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.

It's the small molecule chemical, stupid

Original image source

Updated below.

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

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

Also consider a PubMed search of "glorioso grandi." From this search, further consider, for example, (from where the basis for Oncorus may have come) Grandi et al., "Design and application of oncolytic HSV vectors for glioblastoma therapy," Expert Rev Neurother. 2009 Apr; 9(4): 505–517. Aside from improvements over injectable oncolytic viruses, it's still intratumoral injection as the route of delivery.

Updated (7/31/16): The trend towards immuno-oncology (I-O) via oncolytic virus continues — the first in this class being the October 2015 approval of Amgen's (BioVex's) talimogene laherparepvec (OncoVEXGM-CSF) — with a license transaction between Western Oncolytics and Pfizer for the former's version, this time a smallpox-related oncolytic virus: "Pfizer bags option on oncolytic virus, partners up to advance through PhI" (Nick Paul Taylor, FierceBiotech, July 29, 2016).

Gloriosio's (and Grandi's) work above, and his/their intellectual property, references the same base patent/patent application material BioVex did. See here, here (2008) and here (2011).

The scientific founder of, or the science foundation supporting, Western Oncolytics is Dr. Stephen Thorne, PhD, who comes from the same entity/organization/program — the University of Pittsburgh Cancer Institute's Cancer Virology Program — as Drs. Glorioso and Grandi. Thorne's work has been around as early as 2009 (and probably before; I have not done a thorough desk-based review of this work, but merely am observing the key details and the apparent trend): "Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer," Kirn et al., www.nature.com, January 2009.

There are several things of note to me in regards to Pfizer's involvement and certain other aspects of the deal/technology, such as: (i) no financial deal terms were announced (there's usually a reason for such); (ii) upside beyond "today" is gone; (iii) Western Oncolytics appears to only have raised a few million dollars; (iv) see the UPitt relationship/lineage above; (v) one could argue the trend is oncolytic virus, but one also could argue the trend is the tumor microenvironment (TME) as the gateway and route of delivery as the way to enter the gateway; (vi) there is no mention of Pfizer/Merck KGaA's anti-PD-L1 avelumab; (vii) more interest in the gateway, and the use of intralesional (IL) agents to enter it, and the value IL agents in combination with other therapies, especially immune checkpoint inhibitors; (viii) one could argue that Pfizer, a laggard in the immuno-oncology space, is slowing getting up to speed on where the possibility exists to catch-up (e.g., via TME, injection, oncolytic immunotherapy, etc.); and (ix) was Pfizer late again, beaten to the better UPitt oncolytic immunotherapeutic assets by Celgene and others?

It also is still injection of a biologic, and therein lies the "rub." Said another way: What I know now could be what I wished I knew then. Or perhaps said even another way: An entire pharmaceutical industry unsure or unable to consider or contemplate that the injection of a chemical (Rose Bengal/PV-10/a halogenated xanthene) -- not a biologic (e.g., a Rous sarcoma virus, a herpes simplex virus, a common cold virus, a CpG oligodeoxynucleotide, an avian paramyxovirus, etc.) -- can elicit a systemic immune response.

Recall St. Luke's Dr. Sanjiv Agarwala's presentation at 6th European Post-Chicago Melanoma/Skin Cancer Meeting. Setting aside Rose Bengal and chemotherapy cisplatin, I believe, everything other oncolytic agent is a biologic.

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Rose Bengal to the pharmaceutical industry might as well be battery acid. An intralesional or intratumoral injection of this chemical (sulfuric acid) should kill the injected lesion or tumor. As a I wrote under Do Dr. Jedd Wolchok/Sloan Kettering Understand Immunotherapy's History? (July 12, 2016) on the blog's Current News page, the father of cancer immunotherapy, Dr. William Coley, MD injected dead bacteria -- a biologic -- into the cancer tumors of his patients.

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

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

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

Notes:

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