this work without, it would seem, involvement or interference. I imagine the company, in addition to providing PV-10 drug product to Moffitt, compensates or pays or contributes funding to the cancer center and/or researchers in some form or fashion, like other biopharmaceutical companies do.

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The Methods section of Moffitt's SITC 2014 poster was sparse on experimental method detail, as was the Methods section of their AACR 2013 poster. As such, we will have to wait for an/the associated peer-reviewed paper that would describe the method(s) of the SITC work (as their 2013 PLOS One paper did for the AACR poster and work); specifically, the modifications the cancer center made to their PV-10 injection approach (contrasted with the AACR work's approach) to elicit and elucidate the value of PV-10 in combination with checkpoint inhibitors.

The 2013 "monotherapy" poster/paper appeared to show relatively greater interferon gamma production relative to control than the 2014 "combination therapy" poster did. PV-10's propensity to completely destroy and/or dramatically reduce injected and un-injected tumors -- the subject of Moffitt's August 2013 Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows press release-- must have required modifications to the experimental design in order to facilitate the combination therapy murine model work (i.e., don't kill the tumor completely but "partially kill" it so as to observe and measure the subsequent effect of a checkpoint inhibitor on PV-10-damaged-but-not-destroyed-tumor), such as treating part of a large tumor, reducing PV-10 dose per volume, or diluting the concentration of the drug.

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Peter noted in the company's third quarter 10-Q:
We also have begun to consider co-development transactions with one or more pharmaceutical or biotech companies to combine PV-10 with immunology agents such as those referred to as immune checkpoint inhibitors...Furthermore, the strategy of the Company for the benefit of stockholders is a series of partnerships followed by an acquisition of the Company along the lines of Celgene-Abraxis, although there can be no assurance that such partnerships or acquisition will occur. An interim transaction could be a co-development deal like Roche-NewLink, Bristol-Celldex or AstraZeneca-Incyte. {Underlined emphasis is mine.}
NewLink published preclinical combination study work (their drug + anti-PD1/PD-L1 antibodies) at AACR 2014 (April)*, co-conducted by NewLink employees and Georgia Regents University Research Institute researchers/employees.
* "The current preclinical studies suggest a mechanistic rationale for a combining IDO pathway
inhibitors with agents targeting the PD-1/PD-L1/PD-L2 pathway."

Celldex published preclinical combo work (their drug + checkpoint blockade therapies) at SITC 2013 (November)*, conducted by Celldex employees.
* "These the initiation of combination trials with conventional and immune-based therapies."

Incyte filed a protocol for combining its subject drug with Bristol-Myers' anti-CTLA-4 agent Yervoy in 2012. From what I can gather (and I may be wrong) the trial of the combination therapy was initiated alone by Incyte (I cannot find any publication of preclinical work that may have preceded this trial). At an ASCO 2014 presentation of a Phase 1/2 melanoma study, principal investigators (that included Moffitt Cancer Center's Dr. Jeffrey Weber, M.D., Ph.D.) noted "[p]reclinical data support antitumor synergy for INCB024360 when administered with an antibody antagonist to checkpoint receptors," referencing a October 2013 (submitted)/February 2014 (published) SITC journal paper* (the paper, however, does not present preclinical combo work on the subject drug but another related Incyte compound), co-conducted by Celldex employees and the University of Chicago researchers/employees
* "These three combinations are attractive to pursue clinically..."
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Provectus published preclinical combination study work (PV-10 + anti-CTLA-4 mouse antibodies) in April at AACR 2013. Moffitt published their preclinical combination study work (PV-10 + anti-PD-L1, -PD1, and -CTLA4) in November at SITC 2014, of course.

The company should have sufficient data to establish the rationale for a combination study with a Big Pharma partner:
  • Preclinical from Moffitt's poster, and additional material not included on it,
  • Clinical, perhaps, and in context, from Moffitt's human feasibility study ("Six of 8 patients had metastatic disease refractory to previous ipilimumab, anti-PD-1 and/or vemurafenib therapy"), and
Arriving at an agreement on business terms of a so-called co-development deal is/will be another story; however, this information should be the hard data of PV-10's immunological activity (most of it generated independently of Provectus by Moffitt) that may facilitate a discussion, or two, with Big Pharma.