The first guy through the wall

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Today's joint meeting of the Cellular, Tissue and Gene Therapies Advisory Committee ("CTGTAC") and Oncologic Drugs Advisory Committee ("ODAC") voted by an overwhelming 22-to-1 margin in favor (i.e., yes to the question) of talimogene laherparepvec ("T-Vec") having an overall favorable benefit-risk profile for the treatment of injectable regionally or distantly metastatic melanoma, and thus supporting traditional approval of the drug.

The meeting's positive outcome for T-Vec and Amgen also is a positive for PV-10 and Provectus. Both T-Vec and PV-10 are investigational intralesional ("IL") therapies, often referenced together, and share existing and potential clinical trial investigators and/or paid consultants such as MD Anderson Cancer Center's Dr. Merrick Ross, MD, St. Luke's Cancer Center's Dr. Sanjiv Agarwala, MD, Hunstman Cancer Institute's Dr. Robert Andtbacka, MD, and Moffitt Cancer Center's Dr. Vernon Sondak, MD and Dr. Jonathan Zager, MD.

Two great sources of meeting coverage, with both insightful and observational tweet comments and commentary, were Jamie Singer (@JSwatercooler) and SAC Tracker (@FDAadcomm). Jamie is a consultant to Provectus. Tarius SAC Tracker provides global regulatory intelligence to the healthcare industry, and later wrote a summary of the meeting entitled US FDA Advisory Committee Supports Amgen’s T-Vec to Treat Metastatic Melanoma.

Amgen is seeking approval of T-Vec for the treatment of injectable regionally or distantly metastatic melanoma (side note: unresected or unresectable was not included in Big Biotech's proposed indication). FierceBiotech's John Carroll noted in his article about today's meeting: "The final decision is being left in the hands of the FDA, though today's vote would make T-Vec an odds-on favorite for approval." T-Vec's PDUFA date is October 27th (it previously was July 28th, and pushed back for Amgen to submit additional information.

My takeaways about the meeting's outcome as it relates to PV-10 include:

1. Today's decision was a very big win for IL agents for cancer.

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It bears repeating. The panel concluded that the reduction of injected tumors equates to/is clinical benefit.

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Hwu is MD Anderson Cancer Center's Dr. Patrick, MD (medical oncology), chair of Melanoma Medical Oncology and Sarcoma Medical Oncology, and recently named division head of Cancer Medicine.

Fierce further observed "[a] number of the experts noted that the more "arrows" they had in their therapeutic quiver, the better off patients would be," although Jamie tweeted:

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2. There is more work to do for IL agents to better clarify and demonstrate their role in treating late-stage cancer and patients with heavy disease burden and visceral disease — i.e., an IL agent like T-Vec or PV-10 (a stimulatory agent, co-stimulatory, start the engine, step on the gas pedal) plus an immune checkpoint inhibitor (an inhibitory agent, co-inhibitory, release the brakes).

Nevertheless, today's decision, assuming it is accompanied by FDA approval of T-Vec later this year, first opens the door for IL agents to metastatic or advanced melanoma. Approval would place T-Vec in the same group of approved agents for advanced melanoma that includes ipilimumab (approved in 2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), trametinib (2013), pembrolizumab (2014) and nivolumab (2014). All of the nibs and mabs are systemic agents. Peginterferon is systemically administered.

More than likely, use of IL agents for advanced melanoma as monotherapies will be limited to Stage IV M1a.

Click to enlarge. Amgen CTGTAC / ODAC Meeting Briefing Document, page 53. Purple emphasis is mine.

Click to enlarge. FDA CTGTAC / ODAC Meeting Briefing Document, page 14. Purple emphasis is mine.

Even more likely is the treatment of Stage IV M1a to M1c (especially) with the combination therapy of an IL agent and immune checkpoint blockade. Amgen currently has T-Vec in trials with ipilimumab and pembrolizumab for advanced melanoma (i.e., Stage IIIb to IVM1c Melanoma).

3. Today's decision reaffirmed the value of good IL agents for the treatment of earlier stages of disease (i.e., Stage 3), when all of the disease is accessible for injection, and for use first or second before other treatment options are considered, when the immune system is not overwhelmed by tumor burden and spread (as it is for most Stage 4 patients).

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PV-10's upcoming pivotal Phase 3 trial is for locally advanced cutaneous melanoma, and will be exclusively comprised of Stage IIIb-c patients (although it would appear 50% of the patients in the treatment arm must have failed at least one systemic immunotherapy or not be a candidate for them).

While members of the panel wanted to distinguish T-Vec's use between non-visceral (e.g., Stage IIIb-c and IVM1a) and visceral (IVM1b-c), rather than an overly broad distinction between Stage 3 and 4, one of hypotheses of PV-10's Phase 3 trial is that if the drug make lesions go away it will forestall progression of the patient's disease (which would be shown via the trial's progression free survival primary endpoint.)

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Amgen is pushing further to the left (i.e., earlier use) with T-Vec, comparing T-Vec and surgery to surgery alone in completely resectable Stage 3b-c and IVM1a melanoma: Efficacy and Safety of Talimogene Laherparepvec Neoadjuvant Treatment Plus Surgery Versus Surgery Alone for Melanoma.

4. PV-10 is of course a competitor to T-Vec.

From a 2012 presentation by Huntsman Cancer Center and lead T-Vec Phase 3 trial investigator Dr. Robert Andtbacka, MD (and now paid Provectus consultant and likely PV-10 Phase 3 trial investigator):

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Andtbacka recently said of T-Vec: “Our patients are living longer, and we’re able for the first time in melanoma to potentially talk about a cure, which is something we have not been able to talk about before,” said Dr. Robert Andtbacka, who is a surgical oncologist. Andtbacka said the new treatment teaches the body to heal itself. See Familiarity (April 7, 2015) on the blog's News Page.

Johns Hopkins University's Dr. Suzanne Topalian, MD referred to the drug as an autologous tumor vaccine (along with T-Vec and Allovectin-7). See Keep talking (and keep doing) (January 29, 2015) on the News Page.

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5. PV-10 is a much better IL agent than T-Vec.

Moffitt's Dr. Sondak (again, a paid consultant to both Amgen and Provectus) noted last year at the 4th European Post-Chicago Melanoma Meeting:

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Hunstman's Dr. Andtbacka historically has compared Phase 2 trial results of T-Vec and PV-10, the version below from 2012:

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My comparison (a sampling):

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Click to enlarge. Footnote 6 of above table.
T cells in the peripheral blood mononuclear cell ("PBMC") of melanoma patients

Notepad

1. DAMPs. Following up on my Damage-Associated Molecular Patterns, and Immunogenic Cell Death (August 21, 2014) news item, I'm curious (fascinated) by PV-10's potential role in immunogenic cell death, and thus the release and surface expression of damage-associated molecular patterns ("DAMPs"). DAMPs "..link the dying tumor cell with innate immunity, culminating in adaptive anticancer memory responses."

The recent paper by Panzarini et al. (2014), Rose Bengal Acetate PhotoDynamic Therapy (RBAc-PDT) Induces Exposure and Release of Damage-Associated Molecular Patterns (DAMPs) in Human HeLa Cells, observed that key DAMPs -- ATP, HSP70, HSP90, HMGB1 and CRT -- were exposed and/or released after treatment of cell lines with Rose Bengal acetate and photodynamic therapy. I understand this work involved using PDT and a functional RB derivative, and was carried out on cell lines; however, what interests me about it is the study's goal, which was to determine if RB could trigger apoptosis and autophagy -- cell death -- and thus expose and/or release pivotal DAMPs.

Very interestingly, in my view, the researchers also noted their data represented the fourth demonstration of the exposure of the HSP90 DAMP by indication and third demonstration by drug compound: "In fact, exposure of HSP90 was shown only in lung cancer [36] and myeloma [37] treated with Bortezomib and in bladder cancer cells treated with capsaicin [38]." Bortezomib is a proteasome inhibitor (Millennium Pharmaceuticals [Velcade]/Venus Remedies [Cytomib]). Capsaicin is a neurotoxin and active component of chili peppers.

Moffitt previously showed PV-10 (Rose Bengal) in their murine model work released HMGB1.

2. Innate and Adaptive Immunity. As I wrote above, DAMPs, or their impact once exposed and/or released, form a bridge between the body's innate and adaptive immune systems (or non-specific and specific, respectively). See my blog post PV-10 is not bigger than Mother Nature for a discussion of the immune system; "The immune system protects organisms from infection with layered defenses of increasing specificity."

In 1994, "[t]wo papers appearing in the same year presaged the deeper understanding of innate immune reactivity, dictating the subsequent nature of the adaptive immune response. The first...speculated...free radical-mediated reperfusion injury-was seen to contribute to the process of innate and subsequent adaptive immune responses. The second...suggested the possibility that the immune system detected "danger", through a series of what we would now call damage associated molecular pattern molecules (DAMPs), working in concert with both positive and negative signals derived from other tissues." {Underlined emphasis is mine}

• Land W, Schneeberger H, Schleibner S, et al. (January 1994). "The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants." Transplantation 57 (2): 211–7.
• Matzinger P (1994). "Tolerance, danger, and the extended family." Annu. Rev. Immunol. 12: 991–1045.

I've written that PV-10 harnesses the immune system, rather than restraining, blocking, manipulating, etc. parts of it. Note that Chen & Mellman (2013) title step 3 of their cancer immunity cycle illustration "Priming and activation." {Underlined emphasis is mine}

3. It's A Small World. The authors of the RBa-PDT paper come from Italy's University of Salento, and do not appear to have any disclosures related to Provectus. While the company has engaged certain principal investigators and their respective hospitals in Australia and the United States, as well as Moffitt Cancer Center, there is a body of work from researchers espousing Rose Bengal's potential as a cancer therapeutic who are currently or not at all unaffiliated (or appear to be unaffiliated) with the company. They are, among others (representative papers below):

• The "Italians" (2014): Above,
• The "Iranians" (2014): Rose Bengal suppresses gastric cancer cell proliferation via apoptosis and inhibits nitric oxide formation in macrophages, Updated (8/23/14): One of the Iranian authors co-published work with Provectus in 2006,
• An "American" (2012): Selective toxicity of rose bengal to ovarian cancer cells in vitro, and
• The "Japanese" (1986): Induction of thyroid tumors in (C57BL/6N x C3H/N)F1 mice by oral administration of 9-3',4',5',6'-tetrachloro-o-carboxy phenyl-6-hydroxy-2,4,5,7-tetraiodo-3-isoxanthone sodium (Food Red 105, rose bengal B).

4. Amgen's talimogene laherparepvec ("T-Vec"). Related to Amgen's T-Vec, the FDA announced a November 6th advisory committee ("AdComm") meeting (Cellular, Tissue and Gene Therapies Advisory Committee) to discuss the draft guidance for industry entitled "Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products." Does this bode well or poorly for T-Vec in regards to its ease of administration and use, or lack thereof?

5. Info. An interview with Peter formed the basis for today's Seeking Alpha article Provectus' Latest Developments Spark Investor Interest -- CFO/COO Culpepper Explains Why. Of note to me was his answer to the interviewer's question "What is the anticipated market trajectory for PV-10?"

Peter: "We anticipate PV-10 phase 3 for melanoma to be one path for PV-10 approval. We anticipate also combining PV-10 to treat patients with disease inaccessible to direct injections. We also anticipate treating primary liver cancer patients in an upcoming randomized phase 2 study and seeking an expedited approval path in that important indication as well."

Taking this response at face value would suggest the upcoming (anticipated) liver Phase 2 trial would be for primary liver cancer (hepatocellular carcinoma), and not include cancers metastatic to the liver. A subsequent or concurrent study might examine this aspect of liver cancer, but the contemplated Phase 2 trial would not, or so it seems to me. Liver cancer of course is a very large unmet need in Asia. One would hope Eric garnered the feedback he required [from his recent Asia trip] to finalize and file the liver Phase 2 trial protocol.

What It Means for $MRK to be a Dark Horse for $PVCT

Dr. Perlmutter was responsible for Amgen's acquisition of BioVex and its principal drug compound OncoVEX, now T-Vec (talimogene laherparepvec). T-Vec is a competitor of PV-10.

Perlmutter now runs Merck's R&D organization. Merck's licensing group/function now reports to him, and Dr. Perlmutter is keenly interested in business development and licensing.

Thank you to the blog reader who indicated the prior $MRK posts were hazy in their implication.

Implication: Merck may well be a serious contender [to Pfizer] to license PV-10.

$PVCT: T-Vec & $AMGN's Bottom Line

Amgen trumpets T-Vec oncolytic virus results from PhIII melanoma study by FierceBiotech's John Carroll.

What's good for Amgen & T-Vec is good for Provectus & PV-10, and what's bad for Amgen & T-Vec is good for Provectus & PV-10. The bottom line for T-VEC may be the drug is not ready for "prime time," but perhaps may be suitable for combination with ipilimumab/Yervoy or PD-1 antibodies heralded at ASCO 2013.

"With today's reported interim results, we believe the probability of success for T-Vec demonstrating an OS benefit at final data later this year should increase although more modestly given previous reports of favorable OS trend," ISI's Mark Schoenebaum wrote over the weekend. "Admittedly, T-Vec's role in a subset of advanced melanoma patients as an injectable (injected directly into the tumor) is becoming less clear with increasing competition in the melanoma space, such as the development of PD-1 antibodies."

Regarding the second part of Schoenebaum's quote above from the FierceBiotech article, T-Vec ultimately is not that good of an agent. PV-10 is much more robust in response and systemic potential, both in treated lesions and those untreated, respectively. For example, the response rate percentage for all treated lesions in PV-10's MM Phase 2 trial was (is) astounding, given the trial's treatment protocol, and likely will (should) go up given further flexibility designed into the Phase 3 trial (i.e., no limit to treatment).

The competition in melanoma highlights that available agents are so marginal for end stage disease that there needs to and will be significantly more attention placed on agents like PV-10, and to a lesser extent T-Vec, in combination with appropriate other agents.

Adam Feuerstein: [ASCO '13:] Amgen's Cancer-Killing Virus Shows Skin-Cancer Survival Trend

Read Adam Feuerstein's article on Amgen and T-Vec here. Good for Amgen & T-Vec is good for Provectus & PV-10.

"Amgen is the first company to demonstrate that a so-called "oncolytic virus" -- known as talimogene laherparepvec (T-Vec) -- can eliminate skin cancer in a late-stage clinical trial. T-Vec also works, in part, by harnessing the immune system of patients, which suggests to Amgen that the two different immune therapy approaches to killing cancer cells could be combined." I believe Moffitt has combined PV-10 and PD-1 agents.

"T-Vec's tumor shrinkage rates in the 20-30 percent range for melanoma are slightly lower than responses seen by the so-called PD-1 inhibitors being developed by Bristol-Myers and Merck." PV-10 tumor shrinkage rates in the 30-50% range (Phase 2 data) for melanoma are dramatically higher than T-Vec and PD-1 inhibitors despite being constrained or limited in treatment through the Phase 2 trial protocol. A Phase 3 trial under the SPA (that should be agreed to with the FDA), should such a trial ultimately be run, would have treatment without any limits of any concern (i.e., as many retreatments of as many visible tumors as necessary).

"Additional survival data will be presented this afternoon which shows the survival difference between T-Vec and GM-CSF patients growing over time, Chang says. This is consistent with the idea that cancer immunotherapy takes longer to be effective." 

"Doctors inject T-Vec directly into tumors unlike most cancer drugs that are administered orally (as a pill) or intravenously into a vein. In Jan. 2011, Perlmutter explained that BioVex wouldn't have been worth Amgen's investment if OncoVex proved capable of only eliminating tumors via direct injection. The tumor burden in advanced cancer patients, especially those with skin cancer, is too great to treat them effectively."

"T-Vec, however, appears to activate a patient's immune system enough to target and eliminate tumors that are not directed injected. This so-called off-target or systemic response is what grabbed Amgen's attention and ultimately led to the company's decision to acquire BioVex."

Reuters: Amgen melanoma drug improved survival by 21 percent in interim look

Good for Amgen & T-Vec is good for Provectus & PV-10.

Read Reuters' Deena Beasley's full article here.

"RBC Capital Markets analyst Michael Yee said recently that the Amgen drug - talimogene laherparepvec, or T-Vec - will ultimately need to demonstrate that it improves overall survival by more than 15 percent."

"The trial also showed that patients with earlier-stage disease had the highest rates of durable response. That rate was 33 percent for stage III patients, compared with 8 percent for patients with the most advanced cancer." This success at earlier stage of disease for melanoma patients is key for PV-10. As a monotherapy, clinicians want to use PV-10 before surgery when the immune system is not, moderately or less severely compromised, by itself after surgery too, and in very late stage disease patients with other agents when the immune system is overwhelmed and severely compromised.

"David Chang, head of global oncology development at Amgen, said the company is currently in discussions with the U.S. Food and Drug Administration about how to move forward and seek regulatory approval. Melanoma is diagnosed in about 132,000 people worldwide each year. He also said the company is interested in testing its drug in combination with Yervoy and other new melanoma therapies." All of these groups of compounds are covered by Provectus' joint patent application with Pfizer for the combination of PV-10 and other therapies. The combination of PV-10 and CTLA4, PD-1, PDL-1 and OXO-40 agents are covered by the patent, and I believe these combinations have been investigated by Moffitt.

$PVCT: $AMGN's T-Vex Abstract at #ASC02013

Amgen's abstract for intralesional agent talimogene laherparepvec's (T-Vec's) Phase 3 trial is now available.

Good for T-Vec and Amgen is good for PV-10 and Provectus.

The study author is Robert Andtbacka, M.D., assistant professor, University of Utah Huntsman Cancer Institute. Dr. Andtbacka presented information comparing Phase 2 response rate data of T-Vec with PV-10 and other intralesional agents in March 2013 for injected lesions, non-injected lesions and non-injected systemic lesions.

Amgen's press release is here.

"The study met its primary endpoint of durable response rate (DRR), defined as the rate of complete or partial response lasting continuously for at least six months. A statistically significant difference was observed in DRR with 16 percent in the talimogene laherparepvec arm versus two percent in the GM-CSF arm (95 percent CI, 12-21 percent, versus 95 percent CI, 0-5 percent, p<0.0001). The overall response rate was 26 percent with talimogene laherparepvec as compared to six percent for GM-CSF.  A trend toward overall survival (HR = 0.79, 95 percent CI, 0.61-1.02) was also observed at a predefined interim analysis."

"In regionally and distantly metastatic melanoma (stages III and IV), cancer has spread to skin, lymph nodes, or to other organs distant from the site of origin. The DRR was highest among patients with stage III and stage IVM1a disease. The observed DRR for talimogene laherparepvec were: 33 percent in stage IIIB/IIlC, 16 percent in stage IVM1a, and three and eight percent respectively for stages IVM1b and IVM1c. The DRR with GM-CSF was not higher than four percent in any of the stage subsets."

""Over the last 30 years, the incidence of metastatic melanoma has increased by over 200 percent, so there is a need for new treatment options," said study author Robert Andtbacka, M.D., assistant professor, University of Utah Huntsman Cancer Institute. "The results of this study are encouraging in a disease as devastating as metastatic melanoma.""

ASCO 2013 Data to Watch: The Talimogene laherparepvec (T-VEC) Abstract

T-Vec is one of the three intralesional therapies compared by Andtbacka at the HemOnc conference in March. Recall the table below from this post.

$PVCT: Amgen (I think) Visits The Blog

Based on visitor activity (e.g., IP addresses, location), I think Amgen visited the blog.

$PVCT & $AMGN: T-VEC vs. PV-10

This week, Amgen released partial study results of T-Vec's melanoma Phase 3 trial that compared talimogene laherparepvec (formerly OncoVex) against control therapy GM-CSF.

Some articles on this can be found below:

• Novel Amgen virus-vaccine shrinks melanoma tumors (Linda A. Johnson, Huff Post Business),
• Amgen Trains Herpes Virus to Shrink Skin Cancer (Adam Feuerstein, TheStreet), and
• Amgen scores PhIII success with BioVex virus against melanoma (Ryan McBride, FierceBiotech)

"[16%] of the T-Vec patients reported meaningful tumor shrinkage for at least six months, compared to 2% for patients treated with GM-CSF. The difference in durable tumor response was statistically significant in favor T-Vec, achieving the primary endpoint of the study." (Adam Feuerstein)

Reaction is mixed.

"Until Amgen produces some solid OS rates, though, a number of analysts will remain on the sidelines as to whether the biotech giant has a shot at market success. Amgen likely will have to wait until the arrival of OS data later this year before it can file for an approval, said ISI's Mark Schoenebaum in a note to investors. "In our view, OS is the single most important data point to track for this trial (both from regulatory and commercial perspective)."" (Ryan McBride)

"RBC Capital Markets analyst Michael Yee wrote to investors that he's "cautious" on the likelihood the full survival results later this year will show T-VEC is better than a couple of existing treatments – and they [Yervoy and Zelboraf] don't have to be injected into a tumor every two weeks."" (Linda Johnson)

"UBS Securities analyst Matthew Roden noted T-VEC's 16 percent durable response rate in this study, as well as its 58 percent one-year survival rate in an earlier, mid-stage study, both exceed study results for Yervoy, Bristol-Myers Squibb Co.'s melanoma drug. Roden added that T-VEC doesn't have that drug's severe gastrointestinal side effects."" (Linda Johnson)

"However, Mara Goldstein of Cantor Fitzgerald called the findings "a win for immunotherapy." "We can't help but feel encouraged for other agents in development," she wrote to investors, "particularly in light of the failure" of a study of experimental cancer vaccine Stimuvax, being tested by Merck KGaA of Germany." (Linda Johnson)

Coverage and commentary by biotechnology journalists of Amgen and T-Vex can only help facilitate a more open assessment of PV-10 when the time comes, helping them to better understand treatments that prime or "...activate a patient's immune system enough to target and eliminate tumors that are not directed injected...[the] so-called off-target or systemic response..." (Adam Feuerstein)

""While the regulatory strategy is current unclear, today's news is an incremental positive and T-Vec is not currently in our/Street models, due to overall low expectations for the drug and the practical/commercial limitations of immunotherapies. We await presentation at ASCO and OS data to better assess the clinical and commercial profile of T-Vec," said J.P. Morgan biotech analyst Geoff Meacham in a note to clients Tuesday night." (Adam Feuerstein)

My key takeaway from the Amgen news is Goldstein's comments about the results being a win for immunotherapy. T-Vex, Allovectin-7 and PV-10 have been considered the 3 cancer immunotherapy treatments to watch.

Put into context, and presented again at the HemOnc Today conference in New York, PV-10 possesses a superior response rate advantage over T-Vec (and Allovectin) for injected lesions, non-injected lesions and non-injected systemic lesions.

And on April 8th Moffitt raises the curtain on PV-10's systemic benefit.

"Two recently approved skin cancer drugs -- Roche's Zelboraf and Bristol Myers' Yervoy -- both prolong survival significantly. In order to compete and perhaps even to be approved at all, Amgen will have to demonstrate that T-Vec can help skin cancer patients live longer and not just shrink tumors."  (Adam Feuerstein)

Zelboraf was approved with PFS as primary endpoint. Yervoy was approved with OS as primary endpoint. PFS and OS of course are both considered survival endpoints, and both are described as “time to event” endpoints versus “proportional endpoints” (e.g., ORR, DR, BORR, etc.).

PV-10 already demonstrated shown tremendously robust PFS in Provectus' MM Phase 2 trial. Patients, by definition, are living longer “progression free.” Management, however, believes the Moffitt forthcoming data is all they need prove PV-10 works systemically.

Amgen acquired BioVex in March 2011 for $425 million upfront and up to $575 million milestones. BioVex's purchase should put a firm floor of about $1B under the value of Provectus (or about $5-7 per share fully diluted).