PROVECTUS BIOPHARMACEUTICALS, INC. 10-K

ITEM 1. BUSINESS. General Provectus Biopharmaceuticals, Inc., a Delaware corporation incorporated in 2002 (together with its subsidiaries, “Provectus” or “the Company”), is a clinical-stage biotechnology company developing immunotherapy medicines for different diseases that are based on a class of synthetic small molecule immuno-catalysts called halogenated xanthenes (“HXs”). Our lead HX molecule is named rose bengal sodium (“RBS”). 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. Second, 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 at ClinicalTrials.gov. The Company believes that it is the first and only entity to date to make pharmaceutical-grade RBS successfully, reproducibly, and consistently at a purity of nearly 100%. The Company’s small molecule HX medical science platform comprises several different drug product candidates and preclinical pharmaceutical-grade RBS formulations using different concentrations delivered by different routes of administration specific to each disease area and/or indication. The Company’s HX medical science platform includes clinical development programs in oncology, dermatology, and ophthalmology; in vivo proof-of-concept programs in oncology, hematology, wound healing, and animal health; and in vitro drug discovery programs in infectious diseases and tissue regeneration and repair. Intellectual Property U.S. Patents We hold patents covering the HX medical science platform that we have developed and are continuing to develop for drug product candidates and drug formulations in different disease areas. All patents awarded by the U.S. Patent and Trademark Office (“USPTO”) that are material to an understanding of the Company are listed in the table below: U.S. Patent No. Title Issue Date Expiration Date 7,201,914 Combination antiperspirant and antimicrobial compositions April 10, 2007 May 15, 2024 8,530,675 Process for the synthesis of rose bengal and related xanthenes September 10, 2013 April 21, 2031 9,107,887 Combination therapy for cancer August 15, 2015 March 9, 2032 9,273,022 Process for the synthesis of rose bengal and related xanthenes March 1, 2016 September 17, 2030 9,422,260 Process for the synthesis of rose bengal and related xanthenes August 23, 2016 September 26, 2030 2 9,808,524 Combination of local and systematic immunomodulative therapies for melanoma and liver cancer November 7, 2017 March 9, 2032 9,839,688 Combination of rose bengal and systemic immunomodulative therapies for enhanced treatment of cancer December 12, 2017 March 9, 2032 10,130,658 Method of ex vivo enhancement of immune cell activity for cancer immunotherapy with a small molecule ablative compound November 20, 2018 December 18, 2035 10,471,144 Combination of local rose bengal and systemic immunomodulative therapies for enhanced treatment of cancer November 12, 2019 November 12 2034 11,058,664 In vitro and xenograft anti-tumor activity of a halogenated-xanthene against refractory pediatric solid tumors July 13, 2021 May 15, 2039 11,071,781 Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer July 27, 2021 March 9, 2032 11,419,844 Composition and Methods for Treating Hematologic Cancers August 23, 2022 December 3, 2040 11,426,379 Combination of Local and Systemic Therapies for Enhanced Treatment of Dermatologic Conditions August 30, 2022 November 29, 2038 We received one patent allowance from the USPTO in 2023, U.S. patent application number 17/488,430 titled “Halogenated Xanthenes as Vaccine Adjuvants.” Two patent applications were also published on the USPTO’s website: ● Photodynamic Anti-Gram-Positive Bacterial Activity of Pharmaceutical-Grade Rose Bengal (USPTO application number 18/089,011), and ● Halogenated Xanthene-Containing Topical Anti-Gram-Positive Bacterial Ophthalmic Composition and Method (18/089,134). International Patents In 2023, the Company received a patent award for Mexico for “Method of Ex Vivo Enhancement of Immune Cell Activity for Cancer Immunotherapy With A Small Molecule Ablative Compound,” patent awards for Australia and Mexico for “Combination of Local And Systemic Therapies for Enhanced Treatment of Dermatologic Conditions,” and patent awards for Australia, China, Europe, Hong Kong, and Mexico for “In Vitro And Xenograft Anti-Tumor Activity Of A Halogenated-Xanthene Against Refractory Pediatric Solid Tumors.” Clinical Development and Drug Discovery The Company’s small molecule HX medical science platform includes: Clinical Development Programs ● Oncology: Intratumoral (“ITU”) formulation PV-10 ® (“ITU PV-10”) has undergone and is undergoing multiple, monotherapy and combination therapy, early- to late-stage clinical trials, expanded access programs (“EAPs”) for groups of and individual patients, and/or quality of life (“QOL”) study at multiple clinical sites in Australia, Europe, and the U.S. for the treatments of Stage III and IV melanoma and different types of liver cancers. ITU PV-10 has undergone and is undergoing clinical monotherapy and combination therapy mechanism of action and mechanism of immune response study for melanoma, metastatic uveal melanoma, and metastatic neuroendocrine tumors at and/or with Moffitt Cancer Center in Tampa, Florida, The Queen Elizabeth Hospital in Adelaide, Australia, and MD Anderson Cancer Center in Houston, Texas. 3 ● Dermatology: Topical (“TOP”) formulation PH-10 ® (“TOP PH-10”) has undergone multiple mid-stage, monotherapy clinical trials for the treatments of psoriasis and atopic dermatitis at different clinical sites in the U.S. TOP PH-10 has undergone clinical monotherapy mechanism of action and mechanism of immune response study for psoriasis at The Rockefeller University in New York, New York (“TRU”). Different formulations have undergone preclinical combination therapy study for psoriasis and are undergoing preclinical monotherapy study for skin inflammation at TRU. ● Ophthalmology: The Company believes that clinical monotherapy proof-of-concept (“POC”) of TOP administration of non-pharmaceutical grade rose bengal for the treatment of infectious keratitis has been shown by clinicians and researchers at the University of Miami’s (“UM’s”) Bascom Palmer Eye Institute (“BPEI”) in Miami, Florida, who are now collaborating with the Company to evaluate the potential use of our pharmaceutical-grade RBS. TOP PV-305 has undergone preclinical monotherapy study for diseases and disorders of the eye, such as infectious keratitis at BPEI. In Vivo Proof-of-Concept Drug Discovery Programs ● Oncology: ITU PV-10 has undergone preclinical monotherapy and combination therapy study for the treatment of relapsed and refractory pediatric solid tumor cancers at the University of Calgary’s Cumming School of Medicine in Calgary, Alberta, Canada (“UCal”). The Company believes that the UCal researchers have achieved monotherapy in vivo POC of ITU administration. ● Oral (“PO”) formulations are undergoing preclinical monotherapy study for high-risk and refractory adult solid tumor cancers at UCal. The Company believes that the UCal researchers and the Company have both achieved monotherapy in vivo POC of PO administration, that the Company has achieved monotherapy in vivo POC of PO administration in prophylactic and therapeutic settings, and that the Company has achieved monotherapy in vivo POC of intravenous (“IV”) administration. ● Hematology: PO formulations are undergoing preclinical monotherapy study for the treatment of refractory and relapsed pediatric and other blood cancers, including leukemias, at UCal. The Company believes that the UCal researchers have achieved in vivo POC of PO administration. ● Wound Healing: Different formulations are undergoing preclinical monotherapy study for the healing of full-thickness cutaneous wounds. The Company believes that monotherapy in vivo POC of TOP administration of non-pharmaceutical grade rose bengal for the treatment of this indication has been shown by researchers at the University of Texas Medical Branch (“UTMB”) in Galveston, Texas, who are now collaborating with the Company to use our pharmaceutical-grade RBS. ● Animal Health: Different formulations are undergoing preclinical monotherapy study for the treatment of cutaneous canine cancers at the University of Tennessee’s College of Veterinary Medicine in Knoxville, Tennessee. The Company believes that it has achieved monotherapy POC in canines of ITU administration. In Vitro Drug Discovery Programs ● Infectious Diseases: PO and intranasal (“IN”) formulations have undergone preclinical monotherapy study for the treatment of SARS-CoV-2 at UCal, another Canadian academic research center, the University of Tennessee Health Science Center (“UTHSC”) in Memphis, Tennessee, and a U.S. contract research organization. 4 ● Different formulations have undergone preclinical monotherapy and combination therapy study for the treatment of gram-positive and gram-negative bacterial infections (including multi-drug resistant strains) and have undergone preclinical monotherapy study for the treatment of oral bacterial infections at UTHSC. ● Different formulations have undergone preclinical monotherapy study for the treatment of fungal infections at UTHSC. ● Tissue Regeneration and Repair : Different formulations have undergone preclinical monotherapy study for vertebrate development, wound healing, and tissue regrowth at the University of Nevada, Las Vegas (“UNLV”) in Las Vegas, Nevada. 2023 Activity In April, preclinical research on the Company’s pharmaceutical-grade rose bengal sodium drug substance against colistin-resistant gram-negative bacteria was published in The Journal of Antibiotics, a medical periodical by Nature Portfolio for the Japan Antibiotics Research Association: “Antibacterial effect of rose bengal against colistin-resistant gram-negative bacteria.” In June, the Company initiated a new sponsored research program with the University of Tennessee College of Veterinary Medicine to assess the safety and preliminary efficacy of intralesional injection of a formulation of the Company’s pharmaceutical-grade RBS for canine soft tissue sarcomas. The Company’s stockholders approved the proposals of the Board of Directors (“Board”) to seek the authority to undertake a reverse stock split and an authorized share reduction. In July, the USPTO published the Company’s patent application entitled “Photodynamic Anti-Gram-Positive Bacterial Activity of Pharmaceutical-Grade Rose Bengal” (publication no. 18/089,011). In August, the USPTO published the Company’s patent application entitled “Halogenated Xanthene-Containing Topical Anti-Gram-Positive Bacterial Ophthalmic Composition and Method” (publication no. 18/089,134). In November, preclinical data from ongoing research on the potential use of PV-10 as an adjuvant in vaccines to help them work better was the subject of a poster presentation at the Society for Immunotherapy of Cancer (SITC) 2023 annual meeting, held in San Diego, CA from November 1-5: “The iodinated fluorescein derivative PV-10 enhances the antiviral activity of CD8+ T-Cells by inducing STING dimerization: Implications for enhanced vaccine applications.” The Company provided updated data from an ongoing Phase 1 clinical trial of PV-10 for the treatment of uveal melanoma (UM) metastatic to the liver (mUM) (NCT00986661). The Company also provided updated data from an ongoing Phase 1b/2 clinical trial of PV-10 in combination with standard of care immune checkpoint blockade for the treatment of advanced cutaneous melanoma (NCT02557321). In December, the USPTO allowed patent application 17/488,430, titled “Halogenated Xanthenes as Vaccine Adjuvants.” The allowed patent application covers the use of Provectus’s pharmaceutical-grade rose bengal sodium (RBS) drug substance as an adjuvant in anticancer, antiviral, and possibly other vaccines to potentially make them work better by enhancing T-cell response. 5 Competition In general, the pharmaceutical and biotechnology industries are competitive, characterized by steady and sometimes disruptive advances in products and technology. A number of companies have developed and continue to develop products that address the areas we have targeted. Some of these companies are pharmaceutical companies and biotechnology companies that are international in scope and very large in size, while others are small companies that have been successful in one or more areas we are targeting. Existing or future pharmaceutical, device, or other competitors may develop products that accomplish similar functions to our technologies in ways that may be less expensive, receive faster regulatory approval, or receive greater market acceptance than our products. Many of our competitors have been in existence longer than we have, have greater capital resources, broader internal structure for research, development, manufacturing, and marketing, and may be further along in their respective product cycles. Supply Chain During 2023, we undertook extensive validation testing of our supply of prescription drug candidate PV-10. Federal Regulation of Therapeutic Products All the prescription drug candidates that we currently contemplate developing will require approval by the U.S. Food and Drug Administration (“FDA”) prior to sales within the U.S. and by comparable international governmental healthcare regulatory agencies prior to sale outside the U.S. The FDA and comparable international agencies impose substantial requirements on the manufacturing and marketing of pharmaceutical products. These agencies and other entities regulate, among other things, research and development activities and the testing, manufacturing, quality control, safety and effectiveness claims, labeling, storage, record keeping, approval, advertising, and promotion of our prescription drug candidates. While we attempt to minimize and avoid significant regulatory bars when formulating our products, some degree of regulation from these regulatory agencies is unavoidable. The regulatory process required by the FDA, through which our prescription drug candidates must successfully pass before they may be marketed in the U.S., generally involves pre-clinical laboratory and animal testing, submission of an application that must become effective before clinical trials may begin, adequate and well-controlled human clinical trials to establish the safety and efficacy of the product for its intended indication, and FDA approval to market a given product for a given indication after the appropriate application has been filed. For pharmaceutical products, pre-clinical tests include laboratory evaluation of the product, its chemistry, formulation, and stability, as well as in vitro and animal studies to assess the potential safety and efficacy of the product. We will require sponsored work to be conducted in compliance with pertinent local and international regulatory requirements, including those providing for Institutional Review Board approval, national governing agency approval, and patient informed consent, using protocols consistent with ethical principles stated in the Declaration of Helsinki and other internationally recognized standards and delineated by The International Conference on Harmonisation (“ICH”) Good Clinical Practice standards. If the FDA is satisfied with the results and data from pre-clinical tests, it will authorize human clinical trials. Human clinical trials traditionally are conducted in three sequential phases which may overlap. Each of the three phases involves testing and study of specific aspects of the effects of the investigational product on human subjects, including testing for safety, dosage tolerance, side effects, absorption, metabolism, distribution, excretion, and clinical efficacy. 6 Phase 1 clinical trials include the initial introduction of an investigational new drug into humans, or via a new route of administration or new organ system if previously investigated in humans. These studies are closely monitored and may be conducted in patients but may also be conducted in healthy volunteer subjects. These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. While the FDA can cause us to end clinical trials at any phase due to safety concerns, Phase 1 clinical trials are primarily concerned with safety issues. We also attempt to obtain sufficient information about the drug candidate’s pharmacokinetics and pharmacological effects during Phase 1 clinical trials to permit the design of scientifically valid, Phase 2 studies. Phase 1 studies also evaluate drug metabolism, structure-activity relationships, and the mechanism of action in humans. These studies also determine which investigational drugs are used as research tools to explore biological phenomena or disease processes. The total number of subjects included in Phase 1 studies varies with the drug but is generally in the range of 10 to 80. Phase 2 clinical trials include early controlled clinical studies conducted to obtain preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition. This phase of testing also helps determine the common short-term side effects and risks associated with the drug. Phase 2 studies are often randomized controlled studies that are closely monitored and conducted in a relatively small number of patients, usually involving up to several hundred people. Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained in Phase 2 and are intended to gather definitive information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. Phase 3 studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling. Phase 3 studies usually include several hundred to several thousand people. We have established a core clinical development team and have been working with external and FDA-experienced consultants to assist us in developing product-specific development and approval strategies, preparing the required submittals, guiding us through the regulatory process, and providing input into the design and site selection of human clinical studies. The testing and approval process requires substantial time, effort, and financial resources, and we may not obtain FDA approval on a timely basis, if at all. Success in preclinical or early-stage clinical trials does not assure success in later-stage clinical trials. The FDA or research institution conducting the trials may suspend clinical trials or may not permit trials to advance from one phase to another at any time for various reasons, including a finding that the subjects or patients are being exposed to an unacceptable health risk. Once issued, the FDA may withdraw a prescription drug approval if we do not comply with pertinent regulatory requirements and standards or if problems are identified after the product reaches the market. If the FDA grants approval of a prescription drug candidate, the approval may impose limitations, including limits on the indicated uses for which we may market a drug product. In addition, the FDA may require additional testing and surveillance programs to monitor the safety and/or effectiveness of approved drug products that have been commercialized, and the agency has the power to prevent or limit further marketing of a product based on the results of these post-marketing programs. Further, later discovery of previously unknown problems with a drug product may result in restrictions on the product, including withdrawal from the market. Marketing our prescription drug candidates abroad will require similar regulatory approvals by equivalent national authorities and is subject to similar risks. To expedite development, we may pursue some or all of our initial clinical testing and approval activities outside the U.S., and in particular in those countries where our prescription drug candidates may have substantial medical and commercial relevance. In some such cases, any resulting drug products may be brought to the U.S. after substantial offshore experience is gained. Accordingly, we intend to pursue any such development in a manner consistent with U.S. and ICH standards so that the resultant development data is maximally applicable for potential global approval. 7 Additional Regulation We are subject to various federal, state, and local laws and regulations relating to the protection of the environment, human health, and safety in the U.S. and in other jurisdictions in which we operate. If we violate these laws and regulations, we could be fined, criminally charged, or otherwise sanctioned by regulators. Environmental laws and regulations are complex, change frequently and have become more stringent over time. We believe that our operations currently comply in all material respects with applicable environmental laws and regulations. Human Capital Resources We have four full-time employees who currently serve as CFO, CTO, senior scientist, and controller. We also engage independent contractors, who currently serve as chief operations consultant, director of clinical operations, clinical research associates, and information technology manager. We believe the Company’s success depends on its ability to attract, develop, and retain key personnel. The skills, experience, and industry knowledge of key members of our Board of Directors, employees, and contractors significantly benefit our operations and performance. The Company’s Board of Directors and management oversee various employee and contractor initiatives. Available Information Our website is located at www.provectusbio.com . We make available free of charge through this website our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K, and amendments to those reports filed with or furnished to the SEC pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), as soon as reasonably practicable after they are electronically filed with or furnished to the SEC. Reference to our website does not constitute incorporation by reference of the information contained on the site and should not be considered part of this document. The SEC maintains an Internet site that contains reports, proxy and information statements and other information regarding issuers that file electronically with the SEC as we do. The website is http://www.sec.gov . The Company also intends to use press releases, the Company’s website and certain social media accounts as a means of disclosing information and observations about the Company and its business, and for complying with the Company’s disclosure obligations under Regulation FD: the Provectus Substack account (provectus.substack.com), the @ProvectusBio X account (twitter.com/provectusbio), and the Company’s LinkedIn account (linkedin.com/company/provectus-biopharmaceuticals). The information and observations that the Company posts through these social media channels may be deemed material. Accordingly, investors should monitor these social media channels in addition to following the Company’s press releases, SEC filings, and website. The social media channels that the Company intends to use as a means of disclosing the information described above may be updated from time to time. The contents of the websites provided above are not intended to be incorporated by reference into this Annual Report on Form 10-K or in any other report or document we file with the SEC. Further, our references to the URLs for these websites are intended to be inactive textual references only.