October 18, 2014

"PV-10 delivers greatest effects when all lesions are injected"

The title of an article published this week by medical writer Janet Fricker, who has written several times about PV-10, provided a cogent description of the drug's value proposition for its patient population afflicted with melanoma, and, eventually, I believe, for all solid tumor cancers: PV-10 delivers greatest effects when all lesions are injected, which discussed Provectus' completed Phase 2 trial data presented at ESMO 2014.

Because PV-10 is very safe, the more you give, the more you get. No dose limiting toxicity.

The article frames what might be expected from the upcoming pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma, in large part because of the trial's design whereby all lesions will be injected:
"The latest analysis reported at ESMO reveals that the subgroup of 28 patients who had all their lesions injected achieved a progression free survival of 9.8 months compared to 6.0 months for the seven patients who had a median of five untreated lesions. “The progression free survival of 9.8 months compares favourably with historical progression free survivals of less than 2.5 months for DTIC/TMZ,” commented Sanjiv Agarwala, the first author from St. Luke’s Hospital and Health Network, Bethlehem, Pennsylvania." {Underlined emphasis is mine}
The more lesions into which PV-10 is injected ("the more you give"), the more antigens are created and released, the more antigens then are presented, the more the immune system then is primed and activated, the more T-cells then are trafficked to tumors, the more T-cells then infiltrate tumors, the more cancer cells then are recognized by T-cells, and the more cancer cells finally are killed ("the more you get").

No dose limiting toxicity. PV-10 can deliver its greatest effect because it can be injected into all lesions until they (and occult cancer cells) go away.

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Provectus made a Form D filing on October 15th related to a possible financing of up to $15 million through Network 1 Financial Securities. I previously wrote about this two weeks ago. See Fundraising (October 3, 2014) and Fundraising -- Updated (October 4, 2014) on the blog's News page. The filing noted: "Sales in the offering will be staged incrementally at the sole discretion of the Company."

It has been said the company could require additional cash to meet requested or demanded requirements of the New York Stock Exchange and/or Provectus' accounting firm BDO. Be that as it may, Provectus concurrently is trying to close a regional license transaction with Chinese pharmaceutical distributor Sinopharm and garner sufficient payment at the signing of a definitive agreement in order to obviate the need to raise money via Network 1.

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A deal structure that potentially may provide insight into Provectus' discussions with Sinopharm is Celsion's 2013 license deal, ultimately not consummated, with Zhejiang Hisun Pharmaceutical Company ("Hisun) for China. This deal was constructed as:
  • $25 million at signing of a definitive agreement (Celsion previously received $10 million from two payments, which then were credited against the signing amount),
  • $55 million in upfront milestone and regulatory milestone payments over 18 months,
  • $45 million in sales target milestone payments, and 
  • Escalating double-digit sales royalties over ten years.
Because no further or amended Form D filing has been made as of this writing (to disclose Provectus took in money from the above mentioned offering), I assume Peter is able to "hold off" the NYSE and/or BDO for a period of time until he can ascertain what cash he would receive from Sinopharm upon signing of a definitive agreement (should such a license transaction be completed).

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St. Luke's Cancer Center's Dr. Sanjiv Agarwala, M.D. is presenting at 5:30 pm local time (5:30 am EST) on October 18th (today) at the 2014 Beijing International Melanoma Congress. See 2014 Beijing International Melanoma Congress (October 7, 2014) on the blog's News page. An interview with Peter conducted by BioMedReports, which discussed the Provectus-Sinopharm memorandum of understanding, was published on October 16th. I very much dislike Provectus raising this topic beyond the initial press release of August 18th (much like they repetitively mentioned their breakthrough therapy application earlier this year). Nevertheless, the interview, likely conducted this week, and proximate to Dr. Agarwala's presentation, at which I imagine Provectus principals and/or advisors should be in attendance, contained some noteworthy items, among them:

"We will be able to assign the license agreement and will control the supply chain unless we agree to do otherwise." Being able to assign the license to an end-game acquirer is an important Provectus-Sinopharm contract item. Under what circumstances would Provectus agree to relinquishing supply chain control? I would think Provectus would consider this only in the context of Big Pharma discussions about a transaction for the company, and only in conjunction with a global partner that has an existing (e.g., Pfizer's 2012 national retail strategic cooperation framework agreement) or planned partnership with Sinopharm.

"Also, PV-10 as an anti-tumor agent that is injected is very appealing to the China and India patient population and their caregivers."

Peter also replied, in answer to the question of what is the object PVCT has in doing business in Asia: "For our signature drug, PV-10 to treat liver cancer, most of the liver patients are in Asia versus the US or Western Europe." I think it's obvious the Chinese, in this case Sinopharm, are more interested in seeing or confirming the final and/or filed liver protocol for a Provectus Phase 2 liver trial than they would be in a filed protocol for the Phase 3 melanoma trial.

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Returning to the Celsion deal structure, it seems to me the nature of the discussions and negotiations between Provectus and Sinopharm probably now revolve around how much of near-term money is available (from Sinopharm) to be paid (to Provectus) at (i) signing of a definitive agreement and (ii) upon checking of whatever box(es) to be deemed an upfront payment. This matters for both substantive and cosmetic reasons. For example, more money sooner is better than the same money later...duh. More money sooner makes a bigger splash. All of this assumes the other compoents of the deal structure are sufficiently good.

Ultimately, Provectus shareholders want management to close a good deal that is well structured, and not contrived. Management has not reached for nor agreed to [very likely informal] deal offers in the past that poorly valued their innovation. I do not expect them to start settling now.

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On October 15th the company issued another press release about Moffitt's presentation at the annual meeting of SITC in early-November, and filed an associated 8-K. Of note was the comment Moffitt's poster will be available and presented at two sessions, during the regular poster viewing one and at an evening Presidential reception. In addition, Craig's obligatory quote contained a couple of potentially notable words and phrases, which I hope ultimately are indeed notable.
“Dr. Pilon-Thomas and her team at Moffitt have been doing very interesting work assessing the potential combinations of PV-10 with immune checkpoint inhibitors for melanoma. Their work may be an important step forward as part of our corporate strategy for addressing unmet need in late stage melanoma patients and in other uses of PV-10.” {Underlined emphasis is mine}
I suppose “very interesting” means unprecedented and unique in scientific parlance? Does “other uses” means other indications (like breast cancer, which was included in Moffitt's AACR 2013 poster: Intralesional Injection with PV-10 Induces a Systemic Anti-tumor Immune Response in Murine Models of Breast Cancer and Melanoma)?

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Finally, in a press release and associated 8-K filing on October 16th Provectus confirmed Dr. Agarwala's presentation of PV-10 clinical data and value proposition (as a monotherapy and in combination) as part of a satellite session sponsored by Amgen and titled “Oncolytic immunotherapy – engaging the immune system to target melanoma” on November 15th at the 11th International Congress of the Society for Melanoma Research in Zurich, Switzerland. See Melanoma Congress 2014 (October 15, 2014) on the blog's News page.

Dr. Agarwala's continues his three-month world tour of Spain (September 28th), Russia (October 12th), China (October 18th) and, now, Switzerland (November 15th). Medical oncologist Agarwala may see the potential opportunity to enhance his position as a global key opinion leader with the success of PV-10 as a monotherapy for earlier stages of disease.

Medical oncologist and Moffitt Cancer Center's Dr. Jeffrey Weber probably sees the potential opportunity to further enhance his position as a global key opinion leader responsible for translating investigational compounds into approved drugs with the success of PV-10 in combination with immune checkpoint blockade (inhibitors) for late stage disease. That, however, is for a later discussion and debate once we learn more about Moffitt's presentation and data at SITC 2014 on November 8th.

October 14, 2014

The Immune Checkpoint Inhibitor Global 4 (or 5)

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

Players (2013 ranking by oncology sales) in the checkpoint inhibitor space include:
  • Bristol-Myers (#9): CTLA-4 (approved ipilimumab/Yervoy), and PD-1 (approved internationally nivolumab/Opdivo),
  • Merck & Co. (#8): PD-1 (approved pembrolizumab/Keytruda),
  • Roche (#1): PD-L1 (investigational MPDL3280A), and
  • AstraZeneca (#7): PD-L1 (investigational MEDI4736).
Farther behind, it seems, is Novartis (#3): PD-1 (potential candidates via its CoStim acquisition). It could be late for Novartis to bring a checkpoint inhibitor to market. By the time it gets its version out, Novartis should have four competitors with similarly functioning drugs.

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

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

For example:
  • Pfizer (#11): Merck's PD-1 + targeted therapy (crizotinib/Xalkori),  + targeted therapy  axitinib/Inlyta), and + 4-1BB co-stimulatory agent (PF-05082566), 
  • Amgen (#2): Bristol-Myers's CTLA-4 + intralesional (tamilogene laherparapvec or T-Vec), and Merck's PD-1 + intralesional (T-Vec),
  • Celgene (#4): Bristol-Myers' PD-1 + targeted therapy (paclitaxel/Abraxane), and
  • Novartis (#3): In addition to PD-1s and CAR (chimeric antigen receptor)-T cell therapy, Bristol-Myers' PD-1 + [separately] three targeted therapies (ceritinib/Zykadia, INC280, and EGF816).
SugarCone Biotech's Paul Rennert, in his September 2014 blog post Rational Immunotherapy Combinations: How’s That Work Again?, wrote about "...the question of how to parse the potential immunotherapy combinations that may soon become available, noting that different combinations may prove differentially useful across a wide range of oncology indications." His post is very informative. It is a not-so-simple process to understand and develop the appropriate rationale for why, what and how one combines different agents and therapies, as he clearly illustrates in a cursorily-populated table:
Click to enlarge.
Rennert goes on to write (where I look past his use of vaccines to the broader issue of how to generate many more antigens in order for PD-1s and PD-L1s to be more successful in their individual efforts towards the combination):
"There are other consequences in this new landscape. Nearly every oncology vaccine company claims that as soon as they run a combo trial with an anti-PD-1 or anti-CTLA4 antibody their particular vaccine approach will perform beautifully. There are a few problems with this, notably, very few of these companies have a chance in hell of getting an anti-PD-1 antibody via collaboration, and the rest will pay heavily for the privilege. Second we have no idea of how to rationally pair vaccines with immune checkpoint exposure in order to induce optimal responses. Third, there are not enough patients to go around, a simple fact in many indications."
As recent as the company's ESMO 2014 poster Provectus highlighted the combination study aspect of its business/corporate development strategy.
Click to enlarge.
The value proposition/rationale (but not necessarily the specific medical and scientific rationale and sequencing) for combining PV-10 with a checkpoint inhibitor seems straightforward:
  • Immune checkpoint inhibitors have been and will be combined with intralesional agents. Thus far, Bristol-Myers & CTLA-4/ipilimumab/Yervoy and Amgen's T-Vec, Merck & PD-1/pembrolizumab/Keytruda and T-Vec. As expected, the combination of ipilimumab and T-Vec produced responses rates higher than the individual treatments themselves (ASCO 2014). That is, Response_A+B > Response_B > Response_A (A = ipilimumab, B = T-Vec).
  • The combination produced notable immunologic signaling. This also was reported from the CTLA-4/ipilimumab and T-Vec combination study at ASCO 2014. The greater the immunologic signaling, the greater [one would imagine] the response and interaction of the immune system to fight and hopefully beat cancer. That is, perhaps, Signaling_A+B > Signaling_B > Signaling_A. The poster presented at ASCO of this work only conveyed the immunologic signaling of the combination.
  • PV-10 kills tumors far better than T-Vec. PV-10 produce higher complete responses than T-Vec. The medical community has understood for a while the more antigens produced and presented as a result of tumor destruction (antigenization) the more likely the potential of a greater immune response by the body.
If T-Vec works, PV-10 should work better. But, how much better?

Dr. Agarwala noted in his October 12th presentation at the III Eurasian Melanoma and Skin Cancers Forum that intralesional therapies (PV-10 and T-Vec, since Allovectin-7 failed its metastatic melanoma Phase 3 trial) would form the backbone of combination therapies.
Click to enlarge.
The challenge for Big Pharma, perhaps for some of them more than others, is the lack of "hard data" about PV-10's strong immunologic properties. Presumably Moffitt Cancer Center's presentation on November 8th -- Coinhibition and Costimulation: Targets and Strategies session, Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma poster -- will provide it.

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

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

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

Second, how would Big Pharma and Provectus rationally pair immune checkpoint blockade with PV-10? Moffitt's upcoming SITC work presumably should begin to describe how to rationally pair, and dose and sequence PV-10 and a checkpoint inhibitor. It seems the immune system primer & activator/cancer antigen releaser should be given first, followed by the checkpoint inhibitor. In the ipilimumab + T-Vec trial noted above, the investigators sequenced the drugs in that way:
T-VEC was given intralesionally at week 1, week 4, and then every other week. Ipilimumab was given every third week starting at week 6. Treatment continued until dose limiting toxicity, intolerance, all injectable tumors disappeared or disease progression.
I think Rennert's larger question is the whys of rationally pairing drugs, before getting around to the hows. I liken it to understanding what step or steps of the cancer immunity cycle each drug partner in a combination promotes.

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

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

October 8, 2014

"The few injections needed in this study bode well for patient compliance with PV-10 treatment"

Three articles about Provectus' PV-10 and other investigational drug clinical data presentations from ESMO 2014 were published this week.
  1. Melanoma treatment PV-10 shows promise in phase 2 trial, Dermatology Times online, Bill Gillette, October 6, 
  2. Melanoma studies dominate ESMO, Medical News Today online, Janet Fricker, October 7, and
  3. Intralesional injections show promise for cutaneous melanoma, eCancer News online, Janet Fricker, October 7.
Dermatology Times
“The results of this study provide evidence of a safe and effective intralesional treatment for patients with melanoma metastatic to cutaneous and subcutaneous sites, with a pronounced local and, in addition, systemic effect,” Dr. Agarwala tells Dermatology Times. “It also has the potential to be combined with recently approved systemic immunotherapies that will be the focus of future clinical trials.”
MNT
"The progression-free survival of 9.8 months compares favorably with historical progression-free survivals of less than 2.5 months for DTIC/TMZ," said Sanjiv Agarwala, the first author from St. Luke's Hospital and Health Network, Bethlehem, PA. Such data, he added, suggests PV-10 will deliver significant progression-free survival effects in the phase 3 study, due to start Q4 2014. "The abstract also shows us that we're likely to get the highest responses when all lesions are injected." {Underlined emphasis is mine}
eCancer News
“The few injections needed in this study bode well for patient compliance with PV-10-treatment,” said Eric Wachter, Chief Technology Officer of Provectus.
Clinical data from Provectus' metastatic melanoma Phase 2 trial has been presented at six major oncology conferences, most recently ESMO 2014, which is the setting of the above articles:
  • ASCO 2009, Chemoablation of Melanoma with Intralesional Rose Bengal (PV-10),
  • ASCO 2010, Chemoablation of Melanoma with Intralesional Rose Bengal (PV-10),
  • ESMO 2012, Immuno-chemoablation of metastatic melanoma with intralesional rose bengal,
  • ECCO 2013, Locoregional Disease Control in Metastatic Melanoma: Exploratory Analyses From Phase 2 Testing of Intralesional Rose Bengal,
  • ASCO 2014, Efficacy of intralesional rose bengal in patients receiving injection in all existing melanoma in phase II study PV-10-MM-02, and
  • ESMO 2014, Subgroup Efficacy in Patients Receiving Intralesional Rose Bengal to All Existing Melanoma in Phase II Study PV-10-MM-02.
The theme, from the beginning (ASCO 2009) through today (ESMO 2014), has been defeating or controlling the disease [of melanoma] at Stage III to prevent its spread and metastasis to Stage IV by hitting (injecting) all of the disease (all disease burden, or every accessible tumor/lesion).
Click to enlarge. ASCO 2009
Click to enlarge. ESMO 2014
Click to enlarge. ASCO 2009
Click to enlarge. ESMO 2014
Some would say Provectus' mined* its metastatic melanoma Phase 2 clinical trial data, and/or flogged it to death. A simple counter would be that medical conferences could have said no to each subsequent abstract from and data representation from by the company (although that does not absolve Provectus' principals from not have generating different and more clinical trial data to date).

With the understanding overall survival beyond one year was not among the study's data collection goals, the Phase 2 melanoma data eventually presented a clear picture of how to most efficaciously utilize PV-10 in the most advantaged patient population: Treat all disease burden (put another way: treat patients whose only disease is all and entirely accessible).

Rearranging the contents of the ESMO 2014 table above in a different way, with some different labels* of my own...
Click to enlarge.
...yields the graph below:
Click to enlarge.
What projection of results might one reasonably infer for Provectus' pivotal Phase 3 trial for locally advanced unresected cutaneous melanoma when all lesions (all disease burden) are continuously for 12 weeks before initial comprehensive disease assessment?
Click to enlarge.
Eric's quote regarding minimal PV-10 injections facilitating patient compliance is an important aspect of the drug's value proposition in a clinical (outpatient) setting. While easy to administer for the physician (or nurse practitioner), fewer injections (such as, typically, 1 or 2) also should be easier for the patient to accept.

* Mining data in the negative sense: Finding data to fit an already-decided conclusion

** Without total numbers of treated and untreated lesions per grouping, while "All" means 100%, it is hard to quantify "Most," "Some" and "Not enough."

October 4, 2014

“We should see a difference very quickly between PV-10 and chemotherapy responses”

Medical writer Walter Alexander, who has written several articles and stories about Rose Bengal, PV-10 and Provectus (such as here, here and here), penned another article, Cutaneous, Locoregional Melanomas Show High, Rapid Responses to Injection With Rose-Bengal Solution: Presented at ESMO Congress (October 2, 2014). I found the following noteworthy and repeating.
Intralesional injections of PV-10 accumulate rapidly in tumour lysosomes, causing lysosomal rupture within 30 to 60 minutes and subsequent tumour-cell rupture, noted lead investigator Sanjiv Agarwala, MD, St. Luke’s University Hospital & Health Network, Bethlehem, Pennsylvania, speaking here at a poster session on September 28. Research has shown subsequent tumour-specific T-cell responses to occur within 7 days, he added. {Underlined emphasis is mine. 
 I added the illustration below from Provectus' ESMO 2014 poster for effect.
Click to enlarge.
In the All Lesions Treated group, 121 complete responses were observed after 1 injection, 84 complete responses after 2 injections, 22 complete responses after 3 injections, and 5 complete responses after 4 injections. 
I added the illustration below from Provectus' ESMO 2014 poster for effect. Note the drug's 74% complete response, and that PV-10 was last allowed at week 16. In Amgen's talimogene laherparepvec's ("T-Vec's") pre-specified retrospective analysis of tumor-level responses from its pivotal Phase 3 trial, T-Vec achieved 47% complete response (almost 4000 lesions were included in the analysis).
Click to enlarge.
Progression-free survival in the All Lesions Treated group was 9.8 months. In the uninjected Bystander Lesion group from the original trial, progression-free survival was 8.9 months.
I added the illustration below from Provectus' ESMO 2014 poster for effect. Note PFS calculations are consistent with RECIST 1.1.}
Click to enlarge.
“We should see a difference very quickly between PV-10 and chemotherapy responses,” Dr. Agarwala added.
From my news item How much is enough, and when? (September 16, 2014): In the upcoming Phase 3 trial Provectus will measure PFS as the trial's primary endpoint, utilize RECIST 1.1 to measure it, and inject patients every two weeks until CR or PD is achieved (i.e., the duration of the treatment interval will be until one of the two outcomes is achieved). It then could be reasonable to project a PV-10 arm PFS of 12 months for a 12-month observance period, 9 months for a 9-month period, 6 months for a 6-month period or 3 months for 3-month period -- where, at best, the PFS and its confidence interval are the same line, or, at worst, the CI is a narrow band around the PV-10 PFS figure, which itself would be a horizontal line at 1.0 or 100%. Thus, patients with all of their disease treated by PV-10 would never progress, while patients in the control arm (those treated with DTIC or TMZ) would suffer progression as historically demonstrated through prior use and over many previous clinical trials.
Click to enlarge.
Approximately 1 third of patients with melanoma are diagnosed with predominantly locoregional disease.
From my news item PV-10 is tantamount to surgery? (September 5, 2014): The silent masses who make up the bulk of patients with melanoma (and the much larger addressable market), however, remain without effective options:
Click to enlarge.
SEER Stat Fact Sheets: Melanoma of the Skin, National Cancer Institute

September 29, 2014

Provectus' ESMO 2014 poster (Updated)

A blog post about Provectus' abstract at the 2014 European Society for Medical Oncology Subgroup efficacy in patients receiving intralesional rose bengal to all existing melanoma in phase II study PV-10-MM-02, may be found here. The poster was presented yesterday in Madrid, Spain. The company's press release on it and the associated 8-K filing are here and here, respectively. The focus of the ESMO poster, as with the ASCO poster, was the subgroup All Melanoma Followed of the metastatic melanoma Phase 2 trial highlighted in yellow below, and the two sub-subgroups Bystanders Untreated and All Lesions Treated. The abstract initially stated:
"The high rate of symptom control in refractory patients, manifest in CR of injected lesions after minimal intervention, was the basis for a breakthrough therapy designation application to the US FDA based on the 28 patient “all treated” subgroup..."
The poster notes Provectus is working with ERT to address the measurement and reporting of patient reported outcomes ("PROs"), a secondary endpoint of the upcoming pivotal Phase 3 trial.
The abstract also stated:
"...and implications of the Agency’s ruling on this application will be presented."
These implications appear to be the enablement of the Phase 3's study design through, per the poster:
  • "Facilitating dialog with regulatory authorities on patient population and endpoints
  • Suggesting a substantial PFS advantage for PV-10 over historical data on comparator
  • Enabling optimization of PV-10 dose schedule"
Changes in the Phase 3 trial design in the ESMO poster compared to the ASCO one include:
  • An estimated sample size of 219 (compared to 210),
  • Four week treatment cycles (PV-10 or DTIC/TMZ) during initial 12 week treatment phase (compared to three week), and
  • [From a poster perspective] the reordering of secondary endpoints placing patient reported outcomes ("PROs") above overall survival ["OS"] (compared to OS above PROs)
The poster also teased the upcoming Moffitt murine model work to be presented on a poster at SITC in November (sub-titled in the ESMO poster's conclusion PV-10 with Immune Checkpoint Blockade for Widely Metastatic Disease):
  • "Emerging immunology data supports T-cell mediated tumor-specific response secondary to PV-10 ablation
  • Data to be presented in November on IL PV-10 in combination with immune checkpoint blockade in melanoma models may indicate clinical studies are warranted
  • Design of a Phase 1b/2 combination study is underway"
Contrast the ESMO 2014 poster conclusion below...
Click to enlarge.
...with the ASCO 2014 poster "Path Forward" section below.
Click to enlarge.
Updated 9/30/14: There are several aspects of the poster/press release that warrant further discussion, and they appear cleanly identified by the PR's four quotes.
PR quote #1: Commenting on the poster, Dr. Agarwala said, "Although the primary ablative effect of PV-10 can lead to rapid regression of injected lesions, durability of response may signal the effects of an immunologic process secondary to ablation. In addition to offering the potential to relieve symptoms of cutaneous melanoma, a robust, tumor-specific immunologic response could have the potential of changing the course of the disease." {Underlined emphasis is mine.}
Dr. Agarwala, from St. Luke's University Hospital/St. Luke's University Health Network of Bethlehem, Pennsylvania, addresses two points. First, he notes the durability or length of PV-10's response on lesions following injection (noting the last allowed injection was at week 16). Durability and durable benefit should materially contribute to long-term survival and benefit. The associated poster portion is below.
Click to enlarge
Second, Agarwala addresses both components of PV-10's two-step mechanism of action, (a) rapid ablation and (b) immunomodulation. The associated poster portion is below.
Click to enlarge.
In each case, his comments contextualize cutaneous melanoma -- the most common type of melanoma -- and PV-10's role in defeating or containing it. Defeat would come through complete response. The FDA, however, wanted, at the time of breakthrough therapy designation ["BTD"] application, and wants, via the upcoming pivotal Phase 3 trial, the association (correlation) between complete response and symptom control more fully elucidated. Containment comes through demonstrating that if you truly effectively treat disease in Stage III (or, of course, earlier or much earlier), it forestalls or prevents it from progressing to Stage IV. See blog post Treating Cancer, and news item How much is enough, and when? (September 16, 2014).
Quote #2: Eric Wachter, PhD and Chief Technology Officer of Provectus, said, "We are very pleased to share the patient-level PFS data at ESMO that defined our design parameters for the upcoming phase 3 trial. These study results demonstrate the potential of an intralesional approach to delay progression while alleviating symptoms of locally advanced melanoma." {Underlined emphasis is mine.}
The underlined sentence above asserts the clinical value proposition of PV-10 as appropriate for the treatment of local disease, the vast majority of the melanoma market and comprised of the silent masses for which surgery, chemotherapy, etc. are their only options.
Quote #3: Wachter continued, "We are looking forward to initiation of the phase 3 trial and have assembled an experienced multi-disciplinary team to help us execute this important study. For example, we are thrilled to collaborate with ERT, Inc., experts in quantifying patient reported outcomes for pivotal oncology trials, and expect this collaboration to help place Provectus at the forefront in the study of cutaneous symptoms of locally advanced melanoma." {Underlined emphasis is mine.}
It seems to me the secondary endpoint of PROs is quite important for this patient population indicating cutaneous symptoms of locally advanced melanoma, and is addressed by Agarwala and Eric. Interestingly, and I suppose not the least bit ironically, there does not appear to be medical literature that tabulates and documents that if you stop melanoma at Stage III (when, generally speaking, if you effectively and comprehensively treat the patient you can save him or her) it won't progress to Stage IV. Potential innovational cancer drug treatment progress like PV-10 still seems to boil down to having to show that effective local treatment (where the treatment does not have to be systemic) can be a good thing. It would seem only Provectus is doing this approach of studying cutaneous symptoms in relation to ablation, and ultimately having the goal of showing when disease (melanoma) is ablated in Stage III it is forestalled from getting to Stage IV.
Quote #4: Wachter concluded, "[i] The data presented at ESMO were fundamental in allowing us be in a position to commence pivotal testing of PV-10 in locally advanced melanoma patients. [ii] Furthermore, understanding the bystander effect is critical to rational combination of PV-10 with systemic drugs in patients with significant disease inaccessible to intralesional injection, and [iii] we look forward to seeing additional data on this important topic in coming months." {Parenthetical numbering is mine.}
i. I presume this sentence refers to implications in the abstract where Provectus wrote (see underlined emphasis below): "The high rate of symptom control in refractory patients, manifest in CR of injected lesions after minimal intervention, was the basis for a breakthrough therapy designation application to the US FDA based on the 28 patient “all treated” subgroup, and implications of the Agency’s ruling on this application will be presented." The FDA's BTD denial letter referenced a determination "...based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding)..." According to the portion of the ESMO poster below (this portion also was part of the company's ASCO 2014 poster), only 13 patients in the All Melanoma Followed (N=54) provided trackable data related to symptomatic status. How many of the subset of this group, All Lesions Treated, the basis for the BTD application, provided trackable symptomatic information? In hindsight, the answer was not enough. Eric understood it to be a "measured risk" (a phrase from the company's May 23rd conference call) to submit for BTD without enough symptomatic data; however, as he said on the same call, "...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."
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ii. The bystander effect represents PV-10's immunologic activity, locally in terms of (a) locoregional blistering, which Provectus believed "...may be indicative of nascent local immunologic response" (ECCO 2013) and, I believe, (b) pathologic complete response (ASCO 2014), where presumably even occult cells are destroyed, and systemically. Understanding this immunologic activity, in terms of the steps of the cancer immunity cycle that PV-10 promotes, and seeing more data will be key to the interest of Big Pharma wishing to combine their immune checkpoint inhibitors with PV-10. As the global development team leader of an immune checkpoint inhibitor said to me: "I'm not familiar with hard data on PV-10 having strong immunologic properties...However, if [it] does generate significant anti-cancer immune responses that are inhibited by [their immune checkpoint inhibitor], then such a combo could make sense."

iii. Teasing Moffitt Cancer Center's presentation at SITC 2014, and possible related data publication(s) prior to this conference.

September 21, 2014

Co-stimulatory & Co-inhibitory

Moffitt's PV-10 presentation at the 2014 annual meeting of the Society for Immunotherapy of Cancer ("SITC") is entitled Efficacy of intralesional injection with PV-10 in combination with co-inhibitory blockade in a murine model of melanoma (see Moffitt @ SITC (September 19, 2014) on the blog's News page).

Earlier this month, one of the SITC presentation's co-authors and Moffitt assistant professor and researcher, Dr. Shari Pilon-Thomas, Ph.D., co-authored an online OncLive article entitled Immunotherapy Combined With Chemotherapy for Pancreatic Cancer: A Game Changer? (see blog post Treating Cancer). In it Dr. Pilon-Thomas and her fellow authors write:
Of note, the immune system’s involvement in cancer development and progression has sparked much interest in recent years. The model of the cancer-immunity cycle suggests an interplay of immune-suppression and immune-stimulation. In normal individuals, a state of immunosurveillance is in place. However, within the tumor microenvironment, inhibitory signals and immunosuppressive cells are present and tip the scale in favor of immune suppression. {Underlined emphasis is mine}
Continued: The idea of the cancer-immunity cycle proposes that, for a cancer immune response to be generated, the net balance between immune stimulation versus immune suppression must be tipped in favor of the former. Studies in various cancers have suggested that tumors evade the immunogenic process mostly by factors that promote immunosuppression. {Underlined emphasis is mine}
The theory of immune surveillance suggests, according to Peggs et al., "...that the immune system plays a key role in suppressing tumor growth and that the incidence of cancer would be much greater were it not for the ability of the immune system to identify and eliminate nascent tumor cells...While the immune system appears capable of eliminating or containing early tumor growth, some tumor cells escape detection and eventually cause cancer." Said another way, when thinking about the growing potential role and promise of cancer immunotherapy, "...we continually develop malignant cells every day that are consumed by the immune system to prevent tumor development, and the immunotherapy drugs seem to target the failure of immune recognition and immune response" (Dr. Peter Salgo, M.D.).

The balance between co-stimulation and co-inhibition is described by Inman et al.: "If sufficient co-stimulation is provided in the presence of adequate tumor-associated antigenic stimulation, the immune system will act against tumor antigen and, thus, destroy early tumors before they become fully established. Contrarily, if co-inhibitory signaling dominates, the immune system will be tolerized to tumor antigens, and the tumor will be permitted to grow unfettered and unmolested by the immune system. If neither co-stimulatory nor co-inhibitory signals dominate, the adaptive immune system may remain in a tenuous state of equilibrium, militating against tumor outgrowth with varying degrees of success."

So, it would seem to me, generalizing (or simplifying, perhaps too much):
  • If co-stimulation > co-inhibition, the immune system can act decisively against cancer,
  • If co-inhibition > co-stimulation, cancer overwhelms the immune system and renders it ineffective or useless, and
  • If co-stimulation = co-inhibition (that is, some sort of equilibrium state), the immune system wages battles against cancer to varying degrees of success with potentially no ultimate resolution to the war itself.
[Daniel] Chen & Mellman (2013), authors of Oncology Meets Immunology: The Cancer-Immunity Cycle, note stimulatory and inhibitory factors at step of the cycle.
Click to enlarge. Figure 2 (above) of [Daniel] Chen et al.'s article.
The authors write:
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.
[Daniel] Chen et al. then note "[t]he numerous factors that come into play in the Cancer-Immunity Cycle provide a wide range of potential therapeutic targets."
Figure 3 (below) "...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."
Click to enlarge. Figure 3 (above) of [Daniel] Chen et al.'s article.
In my illustration below, found on the blog's PV-10, and the Cancer Immunity Cycle, I endeavored to show Provectus' drug promoted steps 1, 2, 3 and 7. I believe, but with no confirmation of course, Moffitt has shown via primarily their murine model work (and maybe their human study) that PV-10 promotes steps 4, 5 and 6.
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I revised my table of combination study deals to reflect [as I think they are] stimulatory and inhibitory compounds is below.
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Pilon-Thomas et al. concluded (note the article discussed immunosurveillance in the context of chemotherapy, immunotherapy and pancreatic cancer):
The cancer-immunity cycle is an ideal model to envision how tumor cells evade immuno-surveillance as well as where future modalities may intervene with hopes of potentiating tumor cell death. The cancer-immunity cycle together with the immune-modulating functions of chemotherapies that are used in pancreatic cancer creates a rationale for investigating vaccine-chemotherapy combinations. 
Studies to date have suggested benefits of adding immunotherapies to standard chemotherapy regimens. Additional benefits are also suggested by the indication that immunotherapy may render improved chemosensitivity at later dates. In addition, vaccines are often well tolerated with minimal toxicities, which make them a favorable approach. The hope is that we can identify the appropriate combination of vaccine and immune-modulating chemotherapy that will eradicate the disease. There is also likely to be a role for immune checkpoint therapy with inhibitors of PD-1 and PD-L1. Such phase I single-agent studies are currently in progress for pancreatic cancer. The results of studies so far create hope that the combination of chemotherapy with immunotherapy may be a game changer in the treatment of pancreatic cancer.
PV-10 has some interesting features that cross categories. Provectus management previously had called the drug as a chemoablative immunotherapeutic agent (later revising the descriptor to "immuno-chemoablative"). Underlined portion number one, "chemoablative," described PV-10's chemotherapeutic-like feature of rapid tumor ablation and destruction mechanism of action ("MOA"). Underlined portion number two, immuno," described the drug's MOA whereby it harnessed the immune system to battle cancer locally (at the site of injection) and elsewhere around the body.

While not specifically a vaccine because PV-10 is not antigen-specific, it could be considered vaccine-like because it is minimally or not at all toxic but expresses many, many more than one antigen.

As a side note, immune checkpoint therapy in the above Moffitt comments refers to, I believe, ipilimumab, which is why anti-CTLA4 is in step 3, priming and activation, of the cancer immunity cycle (and why Bristol-Myers is exploring the combination of ipilimumab and anti-PD-1 agent nivolumab.

[Lieping] Chen et al. write, when discussion combination therapies:
Traditional chemotherapy and radiation therapy, together with depleting mAbs or treatment with small-molecule inhibitors, all directly target and kill cancer cells, leading to the destruction of the tumour stroma and the release of tumour antigens. When coupled with these direct killing mechanisms, immunomodulatory biologics promote the priming and expansion of existing tumour-specific T cells and their de novo generation, with a potential to form long-lasting and self-sustained antitumour responses. In recent years, small-molecule inhibitors targeting tumours that harbour mutated BRAF (vemurafenib (Zelboraf; Plexxikon/Roche)) or translocated BCR–ABL (imatinib (Gleevec; Novartis)) have shown high initial response rates in clinical trials165. However, the duration of the antitumour response is limited owing to acquired drug resistance. A combination of these fast-acting small-molecule inhibitors with immune co-inhibitory blockade — for example, with CTLA4-specific or PD1-specific mAbs — could promote the priming and expansion of tumour-specific CTLs against multiple tumour antigens and/or epitopes, prevent the generation of escape variants or drug-resistant mutant cancer cells and induce sustained T cell responses. {Underlined emphasis is mine.}
Circling back to beginning of this post, Moffitt's presumed presentation at SITC potentially entitled Efficacy of intralesional injection with PV-10 in combination with co-inhibitory blockade in a murine model of melanoma, the cancer center previously have described their successful pre-clinical work that combined PV-10 with systemic immunotherapies to mean, I believe, checkpoint inhibitors (e.g., ASCO 2014).

The interplay of co-stimulation and co-inhibition (with the goal of more of the former than the latter), and Moffitt's use of what seems to be the broader term co-inhibitory blockade, I wonder whether their work describes the better therapeutic outcome of PV-10 and inhibitory factors of step 7 of the cancer immunity cycle above (see Figures 2 and 3 of [Daniel] Chen et al.).

September 18, 2014

Treating Cancer

In my September 22, 2013 investment letter entitled Why I'm Long Provectus Biopharmaceuticals, which you can find and/or read in its entirety on the blog's page of the same name (see the right sidebar entitled Pages) I wrote:
PV-10, a novel oncology compound being developed by Knoxville, Tennessee-based Provectus Biopharmaceuticals, Inc. (“Provectus” or the “Company”) (NYSE MKT: PVCT), exemplifies innovation over incrementalism, meaningful over marginal, productized technology over hypothetical, and changing the world over accepting the status quo, with not an insignificant amount of serendipity over contrivance. In sum, these form the quintessential essence of a paradigm shift in the treatment of cancer. 
It seems to me traditional modalities of cancer treatment look like this:
Surgery is the first line of defense when early stage cancer first strikes, while therapies and treatments and repetitions and combinations of them are fall back positions as cancer progresses and recurs towards its later stages.

I contend PV-10 is a paradigm shift in the treatment of cancer because it should play key roles in both ends of the disease spectrum illustrated above:
  • For earlier stages of cancer (shift #1a), the far greater majority or supermajority of those afflicted (the "silent masses"), the drug may effectively defeat or control local-regional disease to deny, prevent or forestall its metastatic and visceral spread, and present itself as a viable and far better alternative to surgery.
  • For later stages (shift #1b), the current focus of most of the biopharmaceutical industry, PV-10 may, as the tip of the treatment spear, in combination with other therapies, bring the immune system back into an immune surveillance (immunosurveillance) state to conquer heavy tumor burden and visceral disease.
See the blog's PVCT page.

Shift #1a. I think the upcoming pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma helps further make the case that if you truly effectively treat disease in Stage III (or, of course, earlier or much earlier), it forestalls or prevents it from progressing to Stage IV. I believe this because Provectus' metastatic melanoma Phase 2 trial data appeared to highlight that PV-10 injection lasted, as illustrated by progression-free survival (the time between initial treatment and tumor progression) approximately for the duration of the treatment interval of the drug. If the treatment interval was longer, PFS would be longer as well, until at some point complete response were achieved.

The FDA denied the company breakthrough therapy designation determined on the basis of the paucity of data, which I take simply to mean not enough of the data previously presented -- specifically, the sub-group of patients in the Phase 2 trial who had all of their disease treated (28 patients), which is the patient population of the Phase 3 trial.

In the upcoming Phase 3 trial Provectus will measure PFS as the trial's primary endpoint, utilize RECIST 1.1 to measure it, and inject patients every two weeks until CR or PD is achieved (i.e., the duration of the treatment interval will be until one of the two outcomes is achieved). This protocol, which is what oncologists presumably would use when treating patients, thus would see patients with all of their disease treated by PV-10 potentially never progress.

Shift #1b. This aspect of my presumed assumption of PV-10 as a paradigm shift in the treatment of cancer has yet to unfold. I was struck by an early-September article published by Moffitt staffers who include a key PV-10 researcher (Dr. Shari Pilon-Thomas) entitled Immunotherapy Combined With Chemotherapy for Pancreatic Cancer: A Game Changer?
Of note, the immune system’s involvement in cancer development and progression has sparked much interest in recent years. The model of the cancer-immunity cycle suggests an interplay of immune-suppression and immune-stimulation. In normal individuals, a state of immunosurveillance is in place. However, within the tumor microenvironment, inhibitory signals and immunosuppressive cells are present and tip the scale in favor of immune suppression.
The authors go on to write:
Chen and Mellman have delineated the cancer-immunity cycle, which depicts the immune system’s role in controlling tumor growth in normal individuals. Understanding this cycle provides insight into how tumors can evade it...The idea of the cancer-immunity cycle proposes that, for a cancer immune response to be generated, the net balance between immune stimulation versus immune suppression must be tipped in favor of the former. Studies in various cancers have suggested that tumors evade the immunogenic process mostly by factors that promote immunosuppression.
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See the blog's PV-10, and the Cancer Immunity Cycle page.

As researchers better understand how to treat late stage cancer, specifically and directly fighting tolerance and recurrence, I believe Moffitt has further their understanding of the cancer immunity cycle as it relates to the potential role(s) PV-10 does and could play. We may learn more about this in early-November at the 2014 annual meeting of the Society for the Immunotherapy of Cancer.
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