Provectus’s Rose Bengal Sodium: A “Proprietary” Molecule and Proprietary Drug Substance
Potentially the only source of pharmaceutical-grade rose bengal sodium drug substance
Rose bengal has been around since the late-18th century, when it was first created as a coal tar-derived fabric dye, the stuff that the global pharmaceutical industry turned into drugs for people when the industry first emerged.
Is rose bengal still a proprietary molecule? Almost by seemingly biotechnology/pharmaceutical industry definition, to some (e.g., unaffiliated researchers, potential biotechnology company competitors, prospective comercial pharmaceutical company partners), it cannot be, because rose bengal has been around for about 150 years.
A lot of data, information, and knowledge about rose bengal – essentially “molecular wisdom” – has been lost to history over that century and a half. As a result, rose bengal may be an effectively proprietary molecule. That is only a small part of the drug development story of rose bengal and its halogenated xanthene (HX) class of molecules, in our view.
Perhaps even more importantly, we believe that Provectus’s pharmaceutical-grade rose bengal sodium (RBS) drug substance is proprietary, and potentially very protected for the reasons that we layout below.
Drugs are made from one or more drug substances that derive from their respective small or large molecules. Both drug product candidates and their drug substances must meet thresholds for pharmaceutical quality or chemistry, manufacturing, and controls (CMC) to be approved.
Thus, no approvable RBS drug substance should mean no approvable drug, for Provectus, and for any current and future competitor (whether commercial, academic, or government entity).
Provectus Substack Post Short-Form
An impure drug substance can be acceptable to the U.S. Food and Drug Administration (FDA) for use in a Phase 1 or 2 clinical trial. An impure drug substance, however, is not acceptable for commercialization.
Provectus believes there is no other RBS drug substance that is currently commercially available at a pharmaceutical quality acceptable for new drug application (NDA) approval.
Provectus believes there is no other RBS drug substance that is currently commercially available at an acceptable pharmaceutical quality from a facility with a filed drug master file (DMF) that could pass a pre-approval inspection (PAI) to enable NDA approval.
Provectus Substack Post Long-Form
Provectus shareholders and various others have asked us over time about Provectus’s intellectual property (IP) protection, such as the competitive landscape of and the potential for competition for Provectus’s RBS drug substance and RBS-based drug products. Competition could come from, among other places:
A novel diagnostic application of rose bengal,
A novel therapeutic application using a novel diagnostic’s rose bengal ingredient as the therapeutic application’s drug substance,
A novel therapeutic application involving a rose bengal drug substance-based drug,
A therapeutic application involving a novel drug delivery system that carries a payload of a rose bengal drug substance-based drug, or
A therapeutic application involving a novel modification of the rose bengal molecule, which in turn becomes a novel rose bengal-based drug substance.
From where is the rose bengal coming – in the form of an FDA-approvable drug substance – for use in any of the above potential competition? Are you buying it from a specialty chemical supplier or directly from the chemical manufacturer, or are you making it yourself?
In Provectus’s Form 10-Q for the period ending September 30, 2022, we noted the following:
Under Business Organization, Nature of Operations and Basis of Presentation:
The Company’s proprietary, patented, pharmaceutical-grade RBS is the active pharmaceutical ingredient in the drug product candidates of our current clinical development programs and the preclinical formulations of our current drug discovery programs. Importantly, our pharmaceutical-grade RBS displays different therapeutic effects at different concentrations and can be formulated for delivery by different routes of administration.
The Company believes that RBS targets disease in a bifunctional manner. First, direct contact may lead to cell death or repair depending on the disease being treated and the concentration of the RBS utilized in the treatment. Secondly, multivariate immune signaling, activation, and response may follow that may manifest as stimulatory, inhibitory, or both.
The Company believes that it is the first entity to advance an RBS formulation into clinical trials for the treatment of a disease, such as those trials reported on the clinical trials registry ClinicalTrials.gov.
The Company believes that it is the first and only entity to date to successfully, reproducibly, and consistently make pharmaceutical-grade RBS at a purity of nearly 100%.
Under Management’s Discussion and Analysis of Financial Condition and Results of Operations:
RBS Drug Substance and Drug Product Candidate Manufacturing
Our pharmaceutical-grade RBS resulted from the Company’s innovation of a proprietary, patented, commercial-scale process to synthesize and utilize the RBS molecule into a viable active pharmaceutical ingredient (“API”) for commercial pharmaceutical use; the development of unique chemistry, manufacturing, and control (“CMC”) specifications for drug substance and drug product candidate manufacturing processes; the production and multi-year stability testing of multiple drug substance and drug product candidate lots; the comprehensive documentation of lot composition and reproducibility; and the review and acceptance of CMC data from these lots by seven different national drug regulatory agencies for use in a prior, multi-country, multi-center Phase 3 randomized control trial of the Company.
The Company’s drug substance and drug product candidate manufacturing processes employ Quality-by-Design principles, current good manufacturing practice (“cGMP”) regulations, and the guidelines of The International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use. These processes utilize controls that eliminate the formation of historical impurities and avoid the introduction of potentially hazardous impurities that the Company believes may have been and could be present in uncontrolled and unreported amounts in non-pharmaceutical-grades of rose bengal.
The Company’s processes of synthesizing the RBS molecule into pharmaceutical-grade RBS and manufacturing RBS drug substance and ITU PV-10 drug product candidate, the processes’ CMC specifications, and the CMC data from the production of stability lots of drug substance and drug product candidate have been reviewed by multiple national drug regulatory agencies prior to granting clinical trial authorizations for the Company to commence a historical Phase 3 study of ITU PV-10 for the treatment of locally advanced cutaneous melanoma, including the U.S. FDA, Germany’s Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Australia’s Therapeutic Goods Administration (TGA) under a clinical trial notification, France’s Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM), Italy’s Agenzia Italiana del Farmaco (AIFA), Mexico’s Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS), and Argentina’s Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT).
Chemical Analytical Comparison
In the first quarter of 2022, the Company began work with a U.S. contract development and manufacturing organization to rigorously and methodically assess three lots of commercial-grade rose bengal, one each from three different specialty chemical suppliers, and compare and contrast these non-pharmaceutical grade materials with the Company’s pharmaceutical-grade RBS. This chemical analytical work was substantially completed by the end of the third quarter of 2022. The Company believes that the preliminary results of these analyses indicate that all three lots of commercial-grade rose bengal had rose bengal purity that was drastically different from what was represented on their respective certificates of analysis (“CofAs”), and that one of the three lots contained gross contaminants that were not represented on its CofA.
We believe that:
Provectus can make highly pure, potentially FDA-approvable, RBS drug substance, and
Commercial-grade rose bengal is impure to varying degrees and is very highly unlikely to be FDA-approvable as a drug substance. Commercial-grade rose bengal has a variable and volatile impurity profile, which is not acceptable to the FDA as a drug substance for the commercialization of a drug product based on it because reproducibility must be ensured.
To this end, we also noted the following in Provectus’s 3Q22 Form 10-Q:
Under Potential Barriers to Entry:
The Company believes that the Company’s proprietary, patented, pharmaceutical-grade RBS possesses several competitive advantages over non-pharmaceutical-grades of rose bengal that researchers, clinicians, and academic, business, and/or governmental competitors have used, are using, and/or may attempt to use for potential biomedical applications. The Company believes that non-pharmaceutical-grades of rose bengal may suffer from the uncontrolled presence of substance-related impurities and/or gross contaminants, substantial lot-to-lot manufacturing variability, inaccurately reported and/or misrepresented purity and contents, and the lack of reproducible, consistent, and fullsome CMC specifications and documentation.
The Company believes that historical and potentially hazardous impurities and other manufacturing and handling issues facing non-pharmaceutical-grades of rose bengal may pose significant scientific, technological, and economic challenges to overcome and validate for compliance with modern drug regulatory standards.
The moats that Provectus has built around our RBS molecule and drug substance include, among others:
Regulatory: We believe that only Provectus’s RBS drug substance supports the CMC thresholds of an NDA and an investigational new drug (IND) program to create, license, and launch modern drugs,
Legal: We believe that Provectus’s IP portfolio covers and protects the innovative synthesis of RBS and related members of this class of HX molecules into actual and prospective proprietary drug substances in all major geographic global markets. We also believe that our IP protects against circumvention of Provectus’s manufacturing process to create competing drug substances. Provectus’s patents and patent applications cover and protect the use of Provectus’s existing and future drug products in combination with other therapies and treatments in different disease areas,
Scientific & Technological: We believe that Provectus’s RBS drug substance, based on our modernization of the rose bengal molecule as RBS is a clear and unequivocal innovation: a new, highly pure, pharmaceutical-grade drug substance that Provectus created and now consistently manufactures to exacting global regulatory standards,
Personnel: The numerous details of manufacturing Provectus’s RBS drug substance as well as analyzing and detecting competing and counterfeit drug substances are company trade secrets, among other knowledge. This molecular wisdom resides with Dr. Eric Wachter, one of Provectus’s original co-founders, and now Dominic Rodrigues, a member of Provectus’s leadership team and formerly part of a “group” of stockholders (i.e., PRH) who entered into a Definitive Financing with the Company in 2017, and
Drug pricing: We believe that pricing can be an important strategic and competitive weapon. RBS’s manufacturing cost structure provides a substantial amount and diversity of business and revenue model flexibility.
We believe that these moats may strongly influence the outcome of a risk-adjusted net present value (rNPV) (or NPV) calculation of Provectus’s potential valuation.
We noted in Provectus’s 3Q22 Form 10-Q that:
Commercial-grade rose bengal is typically used by researchers for preclinical study of the rose bengal molecule for potential biomedical therapeutic applications.
The primary source of this impure material seems to be Sigma-Aldrich, now MilliporeSigma.
If Provectus wants to become the world experts on the RBS molecule (if Provectus is not already), and if Provectus has what we believe is the only source of pharmaceutical-grade RBS drug substance, then would we not want to ensure that every researcher in the world – commercial, academic, and governmental – has access to a potentially drug regulatory agency-approvable source?
We will discuss Veripure in an upcoming Provectus Substack post. Provectus shareholders may know that we applied for a trademark in October 2022.