PROVECTUS BIOPHARMACEUTICALS, INC. 10-K

ITEM 1. BUSINESS. General Provectus Biopharmaceuticals, Inc., a Delaware corporation (together with its subsidiaries, “Provectus” or “the Company”), is a clinical-stage biotechnology company developing immunotherapy medicines for different diseases. Our drug product candidates are based on bioactive, synthetic, small molecule rose bengal sodium (“RBS”), which is a member of a class of molecules called halogenated xanthenes (“HXs”). The Company’s proprietary, patented, pharmaceutical-grade RBS is the active pharmaceutical ingredient (“API”) in all our clinical development and non-clinical research programs. The Company is the first entity to advance RBS into clinical trials for the treatment of disease. The Company is also the first entity, and currently the only one, to date to make pharmaceutical-grade RBS API consistently at a purity of nearly 100%. RBS can be delivered by different routes of administration. RBS may concurrently display stimulatory and inhibitory effects and may target disease in a bifunctional multi-modal manner. Direct contact by RBS with disease may lead to cell death or repair by one or more targeting mechanisms, depending on the disease being treated and the concentration of RBS being utilized in the formulation. Multivariate innate and adaptive immune activation, signaling, and response may follow. The Company’s RBS drug platform and pipeline comprise drug product candidates and non-clinical formulations that use different amounts of RBS and are delivered by different routes of administration specific to each disease area, including: ● Clinical: Development programs in oncology (intratumoral administration), dermatology (topical), and ophthalmology (topical), ● In vivo: Proof-of-concept programs in oncology (oral), hematology (oral), wound healing (topical), and canine cancers (intratumoral), ● In vitro: Early discovery programs in infectious diseases and tissue regeneration and repair, and ● In silico: Computer modeling of amyotrophic lateral sclerosis and other disease targets. Intellectual Property U.S. Patents We hold patents covering RBS and HX medical science. 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. In 2024, we received five patent awards from the USPTO: U.S. Patent No. Title Issue Date Expiration Date 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 11,938,182 Halogenated xanthenes as vaccine adjuvants March 26, 2024 March 35, 2041 11,975,106 Uses of halogenated xanthenes in oncology and virology May 7, 2024 July 6, 2041 11,974,980 In vitro and xenograft anti-tumor activity of a halogenated xanthene against refractory pediatric solid tumors May 7, 2024 October 13, 2038 12,064,507 Composition and method for oral treatment of leukemia August 20, 2024 August 4, 2041 12,133,840 Halogenated xanthene composition and method for treating hematologic cancers November 5, 2024 August 3, 2040 In 2024, four patent applications were also published on the USPTO’s website: ● Anti-bacterial effect of halogenated fluorescein against colistin-resistant gram-negative bacteria (USPTO application number 18/615,444), 3 ● Halogenated Xanthenes as Vaccine Adjuvants (18/581,095), ● In Vitro and Xenograft Anti-Tumor Activity of a Halogenated-Xanthene Against Refractory Pediatric Solid Tumors (18/642,051), and ● Composition and Method for Treating Hematologic Cancers (17/890,659). International Patents In 2024, the Company received patent awards and allowances for eight of our patent families: ● “Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer” in Canada, ● “Combination of Local and Systemic Therapies for Enhanced Treatment of Dermatologic Conditions” in Europe, ● “In vitro and xenograft anti-tumor activity of a halogenated xanthene against refractory pediatric solid tumors” in Canada (allowance), ● “Composition and Methods for Treating Hematologic Cancers” in Japan and Australia (allowance), ● “Novel Uses of halogenated xanthenes in oncology and virology” in China and Japan, ● “Treatment of Solid Cancerous Tumors by Oral Administration of a Halogenated Xanthene” in Japan, ● “Halogenated Xanthene Composition and Method for Treating Hematologic Cancers” in Japan, and ● “Halogenated xanthenes as vaccine adjuvants” in Japan. Clinical Development and Drug Discovery Clinical Development Programs ● Oncology: Intratumoral 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, different types of liver cancers, and breast cancer. PV-10 has undergone clinical monotherapy and combination therapy study of mechanisms of action and immune response for melanoma, metastatic uveal melanoma, and metastatic neuroendocrine tumors at Moffitt Cancer Center (“Moffitt”) in Tampa, Florida, The Queen Elizabeth Hospital in Adelaide, Australia, and MD Anderson Cancer Center in Houston, Texas. The lead indication for intratumoral PV-10 is FOLRINOX-refractory pancreatic ductal adenocarcinoma (“PDAC”) metastatic to the liver (“mPDAC”), where patients would receive the combination therapy of PV-10 and systemically administered gemcitabine and nab-paclitaxel at a single-site early-stage clinical trial at Moffitt. The Company may pursue a secondary indication of pre-operative penile squamous cell carcinoma (“penile SCC”), where patients would receive monotherapy PV-10 at a single-site early-stage clinical trial at Moffitt. ● Dermatology: Topical PH-10, a formulation of PV-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. 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 PV-10 formulations have undergone non-clinical combination therapy study for psoriasis and are undergoing non-clinical monotherapy study for skin inflammation and skin aging at TRU. 4 ● Ophthalmology: The Company believes that clinical proof-of-concept (“POC”) of topical administration of non-pharmaceutical grade rose bengal in combination with a light source medical device 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. Topical formulation PV-305, a formulation of PV-10, has undergone non-clinical combination therapy study (i.e., drug and device) for diseases and disorders of the eye, such as infectious keratitis, at BPEI. The Company launched a clinical-stage start-up biotechnology company named VisiRose, Inc. (“VisiRose”), a collaboration between the Company and UM to commercialize BPEI’s ocular research using PV-305. Proof-of-Concept Programs ● Oncology: Intratumoral PV-10 has undergone non-clinical 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 intratumoral administration for pediatric solid tumor cancers. ● Oral (“PO”) formulations of PV-10 have undergone non-clinical 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 both prophylactic and therapeutic settings, and that the Company has achieved monotherapy in vivo POC of PO administration for adult solid tumors. ● Hematology: PO formulations of PV-10 have undergone non-clinical 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 for blood cancers. ● Wound Healing: The Company believes that monotherapy in vivo POC of topical 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. Topical formulations of PV-10 are undergoing non-clinical monotherapy study for the healing of full-thickness cutaneous wounds at UTMB. ● Animal Health: PV-10 formulations have undergone non-clinical 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 of intratumoral administration for canine cancers. Early Drug Discovery Programs ● Immune vaccine adjuvant: Different formulations of PV-10 have undergone non-clinical study as a vaccine adjuvant to enhance T cell responses for anti-viral and anti-cancer vaccines. ● Infectious Diseases: PO and intranasal (“IN”) formulations of PV-10 have undergone non-clinical 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. Different formulations of PV-10 have undergone non-clinical monotherapy and combination therapy study for the treatment of gram-positive and gram-negative bacterial infections (including multi-drug-resistant strains) and have undergone non-clinical monotherapy study for the treatment of oral bacterial infections at UTHSC. Different formulations of PV-10 have undergone non-clinical monotherapy study for the treatment of fungal infections at UTHSC. ● Tissue Regeneration and Repair : Different formulations of PV-10 have undergone non-clinical monotherapy study for vertebrate development, wound healing, and tissue regrowth at the University of Nevada, Las Vegas in Las Vegas, Nevada. ● Proprietary: Different formulations of PV-10 are undergoing non-clinical study for proprietary diseases at an academic medical center. Computer Modeling Programs ● Computer-based molecular docking of RBS has been done and is being done for amyotrophic lateral sclerosis and other disease targets. 5 Business Strategy The Company is planning to initiate new intratumoral PV-10 monotherapy and combination therapy clinical trials in mPDAC and pre-operative penile SCC indications to generate new clinical data and appropriately utilize historical clinical data from intratumoral PV-10 trials, EAPs, and/or QOL study of injectable solid tumor cancers. Our goals are to pursue drug approval pathways and/or co-development relationships with commercial pharmaceutical companies for intratumoral PV-10 based on these and other indications. The Company is developing a systemically administered formulation of PV-10 for the treatment of cancer. Our goals, when this work is complete, are to file and have accepted an investigational new drug application (“IND”) with the U.S. Food and Drug Administration (“FDA”), take an initial systemic drug product candidate into an early-stage clinic trial for an initial oncology or hematology indication, and/or pursue a co-development collaboration or out-license arrangement for this route of administration and disease area. The Company is developing different formulations of PV-10 and different routes of administration for other disease areas by endeavoring to show non-clinical activity and lack of toxicity. Our goals, when each task of this work is completed, are to file and have accepted an IND with the FDA, take an initial drug candidate into an early-stage clinic trial for an initial indication, and/or pursue a co-development collaboration or out-license arrangement for the respective disease area and route of administration. The Company is endeavoring to fully elucidate the traits and characteristics of the RBS molecule using different academic medical centers under sponsored research and testing agreements. Our goal is to gain and communicate additional knowledge of the RBS molecule’s targeting, mechanism, signaling, immune response, and other features that are common to and/or different from each disease area under research. The Company is doing rigorous chemical analytical comparisons of non-pharmaceutical grades of rose bengal from specialty chemical suppliers against the Company’s pharmaceutical-grade RBS. Our goal is to demonstrate the proprietary nature of the Company’s pharmaceutical-grade RBS and that our pharmaceutical-grade RBS meets the necessary uniformity and purity requirements for commercial pharmaceutical use. 6 RBS API and Drug Candidate Manufacturing Our pharmaceutical-grade RBS resulted from: ● The Company’s innovation of a proprietary, patented, commercial-scale process to synthesize 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 API and drug candidate manufacturing processes, ● The production and multi-year stability testing of multiple API and drug 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 API and drug 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 API and PV-10 drug candidate, the processes’ CMC specifications, and the CMC data from the production of stability lots of API and drug 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 intratumoral PV-10 for the treatment of the Company’s former lead indication of locally advanced cutaneous melanoma (LACM), 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). RBS Non-proprietary Name The RBS name for the Company’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 the Company applied for a non-proprietary name in 2020 and reached the status of recommended International Non-proprietary 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 2022. Non-Pharmaceutical Grades of Rose Bengal Commercial Grade Commercial grade rose bengal can be purchased from specialty chemical suppliers in the U.S. and other parts of the world that manufacture it under non-cGMP conditions. Commercial grade rose bengal appears to have reported purities that may vary between 80% and 95%, which we believe may not be wholly accurate, and may contain substantial amounts of unreported related impurities and/or gross contaminants. Commercial grade rose bengal is typically used by researchers unaffiliated with the Company for non-clinical study of the rose bengal molecule for potential biomedical therapeutic applications. The Company provides PV-10 to researchers affiliated with the Company for their non-clinical study of RBS for potential biomedical therapeutic applications. We believe that commercial grade rose bengal is still manufactured using the original historical process, or a variant thereof, developed by the molecule’s original Swiss creator Rudolph Gnehm in 1881. Some chemical manufacturers may, however, apply purification techniques that the Company believes still result in commercial grade rose bengal possessing questionable purity and contaminants and substantial lot-to-lot manufacturing variability. 7 Diagnostic Grade Diagnostic grade rose bengal describes non-approved rose bengal that is used as an ingredient in historical or current ophthalmic solutions, strips, and devices, 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 for human brucellosis. We presume, but have not yet confirmed, that diagnostic grade rose bengal is derived from commercial grade rose bengal that may have undergone a form of purification under cGMP regulations and/or may have been compounded by a pharmacist, academic medical researcher, or commercial entity under cGMP regulations. Here too, the Company believes that purification may not sufficiently improve the amounts and accuracy of diagnostic grade rose bengal purity and lot contents and may not adequately reduce or eliminate lot-to-lot manufacturing variability. Chemical Analytical Comparison In 2022, the Company began work with a U.S. contract development and manufacturing organization to assess rigorously and methodically three lots of commercial grade rose bengal, one each from three different specialty chemical suppliers, and compare these non-pharmaceutical grade materials with the Company’s pharmaceutical-grade RBS. This chemical analytical work was substantially completed in 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 The Company believes that the Company’s proprietary, patented, pharmaceutical-grade RBS possesses several competitive advantages over non-pharmaceutical-grade rose bengal (i.e., commercial and diagnostic grades) 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-grade 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 grade rose bengal may pose significant scientific, technological, and economic challenges to overcome and validate for compliance with modern drug regulatory standards. 2024 Activity In February, the Company engaged IR Labs, Inc. (“irlabs”) to develop a comprehensive investor relations and corporate communications program for the Company. irlabs was acquired in July 2024 by shareholder engagement and advisory company Alliance Advisors LLC and is now known as Alliance Advisors Investor Relations. The Company also held an investor conference call in February. In March, the USPTO allowed patent application 17/212,723, titled “Novel Uses of Halogenated Xanthenes in Oncology and Virology.” The application covers the use of Provectus’ s pharmaceutical grade rose bengal sodium (“RBS”) drug substance for the treatment of infectious diseases, such as coronaviruses. The USPTO also allowed patent application 17/344,418, titled “In Vitro and Xenograft Anti-Tumor Activity of a Halogenated-Xanthene Against Refractory Pediatric Solid Tumors” in March. This prospective award covers the use of RBS in combination with one or more immune checkpoint inhibitors and is a continuation of U.S. patent 11,058,664 (2021), Provectus’ s first for pediatric oncology. The Company’s previously allowed patent application 17/488,430 in December 2023, titled “Halogenated Xanthenes as Vaccine Adjuvants” and covering RBS’s use as an adjuvant in vaccines to potentially make them work better, was also awarded in March as U.S. patent 11,938,182. 8 The Company entered into an agreement with the University of Miami (the “University”) in March for the exclusive worldwide license of the University’s intellectual property related to rose bengal photodynamic antimicrobial therapy (“RB-PDAT”) for treating bacterial, fungal, and parasitic (acanthamoeba) infections of the eye. The agreement contemplated the Company forming a majority-owned start-up company in which the University would be a minority equity shareholder, aimed at developing and commercializing the University’s RB-PDAT medical device in combination with a formulation of RBS. Provectus would contribute the license to the new entity and have an exclusive RBS supply arrangement with it. In December, the Company launched VisiRose, Inc. (“VisiRose”), the Company’s first Founded Entity and a new clinical-stage biotechnology company focused on commercializing RB-PDAT for the treatment of infectious keratitis and other serious eye infections using a formulation of PV-10, with Provectus having 95% ownership and the University having 5%. In April, data from non-clinical research by Moffitt on intratumoral PV-10 for the treatments of human papillomavirus -positive and -negative head and neck squamous cell carcinoma were presented at the annual meeting of the American Association for Cancer Research held in San Diego, California from April 5-10. The Company’s Board of Directors appointed Ed Pershing as Chief Executive Officer and Dominic Rodrigues as President in April. Data from non-clinical research by the University of Calgary on oral administration of PV-10 for the treatments of solid tumor cancers were published in April in the open access journal of oncology Cancers, “Identification and In Vivo Validation of Unique Anti-Oncogenic Mechanisms Involving Protein Kinase Signaling and Autophagy Mediated by the Investigational Agent PV-10.” In May, the USPTO allowed patent application 17/232,393, titled “Halogenated Xanthene Composition and Method for Treating Hematologic Cancers”. The application covers the use of Provectus’s pharmaceutical grade rose bengal sodium (“RBS”) active pharmaceutical ingredient for the single agent or combination therapy treatment of pediatric and adult leukemias. Clinical and non-clinical data on RB-PDAT were presented at the annual meeting of the Association for Research in Vision and Ophthalmology in Seattle, Washington from May 5-9. Non-clinical data on PV-10 for the topical treatment of full-thickness cutaneous wounds were presented by the University of Texas Medical Branch at Galveston at the annual meeting of the Society for Investigative Dermatology in Dallas, Texas from May 15-18. In June, the Company held its annual stockholder meeting where 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. Meeting activities and the company update were made accessible by Zoom Webinar. In October, the Company held an investor conference call accessible by Zoom Webinar. In August, the USPTO awarded patent 12,064,507, titled “Composition and method for oral treatment of leukemia.” 9 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 2024, we began manufacturing new clinical supplies of PV-10 and PV-305. 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. 10 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 non-clinical or early-stage clinical trials does not assure success in later-stage clinical trials. The FDA or research institutions 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. 11 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 six full-time employees who currently serve as CEO, CFO, CTO, president, senior scientist, and controller. We also engage an independent contractor, who currently serves as an 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.