May 3, 2016

Catching On

Takeaways and a Question:
  • Getting T cells into cancer tumors is important to more successfully fighting the disease.
  • Traditional cancer treatments do not kill enough cancer cells. Immunotherapies like immune checkpoint inhibitors kill more cells than traditional treatments, but they still do not kill enough.
  • Ways of getting T cells into tumors include chemotherapy, radiotherapy, targeted therapies and intralesional (IL) or intratumoral (IT) agents like Amgen's talimogene laherparepvec (T-Vec) (Imylgic®) [approved as a single agent], Provectus' PV-10 [in a pivotal Phase 3 trial as a single agent], Viralytics' Cavatak (another oncolytic virus) [having done Phase 2 trial work as a single agent], etc.
  • The more (quantity) and better (quality) T cells that get into cancer tumors, the greater the immunologic signalling of the drug or drug compound (immunotherapy) that led to said infiltration.
  • If a drug or drug compound's immunologic signalling is so powerful and broad as to enable the Cancer Immunity Cycle to cycle more sustainably and durably, what would have come first, the chicken or the egg (i.e., the left-hand side, or the right-hand side, the antigen cascader or the checkpoint inhibitor)?
Big Pharma-oriented blogger and publisher, and industry consultant, Dr. Sally Church, MD recently wrote a post (on her blog Biotech Strategy Blog; subscription required) asking if chemotherapy was immunotherapy: "Controversy: Is Chemotherapy Immunotherapy?" Her thoughts derived, in part or in whole, from her visit to AACR 2016. She noted in this post (alluding to a prior one) that one of the rate limiting steps in the Cancer Immunity Cycle was "getting more T cells into the tumours so that subsequent immunotherapy can be even more effective." One way to get more T cells into tumors, according to Dr. Church, was chemotherapy.
Click to enlarge. Tweet image source
Getting T cells into cancer tumors, from the perspective of a traditional treatment like chemotherapy, begins with generating antigens caused by killing cancer cells.
Click to enlarge. Figure 3, Chen and Mellman. Immunity 2013; 39: 1-10.
Utilizing therapeutics or therapies (immunotherapies) from the left-hand side of the Cycle to facilitate the infiltration of presumably educated and trained T cells into cancer tumors, therapeutics (immunotherapies) from the right-hand side can be, to use Dr. Church's words "even more effective."

Following Dr. Church's writing, primarily her tweets (and related or associated material) on Twitter (@maverickNY), is necessary for this investment project. She was kind enough to answer some basic questions of mine early on in my due diligence (basic for her, not so basic for me at the time). With 20 years of experience in the pharmaceutical industry that included the development and launch of Gleevec by Novartis (bios here and here), Dr. Church is smart, intelligent, thoughtful, and (I believe) a weather vane of Big Pharma's market/marketing (and, possibly, R&D) interest and direction. For example, she was and presumably remains a fan of checkpoint inhibitors, but has evolved her views (as I believe them to have developed) in regards to treating late-stage disease from such agents strictly as stand-alone, single agent therapies to their greater relevance and effectiveness in combination with other therapeutics and therapies (presumably stimulatory ones complementary to these inhibitory agents).

AACR 2016 not only discussed chemotherapy as a "potential immunotherapy" (viewing this through Dr. Church's prism), the conference also considered and contemplated radiation therapy or radiotherapy — but fractionated treatment, where radiation treatment is given in several, small doses over a period of time. This is about killing cancer cells to begin the antigen cascade (immunogenic cell death). This is about harnessing the cancer patient's tumor(s) to become a vaccine, so to speak (in situ vaccination).

PV-10 + Chemotherapy. Ironically, as an aside, at SITC 2012 (October), three-and-a-half years before AACR 2016 (April), Provectus presented the results of murine model work combining PV-10 and chemotherapy that generated the best response in non-injected (untreated) tumors {underlined emphasis below is mine}:
"The mechanism by which PV-10's bystander effect is produced was investigated using hepatocellular carcinoma (HCC) and melanoma tumors in immunocompetent and immunodeficient mice. In one set of experiments using immunocompetent mice with bilateral HCC tumors (i.e., two HCC tumors in opposite flanks), intralesional injection of PV-10 into one of the two tumors led not only to eradication of the injected tumor, but also to regression of the uninjected tumor. Controls treated with saline exhibited no effect in either tumor. Treatment of mice with systemic chemotherapy (i.e., 5-fluorouracil, "5-FU") had minimal effect on either tumor, while combination of intralesional PV-10 with systemic 5-FU elicited maximal response in uninjected tumors. Data were analyzed by tumor (i.e., injected tumor, uninjected tumor and total tumor burden) for time to progression and for tumor growth. PV-10 alone was favorable to saline control in all categories, while PV-10 combination therapy produced highly significant advantage vs. control for time to progression of treated tumors (p = 0.010), untreated tumors (p = 0.011) and total tumor burden (p = 0.004)." (Source: Provectus press release, October 2012)
Click to enlarge. Image source
Click to enlarge. Image source
PV-10 + Radiation. Even more ironic, and as a further aside, Provectus shareholders await the presentation or publication of an investigator-initiated study in Australia combining PV-10 and radiotherapy in patients with advanced melanoma. You know...what the company's CTO Dr. Eric Wachter, PhD said more than a year ago in response to a question of mine.

As background, Radiation therapy has been combined with PV-10 in two situations. First, in 2010, Foote et al. reported on their combination work on 3 patients in A novel treatment for metastatic melanoma with intralesional rose bengal and radiotherapy: a case seriesMelanoma Research, 20:48, Jan 2010. All of the patients originally were enrolled in Provectus' metastatic melanoma Phase 2 trial (I believe). All patients achieved complete response (CR) (note detailed descriptions in the article's text); however, no discussion was provided regarding survival (that is, keep in the mind the difference or differentiation between [objective] response rate and overall survival). Note: PV-10 was administered firstfollowed by radiation.
Click to enlarge. Fuzzy purple underlined emphasis is mine.
Later, in 2013, Tan and Neuhaus reported on their combination work on 2 patients in Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcomaANZ Journal of Surgery, 83:1-2:93, Jan 2013. Both patients were treated in the company's compassionate use/expanded access program (I believe). One patient achieved a complete response, while the other enjoyed "good" clinical effect before progressing again. Also, no discussion was provided regarding survival of the patient achieving CR. Note: Here, radiation was administered firstfollowed by PV-10.

During the 4Q15/CY 2014 business update conference call on March 11, 2015, I asked about the timing, and possibly the potential venue(s) (medical conference, journal), of Foote et al.'s clinical follow-up work combining PV-10 and radiotherapy? Eric said: "But regarding the radiation therapy publication by Foote, that is of record as having led to an investigator-initiated study that you mentioned, 25 patients. That study has been enrolling slowly. It had very specific eligibility criteria at a single center. We have had discussions over the last several months with the investigator about ways to get data from that study available publicly and we anticipate that sometime in the coming months, that is sometime this year, that there will be some presentation of interim data from that study" {my underlined emphasis; this year = 2015}.

Step #5, Infiltration of T cells into Tumors. PV-10 has been potentially implicated in each and every step of the Cancer Immunity Cycle, with data on Step #5 to come.
Click to enlarge. Image source
Click to enlarge. Image source
If PV-10/Rose Bengal can (has) overcome one of the Cancer Immunity Cycle's rate limiting steps (of getting T cells into cancer tumors) in greater quantity and better quality (than other treatments), would Dr. Church then refer to PV-10 as immunotherapy?

April 21, 2016

Burning Down The House

Wikipedia's tumor infiltrating lymphocytes (TILs) page describes TILs as "a type of white blood cell found in tumors." It goes on to say that "TILs are implicated in killing tumor cells. The presence of lymphocytes in tumors is often associated with better clinical outcomes." The National Cancer Institute's Dr. Steve Rosenberg, MD, PhD pioneered the approach of using TILs via adoptive cell transfer (ACT) to treat cancer patients. The American Cancer Society notes that TILs are "immune system cells deep inside some tumors...These T cells can be removed from tumor samples taken from patients and multiplied in the lab by treating them with IL-2. When injected back into the patient, these cells can be active cancer fighters." One company taking this approach of ACT via TILs is Lion Biotechnologies (NASDAQ: LBIO).

Another variation on this concept of ACT is where immune cells originating from a patient's blood (as opposed to his or her tumor) are extracted, altered and put back "with the goal of transferring improved immune functionality and characteristics along with the cells." Peripheral blood T cells are genetically engineered to express tumor-antigen specific T-cell receptors. Companies using this approach include Bluebird Bio (BLUE), Juno Therapeutics (JUNO) and Kite Pharma (KITE).

Autologous (below left) and genetically engineered (below right) ACT are illustrated below from W. Joost Lesterhuis and Cornelis J. A. Punt, “Harnessing the immune system to combat cancer,” 2012, Nature Reviews/Drug Discovery, supplement to Nature Publishing Group Journals.
Click to enlarge.
Harnessing the immune system to combat cancer, in the context of intralesional (IL) or intratumoral (IT) compounds like Bacillus Calmette–GuĂ©rin (BCG), Interleukin-2 (IL-2), talimogene laherparepvec (T-Vec, Imylgic), velimogene aliplasmid (Allovectin-7), Rose Bengal (PV-10), CAVATAK, Newcastle Virus Disease, HF-10, etc., means more than just destroying the lesion or tumor into which these agents are directly injected —it also means, more critically, the potential to generate a robust immune response, to activate, educate, train and thus enable (collectively, "harness") the immune system to attack cancer elsewhere in circulation.

Mechanism of action (MOA) would explain how an IL or IT agent destroys an injected lesion or tumor. Immune mechanism of action (IMOA?) or mechanism of immune action (MOIA?) would explain how the IL/IT agent harnesses the immune system to destroy uninjected, distant or so-called bystander lesions or tumors. PV-10's IMOA/MOIA also would be very relevant in the context of combining the IL/IT agent with other immunotherapies.

Provectus' CTO Dr. Eric Wachter, PhD analogizes PV-10's systemic response to fire, smoke and ash —where there's smoke and ash, there also is fire. T cells in the [peripheral] blood is the smoke. Regressed tumors are the ash. TILs are what interested observers want to see; that is, the fire.

From here, travel back to February 2013's Cancer Watch article about PV-10 and Moffitt Cancer Center's IMOA/MOIA work (which began in December 2012 [protocol first received date]) in this regard. The article is entitled "Back to Phase 1: Understanding Systemic Effects of PV-10;" Moffitt's work is entitled Detection of Immune Cell Infiltration Into Melanomas Treated by PV-10, a Feasibility Study (lead investigators: Dr. Amod Sarnaik, MD and Dr. Shari Pilon-Thomas, PhD).

Moffitt's work in mice in 2012, and presented and published in 2013, concluded that IL/IT PV-10 treatment led (after lesions/tumors were injected and then destroyed or shrunk) to a systemic response. The Cancer Watch article noted:
"Seeking an immune cell infiltrate 
To find direct evidence of such a systemic immune response is part of the motive behind heading back to the bench—although this time involving human subjects. “A further impetus toward teasing out the precise mechanism of how PV-10 can exert a systemic immune response in patients,” said Dr. Sarnaik in an interview, “is to allow us to rationally combine PV-10 treatment with some of the exciting emerging immunotherapies for metastatic melanoma.” 
The focus at Moffitt, Dr. Sarnaik continued, is on discerning the presence of immune cell infiltrate in untreated tumors after PV-10 injections into other lesions. “We are really interested in harnessing immune cell infiltrate as a form of treatment,” he said, noting also that while creating cancer vaccines has been thought of traditionally as one of the Holy Grails of cancer research, cancer vaccines have turned out to be not strong enough to generate an adequate immune response."
The article then went on to note {underlined emphasis and inserted commentary is mine}:
"Adoptive cell transfer 
The strategy of adoptive cell transfer potentially overcomes the weak vaccine response. With adoptive cell transfer, antigen-specific effector cells are taken from the patient’s tumor and expanded ex vivo under laboratory conditions favoring growth of T-lymphocytes and then re-infused to the patient. This precludes the need to provide antigens or to activate antigen-presenting cells. 
ACT via TILs: In melanoma, T-cells from the tumor are cultured from tumor resection specimens in the presence of interleukin-2. ACT via T cell re-engineering: A second strategy infuses peripheral blood T-cells that have been genetically engineered to express tumor-antigen specific T-cell receptors. 
While adoptive cell transfer offers the advantage that enough T cells can be obtained for infusion in all patients, the T-cell receptors transfected into the T cells have a limited antigen-specificity. The strategy works, Dr. Sarnaik said, only about half the time. “We generate large numbers of T-lymphocytes, but we don’t have control over their quality. 
We think one of the limitations is that the T cells you get out of the tumor just aren’t good enough.” PV-10, however, does cause an immune response, suggesting that a combination treatment may improve the quality of the T-lymphocytes and have a greater impact on the disease. 
When Shari Pilon-Thomas, PhD, also a Moffitt researcher, demonstrated that T-lymphocytes recovered from mice treated with PV-10 do appear to be of a higher quality, as evidenced by stronger tumor reactivity, the stage was set for Dr. Sarnaik’s current 15-patient pilot study. In it, one of two resectable melanoma tumors is injected with PV-10. Both are removed several weeks later. Serum is assessed before and after treatment to look for changes in the infiltration of immune cells. In patients with an immune response, PV-10 therapy can be continued."
Unfortunately, Moffitt's IMOA/MOIA/combination therapy relevancy work was waylaid because PV-10 worked too well — both injected and uninjected lesions or tumors were destroyed too well (pathologic complete response [pCR]) and too quickly (sooner than the study protocol patient biopsy period of 7-14 days post-PV-10 injection).

In April 2014 at AACR, Dr. Pilon-Thomas noted about their human work up to that point (the poster was not released by either Moffitt or Provectus, see the company's press release here):
Too quickly, and "smoke:" "These data are exciting and illustrate successful translation of our pre-clinical work in mice to clinical results in melanoma patients. With only 8 patients we've been able to clearly observe statistically significant increases in beneficial T cell populations in peripheral blood. Ironically, the original aim of the trial to assess tumor-infiltrating lymphocytes was thwarted when biopsies of patient tumors collected just 7-14 days after PV-10 injection no longer contained viable tumor tissue. We are following up both the human data and continuing to design more experiments in mice to better explain the systemic immune effects elicited by PV-10 ablation."
In June 2014 at ASCO, Moffitt further noted:
Too well, and "ash:" "Treatment with IL PV-10 led to pCR in the post-treatment biopsies of both PV10-injected and uninjected study lesions in 4 of the 8 patients, and all 8 exhibited at least partial regression of the injected lesion."
Really, ironically, some of the injected and uninjected going away too quickly in Moffitt's work is reminiscent of Provectus' metastatic melanoma Phase 2 trial, and Eric's argument to the FDA to grant PV-10 breakthrough therapy designation for PV-10 in patients (who would have all of their disease treated) with locally advanced cutaneous melanoma:
"Because of the lack of requirements for patients to have pain symptoms upon enrollment, only a small fraction of patients had clinically significant pain at baseline. So, we analyzed those patients, uh, and presented them that analysis of those data in context of the objective response data. We found that there was a strong relationship between the two types of data, that there was simply not enough of the symptomatic, or symptomology data to show a statistical function. I have to conclude that that’s the principal basis for the rejection of the application. I'd say that it was our assumption going into the application that improvement in symptoms, if we made the patient’s symptoms go away was tantamount to -- I’m sorry -- if we make the patient’s lesions go away that’s tantamount to making the patient’s symptoms of that disease go away. We don’t seem to have been successful in convincing the Agency of that."
Nevertheless, Moffitt found, in humans, smoke — T cells in peripheral blood — and ash — regressed tumors.

The Cancer Watch article went on to note:
"“This is a straightforward study that will give a yes or no answer,” Dr. Sarnaik said. 
If the hypothesis that PV-10 will produce a better immune cell infiltrate is borne out, that would justify testing of combination treatments, Dr. Sarniak said. Likely candidates are adoptive cell therapy, approved drugs like ipilimumab that boost immune response, or PD-1- blocking antibodies (none approved yet)."
Moffitt should have found, in humans, the fire, presumably through the following 7 patients of their originally planned 15-patient study. In November 2015 at SITC they showed they found more smoke: "Increased tumor-specific response was found from those circulating T cells of 5 out of 7 tested patients after IL RB treatment."

The Cancer Watch article concluded:
"What kind of therapy is PV-10? 
Echoing Dr. Sarnaik, Eric Wachter, PhD, Provectus chief technology officer, said that he hopes that the findings of Dr. Sarnaik’s study will point toward rational judgments about combining PV-10 with other documented therapies. “We then might want to try two or more orthogonal therapies to stress tumor cells from several different angles simultaneously, for example an immune therapy plus a metabolic therapy (e.g., a kinase inhibitor), or in a rationally designed sequence.” In a hepatocellular carcinoma model, he added, PV-10 showed significant potential for synergy with 5-fluorouracil. Provectus recently initiated clinical testing of PV-10 with the multikinase inhibitor sorafenib, again bringing in two therapies with divergent mechanisms of action. 
Which category does PV-10 fall into? “I think we are getting a clearer picture of how it might be classified, but it has features of several previously unrelated categories, such as of adoptive cell transfer and vaccination,” Dr. Wachter said. “PV-10 initially reduces tumor burden through chemoablation—but then activates the immune system bringing in capacities completely orthogonal to the ablative tumor destruction,” he added." 
“Amod Sarnaik’s work may give us the molecular basis for closing the loop on one of the founding concepts for going into the clinic in the first place,” Dr. Wachter commented. “Back in the preclinical days at Provectus, Craig Dees, PhD, theorized that ablation of tumors with PV-10 might lead to unmasking of tumor antigenic material. I don’t think he anticipated that it would work as well as it does.”

March 29, 2016

Trying to Understand Provectus' Clinical Development Program (e.g., trial design, protocols, data, etc.)

Reference article: "How to Spot Red Flags in Clinical Trial Data," Adam Feuerstein, Biotech Stock Mailbag, TheStreet.com, March 24, 2016

Adam Feuerstein wrote the above article, which resulted from a conference call he held with Dr. Mark Ratain, MD on March 22nd (conference link in the article) to discuss "a checklist of things to think about when a biotech or drug company announces clinical trial results." Feuerstein and Rattain covered, presumably among other things:
  • Single arm vs. randomized controlled trials (SATs vs. RCTs),
  • Communication of trial results (press releases, and the information contained therein),
  • Changes to trial protocols, and
  • The importance of N (the number of patients enrolled in a trial).
Feuerstein concluded with a comment on the importance of more and further questions, research and due diligence, but noted: "Despite all that work, you can still end up being totally wrong."

Given the potential of a promising investigational oncology drug like PV-10 (active pharmaceutical ingredient [API]: Rose Bengal), together with key intellectual property (IP) protection (e.g., patents and trade secrets covering Rose Bengal's second medicinal use as a therapeutic, method of use, formulation, synthesis, and combination with other therapeutics), clinical trial protocols could be viewed as a biotechnology company's crown jewels. Well-designed clinical trials could be prognostic of outcome; should, as successful early-stage studies, facilitate the transition to pivotal trials; and should, as successful later-stage registration studies, provide eventual labels for drug compounds if and when approved by the FDA.

Diligencing clinical development programs (CDPs) precedes the generation and communication of clinical trial data. So, it's very important to understand Provectus' decision-making, choices and execution of solid tumor cancer indications, supporting preclinical murine model work, eventual patient populations, clinical trial designs and protocols, etc. in advance of sought after study results.

CDPs are intertwined with the FDA, and vice versa. Opaque as the Agency's process may appear to be, and generalized as my analogy below is, it is an understatement to say Provectus' past, present and future has been, is and will be about the company's CDP process. Current emphasis is, of course, finally on the step of generating and presenting more and randomized trial data. This is especially so for a molecule like PV-10 (and API Rose Bengal), and Provectus' approach to treating cancer; the former being very novel and the latter being historically unsuccessful (that is, treating disease locally [i.e., making the tumor your friend] in order to defeat it locally and then, in so doing, systemically) until now.

A door is built when a company achieves a consensus design for a pivotal trial with the FDA. The door is closed of course. But, with its design and construction complete, the drug company can commence a registration study in pursuit of the key the regulator holds to open it. A successful study that also leads to drug approval yields the key from the Agency to unlock the door, opening into the room of a market opportunity for the company to commercialize its therapeutic. Drugs fall down before they reach their doors' respective thresholds by failing their pivotal studies, and thus they are unable to obtain the key.

Designing and building the door, traveling the path to secure the key from the FDA, opening of the door, and entering the room are just steps in the Agency's process. Everyone does not follow the process all of the time. When they do, and if they are successful, the process works, in my view. The FDA's process could be observed as nearly agnostic to the investigational drug going through it. See August 12, 2015 blog post The Door.

Takeaways:


In 2016 Provectus should generate and present data for each PV-10 CDP:
  • As a monotherapy for advanced melanoma,
  • In combination (also: as part of a combination regimen) with pembrolizumab (Keytruda) for metastatic melanoma, and
  • As a monotherapy for hepatic cancers.
Also in 2016 the company should produce mechanism of action (MOA) data that may enable Provectus to advance its investigational dermatology drug PH-10 into pivotal Phase 3 trials for psoriasis and/or atopic dermatitis.

Summary:
  • Melanoma CDP, part 1. Provectus' pivotal Phase 3 trial (a registration study) of PV-10 as a monotherapy (a single agent) for patients with locally advanced cutaneous melanoma (AJCC* Stages III B-C and IV M1a):
    • It is a well-designed trial with a unique feature (clinical assessments every 4 weeks), and
    • Recent protocol changes, made as the study enrolls and treats patients, potentially make it easier to recruit into. 
  • Melanoma, CDP, part 2. The company's Phase 1b trial of PV-10 and Merck & Co.'s immune checkpoint blockade drug pembrolizumab for patients with metastatic melanoma (AJCC Stage IV):
    • It is a well-designed trial that is "enrolling well," 
    • The study's design is flexible enough to pair another checkpoint blockade drug or drug compound with PV-10, like ipilimumab, nivolumab, other anti-PD-1 agents, anti-PD-L1 agents, etc., utilizing their respective prescribing or potential prescribing information,
    • The design also is flexible enough to pair PV-10 with a targeted therapy,
    • It is possible by now that a Phase 1b safety assessment has been successfully completed (or is nearing completion), which then would allow for advancement into an expanded Phase 2 RCT of PV-10 + pembrolizumab vs. pembrolizumab alone; that is, PV-10 + standard of care (SOC) vs. SOC, and
    • A Phase 2 RCT (very likely a registration study) would be well-positioned in a post-monotherapy approval world of PV-10.
  • Liver CDP. Provectus' original clinical (Phase 1) testing of PV-10 in liver cancer explored unresectable hepatocellular carcinoma (HCC) and hepatic metastases in an initial group of patients: 13 patients, or 15 patient-tumors -- a single hepatic lesion was treated [injected] with PV-10; two patients with multiple tumors were enrolled twice to allow additional treatment of their second tumors.
    • At July 2015, 10 of 13 patients were alive after up to 54 months. Three deaths occurred; one due to cardiac comorbidity, one due to a serious adverse event (possibly thromboembolism), and one due to HCC progression,
Click to enlarge. ESMO 17th World Congress on Gastrointestinal Cancer, Abstract #P-116, July 2015
    • The company expects to present more data from this Phase 1 study in July 2016,
    • Initial clinical testing was expanded to (a) continue assessing HCC and potential tumor indications in additional patients and (b) begin assessing HCC patients on a stable dose of sorafenib, with patients still receiving PV-10 treatment of a single hepatic lesion,
    • The advancement of the expanded Phase 1 trial should take the form of a Phase 1b/2 clinical trial approach similar to that Provectus' melanoma CDP (i.e., PV-10 + SOC of pembrolizumab), where after and assuming a Phase 1b safety assessment is successfully completed, the CDP would advance into a Phase 2 RCT of PV-10 + SOC vs. SOC, where SOC would depend on geography (e.g., sorafenib, local ablation technologies like TACE or RFA, etc.).
* AJCC = American Joint Committee on Cancer

Provectus' overall CDP, led from inception (I believe) by the company's CTO Dr. Eric Wachter, PhD, is comprised of at least 5 parts:
  • Oncology (PV-10, a 10% solution of Rose Bengal) (parts 1 to 3)
    • Melanoma
      • Earlier stages of advanced melanoma: Stage III B-C and IV M1a
      • Later stage: Stage IV (visceral: IV M1b-c)
      • Mechanism of action
    • Hepatic cancers
      • HCC (aka primary liver cancer)
      • Cancers metastatic to the liver (aka secondary liver cancer)
      • MOA
    • Other solid tumor cancers (e.g., breast cancer, etc.)
  • An active compassionate use program (CUP)/expanded access protocol (EAP) for cutaneous or subcutaneous tumors (mostly, but not limited to, melanoma) (part 4)
  • Dermatology (PH-10, a 0.001% to 0.01% gel of Rose Bengal) (part 5)
    • Psoriasis
    • Atopic dermatitis
    • MOA
Quotations below are drawn from the above mentioned Feuerstein article. Bolded, underlined and/or italicized emphases in them, or in quotations of other people, are mine. As background, Provectus' two-prong approach to treating cancer comprises, first, making the cancer patient's tumors his or her friends by treating all accessible (injectable) lesions and tumors with PV-10. Second, this direct attack on the patient's tumor burden educates or awakens the immune system to fight back, hold off or destroy cancer elsewhere in the body.

[Quote A]
"Generally speaking, single-arm clinical trials are difficult to interpret because they lack a comparator arm. A single-arm study could produce credible evidence of drug activity in certain circumstances -- a study measuring response rate in deeply refractory cancer patients, for example. Be very skeptical, however, of single-arm studies with progression-free survival or overall survival endpoints. Likewise, the use of an historical control is suspect."
Eric's approach with the FDA prior to the approval of immunotherapy ipilimumab (Yervoy) in 2011 was to seek accelerated approval on the basis of PV-10's "robust response" in metastatic melanoma patients from a Phase 2 SAT. Response rate means objective response (OR) rate (ORR), which equals complete response (CR) rate (CRR) plus partial response (PR) rate: OR = CR + PR. Company presentations from 2009 and 2010 outlined this, prior to agreement with the Agency to undertake a Phase 3 RCT. Relevant slides from these presentations are below:
Click to enlarge
Click to enlarge.
Click to enlarge.
Click to enlarge
Click to enlarge
Co-opting Feuerstein's language from Quote A above: Eric initially sought drug approval on the basis of an SAT that produced credible evidence of drug activity by measuring response rate in deeply refractory cancer patients. It should be noted in addressing Feuerstein's comments that Provectus' SAT, Phase 2 Study of Intralesional PV-10 for Metastatic Melanoma, had:
  • A primary endpoint of ORR (modified RECIST v 1.0**), and 
  • Secondary endpoints of ORR of untreated bystander lesions (see **), progression-free survival (PFS) (see **) (measured for only 52 weeks), and 1-year overall survival (OS).
The following excerpt is from Provectus' November 2010 press release Reports Full Phase 2 Study Data on PV-10 for Metastatic Melanoma. Presentation of preliminary clinical trial results was made at SMR [November] 2010.
"A Complete Response (CR) of PV-10 injected lesions was achieved in 24% of subjects, Partial Response (PR, requiring at least a 30% reduction in tumor volume) in 25% of subjects and Stable Disease (SD, requiring less than 20% increase in tumor volume) in 18% of subjects, with 23% of subjects experiencing disease progression (PD, 20% or greater increase in tumor volume); 
Response was considerably higher in the 55 subjects with cutaneous or nodal disease only (55% OR and locoregional disease control in 78% of subjects) than in the 25 subjects with visceral metastases (35% OR with a 56% rate of disease control); 
An OR was achieved in untreated bystander lesions in 37% of subjects having an evaluable bystander lesion at baseline, with 55% of subjects achieving locoregional disease control in their bystander lesions; 
Bystander response was closely correlated with successful ablation of injected lesions, with 67% of subjects achieving an OR of their bystander lesions if they achieved an OR in their injected lesions vs. 5% in subjects who did not achieve an OR in their injected lesions; 
Mean Progression Free Survival was 8.2 months for all subjects, while the OR cohort had a significantly longer PFS estimated to be 11.7 months vs. 4.1 months for SD or PD subjects; subjects with cutaneous or nodal disease achieved a mean PFS of 8.8 months vs. 6.2 months for subjects with visceral metastases: 
Adverse Experiences ("AE") during the study interval were generally mild to moderate, locoregional and transient, with no deaths or life-threatening experiences attributable to PV-10."
All patients in this Phase 2 trial "had recurrent, locally advanced melanoma after a median of 6 previous interventions (range 1–19), and most had received multiple classes of treatment" (source: journal article below), such as surgical excision, nodal biopsy, regional chemotherapy, immunotherapy, radiotherapy, investigational agents, systemic chemotherapy, distal amputation, and other. Related references include:
The underlined portion of the Phase 2 trial results press release above will be relevant to another Feuerstein comment as well as later in this blog post; that is, the subgroup analysis of the patient population of PV-10's initial pathway to approval. Returning to our story and saga, the FDA directed Provectus to undertake a Phase 3 RCT. Relevant slides from a 2010 company presentation are below:
Click to enlarge.
Click to enlarge.
See also April 2010 press release Reports on Successful End-of-Phase 2 Meeting with U.S. FDA and Gains Clarity for Licensure of PV-10 for Metastatic Melanoma.

Recall comments of melanoma, intralesional agent (IL) and PV-10 key opinion leader (KOL) Dr. Sanjiv Agarwala, MD of St. Luke's Cancer Center at the 2016 HemOnc Today Melanoma and Cutaneous Malignancies conference and in March 19th article "Intralesional therapy ‘here to stay’ for melanoma:"
"“If we’re going to show monotherapy with PV-10 works, you have to design a randomized trial,” Agarwala said. “It is not easy to design a randomized trial for a monotherapy intralesional agent, when you have all of these drugs available. This trial is designed in a very specific way, and it will be very interesting to see the results of this trial compared to the talimogene laherparepvec [Imlygic, Amgen] trial, because that trial was designed in a different era.”"
The primary endpoint identified in the slide immediately above (Phase 3 Study Overview) is durable response (DR) rate (DRR) for at least 6 months, which was the primary endpoint of BioVex's (Amgen's) Phase 3 RCT for intralesional (IL) agent OncoVEX (GM-CSF) (talimogene laherparepvec), A Randomized Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of Treatment With OncoVEX^GM-CSF Compared to Subcutaneously Administered GM-CSF in Melanoma Patients With Unresectable Stage IIIb, IIIc and IV Disease. BioVex's pivotal trial (prior this company's acquisition in 2011 by Amgen) started in 2009, which was about a year before the FDA directed Provectus towards a Phase 3 RCT of IL PV-10.

Returning briefly to Feuerstein's comment of "credible evidence of drug activity," the Agency acknowledged such activity while at the same time denying Provectus' breakthrough therapy designation (BTD) application in May 2014 for patients with locally advanced cutaneous melanoma, the sub-group noted in the November 2010 press release above (but by a different name). BTD was denied because Eric's Phase 2 SAT, designed in c. 2009, did not collect sufficient quality of life and/or patient reported outcome data:
"The preliminary clinical data provided in your request for Breakthrough Therapy designation are indicative of drug activity in the treatment of local, satellite or in-transit recurrence of malignant melanoma; however, the preliminary clinical data do not demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. This determination is based on the paucity of data on endpoints indicative of clinical benefit (e.g., pain, infection, significant bleeding) and our inability to determine the clinical significance of the reduction in the size in one to 10 target lesions in patients with locally advanced melanoma, who may have additional untreated cutaneous, subcutaneous, or visceral sites of disease. " (Source: FDA BTD denial letter, May 16, 2014; see also May 24, 2014 blog post The FDA Response)
Paucity means not enough data. Paucity does not mean the data are not good or not good enough.

It is also important to note, with the benefit of hindsight, that Eric's discussions with the FDA on a prospective Phase 3 RCT were hindered to no small degree (I believe he was reluctant to agree with the Agency) because, first, there was no agreement on the patient population he thought appropriate and applicable. Second, I think he felt there was insufficient IP protection of the therapeutic use of Rose Bengal (and thus PV-10) as well as their (Rose Bengal and PV-10's) manufacture for therapeutic use. Third, I think Eric felt there was inadequate supply of both drug substance (Rose Bengal) and drug product (PV-10) for a pivotal trial and in a post-approval world. See May 30, 2014 blog post "Why did it take four years...to arrive at this point?". I still also think in a post-ipilimumab approval world and pre-Provectus December 2013 Type C meeting with the FDA, there still was debate over the role and utility of an IL agent for treating cancer.

[Quote B]
"Ratain very much likes randomized, controlled studies (preferably blinded as well) for the converse of the reasons stated above."
Almost four years to the date of presenting Phase 2 SAT data (November 4, 2010), Provectus initiated its pivotal melanoma RCT (November 10, 2014) for Stage III B-C disease, PV-10 Intralesional Injection vs Systemic Chemotherapy for Treatment of Locally Advanced Cutaneous Melanoma Without Distant Metastases. Elements of this design were communicated by company management as early as 2013; see the relevant slide below from a March investor presentation:
Click to enlarge.
Provectus understood there was a difference between (a) treating earlier stages of advanced melanoma (Stage III B-C and IV M1a), where all of the disease's lesions and tumors should be accessible to a PV-10-filled needle (e.g., manifested in or pursued by the on-going Phase 3 RCT of PV-10 as a monotherapy or a single agent) and (b) treating much later stages (Stage IV M1b-c), where disease has spread out of the reach of the needle (e.g., now manifested in or pursued by the ongoing Phase 1b/2 program combining PV-10 and immunotherapy pembrolizumab, A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination With Systemic Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma). Relevant slides from Dr. Argawala's SMR 2010 presentation show:
Click to enlarge.
Click to enlarge.
The trial's patient population was expanded from Stage III B-C to include IV M1a in March 2016, via a new trial protocol, when Eric added fellow IL drug talimogene laherparepvec (T-Vec), which was approved in October 2015, as a comparator, PV-10 Intralesional Injection vs Systemic Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma Without Distant Metastases.

[Quote C]
"When the company's press release hits the tape, do these things:
Read the press release. The whole thing. If the headline of the press release states results are "positive," "outstanding" or uses some other superlative, assume there are problems hidden somewhere in the waning paragraphs until proven otherwise. Read the press release again.

The design of the clinical trial, including number of patients enrolled, the type of patient enrolled and the endpoints (primary, secondary), should be explained clearly. There will be a paragraph discussing the study results. Look for these re-assuring words/terms: Intent-to-treat analysis, statistical significance, achieved the primary endpoint. More details, more specific data are better than less.

Be wary of companies which describe "positive" clinical trial results using wishy-washy adjectives."
Although not a comprehensive list of Provectus press releases about preclinical and clinical PV-10 data, let's look at some press releases for melanoma, liver cancer, breast cancer, and dermatology:
    • 4th paragraph: "At final evaluation after injection with a single dose of PV-10, the following results were obtained: 20% of subjects achieved CR of their injected tumors, 20% achieved PR, 35% achieved SD and 25% achieved PD, corresponding to an objective response (CR+PR) in 40% of subjects and local disease control (CR+PR+SD) in 75% of subjects. Among those subjects achieving an objective response of their treated tumors, 25% achieved an objective response of their untreated bystander tumors, and 100% exhibited disease control in their bystander tumors. In contrast, for those subjects failing to achieve an objective response of their treated tumors, only 8% achieved an objective response of their bystander tumors, and 92% exhibited progressive disease in their bystander tumors. These differences in response of bystander lesions as a function of response of target lesions were statistically significant and support the occurrence of a bystander effect in subjects whose target lesions have been responsive to PV-10 chemoablation."
    • 2nd paragraph: "Key interim data from the first 40 subjects in the Phase 2 study included: Objective response of PV-10 treated lesions was observed in 60% of subjects. Locoregional disease control of treated lesions was observed in 75% of subjects. Response of untreated bystander lesions was consistent with observations from Phase 1 testing. Interim safety data were comparable to Phase 1, with transient mild to moderate locoregional pain, vesicles, edema or swelling most common."
    • 3rd paragraph: "Summary data on 20 subjects, including initial data on 4 subjects from the final 40 subjects in the study, who had evidence of macroscopic metastases of the lung, liver, brain or lymph nodes at screening, were presented. Among the first 40 study participants, 7 of the 16 subjects (44%) with visceral or macroscopic nodal metastases at screening exhibited stasis or regression of their lesions, including complete regression of multiple pulmonary metastases measuring up to 1.1 cm in one subject. Detailed data were presented on one Stage IV subject who experienced complete regression of multiple lung metastases and partial regression of multiple brain metastases over the study interval."
    • 2nd paragraph: See above.
    • 4th paragraph: "Dr. Agarwala and co-authors from 7 prominent melanoma centers in the United States and Australia studied the safety and efficacy of IL PV-10 in an 80 patient international, multicenter, single arm phase 2 trial. A subgroup analysis of 28 patients with all existing melanoma lesions injected and an additional 26 patients with only 1-2 uninjected bystander lesions showed that these patients experienced an exceptionally high rate of response. The best overall response rate (BORR) in the 28-patient "all treated" subgroup was 71% (confidence interval of 51-87%), with 50% complete response (CI 31-69%). Among the 54 patients in both of these subgroups (i.e., patients who had all of their disease monitored in the study), CR (Complete Response) was achieved in 232 of 363 injected lesions (64% CR). Furthermore, CR was achieved in 121 lesions after a single injection of PV-10; 84 lesions required 2 injections to achieve CR; 22 lesions required 3 injections; and 5 lesions required all four allowed injections."
    • Data was presented on the poster; however, the press release noted in its 4th and 5th paragraphs: "In the initial study cohort, six subjects received PV-10 injections in two successive escalating dose cohorts of 0.25 and 0.50 mL per cm3 lesion volume. Significant adverse events were limited to injection site and photosensitivity reactions that resolved without sequelae. All injected tumors were stable in size at 28 days, and among four of the initial six tumors that had longer-term assessment, two had partial response. Based on these data, the researchers concluded that preliminary efficacy in treatment of liver tumors with PV-10 was observed with acceptable tolerability. The study is continuing at three study centers with two expansion cohorts to further assess safety and response in HCC and other cancers metastatic to the liver."
Provectus' approach to communication of clinical trial progress and data via press release headlines and content could be described as mixed: sometimes wanting, proper or silent, while at times inconsistent and confusing. For example:
  • Some of the releases above used superlatives, such as "encouraging," capitalization, and "exceptional." Others did not. As to whether the headline superlatives matched the clinical results in the releases, one's stock position (i.e., long, short or none) could dictate or lead one's interpretation,
  • For the company's metastatic melanoma Phase 2 SAT, Provectus press released the opening of each of the trial's seven trial sites, as well as the trial's commencement, enrollments of 25%, 50% and all of the trial's 80 patients, and completion of treatment,
  • Aside from July 2015 medical conference presentations of initial hepatic cancers data (where the company disclosed treatment of 13 patients or 15 patient-tumors), Provectus has not yet communicated the progress of its liver CDP, such as the total number of patients enrolled and treated to date, in which expansion cohorts these patients were treated, etc., and
[Quote D] 
"Other red flag words/terms to watch for: per protocol, retrospective analysis, responder analysis, subgroup(s), modified intent-to-treat, trend, grade five toxicity (that means a patient died.) 
Were any changes made to the trial design, including endpoints? Did the company fully enroll the study as planned? Don't rely on the company to tell you. Compare the company's description of the trial with information listed on ClinicalTrials.gov. You'd be amazed how many times they don't match up."
In the intervening years between (a) the presentation of preliminary full metastatic melanoma Phase 2 trial data (November 2010) and (b) an agreement between the FDA and Provectus on the applicable patient population for PV-10 as a monotherapy (December 2013, see January 2014 press release PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes) and who would form the basis for the Phase 3 RCT, the company undertook retrospective/subgroup/certain responder analyses of the subset of patients in the metastatic melanoma Phase 2 SAT who had all of their disease treated:
    • 2nd paragraph: "The data presented on response rate and progression free survival corroborated previously presented preliminary data on these topics. Key results include: An Objective Response Rate (OR) of 51% in subjects' target lesions (25% Complete Response and 26% Partial Response); 69% disease control in these lesions (combined Complete, Partial and Stable Response subjects); 33% of subjects having an untreated bystander melanoma lesion achieved an OR in their bystander lesions while 50% achieved disease control in these lesions; Response of bystander lesions was highly correlated with outcome in treated target lesions, with a bystander lesion OR of 61% in subjects achieving complete or partial response in their target lesions versus 18% bystander lesion OR in subjects that did not achieve this level or response in their target lesions; Stage III subjects experienced a substantially higher target lesion response rate (60% OR and 79% disease control) versus Stage IV subjects (22% and 33%, respectively); Similar trends were noted in response metrics for bystander lesions between these two subpopulations; Analysis of temporal data showed that Stage III subjects also experienced significantly greater mean Progression Free Survival (PFS) of at least 9.7 months, versus 3.1 months for Stage IV subjects (median PFS for Stage III subjects was not reached during the 12-month study interval); Overall survival (OS) data were also presented by disease stage, with Stage III subjects achieving a mean overall survival of at least 12.6 months (median not reached during the study interval) versus 7.3 months for Stage IV subjects. Case studies on several subjects illustrated potential stasis or regression of untreated visceral lesions following PV-10 treatment of their cutaneous lesions, while data on long-term treatment of one study participant demonstrated successful management of the disease over a period exceeding 3 years."
    • 6th and 7th paragraphs: "Results showed that for all subjects, BORR was 51% (26% CR, 25% PR) with the amount of tumor burden accessible to PV-10 injection prognostic for outcome. In the majority of subjects (68%) the lesions treated with PV-10, together with the up to two untreated bystander lesions, constituted all disease present, and these subjects achieved a BORR of 63%. In subjects where all disease was treated (35% of subjects) BORR further increased to 71% (with 50% achieving CR). Additional new data analyses explored response rates relative to locoregional blistering, a specific reaction observed in 40% of subjects. This phenomenon generally occurred within seven days of PV-10 injection but with no clear pattern of incidence, and typically resolved within four weeks. Appearance of this potentially immune-mediated effect was strongly predictive of outcome. Subjects who developed blisters had 66% BORR (44% CR) vs. 42% (15% CR) for those not developing blisters. The correlation between occurrence of blisters and locoregional disease control was even stronger: among subjects with blisters, 91% achieved stable disease or better vs. 54% of subjects without blisters."
    • 4th and 5th paragraphs: "In the phase 2 PV-10 trial, when all existing lesions were injected with PV-10, tumors were no longer detectable (complete response) in 50% of the patients (Confidence Interval: 31-69%). This subgroup analysis supports the potential of PV-10 as a single agent and provides a rationale for a PV-10 phase 3 randomized controlled trial in locally advanced melanoma patients. This phase 3 randomized controlled trial of PV-10 in patients with unresectable locally advanced cutaneous melanoma will assess response to PV-10 vs that of systemic chemotherapy in patients who have disease limited to cutaneous and subcutaneous sites and who have failed or are ineligible for systemic immunotherapy. Progression-free survival and complete response rate will be assessed using standard criteria (RECIST 1.1). Overall survival and exploratory assessment of patient reported outcomes related to lesion pain and other melanoma symptoms will also be assessed. The study is expected to commence this year, and will allow for interim assessment when 50% of the required events have occurred (i.e., disease progressions)."
As noted above, the pivotal melanoma Phase 3 RCT design was changed, expanding the trial's patient population from its initial population of Stage III B-C patients (November 2014) to include those with Stage IV M1a disease (March 2016).

[Quote E]
"Assuming the study was enrolled fully, can you track all the patients from beginning to end? I always pay attention to the "Ns" -- slang for the number of patients in each arm of the study. Look out for patients missing from analyses for inexplicable reasons. It's not unusual for patients to drop out of a study, but they still need to be accounted for in whatever efficacy analysis is being used. Patients "disappeared" are a red flag."
In Provectus' metastatic melanoma Phase 2 SAT the company noted the number and impact on efficacy of patients withdrawing from the trial.

More importantly, N has been, is and continues to be a critical letter and number for PV-10 and Provectus trials, primarily as it relates to the potential treatment effect or effect size of PV-10 when compared to control drugs in the Phase RCT of systemic chemotherapy and IL T-Vec, and the eventual Phase 2 RCTs of pembrolizumab (compared to PV-10 + pembrolizumab) and sorafenib (cf. PV-10 + sorafenib).

Big Pharma beats multi-efficacy look pivotal clinical trials of somewhat better drugs  (i.e., having smaller effect sizes) by using large numbers of patients. The immune checkpoint inhibitors represent notable relative improvement over prior patient options; however, patient trial numbers were not insubstantial. Effect size is a measure of strength (of something over something else). In the context of a clinical trial where the responses of two groups (a control group and a test drug one) are being compared, the difference in response between that of the control group and that of the test drug group is known as the effect size.

Should the control and test (treatment) groups be close in response, and thus the test drug has a small effect (i.e., it is a less efficacious agent), a large or larger number of patients are needed in order for the test drug to distinguish itself; that is, for the confidence interval (say 90% or 95% interval) of the test drug to not overlap or run into the confidence interval of the control. Conversely, if the test drug is very effective, a large effect size may anticipated, and thus a relatively small number of trial patients are needed; that is, the confidence interval of the test arm, in this case, may be large without overlapping the confidence interval of the control arm. The fact Provectus only is utilizing 225 patients in its pivotal Phase 3 trial signals this study assumes a relatively large effect size for PV-10 (i.e., PV-10 is very efficacious). Generally speaking, the more effective a drug is the less patients would be needed (without taking into account other factors that might influence clinical trial design) in a trial.

A more effective drug, less study or trial patients are needed. Less effective, more patients needed. See June 23, 2014 blog post Trial Math: Meeting the Primary Endpoint, Pt. 1 and July 16, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part II.

Feuerstein's comments about N are made in the context of communicating trial results. When Eric changed the melanoma Phase 3 RCT's protocol to include patients with Stage IV M1a disease, and allow T-Vec as a comparator, better interpretation for "not candidates for" and less restrictive lesion size entry criteria, he did not change the trial's N of 225 at the time. It is possible he could change this figure in the future, although I doubt it.

Eric's original N=180 (when his initial patient population was Stage III B-C), with a hazard ratio (HR) of 0.545; see the slide entitled Planned Phase 3 trial under Quote B. Eric's "final" N=225 was 25% higher. Did he subsequently increase his "final" HR too? Higher HRs are worse than lower HRs. The goal of a clinical trial is to generate an actual HR that is lower than the projected HR for the study. As I noted above, higher Ns make it easier for trials to win and meet endpoints. But PV-10's efficacy, all things being equal (e.g., the Phase RCT protocol for patient treatment of and follow-up with PV-10), would not have changed between the time of his original N and his final one -- thus potentially lowering the trial's hurdle by some, most or all of the 25% associated with the increase in N.

[Quote F]
"A lot of clinical trials fail. This is the bane of biotech... 
Not every subgroup analysis is fraudulent. But getting comfortable with the potential credibility of a subgroup analysis requires asking a lot more questions and research. The press release will only be the start of that journey. This is an incomplete list, but it should get you started. I'll end with a depressing truth. You can work through this checklist and do a lot more in-depth research that validates your investment thesis. 
Despite all that work, you can still end up being totally wrong. This is why we love and curse biotech stocks." 
In June 2014, on an investor conference call, Eric said in regards to Provectus' Phase 3 RCT:
"We firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome. It's critical to understand what the drug is doing, which patients are most likely to benefit, what other options those patients have, and which endpoints would be most convincing for government agencies to approved the labelled indication for the drug."
Time will tell. 

March 19, 2016

It's 2016: Intralesional therapy [for oncology] is "here to stay"

(H/t a regular hatter for the article heads-up and link)

Melanoma, intralesional (IL) agent for oncology, and PV-10 key opinion leader Dr. Sanjiv Agarwala, MD of St. Luke’s Cancer Center (and a HemOnc Today editorial board member) made his presentation Current Trials with Oncolytic Agents at the HemOnc Today Melanoma and Cutaneous Malignancies conference on Friday in New York.

In a March 19th article by Alexandra Todak entitled Intralesional therapy ‘here to stay’ for melanoma, Agarwala said the following.

About Provectus' pivotal Phase 3 trial entitled PV-10 vs Chemotherapy or Oncolytic Viral Therapy for Treatment of Locally Advanced Cutaneous Melanoma:
“If we’re going to show monotherapy with PV-10 works, you have to design a randomized trial. It is not easy to design a randomized trial for a monotherapy intralesional agent, when you have all of these drugs available. This trial is designed in a very specific way, and it will be very interesting to see the results of this trial compared to the talimogene laherparepvec [Imlygic, Amgen] trial, because that trial was designed in a different era.”
About the role of IL agents in a physician's toolkit:
“There is no getting away from the fact that even monotherapy with intralesional agents for the right patient population produces good clinical results. The question is, in what setting are you going to use it? For us, in the medical oncology world, whether we will pick this first or not is a bit of a question.”
About the utility of IL agents for later-stage (i.e., advanced or metastatic) melanoma patients:
“We’ve been able to now make an intralesional therapy applicable to not only patients with M1a disease, but also to patients with M1b and M1c disease. So, patients with multiple metastatic sites might be able to benefit.”
About the combination of IL agents with other cancer therapeutics and therapies like immune checkpoint inhibitors; Provectus' Phase 1b/2 program in this regard is entitled PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma:
“Combinations will be the future. Why not find a way to combine modalities that have different mechanisms of action and have, very importantly, nonoverlapping toxicities?” 
And:
“We have to realize intralesional therapy is not going anywhere, it is here to stay. It is a new paradigm for potential combinations, and perhaps in the future the ultimate melanoma regimen is going to be with an intralesional therapy with a systemic, checkpoint inhibitor. Monotherapy also is applicable to specific patients.”

March 18, 2016

Things May Get Worse Before They Get Better, Unless They Get Better Right Away

On the blog's Current News page I wrote about the tumors of patients who received and responded to treatment with Amgen's talimogene laherparepvec (T-Vec, or trade name Imylgic) that increased in size (i.e., following injection of IL drug T-Vec, the tumors appeared to progress) before they decreased in size or shrunk. See Progression Prior to Response (PPR) (March 17, 2016) and #3 under To Dos (March 16, 2016).

This transient tumor behavior of getting bigger before getting smaller (and hopefully going away) is referred to as pseudo-progression. This phenomenon was observed in patients suffering from glioblastoma multiforme (brain cancer) who received chemotherapy (e.g., temozolomide).

Some patients receiving immunotherapies like anti-CTLA-4 drug ipilimumab (Yervoy) as well as anti-PD-L1 drugs pembrolizumab (Keytruda) and nivolumab (Opdivo) also experienced pseudo-progression in clinical trials. Such transient behavior is with a delayed immune response. See, for example, Pseudoprogression and Immune-Related Response in Solid Tumors, Chiou et al., J Clin Oncol. 2015 Nov 1;33(31):3541-3.

BioVex, which designed T-Vec's pivotal Phase 3 trial, when it was called OncoVEX (GM-CSF), constructed it to facilitate some amount of time to elapse before assessment tumor response -- so as to not mischaracterize pseudo-progression as progression. Some clinical trials may employ so-called immune-related response criteria (irRC) to address pseudo-progression.

Pseudo-progression can occur by 12 weeks of imaging and maybe later.

Provectus' pivotal Phase 3 trial uses RECIST v. 1.1, which as I previously noted defines disease progression as an increase in overall lesion size of >20%. I also observed that half of the responding patients in T-Vec's Phase 3 trial experienced an increase in overall lesion size of ≥25% and/or developed at least one new lesion prior to ultimately achieving a response. T-Vec's trial used a modified WHO tumor assessment method. Provectus' CTO Dr. Eric Wachter, PhD's Phase 3 trial design seems to me to be a pretty down-the-middle-of-the-fairway approach, and a thoughtfully and carefully constructed one at that.

So, my comments about T-Vec, modified WHO vs. RECIST 1.1, pseudo-progression, event generation, etc. need to be taken into context, or better communicated by me.

Tumors injected with PV-10 do have a reaction: There can be some local inflammatory response, and occasionally there is ablation beyond the apparent tumor margin, but in general there's no pseudo-progression over the timeframe experienced by T-Vec, ipi, pembro, nivo, etc.

See, for example, Locoregional Disease Control in Metastatic Melanoma: Exploratory Analyses From Phase 2 Testing of Intralesional Rose Bengal, European Cancer Congress 2013, Abstract No. 3.755, Sep 2013.

One might remember Moffitt Cancer Center's Dr. Shari Pilon-Thomas' comments regarding the center's mechanism of action work: "Ironically, the original aim of the trial to assess tumor-infiltrating lymphocytes was thwarted when biopsies of patient tumors collected just 7-14 days after PV-10 injection no longer contained viable tumor tissue." {my bolded and underlined emphasis} (source: Provectus's April 2014 press release Induction of Systemic Immunity Following Treatment of Tumors with PV-10 Reported by Moffitt Cancer Center Researchers at American Association for Cancer Research Annual Meeting)

Takeaway: PV-10's tumor ablation effectiveness often is not only complete, but it is quickly complete. In the pivotal Phase 3 trial, it might occur before the first clinical assessment, and certainly/hopefully before the assessment to ascertain progression-free survival.

A cycle below is about one month or 4 weeks. A follow-up below is about 3 months or 12 weeks.
Click to enlarge.

March 16, 2016

PV-10 at AACR 2016: T cell mediated immunity after combination therapy with intralesional PV-10

Presentation Title: T cell mediated immunity after combination therapy with intralesional PV-10 and co-inhibitory blockade in a melanoma model

Author Block: Amy M. Weber, Hao Liu, Krithika N. Kodumudi, Amod A. Sarnaik, Shari Pilon-Thomas. H. Lee Moffitt Cancer Center, Tampa, FL

Abstract:
PV-10 is a 10% solution of Rose Bengal, a xanthene dye that was originally developed for ophthalmic use and later used in liver function studies. PV-10 was formulated for intralesional (IL) injection and is currently being investigated as a novel cancer therapeutic. In murine studies, we have previously shown that intralesional (IL) injection of PV-10 leads to a regression of both injected tumors and untreated bystander tumors. We have also shown that combination therapy of IL PV-10 with blockade of PD-1 and PDL-1 leads to increased anti-tumor immunity. In this study, we have examined the role played by specific immune cell populations in eliciting this response in a murine melanoma model. We first investigated the antigen specificity of CD8+ T cells in the spleens of mice treated with the combination therapy of IL PV-10 and systemic co-inhibitory blockade. We found that splenocytes from mice treated with the combination of IL PV-10 and anti PD-1 antibody have an increased mean percentage of OVA antigen-specific CD8+ T cells (5.77%) compared to single treatment with anti PD-1 antibody (3.8%) or IL PV-10 (3.60%) alone in OVA-expressing B16 tumor bearing mice. To investigate the role of T cell subsets in mediating an immune response, OVA-expressing B16 tumor bearing mice were treated with IL PV-10 followed by intraperitoneal injection of anti-PD-1 antibody. In addition, mice were given either 2.43 antibody to deplete CD8+ T cells, GK1.5 antibody to deplete CD4+ T cells, or PC61 to deplete regulatory T cells (Tregs). We found that depletion of CD4+ T cells in combination with IL PV-10 and anti-PD-1 antibody treatment resulted in an enhanced anti-tumor effect, with an average tumor size of 52.8 mm2 on day 25 compared to the control group (173.7 mm2), and depletion of Tregs resulted in an even greater anti-tumor effect, with an average tumor size of 1.2 mm2 on day 25 (p<0.05). In contrast, mice treated with the CD8+ depleting antibody exhibited diminished anti-tumor immunity compared to the control group, with an average tumor size of 200 mm2 on day 25. Together, these studies indicate that the effect of combination therapy with IL PV-10 and co-inhibitory blockade is mediated by CD8+ T cells, and that depletion of both CD4+ T cells and CD25+ Tregs significantly enhances anti-tumor immunity in a melanoma model.
{my bolded and underlined emphasis above}

March 13, 2016

Fourth Quarter, Year-End 2015 Business Update/Conference Call Prep

Image source
Provectus's 4Q15 and CY2015 business update conference call is scheduled for Wednesday, March 16th at 4 pm EDT.

Topics I'd like to hear and read about (or more about) include the below. The list of items and questions is by no means exhaustive.

1. Cash balance, Cash burn, and Stockholders' Equity
  • What was the cash balance at 12/31/15?
  • What was the fourth quarter's [monthly] cash burn?
  • What was stockholders' equity at 12/13/15?
  • What was the research and development expense for the quarter?
  • What was the lab supplies and pharmaceutical preparations expense?
From 1Q14 to 3Q15, the company averaged a monthly cash burn of $1.3 million. This figure was $1.4 million (per month) from 4Q14 to 3Q15. Using a 9/3015 cash and cash equivalents figure of $18.9 million, and a $1.4 million monthly cash burn, Provectus' 12/31/15 cash balance could be $14.7 million.
Click to enlarge.
Maintaining Provectus' listing of both its common stock and tradable warrants requires the company's stockholders' equity (SE) to remain above $6 million. SE equals assets minus liabilities. Net worth (another way of referring to SE), ex-cash for the quarter ending 9/30/15 looks like the below:
Click to enlarge.
Tracking net worth, ex-cash over time provides a cushion of some amount above the mere cash balance to potentially exceed the $6 million SE threshold.
Click to enlarge.
Thus, it is quite possible Provectus' CFO/COO and interim CEO Peter Culpepper does not have to "officially" raise money until well into 3Q16 (i.e., 2Q16 SE might be in the range of >$6 million to $11 million+), rather than the April/May timeframe I originally had projected. Fundraising in this theoretical sense simply compares cash balances, and cash burn and burn rates. In practice, you want to get out ahead-to-well ahead of crossing the threshold, which is what the tender offer is trying to accomplish.

Since pre-clinical, clinical trial and regulatory-related work is reported under research and development on the income statement, it's worthwhile to track, at least or at a minimum, quarterly figures for both research and development expenses, and the sub-expense of lab supplies and pharmaceutical preparations.

From 1Q14 to 3Q14, the company averaged a quarterly research and development expense of $1.2 million. This figure was $2.2 million from 4Q14 to 3Q15.
Click to enlarge.
From 1Q14 to 3Q14, Provectus averaged a lab supplies and pharmaceutical preparations expense (i.e., for both drug substance [Rose Bengal] and drug product [PV-10 and PH-10]) of $200K. This figure was $324K from 4Q14 to 3Q15.
Click to enlarge.
Setting aside of ignoring the mathematical gymnastics in gray above*, the most pertinent observations might be that lab supplies and pharmaceutical preparations expense has increased quarter-over-quarter for the last 6 quarters.

* The above was a very quick 'n dirty calculation that does not include the cost of PH-10 preparation, nor the variation in the number of vials a patient requires based on tumor burden and indication, nor other factors and items.

2. Certain disclosures (among others)
  • What costs and/or cost recoupments, if any, were there or will/could there be related to the resignation of Provectus' Chairman, CEO and a co-founder Dr. Craig Dees, PhD?
  • What is the status of the derivative lawsuits?
3. Stage III melanoma Phase 3 trial
  • Is the timing of the trial's interim data readout/analysis still [early] August 2016?
    • Peter previously said the Phase 3 trial's interim assessment of efficacy and safety would occur around mid-year 2016 or in 2016; however, during the 2Q15 business update conference call on August 6, 2015, he said: "An interim assessment of efficacy and safety will be performed by the independent data monitoring committee when 50 percent of the events required for the primary endpoint have occurred. Therefore, meaningful clinical data are potentially available via an interim analysis on a shorter timeline possibly around this time next year." {my bolded and underlined emphasis}
  • Where is the version of the trial protocol that would include Amgen's intralesional agent (IL) talimogene laherparepvec (T-Vec, or Imlygic) as a comparator?
    • T-Vec would be an investigator's choice of a comparator, together with the trial's other choices of comparator of systemic chemotherapy, either intravenous (dacarbazine) or oral (temozolomide) forms.
  • What is the status of trial site activations in the U.S., Australia, Western Europe (Germany, Poland), South and Central America (Brazil, Mexico), and Asia (China, Hong Kong, Singapore)?
4. Advanced melanoma (Stage IV), combination therapy (PV-10 + Keytruda), Phase 1b trial
  • What guidance is there on the timing, and possibly a potential venue (medical conference), of the presentation of interim clinical trial data?
  • What is the status of trial site activations in the U.S. and Australia?
    • Would these sites, in addition to the single recruiting site to date (long-time PV-10 investigator and medical oncologist Dr. Sanjiv Agarwala, MD's St. Luke's Cancer Center), be part of the Phase 1b portion of the combination therapy program, or the eventual Phase 2 portion?
    • My sense is that currently not-yet-recruiting sites on ClinicalTrials.gov -- long-time PV-10 investigator and surgical oncologist Dr. Merrick Ross, MD's MD Anderson Cancer Center and Australia's Princess Alexandra Hospital -- and others -- e.g., consultants Dr. Paul Chapman, MD's Memorial Sloan Kettering Cancer Center and Dr. Georgina Long, PhD's Australia's Melanoma Institute Australia/University of Sydney-- will be part of the Phase 2 portion when it commences.
  • At this point in recruiting and treatment, what guidance do you have of the Phase 1b's actual or potential impact factor or effect size or treatment effect?
    • The Phase 1b portion of the combination therapy program could recruit up to 24 patients, while the Phase 2 portion has pencilled in an enrollment figure of 120 -- subject to the impact factor or effect size seen from the administration of PV-10 and Keytruda in the Phase 1b study. The better the treatment effect -- that is, the more effective the combination than Keytruda alone -- the lower the Phase 2 trial's N (i.e., a number less or potentially much less than 120).
    • My sense is N_Phase 2 will be less than 120. But, by how much? 
5. Phase 1 liver cancer data presentation/publication
  • What guidance is there on the presentation and/or publication of more and/or initial [expanded] Phase 1 trial data?
    • Eric recently started referring to work on hepatocellular carcinoma (HCC) (primary liver cancer) and cancer metastatic to the liver (secondary liver cancer) as "hepatic cancers." The initial data presentation revealed treatment of multiple liver mets, in addition to the treatment of HCC: colorectal, melanoma, non-small cell lung, and ovarian. Recently, Provectus initiated a trial program to treatment neuroendocrine tumors (NET) liver mets (see #6 below).
    • My primary thoughts here, as it relates to the HCC program in Asia vs. (and) the U.S. and Western Europe (and, maybe, Australia), are that initiating a Phase 1b/2 program (SAT: SOC + PV-10, RCT: SOC +/- PV-10) may take time because of regional regulatory navigation issues; however, that may not necessarily explain time taken for the U.S. where the standard of care (SOC) is sorafenib -- thus, the Phase 1b/2 program could be a randomized controlled trial (RCT) of sorafenib +/- PV-10 because a single-arm trial (SAT) of sorafenib + PV-10 was part of the expanded Phase 1 trial.
6. Follow-on hepatic cancer trials, including NET Phase 1 study
  • Why did the NET hepatic cancer trial commence before any other hepatic cancer trial, early- or late-stage?
    • In the case of an early-stage Asian trial (a Phase 1b), my sense is that Eric still has to navigate regional regulatory issues in China and/or other Asian locales.
      • The patient population of some form of accelerated path (not accelerated approval, but an accelerated regulatory review and action path) might be patients with HCC that is not amenable to resection, transplant or other potentially curative therapy. Clinically significant endpoints might be objective or overall response rate, changes in markets of hepatic function, and perhaps (informally but not formally?) progression-free survival or overall survival (both of which could form the primary endpoints of a subsequent RCT).
7. CUP data
  • How many patients were treated in the compassionate use program (CUP) (aka the expanded access program) in CY2015?
  • What guidance is there on the timing of the publication or publications of CUP clinical results and data?
8. PH-10 MOA data (psoriasis Phase 2 study)
  • What are the results? What guidance is there on the timing of the revelation of clinical results and data?
9. Psoriasis and atopic dermatitis Phase 3 trials
  • What guidance is there regarding additional (if any) regulatory and/or commercial licensing (if applicable or appropriate) steps before the commencement of one or both of these pivotal studies?
10. Further publication/presentation of Moffitt MOA data and other work.
  • What guidance is there on the timing, and possibly the potential venue(s) (medical conference, journal), of further presentation and/or publication of Moffitt Cancer Center mechanism of action (MOA) and other preclinical and/or clinical work?
    • The next presentation of such work will be at AACR 2016 (April), T Cell Mediated Immunity after Combination Therapy with Intralesional PV-10 and Co-Inhibitory Blockade in a Melanoma Model (Provectus press release source link).
11. Further publication/presentation of UIC MOA data and other work
  • What guidance is there on the timing, and possibly the potential venue(s) (medical conference, journal), of further presentation and/or publication of University of Illinois at Chicago (UIC) MOA and other preclinical work?
12. Other preclinical and/or early stage clinical work, More stringers, More indications
  • What other third parties, like Moffitt and UIC, might be undertaking preclinical and/or clinical work on PV-10?
    • During the 4Q15/CY 2014 business update conference call on March 11, 2015, Eric said: "I cannot comment on other third party work that may or may not be underway with regard to nonclinical work with PV-10. Obviously that is something that might be of interest and if it is and we haven’t disclosed it it’s probably of a sensitive nature." The threshold on sensitivity, as time passes and work is completed, can be lowered if Eric wants to lower it. He could lower it if he understands and truly embraces the thoughtful rationale for doing so.
  • What guidance is there on the timing, and possibly the potential venue(s) (medical conference, journal), of Foote et al.'s clinical follow-up work combining PV-10 and radiotherapy?
    • During the same 4Q15/CY 2014 conference call, Eric said: "But regarding the radiation therapy publication by Foote, that is of record as having led to an investigator-initiated study that you mentioned, 25 patients. That study has been enrolling slowly. It had very specific eligibility criteria at a single center. We have had discussions over the last several months with the investigator about ways to get data from that study available publicly and we anticipate that sometime in the coming months, that is sometime this year, that there will be some presentation of interim data from that study."{my bolded and underlined emphasis}
  • In addition to the melanoma, hepatic cancer and dermatology clinical study and trial programs, what other indications do you expect to commence in 2016?
Conclusion

While I don't expect Eric and Peter to address all of the above in the 2015 10-K filing and on Wednesday's call, I hope they try their best to do so, as appropriate, applicable and necessary. One of Craig's most critical and very apparent flaws as a public company manager was his inability or unwillingness or unpreparedness -- or, more likely, parts of all three -- to walk and chew gum at the same time (despite his many protestations over time to the contrary). By the way, I believe Craig had both great strengths and notable weaknesses. On net, Rose Bengal and PV-10 are where they are today in no small part because of him.

As I previously wrote, Provectus is where it is in terms of progress largely -- perhaps exclusively -- because of retail investors. Most traditional investors, including me in a past life, would have utilized them differently in a command chain (without potentially changing, disrupting or corrupting their medical, clinical, treatment philosophies and other approaches) and on the board of directors, and potentially thrown some of them out on their buttocks.

Walking and chewing gum at the same time means dismissing Craig's long-time assertion -- or at the very least placing it in proper context -- of customer prioritization; that his primary customers only were the FDA (the regulator) and Big Pharma (the buyer). Staying power for founders and managers has come from the [retail, and some early institutional] investor.

Good-to-great public company managers balance the needs, wants and desires of most major constituencies. If/when they are successful, the share prices responds accordingly and in due course.

Eric and Peter, in the post-Craig period of the life and emergence of Provectus Biopharmaceuticals, have a clear and present opportunity to speak directly to the investor: existing shareholders as well as prospective ones. I hope they embrace the situation that now presents itself, and robustly exceed the lowered expectations their prior history has established -- because Rose Bengal and PV-10 only can get to where they need and should be tomorrow in no small part because of Eric and Peter.