Modern Rose Bengal Small Molecule: Drug Substance and API for 21st Century Drug Development
Originally Tweeted March 25th to 31st
Provectus’s Rose Bengal Sodium: A Modernized Small Molecule, Drug Substance, and Active Pharmaceutical Ingredient for 21st Century DrugDevelopment. A Post.
“Everyone” seems to know or understand Rose Bengal, but do they (you) really?
Rose bengal is a small molecule (i.e., <1,000 Daltons1), but a “heavy” one at 973.67 Da or g/mol. It is heavy because of its four iodides, which comprise approximately 52% of its molecular weight. Rose Bengal Sodium (RBS), Provectus’s lead Halogenated Xanthene (HX), “weighs” 1,017.64 da. Approximately 50% of its molecular weight is accounted for by the molecule’s four iodides.
As a small molecule, RBS appears to violate only Lipinski’s rule-of-five’s molecular weight criterion of <500 Da. It is important to note the molecular structural “oddity” of Rose Bengal Sodium’s halogens.
Rudolf Gnehm first “invented” rose bengal in 1882 (late-19th century), calling it rose bengale and having two iodides as part of its molecular structure. Some years later, newer version rose bengale II came along, possessing four iodides. With four iodides, rose bengal is the commercial-grade version that most everyone (e.g., industry, researchers, etc.) knows today.
Rose bengal is one of a number of coal tar dyes, or artificial coloring agents (contrasted with organic-based dyes). Synthetic dyestuffs transformed the German dye industry in the late-19th century. Dyestuffs were an integral part of the emergence of pharmaceutical science, and the pharmaceutical industry, in the late-19th and early-20th century (e.g., Bayer, Sandoz [which merged with Ciba to form Novartis], Pfizer, etc.).
“Postulated by Paul Ehrlich in 1906 following more than a decade of research, the concept that synthetic chemicals could selectively kill or immobilize parasites, bacteria, and other invasive disease-causing microbes would eventually drive a massive industrial research program that continues to the present.”
Forbes.com: Lexicon's Quest For A New Blockbuster (2001).
“In a sense, the pharmaceutical industry has been working with a surprisingly repetitive set of compounds. “Most drugs are really German dyes,” says Brent Stockwell, a scientist at the MIT-affiliated Whitehead Institute for Biomedical Research. That’s because they’re based on what has worked before–mostly compounds that evolved from drugs developed at dye companies like F. Bayer & Co. a century ago.”
Dyestuffs used to be the bread and butter of the global pharmaceutical industry. Biologics are now, perhaps more than ever, for honest medical scientific as well as cynical financial reasons, the “rage” of drug development.
Rose Bengal Sodium, via intratumoral delivery (in terms of Provectus’s current clinical-stage datasets), may mount a precise, personalized immune response in cancer patients. Yet, RBS is not immunogenic in that it does not itself produce an immune response, and does not provoke immune adverse events like a strictly-immunogenic agent.
Lots or most (maybe all) of rose bengal’s molecular knowledge and understanding (e.g., structure, formula, stoichiometry, etc.) has been lost to time over the last 140+ years. That knowledge, however, resides in Provectus with Dr. Eric Wachter and PRH.
For purposes of this Substack post, some historical context: A group of stockholders (PRH) entered into a Definitive Financing with Provectus in 2017.
As the Company noted in its Form 10-Q for the quarter ending September 30, 2022:
Provectus’s proprietary, patented, pharmaceutical-grade Rose Bengal Sodium 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 Rose Bengal Sodium 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.
Provectus believes that it is the first entity to advance a Rose Bengal Sodium 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%.
Provectus’s small molecule Halogenated Xanthene medical science platform comprises a number of different drug product candidates and preclinical pharmaceutical-grade Rose Bengal Sodium formulations using different concentrations and delivered by different routes of administration specific to each disease area and/or indication. Our HX medical science platform includes:
clinical development programs in Oncology, Dermatology, and Ophthalmology,
proof-of-concept in vivo drug discovery programs in oncology, Hematology, Wound Healing, and Animal Health, and
preclinical in vitro drug discovery programs in Infectious Diseases and Tissue Regeneration.
Provectus’s pharmaceutical-grade Rose Bengal Sodium resulted from our 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.
Provectus’s processes of synthesizing the Rose Bengal Sodium molecule into pharmaceutical-grade RBS and manufacturing RBS drug substance and intralesional/intratumoral 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 PV-10 for the treatment of locally advanced cutaneous melanoma, including:
the U.S. Food and Drug Administration (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).
The Rose Bengal Sodium name for Provectus’s pharmaceutical-grade API was selected by and passed the review of the World Health Organization (WHO) Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations after we applied for the non-proprietary name in the third quarter of 2020, and reached the status of recommended International Nonproprietary Names (INN). INN Recommended List 88, which includes the RBS name, was published with the No. 3 issue of the WHO Drug Information, Volume 36 in the fourth quarter of 2022.
The aim of the INN system since inception has been to provide health professionals with a unique and universally available designated name to identify each pharmaceutical substance or API, according to the WHO. The existence of an international nomenclature, in the form of INN, is important for the accurate identification, prescribing, and dispensing of medicines to patients, and for communication and exchange of information among health professionals and scientists worldwide.
Of course, you would think that the WHO and Chemical Abstract Services would recognize that Rose Bengal Sodium has two sodiums (2 Na’s) on its molecular structure, but we digress…
Prior Medical Diagnostic Use of Rose Bengal
FDA-Approved Liver Diagnostic Use. In 1971, 131I rose bengal (Robengatope® [rose bengal sodium 131I injection USP]) was approved by the FDA (NDA 016224) for use as a diagnostic aid to determine liver function. In 2009, manufacturer Bracco Diagnostics Inc. withdrew Robengatope from the U.S. market because of the emergence of newer liver imaging methods, such as computed tomography.
Historic Ophthalmic Diagnostic Use. In 1974, Barnes-Hind Pharmaceuticals, Inc. (“Barnes-Hind”) introduced a medical device product of 1% rose bengal in an aqueous solution for the diagnosis of corneal injury, diagnosis of keratitis, keratoconjunctivitis, and sicca, and detection of foreign bodies in the eye. In 1981, Barnes-Hind introduced ophthalmic strips of the same concentration for the same indications.
While both the solution and strip medical device products were accepted by the FDA for marketing, Provectus does not believe that the devices or their respective claims were approved by the FDA because their introductions predated formal FDA review and approval of medical devices.
Non-Pharmaceutical Grades of Rose Bengal
Commercial-Grade. This material may be purchased from specialty chemical suppliers in the U.S. and from other parts of the world; however, the Company believes that the material itself is almost exclusively made in China and India under non-#cGMP conditions. Commercial-grade rose bengal appears to have reported purity that may vary between approximately 80% and 95%, and that may contain substantial amounts of unreported impurities and/or gross contaminants. Commercial-grade rose bengal is typically used by researchers for preclinical study of the rose bengal molecule for potential biomedical therapeutic applications.
Provectus believes that commercial-grade rose bengal is still manufactured using the historical process (or a variant thereof) that was developed by the synthetic molecule’s Swiss creator Gnehm in 1882. Some manufacturers may, however, apply purification techniques that the Company believes still result in material that may possess questionable purity and contaminants and may also be subject to substantial lot-to-lot manufacturing variability.
Diagnostic-Grade. The Company coined this phrase to describe non-approved rose bengal that is used as an ingredient in historical or current ophthalmic solutions and strips, has been historically or is presently compounded by pharmacists for ophthalmic use, and has been or is in other non-ophthalmic diagnostic tests such as the rose bengal test in human brucellosis.
Provectus presumes, but has not yet confirmed, that diagnostic-grade rose bengal is derived from commercial-grade rose bengal that may have undergone a form of purification and/or may have been compounded under cGMP regulations by a pharmacist, academic medical researcher, or commercial entity. Here too, the Company believes that purification may not sufficiently improve the amounts and accuracy of rose bengal purity and lot contents and may not adequately reduce or eliminate lot-to-lot manufacturing variability.
Chemical Analytical Comparison. In the first quarter of 2022, Provectus 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 Rose Bengal Sodium.
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.
Potential Barriers to Entry
Provectus believes that the Company’s proprietary, patented, pharmaceutical-grade Rose Bengal Sodium 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 fulsome 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.
All of this notwithstanding, the onus remains on Provectus to show that its Rose Bengal Sodium medical science “works.” Post end.
The unit of measure of Dalton, also known as an atomic mass unit, is named after John Dalton, the English chemist, physicist and meteorologist. It was not named after John Dalton, the professional “cooler” in Road House.