August 29, 2015

PV-10 has much better gas mileage

Paul Rennert's SugarCone Blog has been and continues to be a good read for this project. Take, for example, his July 18th blog post How far can a CAR get you? The post primarily discusses CAR T cell therapy (CAR = Chimeric Antigen Receptor), concluding with:
"So my hope is that we can engineer CAR T cells with sufficient machinery to “rescue” CAR T technology from the reality of an antigen-poor landscape. The technology is stunning, but I wonder if in the face of such challenges one ought not to look around, and perhaps take another approach. As it turns out, nearly all cellular therapy companies that have taken on the CAR T field have begun to diversify - we’ve been asking what problems we are solving with these clever twists on the basic technology – and this is well worth pursuing. However in the face of a limited pool of targets, lets perhaps consider a technology with a much much larger target list: tumor neoantigens as recognized by T Cell Receptors (TCR). TCR and TIL technologies offer some interesting solutions, and their own unique challenges…" {Underlined emphasis is mine}
Rennert highlights several well known problems of the CAR T field, the below taken verbatim from his post:
  1. CAR T cells must be highly selective for the target cancer to avoid unwanted killing of other cells, tissues, organs
  2. CAR T cells must proliferate and persist once injected into the patient (i.e. in vivo)
  3. Since most CAR T technologies are based on a personalized medicine approach – your cancer attacked by your engineered T cells – there is a fair amount of cell culture to do between harvesting your T cells, altering them (via retroviral or other cell transduction technique), expanding those altered T cells so there are enough to “take” upon injection back into the patient. All of this is expensive, with a typical guess at the price tag of 500K USD
  4. CAR T therapy is dangerous (although a bit like Formula One racing – very dangerous and just barely controlled). The danger comes from the potential for off-tumor cell killing but also from tumor lysis syndrome, which happens when large numbers of tumor cells are suddenly killed – all sorts of cellular signals get released and this causes an intense and systemic physiological breakdown – very dangerous, but controllable in an appropriate intensive care unit (so recovery care is also very expensive)
  5. CAR T therapy to date has had limited success outside of refractory acute lymphocytic leukemia (ALL). Now, while refractory ALL is a poster child of an indication – intensely difficult to treat, with many pediatric patients – there are about 4000 such patients in the US each year. Commercially, this is limiting.
  6. Cancer-specific targets suitable for CAR T technology are very rare.
His list of CAR T technology/company problems are a perfect foil for PV-10 and its own solutions. I believe a new narrative about PV-10 goes something like this: A compound that both agnostically ablates tumors and perfectly primes the immune system. Being copiously liberal with Rennert's list, consider the following below about PV-10.

A. Highly selective
  • Provectus: PV-10 itself exhibits antitumoral activity targeted only on diseased tissue while sparring normal tissue (SITC 2012)
  • Moffitt: “The cells we took from mice treated with PV-10 were indeed activated against B16 melanoma tumors. We demonstrated that by showing that they could be transferred to untreated mice with the same tumor and produce an antitumor response. This is the definitive way to test for a tumor-specific T-cell response.” Against MC-38 adenocarcinoma tumors, the T-cells from treated B16 mice had no significant effect. “This is a very specific response to the B16 tumor,” Dr. Pilon-Thomas said. (AACR 2013)
B. Tantamount to in vivo vaccination
  • Provectus: PV-10's immuno-ablative response is tantamount to "in situ vaccination" (SITC 2012). After all, isn't that what leads to systemic anti-tumor immunity?
C. Inexpensive
  • A 5 mL single-use vial costs tens of dollars to manufacture
  • A melanoma patient may average 6 vials
  • Early-stage liver trial patients thus far may have averaged 5-10 mL (receiving single injections of drug product)
D. Safe
  • 1923: "The patient, a Chinaman with a carcinoma of the pancreas with complete biliary obstruction, showed no toxic effects after the intravenous injection of 100 mg. of the dye. In fact, while observing interest the injection of this beautifully colored “medicine” he stated that he felt much better and wanted more. Frequent injections on this patient gave no toxic effects and led to the subsequent injection of some two to three hundred others."
  • Provectus: PV-10 is not metabolized in the body and has a 30-minute half-life once in the bloodstream.
  • No off-tumor cell killing, no tumor lysis syndrome
E. Broadly indicated
  • Melanoma & Breast Cancer/Moffitt: "These studies have demonstrated that intralesional PV-10, in addition to reducing the growth of a directly injected tumor, leads to the induction of a robust anti-tumor T cell response and supports the use of PV-10 to induce systemic anti-tumor immunity for the treatment of metastatic melanoma and breast cancer." (AACR 2013)
  • Colorectal/University of Illinois at Chicago: "Rose Bengal induced potent cell death in human and murine colon cancer cells in vitro. Intralesional injection in established tumors induced an anti-tumor immune response and significant tumor regressions in vivo. These studies establish that intralesional PV-10 therapy warrants further study as a potential immunotherapeutic agent in colorectal cancer and metastases." (SSO 2015)
I have not included the initial Phase 1 liver data because it only addresses PV-10's tumor ablation, and not yet on the drug's systemic effect.

F. No specific target, receptor or pathway

This item cannot be properly discussed at the current time because knowledge and discussion relies on the presentation/publications of the results of Moffitt Cancer Center's mechanism(s) of action study due later this year.

August 23, 2015

Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part VII

The seventh in a series of blog posts and news items assessing the company's pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma (Stage III patients, and not metastatic [Stage IV] melanoma).
  1. Win or lose: Will the trial succeed in meeting or fail to meet its primary and/or secondary endpoints?
  2. Time-to-success or -failure: How long might it take for the trial to succeed or fail?
  3. Good or bad process: Are there process steps and aspects thereof that may provide hints of potential future trial success or failure.
This blog news item, 3. Good or bad process: The consistency of melanoma patient outcomes from chemotherapy.

Blog post takeaways
  • Stage 3 melanoma patients treated with systemic chemotherapy (dacarbazine or temozolomide) are not more likely to respond than Stage IV patients,
  • A 30-year experience overview of dacarbazine in metastatic melanoma (Stage IV patients) noted an approximately reproducible 20% objective response rate (complete response + partial response), and
  • Thus, Provectus' pivotal Phase 3 trial for locally advanced cutaneous melanoma (exclusively Stage III patients) should see high rates of disease progression (comparable to trials involving Stage IV melanoma patients) occur quickly in its control arm.
Prior analysis (categorized on the blog as Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Parts I-VI, among other posts and news items) primarily utilized Middleton et al. (2000) — Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma (J Clin Oncol. 2000 Jun;18(11):2351). This work yielded chemo disease progression response rates (PD) of 65-70% and median progression-free survival (PFS) of 1.5-1.9 months in primarily Stage IV patients.

Shah et al. (Correspondence author: Chapman) (2010) — Phase II trial of neoadjuvant temozolomide in resectable melanoma patients (Ann Oncol. 2010 Aug;21(8):1718-22) — noted the following in a study of mostly Stage III patients (14 of 19; 5 Stage IV patients):
  • 63% disease progression (12 of 19 patients),
  • Of the 12 patients that had progression of disease, progression was detected at week 4 or 8 (a single cycle or less) in 11 of them. One patient with a mixed response received 4 weeks of a second cycle (less than a second cycle) before progression of disease was evident, and
  • Most patients (12 of 19) only received a single cycle or less of chemo, where a cycle lasted 8 weeks. Six patients received 2 cycles. One patient, who had a complete response (CR), received 3 cycles.
The Shah et al. (inc. Chapman) study outcome is consistent with outcomes in earlier studies despite the earlier stage of disease and the aggressive treatment regimen.

In another study, Rietschel et al. (Correspondence author: Chapman) (2008) — Phase II Study of Extended-Dose Temozolomide in Patients With Melanoma (J Clin Oncol. 2008 May 10;26(14):2299-304) — noted the following in a study of both Stage III and IV patients (25 Stage III/IV M1a/IV M1b patients in one cohort, and 25 Stage IV M1c patients in a second):
  • Objective response rates (CR + PR) in both cohorts were 12.5% (no CRs).
In Serrone et al. (2010) — Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview (J Exp Clin Cancer Res. 2000 Mar;19(1):21-34) — the authors noted:
  • 13 trials involving single agent dacarbazine for advanced melanoma,
  • Objective response rates varying from 12-25%, and
  • Observing, overall, an approximately reproducible 20% objective response rate with median response duration of 5 to 6 months [f/n 1] and complete response rates of 5%.
[f/n 1] Response duration refers to the durability of objective responses, CR and PR, and is not the same as PFS.

Previous entries in the series:
  1. 3. Good or bad process: Patient enrollment. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part I (July 13, 2015) on the blog's Current News page,
  2. 3. Good or bad process: Designing an interim analysis for efficacy into Provectus' pivotal melanoma Phase 3 trial. See July 16, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part II,
  3. 3. Good or bad process: Patient crossover. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part III (July 20, 2015) on the blog's Current News page,
  4. 2. Time-to-success or -failure: Triggering the interim analysis. See July 23, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part IV,
  5. 3. Good or bad process: Patient-reported outcomes. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part V (July 24, 2015) on the blog's Current News page, and
  6. 1. Win or lose: Predicting outcomes, (ii) 2. Time-to-success or -failure: An unusual response in one of the randomized controlled trial arms, and (iii) 3. Good or bad process: Multiple triggers. See August 4, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part VI.

August 15, 2015

Clinical & Business Value Proposition Pillar #5

Image source
On Provectus' August 6th 2Q15 business update conference call, the company's COO/CFO Peter Culpepper introduced five clinical and business value proposition pillars for PV-10:
  1. Intellectual property
  2. Drug supply chain (both substance and product)
  3. Regulatory support
  4. Mechanisms of action
  5. Rational clinical study designs for randomized data generation
Blog post takeaway
  • The focus of this post is pillar no. 5, more data generation, and specifically data generation related to the combination of PV-10 and an immune checkpoint inhibitor (pembrolizumab, and maybe other co-inhibitory blockade agents) in patients with advanced melanoma (Stage IV).
  • Randomized data generation is a process, which starts with a dose escalation component (in this case, the escalation of PV-10's dose in context given the approved Keytruda dose).
  • I'm looking to Provectus' 3Q15 business update conference call potentially in early-November (e.g., Thursday, November 5th) for the company's CTO Dr. Eric Wachter, PhD to discuss and/or have filed the combination therapy Phase 1b and 2 trial protocols. Whether one refers to it as a Phase 1b/2 (as was the case for T-Vec + ipilimumab) or a Phase 1b/3 (T-Vec + pembrolizumab), the second part of the clinical study process is a randomized controlled trial (RCT).
We assume generating randomized clinical data already has started with the commencement of the company's pivotal Phase 3 trial of PV-10 versus systemic chemotherapy in patients with unresectable locally advanced cutaneous melanoma (Stage III). More data is more than likely required to potentially further increase company value.

For advanced melanoma (Stage IV), step #2 of randomized data generation — the RCT component of the melanoma combination therapy two-step clinical study process — starts with step #1, single-arm data generation from a dosing (of the intralesional agent [IL]), safety and response rate evaluation of a pairing of compounds.

On Provectus' March 13th 4Q14 business update conference call Eric said:
"Throughout our consultations with key clinical opinion leaders, we’ve also been attuned to the need to address the needs of patients with more advanced disease. With enrollment now complete in the mechanism of action study of PV-10 of Moffitt Cancer Center, and initial results reported on that study and on the companion nonclinical study to assess combination of PV-10 with immune checkpoint inhibition, we are making progress on design of our proposed study to assess PV-10 in combination with immune checkpoint inhibition in patients with advanced melanoma. 
We continue to expect this to be structured as a Phase 1b/2 study with a modest sized single arm Phase 1b component and expedited safety and efficacy endpoints supporting expansion to a larger randomized Phase 2 component. Endpoints for Phase 1b are likely to comprise acute safety as a combination regimen and objective response rate at three to four months. For Phase 2, we anticipate endpoints of progression free survival at overall survival. With three agents now approved in the US and also available in other key locations abroad, I expect to have very concrete details on this work to discuss at our next quarterly conference call. Importantly now that we have options for this systemic agent, this study can commence with or without the assistance of a partner." {Underlined emphasis is mine}
On the company's May 7th 1Q15 call he said:
And in addition to the progress on the combination therapy patent front that Pete mentioned, we've also made substantial progress towards commencement of our proposed clinical study of PV-10 in combination with immune checkpoint inhibition. We have identified the investigators who will lead this work, the agent to be used in conjunction with PV-10, the patient population and the dosing schedule for both agents along with the study end-point. To assess potential benefit of PV-10 for patients with advance melanoma, this phase 1b/2 study will incorporate a modest sized single arm Phase 1b component with expedited safety and efficacy end point supporting expansion to a larger randomized Phase 2 component. 
End points for phase 1b are expected to comprise assessment of acute safety of the combination regimen and objective response rate at three to four months. For the Phase 2 portion, end points will be progression-free survival and overall survival. 
Once the protocol addressing each of these areas is complete, we believe the pieces are in place to commence clinical work on this important second development path for PV-10 and melanoma. Since the checkpoint inhibitor we expect to use is licensed in the U.S., we can commence this study with or without the systems or a partner." {Underlined emphasis is mine}
By protocol I think Eric means both Phase 1b and RCT protocols (whether one refers to the latter as a Phase 2 or Phase 3 trial).

On the company's August 6th 1Q15 call he said:
"Turning to the other primary component of our development plan for melanoma, we've continued to move towards commencement of a post-clinical study of PV-10 in combination with a new checkpoint inhibition in patients with advanced metastatic melanoma. After thorough consultation with leading investigators who will conduct this work, we have a study design that is undergoing final investigator review and anticipate completing the protocol before the end of the present quarter. 
This includes comprehensive definition of patient population, dosing schedule for both agents, and the study endpoints. As I've indicated previously, to assess potential benefit of PV-10 for patients with advanced melanoma, this Phase Ib/II study will incorporate a modest-sized single arm Phase I key--Phase Ib component of 24 patients with expedited safety and efficacy endpoints. 
Completion of this initial phase is expected to support expansion to a larger randomized Phase II component having an estimated 120 patients. The actual size of the Phase II component will be determined by modeling and response data among Phase Ib participants, that is the socalled observed effect size. 
Endpoints for Phase Ib will comprise assessment of acute safety of the combination regimen and objective response rate at three to four months. For the Phase II portion, endpoints will be overall survival, progression-free survival, and objective response rate. 
We anticipate using the anti-PD1 drug pembrolizumab, also known as Keytruda, as the checkpoint inhibitor. This class of drug has been shown to work favorably with PV-10 in mouse models with melanoma, as presented by our colleagues at Moffitt last November at the Annual Meeting of the Society for Immunotherapy Cancer, and as anticipated in our allowed drug patent application with Pfizer, the two drugs have largely unrelated or orthogonal side effect profiles. 
These factors provide justification for conducting the study. Also, since pembro is standard of care for the study of patient population, it is standard practice to conduct these kinds of studies in an add-on mode where all patients receive standard of care. 
We're optimistic that we can leverage existing investigator and site relationships to commence this study by the end of the calendar year. And since pembrolizumab is licensed in the US, we can commence this study with or without the assistance of a partner. If ongoing negotiations with prospective corporate partners lead to interest in testing PV-10 with a different checkpoint inhibitor, the study is designed to facilitate use with other drugs to enable such testing in a straightforward manner. {Underlined emphasis is mine}
With the Phase 1b and Phase 2 protocols not ready (and thus fileable on ClinicalTrials.gov) all Eric could say was the above. When filed on the .gov site both the T-Vec + ipilimumab and T-Vec + pembrolizumab protocols were two-step ones, as shown below, respectively:
Click to enlarge. Image source. Fuzzy purple emphasis is mine
Click to enlarge. Image source. Fuzzy purple emphasis is mine
In extending my door analogy from August 12th blog post The Door, Eric would have to had to design and construct the first door, design as well as perhaps mostly construct the second in consultation with the FDA (with emphasis on the second door, a presumably pivotal study). There would be placeholders (specifically the size of Phase 2 trial N) for the second door that would be modified pending the outcome of the initial Phase 1b study: "The actual size of the Phase II component will be determined by modeling and response data among Phase Ib participants, that is the socalled observed effect size." (Eric's comments, August 6th business update call).

Securing the keys to the doors from the regulator would require reaching the threshold of each door. I would wonder if yet assume Eric has discussed the path to and through the first door and the path to the second with the FDA. Maybe it's the [paths'] the utilization of a portion of the data (a fraction of the trial N) from the Phase 1b trial — if successful and appropriate — to apply for breakthrough therapy designation, followed by commencing the pivotal study, and the utilization of a portion of the data (a fraction of the trial N1) to be considered for accelerated approval — if successful and appropriate. Of course, maybe that's not entirely or actually the process.

And discussing cost and how to fund these paths (i.e., pros and cons of available and potential options) in the greater context of the company and its overall burn rate is an important matter for another discussion and post.

August 12, 2015

The Door

Image source
Opaque as the Agency's process may appear to non-life sciences investors like me, and obviously highly generalized as my analogy below is, it's an understatement to say Provectus' past, present and future has been, is and will be more about the process (with current emphasis on the step of finally generating randomized clinical trial data). This is especially so for a molecule like PV-10 and Provectus' approach to treating cancer, the former being very novel and the latter being historically unsuccessful (i.e., treating the disease locally in order to defeat it locally and then [in so doing] systemically).

A door is built when a company achieves a consensus design for a pivotal Phase 3 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're unable to get the key.

Unremarkably and yet, I suppose, obviously, 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 parts of or 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. The FDA's process could be observed as almost agnostic to the drug going through it.

1986. After a cursory review of the literature, the first I/O door that appears to have been designed, constructed, unlocked and opened was Interferon alpha (IFN-α) [1].

2010. The second I/O door built and unlocked could be for Provenge (sipuleucel-T) [2].
One could argue for other doors such as Bacillus Calmette-Guérin's (BCG) approval in 1990, Herceptin [trastuzumab] in 1998, Gardasil in 2006, and Xgeva [denosumab] in 2010.
2011. The third door might be for Bristol-Myers' anti-CTLA-4 agent Yervoy (ipilimumab). Pfizer's tremelimumab, a related compound, fell down before the threshold by failing its pivotal Phase 3 trial.

2014. The fourth and fifth doors then would be those for anti-PD-1 agents Keytruda (Merck U.S.' pembrolizumab) and Opdivo (Bristol's nivolumab).
Other similar doors may be designed, constructed and unlocked for companies entering pivotal trials of their anti-PD-1 or anti-PD-L1 agents. One also might consider Perjeta's (pertuzumab) approval in 2012.
2015. A sixth door has been designed and built for but currently remains unlocked to Amgen's talimogene laherparepvec (T-Vec).
April's 22-1 advisory committee vote in favor of the drug should encourage the FDA to give Amgen the key in or by October 27th (the drug's PDUFA date). This outcome, while probable, is not certain. Unlocking T-Vec's door, irrespective of the debate about the size of the room into which the opened door permits entry, could and should be a catalyst (in context) for PV-10. 
Provectus' CTO Dr. Eric Wachter, PhD designed and built PV-10's door last year and this year for melanoma (specifically, unresectable locally advanced cutaneous melanoma) by working with the FDA to achieve a consensus pivotal study design. In so doing he convinced the regulator the drug could be a viable treatment option for patients if the trial successfully meets its endpoints.

For Provectus unlocking T-Vec's door could substantially further discussion about or potentially lead to a license, co-development and/or collaboration deal with and/or an minority equity investment by Big Pharma. The issuance of the joint Pfizer-Provectus combination therapy patent allowed in April, more pivotal melanoma Phase 3 site activations, and/or the presentation/publication of Moffitt Cancer Center's PV-10 mechanism of action study also could contribute to the discussion or potentially lead to a deal or deals.

T-Vec and PV-10's doors are similar and different. While T-Vec's door is similar to those of Yervoy, Keytruda and Opdivo in that they have metastatic melanoma labels, PV-10's door possesses the different feature of treating patients at an earlier stage of the melanoma disease cycle. Its pivotal study embraces the potentially more profound outcome of being the local agent with the opportunity to prove that, delivered locally, PV-10 can forestall, prevent or stop the spread of the systemic disease that is cancer (melanoma).


[1] FDA-Approved Cancer Immunotherapies and CRI’s Impact, April 9, 2015, Alexandra Mulvey
[2] Issues Impacting Stakeholder Adoption of Immuno-Oncology, February 16, 2015, AJMC, Dr. Bruce Feinberg, DO

August 9, 2015

Potential Catalysts & "Catalysts"

Caveat: I have been hilariously off-base in the past. See, for example, my August 31, 2014 blog post Potential Catalysts.

Updated (8/9/15): To reflect a longer period of pivotal melanoma Phase 3 site activation, and to include as a catalyst the potential approval of Amgen's intralesional agent for metastatic melanoma talimogene laherparepvec (T-Vec).

Updated (8/9/15):
 To reflect a year-end start to a Phase 1b trial combining PV-10 and an immune checkpoint inhibitor in patients with advanced melanoma.
Click to enlarge.
Click to enlarge.

August 4, 2015

Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part VI

The sixth in a series of blog posts and news items assessing the company's pivotal Phase 3 trial for unresectable locally advanced cutaneous melanoma (Stage III patients, and not metastatic [Stage IV] melanoma).
  1. Win or lose: Will the trial succeed in meeting or fail to meet its primary and/or secondary endpoints?
  2. Time-to-success or -failure: How long might it take for the trial to succeed or fail?
  3. Good or bad process: Are there process steps and aspects thereof that may provide hints of potential future trial success or failure.
This blog news item, (i) 1. Win or lose: Predicting outcomes, (ii) 2. Time-to-success or -failure: An unusual response in one of the randomized controlled trial arms, and (iii) 3. Good or bad process: Multiple triggers.

Blog post takeaways
  • Provectus' pivotal melanoma Phase 3 trial should be successful, meeting its primary endpoint of progression-free survival (PFS).
    • Meeting the secondary endpoint of overall survival (OS) in the context of PFS as a surrogate for OS, assuming the beneficial support of patient-reported outcomes (PROs), is worth a separate discussion and blog post or news item,
  • It appears the single planned interim analysis for efficacy and safety (based on a prescribed number of events) is very unlikely to (can't) be triggered. There [probably] won't be enough events. As a result, trying to project the timing of trial success, on an interim data readout basis, ultimately must rely on speculating what triggers, boundaries, safeguards, etc. have been designed into the trial to compensate for PV-10's non-normal or unexpected distribution of events to assure a timely readout of interim study results.
  • If Provectus management believe they can adequately predict the outcome of the pivotal trial, then such adequacy may extend beyond whether the trial would be successful to when they think it could be so. Fundamental to these beliefs is the trial's actual enrollment rate.
An article like Seeking Alpha contributor Steven Giardino's June 2014 one (h/t InvestorVillage PVCT poster leave_the_gun) discussing the role, responsibilities and mandate(s) of a pivotal trial's data monitoring committee (DMC) could encourage us to take a step back when assessing Provectus' Phase 3 trial, before rejoining more analysis and opinion-making as well as prior deep dives.

1. Win or lose: Predicting outcomes 

The trial's outcome of winning or losing, succeeding or failing, may simply boil down to observing that PV-10 just kills cancer, which is how I believe the company's Chairman and CEO Dr. Craig Dees, PhD would see and say it. The preclinical and clinical dataset of PV-10 ablating a cancerous tumor or lesion continues to grow, while also demonstrating the drug's agnosticism to disease presentation: e.g., clinically in potentially different melanomas (mutations or variations, but lesions don't appear to be categorized by Provectus), hepatocellular carcinoma (Hepatitis B and C, cirrhosis), breast cancer, and liver metastases (colorectal, non-small cell lung, melanoma, ovarian), and preclinically in at least melanoma, liver, renal, breast and pancreatic tumors. If PV-10 just kills cancer, then the Phase 3 trial ultimately should win or succeed. If it doesn't, it won't.

Provectus' CTO Dr. Eric Wachter, PhD on the other hand already said "[w]e firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome" when considering what PV-10 does or can do, what chemo does, the trial's patient population, the primary endpoint, secondary endpoints, etc., all in the context of the company's pivotal trial. If Eric thinks he can predict the trial's outcome, then he clearly also believes the trial will win or succeed.

"It just kills.." or "being able to predict the outcome..." could present itself, in my over-analytical or analyzed manner, as:
  • In the melanoma Phase 2 trial the overall response rate (ORR) for patients who had all their existing melanoma lesions injected with PV-10 was 71%, with 50% achieving a complete response (CR) despite receiving PV-10 up to four times over a 16-week period (i.e., week nos. 0, 8, 12 and 16) [1],[2],
    • In the Phase 3 trial patients in the PV-10 treatment arm would receive the drug every 4 weeks until CR or disease progression (e.g., week nos 0, 4, 8, 12, 16, 20, etc.).
  • In the Phase 2 trial the ORR for the lesions of patients who had all their lesions injected with PV-10 was 80%, with 74% achieving a CR [1], and
  • In the Phase 2 trial the progression-free survival (PFS) of patients who had all their lesions injected was 9.8 months [1].
    • In the pivotal Phase 3 trial the control arm is systemic chemotherapy of either dacarbazine (DTIC) or temozolomide (TMZ), which have PFSs of less than 2.5 months for DTIC/TMZ [2].
    • I believe Eric designed the trial for a 90% power to detect a 70% improvement in median PV-10 PFS (over DTIC/TMZ PFS) — if the trial's DTIC/TMZ median PFS is 1.5 months then PV-10's must be >2.55 months, or if 2 then >3.4, or if 2.5 then >4.25.
[1] Subgroup Efficacy in Patients Receiving Intralesional Rose Bengal to All Existing Melanoma in Phase II Study PV-10-MM-02, European Society For Medical Oncology, Abstract #1120P, September 2014. [2] Janet Fricker, PV-10 delivers greatest effects when all lesions are injected, Pharmiweb.com, October 15, 2014
  • As the pivotal trial's principal (lead) investigator, St. Luke's Cancer Center's Dr. Sanjiv Argawala, MD, said last year following ESMO 2014, “The progression free survival of 9.8 months compares favourably with historical progression-free survivals of less than 2.5 months for DTIC/TMZ.” [2]
2. Time-to-success or -failure: An unusual response in one of the randomized controlled trial arms

Compare and contrast PV-10 and chemotherapy above, or the distribution of responses ("events") for chemotherapy and PV-10 below.
Click to enlarge.
See July 23rd blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part IV
I think it's fair to describe PV-10's historical objective tumor response results for melanoma as non-normal distribution curve or very likely to produce an unexpected distribution of events, where the baseline of what is or should be expected being chemotherapy's distribution curve. Thus, trying to estimate the timing of early and/or interim readouts of Provectus' pivotal study results must rely heavily on what if any as yet unmentioned multiple triggers, boundaries or safeguards Eric designed into the trial to augment the publicly discussed planned interim analysis for efficacy and safety based on a prescribed number of events (which is probably never going to [won't] get triggered).

In my July 23, 2015 Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part IV blog post I tried to make the argument Eric designed a planned interim analysis of efficacy and safety based on prescribed time, in addition to the planned one based on prescribed events. The analysis suggested the timing of this second trigger (starting in July 2016) was generally in line with (but later than) public comments by management of when an interim analysis might occur ("likely in the first half of 2016"). If there can be two interim analysis trigger, why cannot there be more for a drug with an effect size large enough to withstand the statistical dings or alpha spend of additional efficacy looks?

3. Good or bad process: Multiple triggers

Planned/prespecified or unplanned/not prespecified reviews of safety data of randomized controlled trials do not cause bias or incur alpha spending, and thus do not result in statistical dings of study results. Reviews of or "looks" into efficacy data, however, do incur dings or spend alpha (if you take multiple looks at the data, there is an increase in the risk of Type I error). Thus, if the addition of a second trigger (a prescribed time one) indeed is true (the first being a prescribed event trigger), then Provectus' statistical analysis plan (SAP) would have to address and thus account for three efficacy looks: (i) a final analysis, (ii) the single planned prescribed event interim analysis and [potentially] (iii) a prescribed time interim analysis. As an aside, the aim of an SAP is "to minimize bias by clearly stating the proposed methods of dealing with protocol deviators, early withdrawals, missing data, and the way(s) in which anticipated analysis problems will be handled as well as many other possible issues."

Using current parameters (such as the trial's N of 225), Eric's design yields a 90% power to detect a 70% improvement in median PFS. As I noted above, if the trial's actual DTIC/TMZ median PFS turns out to be 1.5 months then for the trial to win PV-10's actual median must be >2.55 months, or if 2 then >3.4, or if 2.5 then >4.25. PV-10's median Phase 2 trial PFS of 9.8 months (out of a 12-month follow-up period) compared to a 70% improvement of 4.25 over Agarwala's 2.5 month historical median PFS for DTIC/TMZ should mean PV-10 has a lot more alpha to spend if Eric wants to spend it. And if he spends his alpha early (on a much earlier interim analysis than expected) and never has to spend it again (on the planned interim analysis), then he can continue through the final analysis with the planned spend equalling the actual spend.

What might these additional triggers be and when (if at all) could they facilitate earlier study readouts than the interim analysis (prescribed event or time)? My guess tries to keep simple: There may be efficacy looks that of course cost alpha, presumably planned or prespecified but not publicly discussed, that occur after a certain number of events (one event per person). The planned interim analysis requires 113 events for a trial N of 225 (50%). Maybe another trigger is 20 events, 30 events, etc. The analysis of what "early" eventually could be defined as may boil down to the number of patients (and thus events) required to show statistically significant PV-10 and chemotherapy PFS curve separation acceptable to a DMC and/or the FDA. Returning to 2. Time-to-success or -failure above, the timing of success then becomes the sum of (i) the enrollment time of the patients (e.g., 60, 90, etc.) required to generate the smaller number of events (e.g., 20, 30, etc.) and (ii) the separation time required of the last patient treated in that smaller trial n.
Click to enlarge. 20 events.
Click to enlarge. 30 events.
Eric has been repeatedly and consistently wrong in the past with regard to the timing of things. Peter's guidance of a 1H16 interim data readout, based presumably on Eric's guidance, thus is questionable because it requires the trial's actual enrollment rate to track Eric's projected monthly enrollment rate figure. A interim analysis trigger requiring a lower number of events, and thus patients, might fit into Peter/Eric's sense of timing given lower actual enrollment rates. Or it may not.

Previous entries in the series:
  1. 3. Good or bad process: Patient enrollment. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part I (July 13, 2015) on the blog's Current News page,
  2. 3. Good or bad process: Designing an interim analysis for efficacy into Provectus' pivotal melanoma Phase 3 trial. See July 16, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part II,
  3. 3. Good or bad process: Patient crossover. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part III (July 20, 2015) on the blog's Current News page,
  4. 2. Time-to-success or -failure: Triggering the interim analysis. See July 23, 2015 blog post Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part IV, and
  5. 3. Good or bad process: Patient-reported outcomes. See Assessing Provectus' Pivotal Melanoma Phase 3 Trial, Part V (July 24, 2015) on the blog's Current News page.

July 27, 2015

Provectus Biopharmaceuticals: Advancing a New Front in the War against Cancer

[A post written and published September 1, 2015 but backdated to July 27th, the date when I sent the draft article below to Michael Porter, President of Porter, LeVay & Rose (PLR), Provectus' investor relations firm.

Backdrop: My draft article, reproduced below, appears to have mostly formed the article Provectus Biopharmaceuticals: Advancing a New Front in the War against Cancer that appeared on pages 6-8 of the Summer/Fall 2015 edition of MicroCap Review, a magazine published by SNN. The last sentence of the magazine article notes the disclosure: "The company [Provectus] paid consideration to SSN or its affiliates for this article." I believe the consideration was payment to place the article in the magazine. I neither sought nor received compensation (or its implicit or explicit promise) from Provectus, PLR or SNN/its affiliates for my writing.

As background, Michael approached me in April 2015 to write an article about Provectus for insertion into MicroCap Review. He offered no explicit or implicit compensation to me at the time (nor since) for the proposed work. I agreed to write a draft article, turning it over to him in July, after which I assumed his staff and/or he might edit the material prior to submission to the magazine.]


Provectus Biopharmaceuticals: Advancing a New Front in the War against Cancer

Outsiders to the pharmaceutical industry, three award-winning research scientists from the Department of Energy’s East Tennessee-based Oak Ridge National Laboratory embarked on a path of their own in the 1990s to develop a better way to fight cancer. Hailing from the nationally recognized federal government science and technology facility with a rich history of discovery and innovation, these three technology inventors had been searching for a drug candidate capable of killing cancer cells safely, specifically, completely and quickly. By the end of the decade Drs. Craig Dees, PhD, Timothy Scott, PhD and Eric Wachter, PhD had re-discovered what could turn out to be the ideal cancer killer: Rose Bengal, a molecule with a long and diverse medical history. Ironically the compound had lain around in plain sight of the global pharmaceutical industry for nearly 85 years before Dees et al. began their journey of demonstrating Rose Bengal’s cancer fighting potential.

Safely and effectively engaging the body’s immune system and its natural anti-cancer defenses, instead of destroying or misusing them, underscored the Tennessee trio’s approach to defeating the disease. They believed killing cancer tumors in the correct way held the key to successful medical treatment because a proper approach could enable the immune system to stimulate cancer-killing cells throughout the body. Dees, Scott and Wachter eventually founded Knoxville, Tennessee-based Provectus Biopharmaceuticals, Inc. (NYSE MKT: PVCT) in 2002 with the goal of developing Rose Bengal-based drugs to treat cancer. The founders’ vision was to have the company’s lead investigational oncology drug PV-10, an injectable 10% solution of Rose Bengal in saline, employed in the treatment of all solid tumor cancers before, during and after surgery, in combination with other therapeutic agents and therapies, and after all else fails.

Rose Bengal is the active pharmaceutical ingredient in PV-10. A water-soluble dye first created in 1882[1], it is a small molecule that has been used in the clinic for more than a century, as an additive to safranin victoria yellow for ocular pneumococcal infection[2], a stain for visualizing corneal ulcers[3], a marker for impaired liver function[4] and now a cancer therapeutic. Prior to Provectus’ founding Rose Bengal already had an established FDA safety profile as an intravenous hepatic diagnostic called Robengatope®, and as a topical ophthalmic diagnostic under the trade names of Rosettes® and Minims®. Rose Bengal’s therapeutic benefits remained hidden until the 1980s when sufficient quantities were administered orally in preclinical studies carried out by Japanese researchers.[5] Ironically, while investigating the tumorigenicity of red food dye No. 105 (also made from Rose Bengal) they observed dose-dependent survival increases in test mice.

In the view of Dees, Scott and Wachter properly destroying cancer tumors meant killing only tumors and doing so completely, quickly and, very importantly, safely (that is, leaving healthy tissue unharmed). They believed this approach was the only effective way of sustainably stimulating a person’s natural anti-cancer defenses. Instead of bathing the entire body or even parts of it with radiation, or filling the bloodstream with oral or intravenous chemotherapies or present-day immunotherapies, Dees et al. firmly held the position that stimulating the immune system was best achieved through treating tumor tissue by injecting into it a drug capable of destroying the entire tumor as quickly as possible without damaging surrounding healthy cells. Completely also meant everything from visible tumor tissue to occult or hidden cells in and immediately around the injection site. Quickly meant having the drug processed through and excreted from the body in short order. Antigens generated from the tumor destruction caused by drug injection then could be presented to the body’s cells responsible for selecting the best and most relevant antigens in order to encourage cancer-killing cells to replicate themselves throughout the body. Importantly, tumor antigens had to be viewed in context; physical tumor destruction techniques such as heating or freezing tissue destroyed fragile antigens and disrupted their relevant contextual structures. Disruption of cell membranes and removal of lipids, proteins, and complex carbohydrates destroyed the antigens’ context, which is to what immune system cells responded. Thermal destruction denatured potential antigens, changing their chemical structure so that they were no longer representative of the tumor cell. In order to work rapid destruction of tumors had to preserve both antigenic structure and biological context.

Provectus’ lead investigational oncology drug PV-10 has a two-prong approach to fighting cancer. First, the “local effect” of tumor ablation (destruction) sees a patient’s tumor burden rapidly reduced after injection of PV-10 into his or her accessible cancerous lesions. Selective targeting by Rose Bengal minimizes side effects. Unlike many other cancer drugs, PV-10 does not rely on a single pathway to work and also has no known resistance. Second, the “systemic effect” of a tumor-specific immune response causes regression of untreated tumors, potentially prolonging progression-free survival and possibly enabling PV-10’s combination with immunomodulatory drugs and other systemic therapies for use in lesions that are inaccessible to a direct injection.

PV-10’s potential clinical value proposition to patients and their physicians is multi-faceted: It is simple to store, handle, and use and reuse. The drug thus far has shown modest local and transient toxicity that is predominantly confined to the injection site and minimal-to-no systemic toxicity. In regards to local efficacy PV-10 injection may lead to rapid, durable, complete tumor destruction, and induction of antigen release in injected lesions. It may promptly heal injected lesion sites completely after tumor destruction. In regards to systemic efficacy the drug may reliably, reproducibly induce regional and systemic immune effects potentially capable of destroying occult tumor cells, “bystander” lesions and distant metastatic lesions regardless of prior treatments. PV-10 may have multi-indication viability. Clinical trials to date and an ongoing expanded access program have treated more than 240 cancer patients (recurrent breast cancer, hepatocellular carcinoma and metastatic liver cancer, melanoma). It may be orthogonal, potentially having a low risk of clinically relevant drug-drug interactions. The drug may be agnostic, possibly compatible with all disease presentations. PV-10’s pharmacokinetics may be comparable and consistent.

Researchers at Moffitt Cancer Center in Tampa, Florida and the University of Illinois in Chicago have reproduced Dees et al.’s original preclinical work that first demonstrated PV-10’s two-prong approach and ability to fight cancer in multiple indications: e.g., the tumor ablation (the local effect) through the destruction of injected tumors, a tumor-specific immune response through the destruction of non-injected tumors and tumor-specific IFN-γ production in melanoma, breast cancer and colorectal cancer.
 
Provectus’ clinical development program is spearheaded by a pivotal trial currently being conducted in melanoma, and an early stage trial hepatocellular cancer (“HCC”) and metastatic liver cancer. In a Phase 2 trial that formed the basis for the current pivotal Phase 3 trial (registration study), 80 patients with stage IIIB-IV melanoma refractory to a median of six prior interventions received injections into their melanoma lesions up to four times over a 16-week period and were followed for 52 weeks.[6] The overall response rate for the 28 patients who had all their existing melanoma lesions injected with PV-10, was 71% with 50% achieving a complete response. This subgroup of 28 patients who had all their lesions injected achieved a progression free survival of 9.8 months, which according to the Phase 3 trial’s principal investigator Dr. Sanjiv Agarwala, M.D at St. Luke’s Hospital and Health Network of Bethlehem, Pennsylvania compares favorably with historical progression free survivals of less than 2.5 months for systemic chemotherapy dacarbazine and temozolomide.

The company’s current early-stage study of 6 patients with non-resectable HCC (primary liver cancer) and 7 patients with other forms of cancer metastatic to the liver (secondary liver cancer) saw then undergo a single percutaneous injection of PV-10 guided by CT to one target lesion in the liver.[7] At up to 54 months follow-up 10 out of these 13 initial patients were alive, with one death due to cardiac comorbidity, one to serious adverse events and one to HCC progression. Adverse events were generally limited to injection site reactions and photosensitivity and resolved without sequelae, with elevated liver enzymes observed during the first week after treatment. As with melanoma, PV-10 is believed to have a local chemoablative effect in HCC and metastatic liver disease where the agent enters lysosomes causing tumor necrosis that can stimulate immunological effects. Studies in melanoma patients injected with PV-10 have shown increased T cells in peripheral blood following injection including CD8+, CD4+, CD3+ and NKT.

Provectus recently announced the signing of a letter of intent with Boehringer Ingelheim China to collaborate in bringing PV-10 to market in mainland China.



[1] Gnehm R.Ueber Tetrachlorphtalsäure. Justus Liebigs Annalen der Chemie 1887; 238:318–338
[2] Feenstra RPG and Tseng CG. Arch Ophthalmol 1992; 110:984–993
[3] Norn MS. Acta Ophthalmol 1970;48(3):546-559
[4] Delprat GD. Arch Int Med 1923; 32(3):401–410
[5] Ito A, Watanabe H, Naito M, Aoyama H, Nakagawa Y, Fujimoto N. J Natl Cancer Inst 1986 Jul; 77(1):277–81
[6] Janet Fricker, PV-10 delivers greatest effects when all lesions are injected, Pharmiweb.com, October 14, 2014
[7] Janet Fricker, New chemoablative approach for hepatocellular carcinoma and metastatic liver disease, Pharmiweb.com, July 13, 2015