Provectus's Pharmaceutical-Grade Small Molecule Immunotherapy Rose Bengal Sodium, Intratumoral Injection of Cancer, and Canine Soft Tissue Sarcomas
Provectus initiated a new sponsored research program with the University of Tennessee College of Veterinary Medicine to accelerate drug development in cancer for companion animals
This past week, Provectus announced that the Company had initiated a new sponsored research program with the University of Tennessee College of Veterinary Medicine (UTCVM) to assess the safety and preliminary efficacy of intralesional (IL; a.k.a. intratumoral) injection of a formulation of Provectus’s pharmaceutical-grade rose bengal sodium (RBS) for canine soft tissue sarcomas. You can read the Company’s press release (PR) here. UTCVM’s lead principal investigator (PI) for this work is clinical pathologist, comparative cancer biologist, and Assistant Professor Nora Springer, DVM, PhD, DACVP.
The program comprises:
A research agreement between Provectus and UTCVM, with the scientific aims of determining:
the in vitro cytotoxicity of RBS in canine cell lines,
the local and systemic safety of RBS-injection in healthy rabbits, where RBS is administered subcutaneously and intravenously to purpose-bred rabbits,
the systemic safety of RBS in healthy dogs, where RBS is administered intravenously to purpose-bred Beagles, and
via a Phase 1 clinical trial, the safety, tolerability, and preliminary efficacy of RBS in tumor-bearing dogs, where RBS will be administered intralesionally into soft tissue sarcomas of client-owned dogs.
A material transfer agreement between Provectus and UTCVM to enable the Company to send a formulation of pharmaceutical-grade RBS to Dr. Springer for the above-mentioned preclinical and clinical work.
Provectus also noted in the Company’s PR that this veterinary medical research and veterinary-directed drug development is being undertaken as part of the State of Tennessee’s funding to develop animal health drug products in partnership with state universities that have agriculture and veterinary medicine programs and Provectus. You can read the PR on this topic here.
Rookie, the German Shepherd
Among Provectus’s first patients (i.e., canine patients) was a German Shepherd named Rookie who received the Company’s rose bengal-based treatment (the precursor to PV-10) at UTCVM: intratumoral injection of a fibrous histiocytoma tumor (see below).
Other Provectus canine treatments and studies included:
IL injection of a mast cell tumor in a dog (Golden Retriever),
IL injection of squamous cell carcinoma in a cat,
IL injection of melanoma in a dog (Chow Chow),
Bladder instillation of transitional cell carcinoma in a dog (West Highland Terrier), and
Injectable intrahepatic and intraprostatic safety studies in dogs (Beagles).
Australian Veterinarian Dr. Ann Nevill
We know that Dr. Ann Nevill, founder of East West Veterinary Group in Melbourne, Australia, treated more than 100 dogs, several cats, and two horses with rose bengal (RB) for various types of cancer tumors.
She did so after reading “Chemoablation of metastatic melanoma using intralesional Rose Bengal” (Melanoma Research 18(6):p 405-411, December 2008), Provectus’s first-in-human Phase 1 clinical trial of PV-10. The paper’s lead author was Professor John Thompson, Emeritus Professor of Melanoma and Surgical Oncology at The University of Sydney, former Director of Sydney Melanoma Unit, Executive Director of Melanoma Institute Australia, and the author of more than 900 peer-reviewed scientific articles.
We have communicated a number of times with Dr. Nevill, who provided case notes to us in 2021. While she was initially challenged to treat mast cell tumors with her RB therapy (as noted in the right-most image above), Dr. Nevill said to us that she was eventually able to successfully do so. In a unsurprisingly-to-us consistent manner, Provectus was able to successfully address mast cell tumors.
We discussed companion animal (e.g., canine) cancer collaboration and research with UTCVM in 2018, facilitating a discussion between Dr. Nevill and UTCVM leadership and oncologists about her IL RB treatment of cancer, and her observations and experiences; however, the oncologists dismissed her work. This was in no small part due to their unfortunate misperception of and reaction to her veterinary practice’s approach of treating animals with modern Western medicine alongside Chinese medicine, acupuncture, and other forms of natural therapies.
Do as Regulators Say, Not as You Do
As prolific and apparently successful as Dr. Nevill’s IL RB-based cancer treatment was, it shares a stark similarity to the University of Miami’s (UM’s) Bascom Palmer Eye Institute’s (BPEI’s) Ophthalmic Biophysics Center’s (OBC’s) apparently successful preclinical and clinical work on RB photodynamic antimicrobial therapy (PDAT) (RB-PDAT) for the treatment of infectious keratitis, an infection of the eye (cornea) from bacterial, fungal, and viral pathogens.
The RB in Dr. Nevill’s and BPEI’s work is actually/effectively commercial-grade RB. It is not Provectus’s pharmaceutical-grade RBS.
To put a drug regulatory-oriented point on this:
RB is not manufactured to current Good Manufacturing Practices (cGMPs).
Manufacturing sites where RB is produced must be registered with U.S. Food and Drug Administration (FDA) and be able to pass Pre-Approval Inspections (PAIs). A lack of either requirement will prevent approval of a New Drug Application (NDA).
One is not able to obtain chemistry, manufacturing, and controls (CMC) information needed for NDA submission and approval to produce reproducible DP.
RB is not of acceptable purity and quality for commercial pharmaceutical use.
Notably, however, the quality of RB — that is, commercial-grade rose bengal — is only acceptable for early-stage drug development (i.e., different FDA regulations apply).
Our interaction with Dr. Nevill, primarily to listen to her about her apparently successful IL RB treatment (using RB purchased from Sigma-Aldrich, now MilliporeSigma), her experiences, and her observations, and with BPEI, exclusively to collaborate with a world-renowned medical institution and academic center that had achieved clinical proof-of-concept (i.e., a pilot clinical study) for a therapeutic use of RB (using RB purchased from Sigma-Aldrich and RB extracted from an unapproved ophthalmic medical product) were in the service of trying to chew multiple different gums and run at the same time, while trying to maintain our focus on IL PV-10’s clinical development for solid tumor cancers so as to potentially protect and increase Provectus stockholder value.
Reproducibility & Replicability are Hallmarks of Good (Great?) Science
Returning to Provectus’s and Dr. Nevill’s canine cancer work, these are examples of replicable outcomes of IL RBS/rose bengal-based companion animal cancer treatment that also support and contribute to Provectus’s adult human preclinical and clinical work and the Company’s preclinical work in pediatric solid tumors.
Think Provectus’s consistent pharmaceutical-grade RBS medical science.
Execution Risk
Provectus feels that there is a potential addressable market for IL treatment of solid tumor cancers in companion animals with RBS that is large, global, and underserved. The Company believes that the primary risk of this work is execution risk:
Can Provectus generate a biopharmaceutical industry-standard set of preclinical and/or clinical data, via UTCVM and Dr. Springer, that facilitates the partnering and monetization of the cancer portion of the animal health portion of the Company’s RBS drug substance (RBS DS) medical science platform and RBS drug product candidate (RBS DP) pipeline?
We have long believed of the patient and market opportunities of the potential widespread use of RBS DPs to treat multiple different animal health diseases and disorders. We believe that even more strongly today.
The Comparative Oncology Program at the National Cancer Institute
At a 2018 medical conference attended by the Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (POETIC) (see also The POETIC Foundation), a member of POETIC was approached by a member of the Comparative Oncology Program (COP) of the Center for Cancer Research at the National Cancer Institute (NCI) of the National Institutes of Health (NIH) because the COP member was interested in potentially doing animal studies on PV-10.
In subsequent dialog with the COP member, we learned that COP’s efforts were integrated into the human work at NCI, and not focused on the development of new veterinary cancer drug products. Rather, COP was focused on how dog models, not murine models, could help fill holes or gaps in the understanding of a drug’s utility for humans. It struck us that COP wanted and needed to work with a drug sponsor’s team to do COP’s work on dogs, rather than developing their own pure ideas or thoughts or leads about the/a drug itself.
It made sense that there were some gaps in POETIC’s pediatric understanding of PV-10, and that a COP collaboration could help fills those (i.e., spontaneous cancers in dogs share many features with human adult and, in particular, pediatric cancers). Given the then-substantial clinical work already done by Provectus in adult solid tumor cancers and the foundational preclinical work completed and ongoing in pediatric solid tumor cancers (by Aru Narendran, MD, PhD of the Cumming School of Medicine at the University of Calgary), it struck us that eventually developing a relationship with COP would have been, in effect, an important exercise in validation and brand association with NCI. It did not appear to Provectus that a COP relationship would have advanced the development of a canine cancer DP. We were unable to establish a then-relationship with COP due to “personality issues” outside of our control and unrelated to the medical science of RBS.
The University of Tennessee College of Veterinary Medicine
It took UTCVM approximately 18 months, after our first meeting with them in mid-2021 that followed Provectus’s notification of the award of the State of Tennessee’s grant, to identify and secure a lead PI and to conclude paperwork for this the preclinical and clinical veterinary study, which is being led by Dr. Springer.
As noted in Provectus’s PR, she graduated from Marietta College with a Bachelor of Science in Chemistry, LaGuardia Community College with an Associate in Applied Science in Veterinary Technology, Kansas State University with a Doctor of Veterinary Medicine (DVM), and Cornell University with a Doctor of Philosophy (PhD) in Translational Medicine. Dr. Springer completed the American College of Veterinary Pathologists (ACVP) certifying examination to become a Diplomate Member (DACVP), and has co-authored a number of medical journal publications to date.
Provectus’s Distributed Research Network and UTCVM
As we have discussed in the past and also broached at the Company’s 2023 Annual Stockholder Meeting, Provectus actively undertakes basic medical, translational, and clinical research in a distributed network manner. Different researchers and/or clinicians pursue different medical scientific hypotheses of RBS’s therapeutic potential in different disease areas based on their respective areas of expertise and in consultation with the Company. We emphasize the observations and conclusions of one researcher, and Provectus’s knowledge and prior experience, in one disease area with other researchers and clinicians in other disease areas. We encourage collaboration between our various researchers to assist Provectus in building the Company’s RBS DS medical science platform and RBS DP pipeline.
Our work to oversee and facilitate the regular connectivity of this distributed research network endeavors to affirm that outcomes are, or are not, mechanistically consistent. Our research collaborators and we are working to show that RBS’s bifunctional targeting of disease (i.e., direct contact between RBS and disease potentially leading to cell death or repair; such contact then potentially catalyzing multivariate immune signaling, activation, and response) is, or is not, consistent from one disease area to another.
Utilizing academic medical institutions and their researchers as part of a drug program’s early development work, can have strong pros and frustrating cons. Giving your drug product candidate, or a formulation of your drug substance, to a third-party researcher may provide more veracious assessment, whether positive or negative.
If a researcher affirms the investigational drug or formulation, one could point to scientific replicability; however, working with researchers, especially those who have no prior experience with or knowledge of a drug product candidate (other than what they read in the published medical literature) requires drug sponsors such as Provectus to “begin from scratch” in regards to the “standard process” of in vitro (i.e., “petri dish”) study of cytotoxicity/activity, in vivo study (i.e., mouse [murine] models) of efficacy/activity, in vivo study (i.e., certain species) of safety, and eventually clinical study (i.e., in humans or the subject species) of safety, tolerability, and efficacy/activity.
Provectus’s investigator brochure (IB) for PV-10 contains a copious amount of preclinical and clinical data, particularly the foundational components that perhaps could accelerate or obviate steps of this standard process (e.g., pharmacodynamics, pharmacology, pharmacokinetics, product metabolism, absorption, distribution, excretion, toxicity, genotoxicity, carcinogenicity, etc.
The Company had several thoughtful and collaborative discussions with UTCVM about PV-10 in human adult clinical and pediatric preclinical settings; however, Dr. Springer contemplated and eventually settled on the path of drug discovery and development with which she (and UTCVM oncologists) felt comfortable (i.e., the scientific aims outlined above). The Company feels comfortable about Dr. Springer’s comfort level, and believes that her plan, approach, methodology, and detail could efficiently and effectively provide a comprehensive and industry-standard data set (as little as preclinical data, as much as preliminary clinical efficacy data) for Provectus to utilize to potentially approach animal health specialist companies or animal health divisions of pharmaceutical companies possibly for partnering and co-development or for out-license of an initial animal health product candidate such as a canine cancer drug.
The Competitive Landscape
An IL formulation of pharmaceutical-grade RBS for the treatment of canine cancer potentially could, among other things:
Complement/compete with surgery, and its cost,
Complement/compete with radiation therapy, and its cost,
Compete with chemotherapy, and its cost, and
Compete with an approved IL therapy for unresectable non-metastatic canine mast cell tumors called Stelfonta (tigilanol tiglate), which was developed by Australia’s Qbiotics Group Limited, and is marketed and distributed in the U.S. and Europe by Vrbac Corporation, and its cost.
Qbiotics’s tigilanol tiglate is a plant-derived small molecule (Provectus’s RBS is a synthetic small molecule), and has generated interesting clinical data in dogs and human adults, including impressive response rates (upon IL injection) of canine mast cell tumors, lower response rates for canine soft tissue sarcomas, and lower response rates in human solid tumors.