Oncolytic

Source of tweet image below: Paul D. Rennert (@PDRennert).

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On the SITC slide above, I imagine PV-10 (in combination with a/the PD/PDL1 "backbone") would fall under "oncolytic" in the pembrolizumab column (second from the left). The slide clearly illustrates an amazing amount of work underway to augment this fundamental concept of combination therapy or treatment in cancer.

The slide reinforces an important theme of Provectus' Dr. Eric Wachter, PhD's November 14th presentation (as part of the 3Q16 business update call): there is considerable interest and clinical activity in melanoma, and while he believes there is no doubt about the relevance of PV-10, cutting through the crowd to the front of the pack will require continued effort on Provectus' part. See, for example, the slides below from his presentation:

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Under Additive: 1 + 1 < 2. Synergistic: 1 + 1 > 2 (best case, >> 2) (June 25, 2016) on the blog's Archived News VI page I co-opted a slide from MD Anderson's Dr. Merrick Ross, MD's presentation -- see ASCO 2016: "The Role of Immunotherapy in the Medical Management of Melanoma: An Overview for the Oncologist" (June 22, 2016) -- that provided results from various combination therapy studies for advanced or metastaic melanoma slide in order illustratively model the difference between additivity and synergism:

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The table above was updated to include recent combination therapy data of oncolytic virus CVA21 (Coxsackievirus A21, a cold virus) and anti-PD-1 drug pembrolizumab (Keytruda) presented at SITC 2016: "According to the preliminary data from the first 10 patients evaluable for best overall tumour response assessment, a disease control rate (DCR) of 100 percent (10/10 patients) was demonstrated, including seven patients (70 percent) with an objective tumour response and three patients (30 percent) with stable disease" {Viralytics’ CAVATAK™ in Combination with KEYTRUDA® Provides Promising Results in Advanced Melanoma from the CAPRA 1b study}.

Interestingly, however, Viralytics' combination therapy above yielded no complete responses in its Best irRC Overall Response (see the SITC poster here), and did not use RECIST 1.1 in its tumor response measurement. Median doses of CVA21 and pembrolizumab (for the ten patients noted above) were 8 (range 6-11) and 6 (3-11), respectively. CVA21, like T-Vec, has to be delivered often for its effect to manifest, weak or weaker (than PV-10's immunologic signalling) as it is.

Viralytics previously established a collaboration with Merck & Co. in November 2015 to combine CVA21 and pembro in either advanced stage non-small cell lung cancer (NSCLC) or metastatic bladder cancer. In June 2016 the parties initiated a Phase 1b study, one-site (Australia) program for NSCLC where CVA21 would be delivered intravenously (three different dosing levels of CVA21), and not intralesionally or intratumorally.

In his November 21st article "Viralytics' anticancer virus aces checkpoint inhibitor combo trials," FierceBiotech's Phil Taylor provides or references several examples of funded or acquired oncolytic virus companies:

• 2011: Amgen's acquisition of BioVex (U.S.), and thus T-Vec (Imlygic) (formerly OncoVEX) ($1 billion: $425 million upfront and a $575 million earn out), which was approved in 2015,

• 2016: Bristol-Myers' license deal with PsiOxus Therapeutics for $10 million upfront,

• 2016: Celgene's investment in Oncorus' $57 million Serie A financing round,

• 2016: Germany's Boehringer Ingelheim's [option to buy] deal with Austria's ViraTherapeutics for up to $236 million.

Edison Investment Research's Dennis Hulme and Lala Gregorek's November 21st equity research note on Viralytics entitled "Cavatak data continue to impress" presents the valuation rationale below:

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Interestingly, again, a Viralytics abstract/poster at SITC 2016, "O14 Phase I/II CANON study: oncolytic immunotherapy for the treatment of non-muscle invasive bladder (NMIBC) cancer using intravesical Coxsackievirus A21," noted:

"Notable changes in immune cell infiltrates and expression of PD-L1 within the CVA21-treated NMIBC tissue were also observed. Increased urinary levels of the chemokine, HMGB1, was observed in six of eleven patients following exposure to CVA21."

Moffitt Cancer Center noted increased HMGB1 levels in sera of melanoma patients after intralesional PV-10 treatment.

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Moffitt did not report the number of patients with elevation, but rather the change in mean. Inspection of Figure 6 in Liu et al. suggests most patients (n = 14) exhibited increased HMGB1.

Oncolytic, as a label or category, can be somewhat deceiving.

Intralesional (IL) oncolytic virus (e.g., T-Vec, CVA21, HF10, etc.) is different than IL chemical small molecule (i.e., PV-10), both of which might be referred to as oncolytic immunotherapy.

Oncolytic virus immunotherapy however delivered (e.g., intralesionally/intratumorally, intravenously) is different from ablative immunotherapy (i.e., PV-10).

Takeaway: There's a real opportunity for Provectus and PV-10. There is no doubt about the relevance of PV-10, but cutting through the crowd to the front of the pack will require continued effort on the company's part.

Clash of Clans

Image source

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

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

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

I believe, by virtue of this blog and talking our book, that our clan(s) is(are):

• First, PV-10, and Rose Bengal, which fall into the category of small [chemical] molecules that rely on their physical (and not biological) chemistry properties, and

• Second, intralesional (IL) or intratumoral (IL) therapies (aka local, loco-regional or local-regional, and regional therapies), because route of delivery matters.

But there is good reason for the biopharmaceutical industry ecosystem to be skeptical of the class of IL therapies. First, until very recently (October 2015 for talimogene laherparepvec or T-Vec), there had been no history of clinical success and, thus, regulatory approval. Second, what promising, approved therapy there has been (T-Vec) has turned out to be a marginal product with an uncompelling clinical value proposition. Before Amgen's T-Vec was approved in 2015 as Imlygic for advanced melanoma, failure preceded it more than two year before in the form of Vical's IL agent velimogene aliplasmid (Allovectin-7) in August 2013 for the same indication. Before Vical, there was the failure of IL agent bacillus Calmette-Guérin (BCG) in 1978, also for advanced melanoma. Taken together, IL therapies would have a modest-to-no history of regulatory validation for nearly 40 years.

Now consider HemOnc Today's July 10, 2016 article entitled "Intralesional agents show promise in melanoma but may serve ‘narrow clientele.’" After reading it, I am struck by what seems to be physician clan members -- of the IL therapy clan -- endeavoring to frame the potentially notable clinical benefits and patient outcomes IL cancer therapies could generate or yield if only there was a better IL therapy to be their flagbearer. T-Vec was the first guy through the wall, opening the regulatory and commercial doors for IL therapies. The article made me think these clan members were waiting for PV-10 to bust through the door, breaking its frame in the process.

• HemOnc Today's article's page links

• Page 1,
• Page 2,
• Page 3,
• Page 4,
• Page 5, and
• Page 6

• Quoted physicians

• Sanjiv S. Agarwala, MD (medical oncologist, aka Dr. Rose Bengal) —a T-Vec and PV-10 clinical trial investigator from St. Luke's University Health Network in Bethlehem, Pennsylvania,

• Robert H.I. Andtbacka, MD (surgical oncologist) — a T-Vec and PV-10 clinical trial investigator from Huntsman Cancer Institute in Salt Lake City, Utah,

• Dale Han, MD (surgical oncologist) — no affiliations were disclosed, and from Yale School of Medicine in New Haven, Connecticut,

• Vernon K. Sondak, MD (surgical oncologist) — a consultant to Amgen and Provectus from Moffitt Cancer Center in Tampa, Florida, and

• Jeffrey S. Weber, MD, PhD (medical oncologist) — an advisor to Amgen and a PV-10 clinical researcher from NYU Langone Medical Center.

Article paragraphs and quotes of interest to me:

• "HemOnc Today spoke with medical and surgical melanoma specialists about the future of intralesional agents for melanoma, whether oncolytic agents likely will be used as single agents or in combination with immunotherapies, and the lingering questions surrounding T-VEC’s efficacy based on the OPTiM trial."

• "“If you look specifically at patients with stage IIIB or stage IIIC disease on the OPTiM trial, their response rate was 52%,” Robert H.I. Andtbacka, MD, CM, FACS, FRCSC, associate professor of surgery at Huntsman Cancer Institute at University of Utah, as well as a HemOnc Today Editorial Board member, told HemOnc Today. “None of the other immunotherapies and checkpoint inhibitors have come close to having that response rate in that patient population.” 

Andtbacka, who served as an investigator on the OPTiM trial, said the positive outcome and FDA approval signal the utility of intralesional agents in the rapidly expanding melanoma landscape."

• "The relatively mild toxicity profile of T-VEC may make it more appealing to some patients than immunotherapies, which can produce virulent adverse events, Sondak added.

“Adverse events can be quite modest when you are just injecting a [lesion], rather than trying to treat the entire patient,” Sondak said. “If we can get the immune system to pay attention to the melanoma and do something good because of it, then you are looking at a low-toxicity means of producing an important, clinically relevant immune response.”" 

• "Although most oncologists agree T-VEC has a role in the melanoma treatment armamentarium, the design of the OPTiM trial has prompted a number of clinicians to question how large that role should be.

The primary reason for concern is the use of GM-CSF as the control. 

“T-VEC was approved on the basis of a clinical trial design that will certainly never be replicated,” Sondak said. “The control arm was basically a placebo, with no basis in why one would choose to use that particular regimen. I don’t know if that design would be approved today by the FDA.” 

OPTiM researchers enrolled patients between May 2009 and July 2011. The majority of new melanoma therapeutic options were approved after that period, leaving some oncologists to wonder how the results might differ if the trial were conducted now."

• "“There are many patients who have tumors that do not have tumor-infiltrating lymphocytes, and checkpoint inhibitors cannot work unless those lymphocytes are there,” Andtbacka said. “Using an oncolytic therapy can actually change the tumor microenvironment, and essentially make a ‘cold’ tumor become a ‘hot’ tumor. When we do that, it appears that we can make a nonresponder into a responder.”"

• "“The preliminary data for T-VEC combinations look promising,” Han said. “The whole idea of treating systemic melanoma has really blossomed into the idea of combination therapy. Combining T-VEC with other effective systemic treatments was the natural next step to see if we could further improve outcomes.”"

• "“The beauty of combinations is that you can take a patient who has an in situ tumor reachable by a needle and inject it with something that makes the tumor more immunogenic,” Agarwala said. “If you throw in a confirmed immunotherapy that works well, you have the potential for synergy.”

Because melanoma has been shown to respond to combinations, the use of these regimens should be considered when possible, Agarwala added. 

“I like to say, ‘Make the tumor your friend, and make it your ally,’” he said. “If you can’t remove the tumor — if you’ve tried everything and it keeps coming back — instead of just trying to remove it again or giving systemic therapy, why not add an intralesional agent that gets into the microenvironment and releases antigens? That is a concept that highly appeals to me.”"

• "The labor involved in preparing a T-VEC injection may drive cost-related considerations.

“The biggest cost factor with an intralesional therapy, aside from the drug, is time,” Agarwala said. “It’s not just a nurse hanging a bag. You have to have a doctor or a provider actually do a procedure, and that procedure is billable. It taxes the provider’s time. I am not sure if anyone has studied the total cost yet, but the short answer is that it’s an issue.” 

Weber agreed. 

“An injection like this can take up a room for 20 minutes and might be viewed as a hassle by a doctor with a busy practice,” Weber said. “If a nurse practitioner is doing the injection, that’s time she or he is not seeing other patients. I do not think it is unreasonable to say that some busy oncologists view it as more work than it is worth.”"

• "T-VEC is the first intralesional agent to be approved as monotherapy for the treatment of advanced melanoma. However, it is far from the only oncolytic agent under investigation.

“These agents are safe and produce good response rates,” Agarwala said. “Some of the ongoing trials of new oncolytic agents can address the concerns left over from the OPTiM trial.” 

Agarwala serves as an investigator on a phase 3 study investigating PV-10 (Provectus Biopharmaceuticals), an injectable form of rose bengal disodium that received FDA orphan drug designation for melanoma and hepatocellular carcinoma."

• "“The current PV-10 randomized trial only includes patients who have failed immunotherapy or are not candidates,” Agarwala said. “In that sense, it is much more of a real-world trial [than OPTiM]. The control arm of the trial is chemotherapy, which is reasonable, because if you have tried everything else, it is a fair comparator.”"

• "“These agents may have theoretical or practical advantages compared with T-VEC,” Sondak said. “They are all worthy of investigation, without question, and some could be real advances. There is value to having T-VEC available, but it will also be important for these other agents to have their chance to show what they can do.”"

For the first time that I can recall, an article discussing by therapies addressed treatment administration by non-physician providers (e.g., nurse practitioners, physician's assistants, nurses). See page 6 of the article here.

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

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.”

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.

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With PV-10: One shot, one kill

The University of Illinois at Chicago's College of Medicine's Department of Surgical Oncology's Ajay Maker Laboratory's PV-10 (rose bengal)-related preclinical colorectal cancer work in 2014/2015 employed a single injection of intralesional PV-10.

"Treatment of subcutaneous tumors with a single injection of intralesional PV-10 led to near complete responses in all animals within days of exposure and significant regression of the injected lesions compared to controls (n=6 per group, p=0.027)." See my blog post Intralesional Injection of Rose Bengal Induces an Anti-tumor Immune Response and Potent Tumor Regressions in a Murine Model of Colon Cancer.

Moffitt Cancer Center's preclinical and clinical multi-indication work from 2011 to date also employed a single injection of Provectus' lead oncology agent:

"Treatment of the subcutaneous lesion with a single injection of IL PV-10 led to regression of the injected lesion as well as the distant B16 melanoma lung metastases." See Moffitt's publication Intralesional Injection of Rose Bengal Induces a Systemic Tumor-Specific Immune Response in Murine Models of Melanoma and Breast Cancer.

Single injections of PV-10 were used in Moffitt's clinical feasibility study at AACR and ASCO 2014, and their combining of PV-10 with immune checkpoint inhibitors at SITC 2014. You may even recall Moffitt's rather sensational August 2013 press release: Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows.

These single injections more often than not completely destroy the tumors into which they are injected. At ESMO 2014 (and ASCO 2014) Provectus' presented exploratory analysis work of the company's melanoma Phase 2 trial that showed most lesions required 1-2 injections of PV-10 for complete destruction (i.e., complete response). Provectus' primary and secondary liver cancer Phase 1 and expanded Phase 1 liver trials sees tumors injected once, too. The company's recurrent breast cancer Phase 1 trial of several years ago also saw patients have their lesions injected once.

A single injection of PV-10 matter...so what?

First, few injections or one injection per lesion bodes very well for patient compliance with PV-10.

Second, one injection achieving complete response should mean PV-10 is absolutely and relatively more effective than other approved and investigational agents also trying hard to destroy tumors. More with less might lead to much more with more.

Third, more robust efficacy at the so-called local level of lesion injection that leads to complete response (complete destruction) might mean greater immunological signalling of the immune system and thus a better result for destroying cancer elsewhere in the body.

Big Pharma admits that while they are pretty good at shrinking tumors, they are not good at getting rid of them. See my February 2014 blog post Big Pharma has a Shrinkage Problem.

Oddly, at ASCO 2015 Dr. James Allison, PhD said ignore the tumor and just work on the immune system, while attempting to patent the treatment combination of an oncolytic virus and immune checkpoint inhibition. See the blog's news page's ASCO Day #3, sampling (May 31, 2015).

"Up-and-coming" oncolytic virus company Viralytics' lead investigational drug based on Coxsackievirus A21 requires a multi-day, multi-injection per lesion approach (i.e., 10 series of injections).

Amgen's talimogene laherparepvec, as part of their collaboration with Bristol-Myers to combine T-Vec and ipi, was administered by intratumoral injection on day 1 of week 1, day 1 of week 4, and then every two weeks thereafter.

Amgen's preclinical work of T-Vec presented at AACR 2015 exploring the efficacy of the combination of T-Vec and immune checkpoint blockade required multiple injections of the intralesional/intratumoral agent.

Idera's recent "strategic clinical research alliance" with MD Anderson Cancer Center to combine the company's intratumoral toll receptor with ipilimumab in patients with advanced melanoma is the logical combination of a co-stim agent (Idera's IMO-2125) with a co-inhibitory agent (CTLA-4 ipi). Interestingly, or perhaps not so interestingly, IMO-2125 requires injections over multiple days (i.e., 4-5) and achieves less efficacy than PV-10.

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

All a Flitter (sort of) on Twitter about $PVCT

Moffitt's August 22nd PR, Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows (and perhaps the Agora Financial Breakthrough Technology Alert-sparked volume and share price rise) sparked several tweets yesterday from life sciences-focused folks I follow and/or read on Twitter.

This is just the public discourse the company and stock need to and should have, as folks of varying influence following and opining about the biotechnology sector start, I hope, weighing in more frequently and regularly on PV-10, Provectus and the stock.

Too good to be true. Snake oil.
@JPZaragoza1: Total BS
Understandable. Moffitt's headline is, after all, pretty heady: "Single injection," "may revolutionize." As a DVM, I would be interested in getting his perspective on the use of rose bengal in animals, such as the case studies posted by Australia's East West Vets.

No progress.
@chasingthealpha $PVCT been around forever, still no real progress
Understandable. Consider the metastatic melanoma Phase 2 final clinical study report only recently was completed, with limited data availability and no Phase 3 trial has started yet. 6 years. I suppose, could be considered "forever:"

• The trial started in September 2007: Begins Phase 2 Clinical Trial for Metastatic Melanoma,
• Preliminary data was released at Melanoma 2010 in November: Full Phase 2 Study Data on PV-10 for Metastatic Melanoma,
• Final trial data was released at ESMO in October 2012: Final Phase 2 Melanoma Data,
• A complete data set (as well as local observations as yet unreported) should be released at ECCO in September 2013: PV-10 Data on Locoregional Disease Control in Metastatic Melanoma.

No proof of systemic benefit.
@JPZaragoza1 smells of $VICL all over. Crap.
Understandable. Predecessor local (intralesional) agents T-Vec (talimogene laherparepvec) and Allovectin-7 have produced modest to no systemic benefit, and certainly not robust and/or immune-mediated ones, and not to mention modest to failed Phase 3 clinical results.

High profile, peer-reviewed publications, please.

@MaverickNY when there’s a NEJM or JCO article, I pay attention #brutalhonesty
Understandable. There has been no validation of Provectus and third party research and clinical trial results many folks require by virtue of publication in high profile journals like the New England Journal of Medicine or Journal of Clinical Oncology.

KOL skepticism.

@MaverickNY if I’m really honest, the ones not in the trial don’t. really sorry (in response to @JSwatercooler ‏Ouch. KOLs love PV-10. Read the PLOS ONE article.)
Interesting. I would like to understand the veracity of Dr. Church's perspective about KOLs' views of PV-10 not "related" to the drug (i.e., principal investigators like Agarwala, Ross or Thompson, or researchers like Sondak and Weber). According to Provectus, management has been told by top clinicians [unnamed to me] in very clear terms they will use PV-10 to treat all manner of cancer stricken patients – melanoma, liver cancer, breast cancer, bladder cancer and pancreatic cancer – because the drug is very user friendly (i.e., it has a favorable adverse event profile and is easy to administer). These clinicians want to use it earlier and if other treatments fail. So, who's right...?

Too good to be true. Snake oil. No progress. No proof of systemic benefit. No high profile peer-reviewed publications. Key opinion leader skepticism. I think management has heard all of this before.

It's always good to know the other side. This early Twitter discussion is more banter than actually the other side of the/a trade...for now.

Regulatory clarity and commercial validation cure a lot, and it would seem both are on the way.

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.

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.""

@adamfeuerstein: What Wall Street's Watching at ASCO (The Burrill Report)

This podcast, featuring Adam Feuerstein, senior columnist for TheStreet.com, is worth hearing. Click on this link: The Burrill Report (May 28, 2013): What Wall Street's Watching at ASCO.

Notes:

• ASCO 2013 likely will be about so-called "second generation" immunotherapies: anti-PD-1 and anti-PDL-1 agents. Ipilimumab (and, I suppose, vemurafenib) were/are first generation,
• Combination therapies, like ipi + nivo (both Bristol-Meyers drugs), have potential utility if/because you get synergism,
• Cancer disguises itself or is cloaked from the immune system? Craig's view (when treating cancer like an infectious disease) is the immune system is overwhelmed by cancer, not hidden or disguised from it. I don't think this is a semantic difference. Uncloaking, better distinguishing, etc. suggest artificial solutions or constructs.
• Key abstracts include Amgen's T-Vec.

Anything positive about T-Vec enhances the view the pharmaceutical industry has about intralesional agents in general.  So, we all should root for T-Vec. That said, if Amgen's compound bombs, the view still remains that intralesional agents are back, and PV-10 is the leader of the pack.

I Think it's a Good Time to be a $PVCT Shareholder

Shareholders are closer to the end-game for the stock than to their journey's beginning. The company's  life sciences technology is head and shoulders above its peers. The lead compound presents a compelling clinical value proposition capable, perhaps, of indeed shifting the paradigm of cancer treatment (and treatment of inflammatory skin disorders). The drug already is productized, with a product business proposition to match that of the underlying technology. Provectus appears to be nearing transparency regarding regulatory clarity for oncology. The company also appears to be nearing certain license deals that will provide initial market validation. In sum, management, Provectus and its shareholders are nearing the end-game.

Provectus' technology is a game changer, productized to effect the change, and can be delivered and scaled to profit from the change to come.

The technology, PV-10 for oncology, is an effective local treatment capable of as effectively treating distant disease and visceral metastases. The drug, through expression of antigens in context in tumors into which PV-10 is injected fortifies the immune system against cancerous agents. Immunization occurs because PV-10's chemoablation causes rapid, complete, durable necrosis of tumor lesions.

"Scientists have been trying for decades to understand why the body's immune system didn't see cancer cells as the enemy and attack them. Recent discoveries revealed that tumors are adept at cloaking themselves by hijacking the body's own mechanism for preventing the system's T-cells, the infection- and disease-fighting cells of the immune system, from running amok against healthy tissue."

The above quote from Wall Street Journal (WSJ) article New Cancer Drugs Harness Power of Immune System (5/15/13) is not quite on-point. Rather, the quote below from Bloomberg article Human Immune-Boosting Cancer Drugs Seen Extending Lives (5/12/13) is more to the point.

"Now many believe that by strengthening the immune system’s ability to identify and kill cancer cells, they can broaden the attack so it will fight any dangerous malignancy. “You’re setting up a fair fight” with the disease, said Nils Lonberg, a senior vice president at Bristol-Myers, in a telephone interview. “The immune system is just as adaptable as the cancer.”"

How do you strengthen the immune system? Medical science has done it before with infectious diseases. Immune systems can be overwhelmed and, thus, are unable to help the human body fight back. Antibiotics themselves do not cure patients of infectious diseases that have afflicted them. Rather, the immune system cures the hosts with the help of antibiotics. Treating infectious diseases requires that antibiotics should have near absolute specificity for the infectious agent. Tough infections require multiple agents.

I think it's a good time to be a Provectus shareholder.

The volume of the conversations about immunotherapy has grown much, much louder. Take Xconomy's Luke Timmerman's article Genentech Follows Fast at ASCO as Cancer Immunotherapy Picks Up (5/15/13) for example.

"Genentech made its name in cancer by creating targeted antibody drugs that zero in on tumor cells while mostly sparing healthy tissue. Now it’s seeking to compete in the next wave of cancer immunotherapies, which are designed to spark the immune system to attack tumors like a virus."

Or take NBC's Nightly News report Immunotherapy targets cancer cells with remarkable results (5/15/13).

"Cancer cells typically put up a chemical shield to protect against the body’s disease-fighting T cells. But immunotherapy can break down the shield and let the T cells get to work."

The more the biopharmaceuticals industry, investing community and general public talk about immunotherapy, the better the environment or atmosphere for PV-10 and Provectus to flourish.

From the same WSJ article above: "More broadly, Leerink [Swann, a middle market investment bank] believes the "immuno-oncology" drug market could amount to a $20 billion category annually, putting it on a par with the cholesterol-lowering statin market at its height."

From dendritic cells (Dendreon's Provenge) to antitumor antibodies (Bristol-Myers' anti-CTLA-4 agent Yervoy) to immune checkpoint blockades (ASCO 2013's anti-PD1 and anti-PDL-1 agents):

"The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology...[t]he pillars of human cancer therapy have historically been surgery, radiotherapy, and chemotherapy, but a fourth modality of immunotherapy has been well documented since 1890..." (Kirkwood et al.).

Big Pharma is tacking closer to the ultimate goal, but they mostly still are sailing wide of the objective.

"If the new generation of immune therapies lives up to its promise, “this is going to be a paradigm shift for treating cancer,” said Merck senior vice president Gary Gilliland in an interview. “We are pretty good at shrinking tumors, but not good at getting rid of them. Immune therapy is a way to begin to approach that.”"

Yes, Big Pharma is pretty good at shrinking cancerous tumors, but not yet good enough at making them go away.

Craig's postulation that you treat cancer like you treat an infectious disease requires a/the drug treatment to possess near absolute specificity for diseased tissue (spare normal tissue and clear rapidly from it) and induce a host response (combined apoptosis-autophagy of treated targets because intralesional delivery produces a “vaccine-like” systemic effect that enhances normal human body defenses) over a very wide range of activity (broad spectrum antibiotic-like)


PV-10 chemoablation causes rapid, complete, durable necrosis of tumor lesions.

I think it's a good time to be a Provectus shareholder.

The general discourse at the moment about immunotherapies, however, is far from well understood or a consensus. Take last week's exchange on Adam Feuerstein's Twitter feed @adamfeuerstein below.

Feuerstein had been explaining the fundamental bear case for Vical's Allovectin-7, but aside from perhaps some valid trial design questions, his "red flags" included a lack of positive statements by melanoma experts and institutional healthcare investors as well as a lack of immune-related toxicity by Allovectin-7. Church is not a fan of immune-related toxicity because of the long-term dangers of altering the immune system in order to use it. All of this despite the on-point replies of other respondents: directing T-cells to attack tumors rather than a broad uncontrolled response, the beauty of local treatment is limited toxicity, revolutionary if the local treatment works on visceral mets, etc.

Many monoclonal immunotherapies do cause terrible toxicities, which are related not just related to "taking the brakes off" the immune system. Their target antigens are not only on/in the immune cells they wish to suppress. Just like chemotherapy agents, immunotherapy agents also can cause collateral damage with more adverse side effects like cancer and death.

The nature of the conversation Feuerstein, Church and the others need to have has to be deeper and more substantive. It's too simplistic to say Allovectin-7 does or will not work. Whether it's Allovectin-7 or talimogene laherparepvecone (T-Vec, formerly OncoVEX), or PV-10 itself, one has to balance positive effects with side effects. Think of it as a biological signal-to-noise ratio. One can titer up dosages until one sees bad things happen.

I think Pfizer probably refused to do this with its anti-CTLA-4 agent tremelimumab, which is why it has a greater failure record in clinical trials than it's Bristol-Myers' ipilimumab. Bristol-Myers probably had a higher tolerance for "bad things to happen" in order to suss out the optimal or near-optimal signal-to-noise or benefit-to-side-effect ratio.

Remind yourself of Provectus' combination therapy work at AACR 2013 utilizing PV-10 and a systemic anti-CTLA-4 antibody. The highest dose of the latter killed the murine subjects more quickly. Lower doses were less effective but also less dangerous. Interestingly, the results the company concluded that while PV-10 is highly effective when all existing tumor is accessible for injection, for visceral or other inaccessible disease the combination of PV-10 with CTLA-4 blockade has important potential synergy. Nevertheless, the apparent toxicity at high doses of the anti-CTLA-4 antibody markedly reduced the effect of the antibody alone and the combination of PV-10 and the antibody.

If an immunotherapy is working, there has to be some response (e.g., inflamation, redness, blistering, itching, etc.). These "side effects" come with the territory, and merely are signs the immune system is now in the game. So, while one indeed is generating a toxic response by recruiting the immune system, the key is focusing this toxicity as much as possible.

The problem with Yervoy, and perhaps immunotherapies like anti-PD-1, anti-PDL-1 agents and other treatments, is the collateral damage they cause to the body. PV-10's great strength has been and is its ability to the target only what it kills and kill only what it targets. Another strength is the drug's ability to generate a very specific, targeted, immune response with very little collateral damage to anything but the tumor itself. So, some blistering occurs, body temperature rises, etc. Nothing more.

I think it's a good time to be a Provectus shareholder.

Still, regulatory clarity has to become transparent. Is it an MM Phase 3 trial under SPA powered for for a 6-month progressional free survival for PV-10 vs. 2-month plus PFS for the comparator DTIC?Or is it breakthrough designation therapy and accelerated approval or another accelerated pathway?

Further still, commercial validation through one or more meaningful license transactions (global, regional, dermatology) is required. For example, will it be Hisun-Pfizer Pharmaceuticals in China? Or another company or entity? The Hisun-Pfizer joint venture was established in 2012 to sell off-patent medicines in China and other emerging markets. But economics are economics. Pfizer's 49% equity ownership and thus 49% ownership of any PV-10 sales in China would be a strong inducement to widening the entity's mandate through a license deal with Provectus.

Who will it be in India? In Japan? When will PH-10 be licensed, and to whom?

Provectus is squarely in the eye of key cancer patient advocates. The company participated in Melanoma Research Alliances' (MRA's) Fifth Annual Scientific Retreat in February. In April Peter joined MRA's President and CEO Wendy Selig, LiveSTRONG's President and CEO and Provectus corporate advisory board member Doug Ulman, Moffitt Cancer Research Center's Dr. Shari Pilon-Thomas and some media for dinner.

Key opinion leaders like Moffitt's Dr. Jeff Weber and Dr. Vernon Sondak and Pfizer's Dr. Craig Eagle are enthused about PV-10 as both a monotherapy and combination therapy.

More data is on the way. And data is driving and will drive the deals.

Yes, I think it's a good time to be a Provectus shareholder.