September 14, 2016

Life & Death, and the Biggest Checkbook

Without being in the situation (because, um, close to doesn't cut it), a Provectus shareholder cannot fully evaluate the possible quality/quantity of potential introductory, follow-up and/or advanced meetings Provectus could/may have had, and/or could/may be having, with prospective Big Pharma partners about combination or cocktail therapy for end-stage cancer patients. The question a shareholder asks of course is to what extent is Big Pharma interested in and/or kicking the tires of chemical small molecule, ablative immunotherapy PV-10 for potential combination with their respective systemic immunomodulatory or targeted cancer agents, with the goal of such discussions being to hopefully and eventually arrive at a clinical combination and business collaboration.

Some shareholders may have read about or heard rumors of recent discussions with Big Pharma that on the surface seem to denote interest. I cannot speak to that; all I can observe are the single or multiple, domestic or international, visitors and visits to or brush bys this blog via corporate-named routers from Amgen, Astellas Pharma, Bristol-Myers, F. Hoffmann-La Roche, Genentech (Roche), Gilead Sciences, Johnson & Johnson, MedImmune (AstraZeneca), Merck and Co., Novartis, Onxeo, and Pfizer. Visits could suggest blog reading. Brush bys may be the result of Internet search engine keyword searches. There could be other or more visits from Big Pharma and/or biotech folks via visitors' Internet service providers but I have no way of telling other than the occasional, reasoned guess about a location, such as Kenilworth, New Jersey (possibly for Merck and Co.) or Abingdon, Oxfordshire, UK (possibly for PsiOxus Therapeutics).

What is it that we really know about Provectus' progress, if any, towards a so-called co-development transaction that company management has insinuated, implied, suggested or said is imminent, around the corner, near-term, close, etc. for several years now (the volume of which seems to have grown louder this quarter)?

As early as the summer of 2014, I recall hearing of entreaties regarding combination studies to Merck and Co. by a strategic advisory board member and an oncology key opinion leader on behalf of Provectus. There also were rumors of several possible related interactions over time, such as a visit by a Merck executive to a medical conference to hear a Moffitt Cancer Center speaker talk about PV-10, and preclinical oncology work by the Big Pharma using off-the-shelf Rose Bengal.

As 2015 turned to fall, with apparently no partner(s) in sight, let alone in hand, to pay for a checkpoint inhibitor-based clinical combination study involving PV-10, Provectus issued press release "Announces Initiation of Phase 1b/2 Clinical Trial to Study PV-10 in Combination with Immune Check Point Inhibitor Pembrolizumab" in September to commence its own clinical combination work on advanced (metastatic; Stage IV) melanoma. The trial protocol for this study obviously was developed well before the announcement. There was no need for a supply agreement with Merck (i.e., no official collaboration) because pembro already was approved for the solid tumor cancer indication under investigation, and its trial cost thus would have been reimbursed. Provectus was going to be the sole sponsor of the clinical work.

The press release laid out management's then preclinical, clinical and intellectual property management plan to present and protect PV-10 as the ideal (perfect?) primer or front-end for Big Pharma's so-called checkpoint inhibitor backbone for treating end-stage cancer patients:
At the time Provectus management seemed to have a heightened sense of expectation Pfizer would make a big deal of the patent award, which did not materialize save for a tortured inclusion of Pfizer's name in a press release. This perspective of "let's not undermine Pfizer" emanated at the time from both COO and Interim CEO Peter Culpepper and CTO Dr. Eric Wachter, PhD, who preferred I not blog about the patent award date (that I had learned about several weeks earlier via the US PTO's Patent Application Information Retrieval website) until after the patent award was awarded (patent awards are made on Tuesdays by the PTO). See Pfizer's Just Not That Into You (August 21, 2015) and Intellectual Property (August 18, 2015) on the blog's Archived V News page,
  • The initiation of the company's own melanoma combination therapy study program in September was Step #2.
By sponsoring/conducting the trial by itself, Provectus owns all study data (per standard contract language applicable to clinical investigators, trial sites, CROs, etc. involved in the study). It will be customary to report top-line data in public venues like biomedical conferences and journals (e.g., potentially a 1Q17 conference); however, the full data set remains under the company's control, which is typical of any sponsored clinical trial. The detailed clinical data regulators ultimately would review, however, remains solely the property of Provectus, unless the company enters into a deal that affords access or rights to a third party, and
  • Step #3 was the completion/publication in May 2016 of Moffitt Cancer Center's mechanism of action work in melanoma on PV-10.
Entitled "Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1," Eric noted its importance and context on Provectus' August 10th 2Q16 business update call, saying that after "...years of work conducted by Moffitt Cancer Center both in animals and is now clearly accepted that tumor ablation with PV-10 can lead to stimulation of a useful anti-tumor immune response." In other words, PV-10 is an immunotherapy. See January 19, 2016 blog post PV-10 is an immunotherapy and May 12, 2016 blog post Moffitt: IL RB in melanoma elicits tumor immunity via activation of DCs by the release of HMGB1.
But by this time, the spring of 2016, there still was no co-development transaction (let alone multiple ones the company thought, and still thinks, could materialize). Possible explanations, aside from simply lack of interest on the part of Big Pharma, might have included to a greater or lesser degree:
  • The September 30, 2015 approval of the combination of nivolumab and ipilimumab for patients with advanced melanoma (BRAF V600 wild-type), which may have temporarily stymied interest in combination therapies for this indication,
  • The need to at least wait for the October 2015 approval of fellow intralesional (IL) or oncolytic therapy talimogene laherparepvec (T-Vec, Imlygic®),
  • Pfizer saying, at the January 2016 JP Morgan Healthcare conference, that is would bypass melanoma for its checkpoint inhibitor, anti-PD-L1 agent avelumab, to pursue "less competitive" cancer indications. If Pfizer were uninterested in melanoma for avelumab as a monotherapy, it would seem to suggest the Big Pharma also would be uninterested in combination therapy just for melanoma too, and
  • The growing realization checkpoint inhibitors no longer were/are the panacea the pharmaceutical industry and its constituent sycophants first thought they were. Clear, unequivocal limitations include:
    • Applicability to 20-30% of cancer patient population,
    • Ineffectiveness in less immunogenic cancer indications (i.e., cold or colder tumors),
    • Reaching toxicity and adverse event limits of checkpoint inhibitors (and targeted therapies) as both monotherapies and combination therapies (but since they are better than chemotherapies, management of such has grown acceptable), and
    • Realizing another set of tools, so-called primers or front-ends (i.e., co-stimulatory, agonists, "turn on the engine," "press the gas pedal," etc.), were necessary to combine with "back-end" co-inhibitory blockade.
If I had to summarize the above "explanations" in hopes of elucidating why a co-development transaction has not yet materialized for Provectus, I now might solely focus on the need for Provectus to:
  • Move beyond melanoma to show combinatorial, primer or front-end relevance in other solid tumor cancer indications, and
  • Establish predictive tools or measures of treatment success in a nascent, overhyped era of precision medicine, like immune biomarkers derived from both peripheral blood and tumor tissue, also in multiple solid tumor cancer indications.
Nevertheless, one could reasonably argue Provectus and other biomedical researchers have made preclinical, clinical and intellectual property management progress toward presenting and protecting PV-10 as the perfect primer or most complementary front-end to most if not every major cancer treatment category: chemotherapy, radiation therapy, targeted therapy, and immunotherapy.
  • Preclinical data related to combination therapy
  • Clinical data related to combination therapy
    • PV-10 + radiotherapy
  • Intellectual property related to combination therapy
It is possible at least three Big Pharma could have some level of interest in pairing PV-10 with their immunotherapy agents: Pfizer (anti-PD-L1 with Merck KGaA), Merck & Co. (anti-PD-1), and Bristol-Myers Squibb (anti-PD-1).

Pfizer Inc. Over at least the last five years Pfizer has been consistently wrong or late to the oncology/immuno-oncology (I-O) game:
  • November 2014: Pfizer buys (out-licenses) an anti-PD-L1 agent, later named avelumab, from Merck KGaA for an $850 million upfront payment and other considerations. Merck gets anti-PD-1 drug pembrolizumab approved for metastatic melanoma as Keytruda® in September 2014, while Bristol-Myers gets its anti-PD-1 relative nivolumab approved for the same indication as Opdivo® in December of the same year,
  • September 2015: Bristol-Myers gets its combination of anti-CTLA-4 Yervoy® and anti-PD-1 Opdivo® approved for metastatic melanoma. Following Bristol-Myers' non-small cell lung cancer trial failure of Opdivo as a monotherapy, Wall Street analysts peg AstraZeneca's combination of anti-CTLA-4 tremelimumab (previously in-licensed from Pfizer) and anti-PD-L1 durvalumab as capable of potentially taking market share away eventually from Bristol-Myers' approved combination therapy. See Pfizer sale/outlicense above,
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  • January 2016: Having admitted the company was late to immuno-oncology, Pfizer says during the JPMorgan Healthcare Conference that it will be "a leading player in the second wave of combinations." As of this writing, Pfizer has 8 open oncology combination studies, compared to 180 for Merck and 132 for Bristol-Myers, and
  • August 2016: Pfizer buys Medivation for $14 billion, more than 50% higher than Sanofi's initial April bid in April.
But, Pfizer is the one of these three Big Pharmas with the biggest checkbook, and into August 2016 still was working with Provectus to advance their joint oncology combination therapy patent portfolio (one patent and two patent applications). See More Intellectual Property Management (September 11, 2016) and Is Pfizer paying more [IP] attention to Provectus? (September 2, 2016) on the blog's Current News page.

Pfizer seemed to have entered Provectus' picture around late-2010 to early-2011 when Provectus and it appeared to have begun writing and then initially filing (in March 2011) the combination therapy patent application that eventually would be jointly awarded to them by the U.S. Patent and Trademark Office (US PTO) in August 2015 as "Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer" noted above.

Initial interest in and the rationale for combining an immunomodulatory agent (anti-CTLA-4 compound tremelimumab) with PV-10 began with Provectus strategic advisory board member and Pfizer executive Dr. Craig Eagle, MD, who apparently conceived of the idea apart from Provectus' co-founders. Eagle reasoned an antigen cascade or "storm" ("antigenization") would be kicked off or initiated by the substantial size and scope of tumor destruction initially caused by PV-10 ablation (injection). The subsequent PV-10-based antigenization would induce an immune response -- otherwise known as priming -- that then could be boosted by the immunomodulatory (or targeted) agent. CTO Dr. Eric Wachter, PhD noted as much in a recent US PTO filing when he wrote "President" and co-founder Dr. Tim Scott, PhD did not anticipate tumor ablation would have "a downstream immune system priming systemic effect" and that this systemic priming effect could "synergize with known systemic agents."

Ironically, from today's perspective and pharmaceutical industry focus on oncology combinations and cocktails, it would seem Eagle thought enough of PV-10 to suggest its combination with anti-CTLA-4 agent and ipilimumab relative tremelimumab, but not enough to expansively protect Pfizer's interest in the ensuing combination therapy patent. According to Provectus, Pfizer does not benefit from its co-ownership of the combination therapy patent portfolio unless it acquires the company.

But, as I wrote before, Pfizer has the biggest checkbook -- if it wishes to open it -- in the event it again is late to the I-O game by not initially entering into a co-development relationship with Provectus before another Big Pharma does.

Merck & Co. Anti-PD-1 drug pembrolizumab (trade name: Keytruda®), first approved in for patients with advanced melanoma in September 2014, breathed new life into Merck's oncology franchise almost 18 months after current head of R&D Dr. Roger Perlmutter, MD, PhD re-joined this company from Amgen in March 2013.

In a Barron's August 31st article entitled "Merck: Lung Cancer Lead Depends On “How Smart It Plays Its Hand,”" Bernstein analyst Tim Anderson said:
"One of the frequent criticisms with MRK’s I/O program has been that, relative to competitors like BMY/AZN and Roche, its “combination” strategy is less clear, with many believing MRK could be left in the cold over the long run because of this. This is too simplistic of a view, in our opinion. 
MRK has already placed its bets on “chemo combo” through the earlier initiation of trials like Keynote-189 and Keynote-407. In the area of CTLA4 combinations, we believe the chances are high that MRK will soon initiate a phase 3 development program (exact scope unclear) if only to hedge its bets in the event that trials like Checkmate-227 and MYSTIC/NEPTUNE are positive. 
While the onus is on BMY and AZN to fully validate CTLA4 combinations, all MRK has to do is imitate given its sudden lead in the monotherapy 1L lung cancer market that came about through the very different fates of Keynote-024 and Checkmate-026. 
In other potential combination areas with anti-PDx therapies and “3rd generation” agents (e.g. OX40, GITR, IDO, and more) the playing field is more level across the different drug companies. Like its competitors, MRK already has various assets in development – either owned in entirety or accessed through partnership. Progress with almost all of these later generation drugs, across all companies, has seemed to be on the slower side; activity in a single-agent setting, for example, has often seemed underwhelming, in contrast to the single agent activity seen with the anti-PDx’s and anti-CTLa4′s. 
Lastly, even if “combination therapy” comes to fruition and the data is compelling (whatever the regimen), there will likely be the attendant trade-offs of incremental toxicity and higher cost. Therefore, it seems likely that some segment of the 1L lung cancer market will continue to exist for anti-PDx monotherapy, where MRK has a first-mover advantage. 
On balance, we continue to think investors under-appreciate the potential durability (and value) of MRK’s coming lead in 1L lung cancer. Part of this depends on how smart MRK plays its hand from here."
I recounted above what I believe is Merck's historical curiosity or interest (is there a better descriptor?) in PV-10. Below is a quickly constructed, cursory overview of combination collaborations (e.g., announced, supply agreements only, etc.) between Merck and other companies for pembrolizumab in advanced melanoma.
Click to enlarge.
A search of for "pembrolizumab combination melanoma intratumoral" yields six open studies; there are three other trials for different indications (a total of 9). "Pembrolizumab combination intralesional" yields two trials (PV-10, T-Vec).

What kind of agent is Merck searching for to pair with pembrolizumab? What defines an ideal drug partner for pembro? One way to answer these questions is to consider former Moffitt and current NYU Langone Medical Center key opinion leader's comments to me that (paraphrasing) the utility of a primer is simply its ability to synergize with the immune agent in question in terms of clinical effect when given prior to the second agent. Moffitt data showing the strength of the systemic responses PV-10 can stimulate (i.e., efficacy of PV-10 plus a checkpoint inhibitor >> efficacy of the checkpoint inhibitor alone) should make this/his point). See August 17, 2014 Immune Surveillance.

Another way is to recount Moffitt's Dr. Vernon Sondak, MD's (and Provectus consultant's) characterization of PV-10; see June 29, 2014 blog post Properties of PV-10:
  • Simple to store, handle and use and reuse,
  • Modest local toxicity and minimal to no systemic toxicity,
  • Rapid and complete induction of necrosis/antigen release in injected lesions,
  • Excellent healing of the injected site after tumor necrosis, and
  • Reliable and reproducible induction of regional and systemic immune effects capable of destroying occult tumor cells, "bystander lesions" and distant metastatic lesions regardless of prior treatments.
If Merck settles on what it believes to be a more ideal partner for pembrolizumab, it further breathes life into its cancer immunotherapy franchise. As such, I am intrigued by Merck's most recent collaboration with Biothera, which pairs pembro with a pathogen-associated molecular pattern-based (PAMP-based) compound. PAMPs are "molecules associated with groups of pathogens, that are recognized by cells of the innate immune system." It would seem Merck is creeping closer and closer to understanding how to turn (induce) cold or cold tumors hotter (via Biothera's PAMP) so as to boost the immune response subsequently generated by pembro.

Well, PV-10 could be called a DAMP-based compound. "Damage-associated molecular pattern molecules (DAMPs) also known as danger-associated molecular pattern molecules, are host molecules that can initiate and perpetuate a noninfectious inflammatory response." And, DAMPS are recognized by both the innate and adaptive immune systems. See Immunological “ignition switch” (August 26, 2016) on the blog's Current News page.

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Bristol-Myers Squibb. And then there's Bristol-Myers, which has the most to lose of these three Big Pharmas with its interchangeable, anti-PD-1 drug nivolumab (Opdivo®), also approved initially for melanoma shortly after Merck's version. Bristol executives faced a "near-death experience" on August 5th that continues by virtue of a declining share price that currently shows no sign of abating. See August 30, 2016
The Day Big Pharma's Earth Stood Still, which was visited by several times by Bristol-Myers Internet Protocol addresses (among other visits to this blog).

If nivolumab and pembrolizumab are interchangeable, and Bristol-Myers has no meaningfully different marketing department than Merck's, Bristol-Myers' "death" potential remains viable so long as it does not find an ideal combination partner for Opdivo® and Merck does. Should cancer combinations (or cocktails) rule the day for late-stage cancer patients for the time being, the ideal primer or most complementary front-end for a combination therapy would seem to be the greater or greatest differentiation. See February 18, 2015 The Early Obsolescence of Checkpoint Inhibitors. Own it, live. Lose it, die.

September 2, 2016

There's additivity, synergy, and then there's PV-10 (1 + 1 = 3)


I previously wrote about the concepts of additivity and synergy when adding two agents together (a "combination") or three or more together (a "cocktail"). See The bar (June 24, 2016) and Additive: 1 + 1 < 2. Synergistic: 1 + 1 > 2 (best case, >> 2) (June 25, 2016) on the blog's Current News page.

Additive in the context of immuno-oncology combinations and cocktails represents one plus one is less than or equal to two (or, in the case of three agents, one plus one plus one is less than or equal to three). Efficacy (e.g., response rate, and perhaps other survival and survival surrogate endpoints) of the combination is better than the individual efficacies of the pair's components. That is, the sum of the parts is greater than the whole.
  • 1 + 1 < 2, 1 + 1 + 1 < 3
A synergistic combination, however, should generate efficacy greater than the sum of the individual efficacies, and, in a best case, much greater than the sum, That is, the whole is greater than the sum of the parts
  • 1 + 1 > 2, and in the best case 1 + 1 >> 2
I updated MD Anderson's Dr. Merrick Ross, MD's slide no. 160 of ASCO 2016 Melanoma Symposium's "The Role of Immunotherapy in the Medical Management of Melanoma: An Overview for the Oncologist" for preliminary combination data of oncolytic virus CVA 21 (Coxsackievirus A21) and ipilimumab/Yervoy in Stage III and IV melanoma patients. The upshot for this latest addition, which Dr. Ross probably didn't include because the data is partial (some of the patients treated, but not all) and preliminary, is that CVA 21 and ipilimumab are synergistic, as are oncolytic virus T-Vec and ipi; however, T-Vec and pembro are potentially additive but not synergistic.
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As I noted under Is Pfizer paying more [IP] attention to Provectus? (September 2, 2016) on the blog's Current News page, Provectus recently advanced daughter combination therapy patent application '318 (co-assigned with Pfizer) after an initial non-final rejection decision by the U.S. Patent and Trademark Office. Provectus' CTO Dr. Eric Wachter, PhD had a document, as part of this advancement, filed on August 31st. See the several pages below, with my orange emphasis.
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H/t InvestorVillage poster STARLIGHT66 for a Barron's August 31st article entitled "Merck: Lung Cancer Lead Depends On “How Smart It Plays Its Hand,”" notably the quote by Bernstein analyst Tim Anderson:
"One of the frequent criticisms with MRK’s I/O program has been that, relative to competitors like BMY/AZN and Roche, its “combination” strategy is less clear, with many believing MRK could be left in the cold over the long run because of this. This is too simplistic of a view, in our opinion. 
MRK has already placed its bets on “chemo combo” through the earlier initiation of trials like Keynote-189 and Keynote-407. In the area of CTLA4 combinations, we believe the chances are high that MRK will soon initiate a phase 3 development program (exact scope unclear) if only to hedge its bets in the event that trials like Checkmate-227 and MYSTIC/NEPTUNE are positive. 
While the onus is on BMY and AZN to fully validate CTLA4 combinations, all MRK has to do is imitate given its sudden lead in the monotherapy 1L lung cancer market that came about through the very different fates of Keynote-024 and Checkmate-026. 
In other potential combination areas with anti-PDx therapies and “3rd generation” agents (e.g. OX40, GITR, IDO, and more) the playing field is more level across the different drug companies. Like its competitors, MRK already has various assets in development – either owned in entirety or accessed through partnership. Progress with almost all of these later generation drugs, across all companies, has seemed to be on the slower side; activity in a single-agent setting, for example, has often seemed underwhelming, in contrast to the single agent activity seen with the anti-PDx’s and anti-CTLa4′s. 
Lastly, even if “combination therapy” comes to fruition and the data is compelling (whatever the regimen), there will likely be the attendant trade-offs of incremental toxicity and higher cost. Therefore, it seems likely that some segment of the 1L lung cancer market will continue to exist for anti-PDx monotherapy, where MRK has a first-mover advantage. 
On balance, we continue to think investors under-appreciate the potential durability (and value) of MRK’s coming lead in 1L lung cancer. Part of this depends on how smart MRK plays its hand from here."
I think it's pretty clear Eric is signalling or outright saying the combination of Provectus' intralesional agent PV-10 (Rose Bengal) and Merck & Co.'s anti-PD-1 drug pembrolizumab for patients with advanced melanoma is synergistic. Is he foretelling the results are stellar? Could efficacy exceed, at a minimum, the response rate of Bristol-Myers' combination of anti-CTLA-4 drug ipilimumab and anti-PD-1 drug nivolumab?

The Barron's article suggests Merck is searching for the ideal front-end (perfect primer) to marry to/combine with pembrolizumab. How will the Big Pharma "play its hand?"

August 30, 2016

The Day Big Pharma's Earth Stood Still

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Updated below: 9/1/16 and 9/10/16.

Prior to Bristol-Myers' failure of its anti-PD-1 drug and cancer immunotherapy nivolumab/Opdivo as a monotherapy for patients with advanced non-small-cell lung cancer (NSCLC), when in the "era" of anti-PD-1/PD-L1 therapy had one of these drugs or drug compounds failed a pivotal clinical trial.

Since the Big Pharma's announcement on August 5th of this "shocking" or "stunning" outcome, as of this writing, BMS' share price has fallen about 25% (while MRK's has risen about 7%, with a roughly flat S&P 500), which would be equivalent to a loss in market capitalization of about $30 billion.

The "era" of course can be measured in a mere handful of years. It was not that long ago, in 2011, when anti-CTLA-4 drug ipilimumab (Yervoy, Bristol-Myers) was approved for metastatic or advanced melanoma, while "relative" tremelimumab (Pfizer, subsequently licensed to AstraZeneca and MedImmune) failed its own pivotal melanoma trials.

Bristol's failure was attributed by some (or many) to a failure in trial design, and its share price was treated like that of a small biotechnology company that failed its pivotal study. When has that happened? Was failure really attributable simply and strictly to trial design, or was there a calculated risk-reward calculation that merely did not pan out? Consider that Bristol-Myers was running two pivotal trials essentially for the same indication and patient population; one of nivo as a monotherapy, and one of nivo and ipi as a combination regimen.

Nivolumab's August failure may have the exposed anti-PD-1/PD-L1 therapy in at least two ways. First, anti-PD-1/PD-L1 drugs need help. And second, combinations (two therapies and/or treatments) and cocktails (three or more) "now" are the order of the day for end-stage cancer patients.

What started out a few years ago as throwing poop on a wall and observing what stuck in regards to exploring combinations and cocktails for end-stage patients appears to have evolved into or towards thinking more about the poop before it is thrown and wondering what each poop in the pairing or triplet brings to the table individually and collectively in regards to baseline immunologic signalling, biomarkers, pharmacokinetics, etc. -- that is, clear, definable, understandable, synergistic value. See, for example, Immunological “ignition switch” (August 26, 2016) on the blog's Current News page.

What happens to a Big Pharma owner of an anti-PD-1/PD-L1 drug or agent if it doesn't find the right (i.e., synergistic) partner for its checkpoint inhibitor, and when a/one competitor does?

Updated (9/1/16): A Bristol-Myers (BMS) location visited this blog post yesterday (August). In July this same Internet Protocol (IP) address visited September 9, 2014 blog post Bristol-Myers vs. The Field (ex-Provectus):
"Last week Bristol-Myers filed a lawsuit against Merck over [anti-]PD-1 agent pembrolizumab (trade name Keytruda), which was approved last week by the FDA for late-stage or metastatic melanoma
Specifically, Bristol-Myers claims that Merck is violating the patent on its Opdivo mediation for tackling melanoma, which was recently approved in Japan and became the first so-called PD-1 inhibitor to win regulatory backing anywhere. A PD-1 inhibitor blocks a protein that acts as a brake on certain immune system cells and prevents them from attacking healthy tissue. (Bristol-Myers Sues Merck Over a Patent on its new Cancer Drug, The Wall Street Journal, September 8, 2014)"
In February this visitor exited via a link to November 5, 2015 press release, Reports Immune Mechanism of Action Data for PV-10 Presented at Society for Immunotherapy of Cancer Annual Meeting Authored by Researchers at Moffitt Cancer Center.

A second BMS IP address from the same location (e.g., the same visitor from a different spot, a different visitor from a different spot) visited the blog's Current News page. This same IP address exited the three links below in May 2015 (I cannot recall yet from which blog post or news page these links came):
Updated (9/10/16): One of the above BMS IP addresses visited the blog's landing page on September 7th.

A different location (and thus IP address) from the one location/2 IP addresses above brushed by (did not visit, but rather clicked on and then quickly closed the tab or went away) June 1, 2016 blog post Intralesional PV-10 for In-Transit Melanoma—A Single-Center Experience via Google Japan.

August 15, 2016

Seeking Co-Development

Updated below: 8/17/16.

The company's CTO, board of directors member and a co-founder Dr. Eric Wachter, PhD said several things in regard to PV-10 as an immunotherapy on Provectus' August 10th 2Q16 business update conference call.

Among them, in no particular order:
  • "After a long haul, it is now clearly accepted that tumor ablation with PV-10 can lead to stimulation of a useful anti-tumor immune response."
  • "...over the last several years we have worked with colleagues at Moffitt Cancer Center, we have done some work internally, and we have done some work at the University of Illinois-Chicago to show that PV-10 unambiguously triggers that first step, the destruction of tumor. And that event performs all of the expected downstream signaling of the immune system, leading eventually to a functional immune response against an untreated tumor."
  • "So, when we started this work in Australia in the clinic in 2005, we described that as a an bystander response, which was the common terminology at the time. Immuno-oncology was not particularly well regarded at that period. It got to be even less of an important area of investigation as we approached the end of the first decade of the 21st century. And then, it became a very hot area with the approval of anti-CTLA drug Urvay [sp] and subsequent approvals of a number of anti-PD-1s and presumably eventually anti-PD-L1s, all drugs that harness T cells to have a functional--or improve their functional response against tumor tissue."
  • "So, I think that the story [that ] is now very well documented in the literature. We have shown that this occurs in [unintelligible] models of melanoma. We have shown this occurs in [unintelligible] models of colorectal carcinoma. We have evidence to show that this happens in [unintelligible] breast carcinoma. And, most importantly, we have shown that key elements of this signaling are occurring in melanoma patients."
    • "Our next tumor on the radar will be hepatocellular carcinoma because there are challenges in HCC that are comparable to those in melanoma. We already know that we can destroy HCC with this ablative process and the hypothesis that that should lead to similar signaling, which can have implications for--well, single-agent therapy [unintelligible] HCC, but more importantly for combination with things like anti-PD-1 [unintelligible] . We have already shown that the basic immunology occurs in HCC models, so I would say that--one of the things I’m highly confident in, I’m highly confident that we will show that this same functional immune signaling functions in HCC."
    As I noted under Church (August 15, 2016) on the blog's Current News pageDr. Sally Church, PhD wrote a Biotech Strategy Blog post entitled "Beyond T-Vec - a look at oncolytic viral immunotherapy." Dr. Church does not appear to be either an innovator or an early adopter (as labeled on the technology adoption life cycle). Rather, her professional experience, among other things, biases her (which is neither "right" nor "wrong") towards early or late majorities (I'd lean towards early). I think it is worth paying attention when she begins to opine on a newer or novel category of drug. In the case of oncolytic viruses (OVs) (she does not categorize them explicitly as intralesional or intratumoral presumably because OVs have been explored via both intralesional and intravenous administration), she is commenting as the majorities begin to pick up on what the innovators and early adopters (e.g., Agarwala, Andtbacka, Weber, etc.) have been saying for a while. She is, however, rightfully wanting to know more about durability of responses and survivability, which these innovators and early adopters also have been wanting to see as well.

    Two thoughts crystallized quickly [in my head] but only after reading Dr. Church's blog post. The second one is the field of melanoma, and for Provectus, what immunology in other indications they must show to secure a co-development transaction more on their terms than not. This is represented by the screenshot from her post below, and which is the subject or focus of this blog post.
    Click to enlarge. Image source
    First, the threshold for differentiating one's combination therapy for melanoma appears to be, in Dr. Church's mind, is the approved combination of anti-CTLA-4 ipilimumab (Yervoy) and anti-PD-1 nivolumab (Opdivo).

    Second, is combination data of PV-10 and pembrolizumab in advanced melanoma sufficient to get any co-development deal for Provectus, let alone the deal management presumably desires? Probably not, and I believe they already have recognized such. Big Pharma also may want certain immunology (and not just ablation) data for other indications, such as hepatocellular carcinoma.

    Updated (8/17/16): For some time Provectus' COO and interim CEO Peter Culpepper has publicly and routinely described the kinds of co-development combination therapy deals there could be and he seeks. As recently as the 2Q16 quarterly financial statements filing, the company noted:
    "An interim transaction could be a co-development deal like Roche-NewLink, Bristol-Celldex or AstraZeneca-Incyte. The Company is not in discussions regarding the sale of its business, and there can be no assurance that the Company will be able to monetize PV-10 or PH-10 in the manner described herein."
    Setting aside both Peter and Eric's immense historical difficulties with expectation setting (e.g., in the case of co-dev combo deals as early as June 2014 that one could be/was coming), the above quote is endemic of their historical challenge with guidance (see Forward Guidance (August 14, 2016) on the blog's Current News page).

    What is it that you mean? What do you want to say, and why do you want to say it?

    I don't believe they are saying things that are not true, or that they don't believe; however, in trying to communicate strategy and tactics, Provectus management often conflates the desire to provide genuine insight into what is going on (Peter, Eric) with poorly set or communicating expectations (Eric, Peter) and ineffective (Peter) or ideological-driven approach to providing (Eric) guidance. Eric's comments on the August 10th 2Q16 business update conference call regarding PH-10 are another example:
    "Turning to PH-10, we're sorting through the immunologic and histopathologic data from our mechanism of action study of topical PH-10. I, unfortunately, can't go into detail yet about what we're learning, but in general, my assessment is that these results will be as important to PH-10 as the Moffett work has been to PV-10. 
    When new kinds of therapy come along, everyone likes to understand the biologic story underlying clinical observations, and it appears that this may be a very interesting story that explains observations we've made throughout clinical development of the drug. I look forward to sharing details on this with our stakeholders in the next few months."
    While Eric's first paragraph is more appropriate to describe his perspective of the PH-10 mechanism of action (MOA) results that Rockefeller University's Dr. James G. Krueger, MD, PhD and his Laboratory for Investigative Dermatology have arrived at thus far, Eric's second paragraph conveys his excitement about the results (imprecise as those comments are by phraseology like "very interesting"). Eric is saying Rockefeller's MOA work and results should be as important to PH-10 as Moffitt's work/results were to PV-10, which established the oncology use of Rose Bengal as immunotherapeutic (i.e., "After a long haul, it is now clearly accepted that tumor ablation with PV-10 can lead to stimulation of a useful anti-tumor immune response") and that is of assistance in discussions with Big Pharma (among other preclinical and clinical work/data).

    So, when Peter "talks" Bristol-Celldex, AstraZeneca-Incyte and Roche-NewLink (in chronological order), what does he mean? What does he want to say, and why does he want to say it?

    Whether you agree with this or not (I agree with him in context), to the get the valuation he wants for Provectus Peter believes the company requires an interim value-creating (-recognizing) transaction. This transaction, in his view, is more likely a co-dev combo deal/relationship rather than a geographic license deal/relationship because of factors such as size, scope, validation, etc.
    Click to enlarge.
    His illustrative co-dev combo deals provide a range of potential outcomes for Provectus and the prospective Big Pharma partner, and thus for Provectus shareholders:
    • Deal type A (Bristol-Myers/Celldex), where there would be clear recognition of the partner's interest in Rose Bengal as a promising component of the pairing/combination regimen. A combo collaboration begins,
    • Deal type B (Genentech-Roche/NewLink), where there would be much, much stronger recognition of the partner's interest by its licensing of PV-10 for cancer combo therapy, or
    • Deal type C (MedImmune-AstraZeneca/Incyte), where there would be overt or tacit recognition of the partner's interest or acquiescence but with no strings attached.
    Provectus of course understands there is no reason now to enter into a type C because the company's combination therapy study work already is underway (i.e., PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma), together with prior work such as that of Moffitt's (e.g., "Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma"). A recent type C deal (August 15th) is Bavarian Nordic's drug supply agreement with Bristol-Myers of anti-PD-1 nivolumab (Opdivo) for use in a combination therapy clinical study of the former's vaccine CV301 and the latter's checkpoint inhibitor for patients with previously treated non-small cell lung cancer (NSCLC).

    The difference between type A and B deals is the prospective partner's interest to dip a toe into the pool, or to dive into it. The decision of how wet to get probably depends on how much data each Big Pharma requires for whatever degree of waterlogged-ness they seek or with which they are comfortable. Both types, however, can co-exist with an eventual transaction to buy the company because Provectus management wants to advance the therapeutic use of PV-10 as a monotherapy and in combination with other cancer treatments.

    The co-dev combo relationship Peter has been seeking for some time (i.e., the company ineffectively stated strategy) comprises something to the effect of:
    • A multi-indication collaboration (e.g., melanoma, HCC, NSCLC, etc.),
    • An upfront payment and/or paid-for study/development costs. No upfront payment but paid-for costs could be a nice second. Peter understands the stock market and industry recognize validation is seen with Big Pharma dollars in the deal, whether soft, hard or both,
    • Trial sponsorship is an interesting topic because I would imagine Eric would want to have Provectus conduct (control) it; however, Big Pharma might want to do it in a more expeditious manner than for which Eric has been known,
    • Non-exclusive clinical combination would be preferable to Provectus since PV-10 is orthogonal to the class of PD-1s (and PD-L1s); that is, PV-10 would be synergistic to any checkpoint inhibitor, as management has publicly stated of Keytruda and Opdivo. Why not do combination therapy trials with both PD-1s? Because non-exclusivity might/would not be preferable to the prospective partner, and
    • Time-limited right of exclusive negotiation for licensing rights likely would be a given. If Provectus can get what it wants (vis a vis core business terms), the prospective partner would like a right of first something.
    The 2016 "version" of the 2014 Bristol-Myers-Celldex type A deal (aside from some stuff related to the historical relationship prior to the combo co-dev transaction that may have manifested themselves in the co-dev deal) would appear to be the Bristol-Myers-PsiOxus transaction. The latter essentially is the sentiment and structure of what Peter is seeking on behalf of Provectus. There will be continue to be an open question from many-to-most company shareholders (and I would imagine the Street, the stock market, and the industry ecosystem at large) about whether he can get the deal Peter wants for Provectus, however, until he answers the question and does.

    August 13, 2016

    The Untrigger

    Updated below: 8/15/16.

    I have written a lot about the so-called clinical trial math of Provectus' ongoing pivotal Phase 3 study entitled PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma (official title). The company's CTO, board of directors member and a co-founder Dr. Eric Wachter, PhD discussed some of this math on Provectus' August 10th 2Q16 business update conference call.

    Eric said the number (not the percentage) of disease progression events required to trigger the interim and full study analyses were 81 and 162, respectively. I discussed this as item 5. Clinical trial math under Quick: 2Q16 (August 9, 2016) on the blog's Current News page.

    It was helpful and insightful, but disappointing, to hear Eric say the trial does not have a scheduled assessment (a prescribed time trigger):
    "So, when we began designing the study several years ago, we looked at the issue of how to schedule an interim assessment. And while that was a rather uncommon idea, we looked at that very carefully. We even had discussions with FDA on that topic. And they were adamant that they were strongly opposed to any sort of effort to schedule an interim assessment. Our hypothesis at the time was that, for example, because the interim assessment and the final assessment are based on a number of progressions, they're modeled using standard statistical models. If there was a longer progression-free survival in the PV-10 arm than expected, there would not be the required number of progressions in that arm to add up to the required number of events."
    As such, as I hear and read it, one should consider that there only is one trigger (a prescribed event trigger), stated on the trial's page as "[a]n interim assessment of efficacy and safety will be performed by the IRC when 50% of the events required for the primary endpoint have occurred." As a number, rather than a percentage, this figure is 81.

    Eric said on the call that "one of our crown jewels is our study protocols because they represent everything that we've invested in the company up to the point that that protocol is issued." He certainly is reluctant to show his jewels if he doesn't have to (although it is possible he may fondle them from time to time). He "teased" two sections of the Phase 3 trial protocol. First, section 4.9 (with my underlined emphasis):
    "An interim assessment of efficacy and safety will be performed when the IRC--that's Independent Root [sp] Committee--will be performed by the IRC when 50 percent of the events required for the primary endpoint, that is 81 disease progressions as defined in the study protocol, have occurred. And so, that explains to you that there's a set number. It's designed at the beginning of the study, and that's the point when that number of progressions have occurred."
    Second, section 4.10 (with my underlined emphasis):
    "It doesn't matter if they're all in the PV-10 arm, if they're all in the comparator arm, which isn't possibly because there aren't enough patients in the comparator arm. We have to have enough progressions to hit that metric. Now, we had hoped, as I said, to have some sort of a mechanism in the study that would allow that to be triggered early if, for example, we're going along and we're not seeing progressions as we expected. And so, while we worked on that with the agency, as I said, they're adamant that that was not appropriate for a pivotal study. So, what we managed to compromise on was that in Section 4.10, which is captioned "Study Duration", that subjects will be monitored until survival--for survival until death, loss to follow up, withdrawal of consent, or study termination by the sponsor."
    Rather than hash out or re-hash my work/writing about prescribed event and time triggers, the number of patients needed to be enrolled to hit 81 events, etc., I'd like to state (speculate) the following -- [I believe] there is a trigger Eric does not want to explicitly speak about or affirm, which could/would be an imbalance in the number of events between the treatment and control arms, which could/would cause a statistical and ethical dilemma for the study's IRC. What would an imbalance look like or comprise? In the extreme, or potentially actually, there would be no events in the PV-10 treatment arm, and events of whatever frequency or magnitude in the chemotherapy/oncolytic virus control arm. Takeaway: The pivotal trial does not have to reach 81 events for the interim analysis to be triggered.

    In his own special way I believe Eric said this on the call (with my underlined emphasis):
    "And so, we are able to monitor at the terminal end of the study, and if the clinical trial data monitoring committee determines that it's in the best interest to end the study, it could end before we had all of the progression events occurring. I doubt that'll happen. It will be a very unusual circumstance, but it would probably be positive for the drug because it would suggest that a large number of patients weren't progressing because of the majority of the patients in a two-to-one randomized study are from the PV-10 arm, and that probably would imply that the PV-10 patients weren't progressing. 
    But, this is all speculation."
    The statistical dilemma is having a treatment arm with no or very few events, and a control arm with many, many more (like 0 and 15, or 0 and 20). The ethical dilemma is a treatment arm that works and works very, very well (i.e., no disease progression), and a control arm that demonstrates what everyone already predicted (i.e., everybody progresses).

    The question then would be, "how many events in total and across the two arms would be required for the IRC to recognize an imbalance, and thus trigger the interim analysis?" Twenty events in the control arm (and none in the treatment arm)? Thirty? A two-to-one study randomization then would suggest enrollment and treatment of 60 patients. Or 90.

    Math, math, math.

    Updated (8/15/16): My projection for enrollment in the pivotal melanoma Phase 3 trial is below (having adjusted only for 5 months of no enrollment as a result of the major amendment related to Amgen's intralesional (IL) drug Imlygic, and also differentiating enrollment rates between medical and surgical oncology sites). The study may generate enough events to highlight the imbalance between the two arms in 1Q16, where the idea is that most-to-all of the control arm patients generate events, and few-to-none of the treatment arm ones do.
    Click to enlarge.

    What proportion of events in each arm ("proportion"), and what number of events in each arm ("sample size") gets you to a sufficiently low p-value?

    If 75-100% of the control arm generate events, and 0-25% of the treatment do too, who you got?! Using this calculator, which is a simple analysis, and may even be simplistic, may require upwards of 30 patients; however, this may be too low.

    E.g., Sample 1: Proportion of Control Arm Events (Number of events generated in the control arm ÷ Number of control arm patients); Sample 2: Proportion of Treatment Arm Events (Number of events generated in the treatment arm ÷ Number of treatment arm patients)
    Click to enlarge
    Click to enlarge

    July 19, 2016

    It's the small molecule chemical, stupid

    Original image source
    Updated below.

    Sometimes it takes a piece of news to (again) put things into almost complete perspective.

    Consider today's press release Oncorus®, Inc. Launches with $57 Million Series A Financing. This was a topical, straightforward, sizable, early-stage (Series A) biotechnology startup company financing by notable financial (MPM) and corporate (Celgene) life sciences investors of a cancer treatment approach akin to Provectus'. The scientific basis for the company and financing (the "scientific founders," or foundation, so to speak) is the work by Drs. Joseph Glorioso III, PhD and Paola Grandi, PhD around oncolytic viruses, intralesional or intratumoral injection, and immunotherapy.

    Also consider a PubMed search of "glorioso grandi." From this search, further consider, for example, (from where the basis for Oncorus may have come) Grandi et al., "Design and application of oncolytic HSV vectors for glioblastoma therapy," Expert Rev Neurother. 2009 Apr; 9(4): 505–517. Aside from improvements over injectable oncolytic viruses, it's still intratumoral injection as the route of delivery.
    Updated (7/31/16): The trend towards immuno-oncology (I-O) via oncolytic virus continues — the first in this class being the October 2015 approval of Amgen's (BioVex's) talimogene laherparepvec (OncoVEXGM-CSF) — with a license transaction between Western Oncolytics and Pfizer for the former's version, this time a smallpox-related oncolytic virus: "Pfizer bags option on oncolytic virus, partners up to advance through PhI" (Nick Paul Taylor, FierceBiotech, July 29, 2016).
    Gloriosio's (and Grandi's) work above, and his/their intellectual property, references the same base patent/patent application material BioVex did. See here, here (2008) and here (2011).
    The scientific founder of, or the science foundation supporting, Western Oncolytics is Dr. Stephen Thorne, PhD, who comes from the same entity/organization/program — the University of Pittsburgh Cancer Institute's Cancer Virology Program — as Drs. Glorioso and Grandi. Thorne's work has been around as early as 2009 (and probably before; I have not done a thorough desk-based review of this work, but merely am observing the key details and the apparent trend): "Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer," Kirn et al.,, January 2009.
    There are several things of note to me in regards to Pfizer's involvement and certain other aspects of the deal/technology, such as: (i) no financial deal terms were announced (there's usually a reason for such); (ii) upside beyond "today" is gone; (iii) Western Oncolytics appears to only have raised a few million dollars; (iv) see the UPitt relationship/lineage above; (v) one could argue the trend is oncolytic virus, but one also could argue the trend is the tumor microenvironment (TME) as the gateway and route of delivery as the way to enter the gateway; (vi) there is no mention of Pfizer/Merck KGaA's anti-PD-L1 avelumab; (vii) more interest in the gateway, and the use of intralesional (IL) agents to enter it, and the value IL agents in combination with other therapies, especially immune checkpoint inhibitors; (viii) one could argue that Pfizer, a laggard in the immuno-oncology space, is slowing getting up to speed on where the possibility exists to catch-up (e.g., via TME, injection, oncolytic immunotherapy, etc.); and (ix) was Pfizer late again, beaten to the better UPitt oncolytic immunotherapeutic assets by Celgene and others?
    It also is still injection of a biologic, and therein lies the "rub." Said another way: What I know now could be what I wished I knew then. Or perhaps said even another way: An entire pharmaceutical industry unsure or unable to consider or contemplate that the injection of a chemical (Rose Bengal/PV-10/a halogenated xanthene) -- not a biologic (e.g., a Rous sarcoma virus, a herpes simplex virus, a common cold virus, a CpG oligodeoxynucleotide, an avian paramyxovirus, etc.) -- can elicit a systemic immune response.

    Recall St. Luke's Dr. Sanjiv Agarwala's presentation at 6th European Post-Chicago Melanoma/Skin Cancer Meeting. Setting aside Rose Bengal and chemotherapy cisplatin, I believe, everything other oncolytic agent is a biologic.
    Click to enlarge. Image source
    Rose Bengal to the pharmaceutical industry might as well be battery acid. An intralesional or intratumoral injection of this chemical (sulfuric acid) should kill the injected lesion or tumor. As a I wrote under Do Dr. Jedd Wolchok/Sloan Kettering Understand Immunotherapy's History? (July 12, 2016) on the blog's Current News page, the father of cancer immunotherapy, Dr. William Coley, MD injected dead bacteria -- a biologic -- into the cancer tumors of his patients.

    Oncorus' algorithmic creation (by the VC MPM) and funding (by financial and corporate investors) in today's environment is proof positive the immuno-oncology space still remains wanting for a solution to vast amounts of unmet patient need, and that solution (or an important contributor to it) could be intralesional/intratumoral cancer therapy. Of course, what Oncorus is injecting is a biologic.

    Provectus' data, in context, necessary and presumably sufficient to assuage the industry's concern over a [small molecule] chemical being capable of generating a systemic immune response are the results of the company's two ongoing melanoma trials, one of PV-10 as a monotherapy or single agent, and the other of PV-10 in combination with an immune checkpoint inhibitor.

    Management teams, boards of directors, addressable markets, worth, valuation, etc.; those are all straightforward, and cut across industry sectors. But as a non-life sciences investor, perhaps I did not fully appreciate the apparent very high hurdle of the intralesional therapy of a small molecule chemical. Knowing what I know now, how would I have invested differently, if [I would have invested differently] at all...?

    • Rous sarcoma virus: Allovectin-7 (Vical)
    • Herpes simplex virus: talimogene laherparepvec/T-Vec/Imlygic (BioVex/Amgen), HF10 (Takara Bio)
    • Common cold virus: CAVATAK/Coxsackievirus (Viralytics)
    • CpG oligodeoxynucleotide: SD-101 (DynaVax)
    • Avian paramyxovirus (Wolchok, Allison, etc.)

    July 11, 2016

    Clash of Clans

    Image source
    Every drug or drug compound, and drug category or class has a clan.

    Clan members comprise all manner of biopharmaceutical industry constituency or stakeholder; from physicians, clinicians and medical researchers to global regulatory agency staff to Big Pharma/Biotech executives and employees to pharma and biotech investors and traders to media, journalists and commentators to medical conferences to...

    Whether one's "schtick" are immune checkpoint inhibitors, targeted therapies, radiation or radiotherapy, intralesional therapies, etc., we've all got our clan or tribe.

    I believe, by virtue of this blog and talking our book, that our clan(s) is(are):
    • First, PV-10, and Rose Bengal, which fall into the category of small [chemical] molecules that rely on their physical (and not biological) chemistry properties, and
    • Second, intralesional (IL) or intratumoral (IL) therapies (aka local, loco-regional or local-regional, and regional therapies), because route of delivery matters.
    But there is good reason for the biopharmaceutical industry ecosystem to be skeptical of the class of IL therapies. First, until very recently (October 2015 for talimogene laherparepvec or T-Vec), there had been no history of clinical success and, thus, regulatory approval. Second, what promising, approved therapy there has been (T-Vec) has turned out to be a marginal product with an uncompelling clinical value proposition. Before Amgen's T-Vec was approved in 2015 as Imlygic for advanced melanoma, failure preceded it more than two year before in the form of Vical's IL agent velimogene aliplasmid (Allovectin-7) in August 2013 for the same indication. Before Vical, there was the failure of IL agent bacillus Calmette-Guérin (BCG) in 1978, also for advanced melanoma. Taken together, IL therapies would have a modest-to-no history of regulatory validation for nearly 40 years.

    Now consider HemOnc Today's July 10, 2016 article entitled "Intralesional agents show promise in melanoma but may serve ‘narrow clientele.’" After reading it, I am struck by what seems to be physician clan members -- of the IL therapy clan -- endeavoring to frame the potentially notable clinical benefits and patient outcomes IL cancer therapies could generate or yield if only there was a better IL therapy to be their flagbearer. T-Vec was the first guy through the wall, opening the regulatory and commercial doors for IL therapies. The article made me think these clan members were waiting for PV-10 to bust through the door, breaking its frame in the process.
    • HemOnc Today's article's page links
    • Quoted physicians
      • Sanjiv S. Agarwala, MD (medical oncologist, aka Dr. Rose Bengal) —a T-Vec and PV-10 clinical trial investigator from St. Luke's University Health Network in Bethlehem, Pennsylvania,
      • Robert H.I. Andtbacka, MD (surgical oncologist) — a T-Vec and PV-10 clinical trial investigator from Huntsman Cancer Institute in Salt Lake City, Utah,
      • Dale Han, MD (surgical oncologist) — no affiliations were disclosed, and from Yale School of Medicine in New Haven, Connecticut,
      • Vernon K. Sondak, MD (surgical oncologist) — a consultant to Amgen and Provectus from Moffitt Cancer Center in Tampa, Florida, and
      • Jeffrey S. Weber, MD, PhD (medical oncologist) — an advisor to Amgen and a PV-10 clinical researcher from NYU Langone Medical Center.
    Article paragraphs and quotes of interest to me:
    • "HemOnc Today spoke with medical and surgical melanoma specialists about the future of intralesional agents for melanoma, whether oncolytic agents likely will be used as single agents or in combination with immunotherapies, and the lingering questions surrounding T-VEC’s efficacy based on the OPTiM trial."
    • "“If you look specifically at patients with stage IIIB or stage IIIC disease on the OPTiM trial, their response rate was 52%,” Robert H.I. Andtbacka, MD, CM, FACS, FRCSC, associate professor of surgery at Huntsman Cancer Institute at University of Utah, as well as a HemOnc Today Editorial Board member, told HemOnc Today. “None of the other immunotherapies and checkpoint inhibitors have come close to having that response rate in that patient population.” 
    Andtbacka, who served as an investigator on the OPTiM trial, said the positive outcome and FDA approval signal the utility of intralesional agents in the rapidly expanding melanoma landscape."
    • "The relatively mild toxicity profile of T-VEC may make it more appealing to some patients than immunotherapies, which can produce virulent adverse events, Sondak added.
    “Adverse events can be quite modest when you are just injecting a [lesion], rather than trying to treat the entire patient,” Sondak said. “If we can get the immune system to pay attention to the melanoma and do something good because of it, then you are looking at a low-toxicity means of producing an important, clinically relevant immune response.”" 
    • "Although most oncologists agree T-VEC has a role in the melanoma treatment armamentarium, the design of the OPTiM trial has prompted a number of clinicians to question how large that role should be.
    The primary reason for concern is the use of GM-CSF as the control. 
    “T-VEC was approved on the basis of a clinical trial design that will certainly never be replicated,” Sondak said. “The control arm was basically a placebo, with no basis in why one would choose to use that particular regimen. I don’t know if that design would be approved today by the FDA.” 
    OPTiM researchers enrolled patients between May 2009 and July 2011. The majority of new melanoma therapeutic options were approved after that period, leaving some oncologists to wonder how the results might differ if the trial were conducted now."
    • "“There are many patients who have tumors that do not have tumor-infiltrating lymphocytes, and checkpoint inhibitors cannot work unless those lymphocytes are there,” Andtbacka said. “Using an oncolytic therapy can actually change the tumor microenvironment, and essentially make a ‘cold’ tumor become a ‘hot’ tumor. When we do that, it appears that we can make a nonresponder into a responder.”"
    • "“The preliminary data for T-VEC combinations look promising,” Han said. “The whole idea of treating systemic melanoma has really blossomed into the idea of combination therapy. Combining T-VEC with other effective systemic treatments was the natural next step to see if we could further improve outcomes.”"
    • "“The beauty of combinations is that you can take a patient who has an in situ tumor reachable by a needle and inject it with something that makes the tumor more immunogenic,” Agarwala said. “If you throw in a confirmed immunotherapy that works well, you have the potential for synergy.”
      Because melanoma has been shown to respond to combinations, the use of these regimens should be considered when possible, Agarwala added. 
      “I like to say, ‘Make the tumor your friend, and make it your ally,’” he said. “If you can’t remove the tumor — if you’ve tried everything and it keeps coming back — instead of just trying to remove it again or giving systemic therapy, why not add an intralesional agent that gets into the microenvironment and releases antigens? That is a concept that highly appeals to me.”"
      • "The labor involved in preparing a T-VEC injection may drive cost-related considerations.
      “The biggest cost factor with an intralesional therapy, aside from the drug, is time,” Agarwala said. “It’s not just a nurse hanging a bag. You have to have a doctor or a provider actually do a procedure, and that procedure is billable. It taxes the provider’s time. I am not sure if anyone has studied the total cost yet, but the short answer is that it’s an issue.” 
      Weber agreed. 
      “An injection like this can take up a room for 20 minutes and might be viewed as a hassle by a doctor with a busy practice,” Weber said. “If a nurse practitioner is doing the injection, that’s time she or he is not seeing other patients. I do not think it is unreasonable to say that some busy oncologists view it as more work than it is worth.”"
      • "T-VEC is the first intralesional agent to be approved as monotherapy for the treatment of advanced melanoma. However, it is far from the only oncolytic agent under investigation.
      “These agents are safe and produce good response rates,” Agarwala said. “Some of the ongoing trials of new oncolytic agents can address the concerns left over from the OPTiM trial.” 
      Agarwala serves as an investigator on a phase 3 study investigating PV-10 (Provectus Biopharmaceuticals), an injectable form of rose bengal disodium that received FDA orphan drug designation for melanoma and hepatocellular carcinoma."
      • "“The current PV-10 randomized trial only includes patients who have failed immunotherapy or are not candidates,” Agarwala said. “In that sense, it is much more of a real-world trial [than OPTiM]. The control arm of the trial is chemotherapy, which is reasonable, because if you have tried everything else, it is a fair comparator.”"
      • "“These agents may have theoretical or practical advantages compared with T-VEC,” Sondak said. “They are all worthy of investigation, without question, and some could be real advances. There is value to having T-VEC available, but it will also be important for these other agents to have their chance to show what they can do.”"
      For the first time that I can recall, an article discussing by therapies addressed treatment administration by non-physician providers (e.g., nurse practitioners, physician's assistants, nurses). See page 6 of the article here.

      The article's author should have discussed this topic with Dr. Agarwala's NPs, PAs and/or RNs, and solicited their opinions of PV-10.