What changed in this filing

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Item 1. Business

2024-03-28 compared with 2023-03-30 · 78 added, 149 removed, 196 unchanged (54% of the section changed)

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molecule is named rose bengal sodium (“RBS”).

Company’s proprietary, patented, pharmaceutical-grade RBS is the active pharmaceutical ingredient (“API”) 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,

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.

Company believes that RBS targets disease in a bifunctional manner.

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on the disease being treated and the concentration of the RBS utilized in the treatment.

Second, such contact may catalyze multivariate

immune signaling and activation, and response may follow that may manifest as stimulatory, inhibitory, or both.

Second, multivariate immune signaling, activation,

and response may follow that may manifest as stimulatory, inhibitory, or both.

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.

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%.

Company’s small molecule HX medical science platform comprises a number of different drug product candidates and preclinical pharmaceutical-grade

RBS formulations using different concentrations and delivered by different routes of administration specific to each disease area and/or

The Company’s HX medical science platform includes:

development programs in oncology, dermatology, and ophthalmology

vivo proof-of-concept drug discovery programs in oncology, hematology, wound healing, and animal health, and

vitro drug discovery programs in infectious diseases and tissue regeneration and repair.

hold a number of 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.

as those trials reported on the clinical trials registry at ClinicalTrials.gov.

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%.

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

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.

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:

Patent and Trademark Office (“USPTO”) that

are material to an understanding of the Company are listed in the table below:

antiperspirant and antimicrobial compositions

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of Local and Systemic Therapies for Enhanced Treatment of Dermatologic Conditions

received two patent awards from the USPTO in 2022, U.S.

patent numbers 11,419,844 and 11,426,379.

Three patent applications were also

published on the USPTO’s website:

of local and systemic immunomodulative therapies for enhanced treatment of cancer (USPTO application number 17/382,943),

Xanthenes as Immune Adjuvants (17/488,430), and

of Local and Systemic Therapies for Enhanced Treatment of Dermatologic Conditions (17/466,600).

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:

Anti-Gram-Positive Bacterial Activity of Pharmaceutical-Grade Rose Bengal (USPTO application number 18/089,011), and

Xanthene-Containing Topical Anti-Gram-Positive Bacterial Ophthalmic Composition and Method (18/089,134).

International

2022, the Japanese Patent Office granted two of the Company’s patent applications, “ In Vitro And Xenograft Anti-Tumor

Activity Of A Halogenated-Xanthene Against Refractory Pediatric Solid Tumors” and “Combination of Local and Systemic Therapies

for Enhanced Treatment of Dermatologic Conditions.”

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.”

Development and Drug Discovery

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who are now collaborating with the Company to evaluate the potential use of our pharmaceutical-grade

PV-305 is undergoing preclinical monotherapy study for diseases and disorders of the eye, such as infectious keratitis at BPEI.

PV-305 has undergone preclinical monotherapy study for diseases and disorders of the eye, such as infectious keratitis at BPEI.

Vivo Proof-of-Concept Drug Discovery Programs

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Vitro Drug Discovery Programs

PO and intranasal (“IN”) formulations have undergone and are undergoing 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.

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.

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 are undergoing preclinical monotherapy study for the treatment

bacterial infections (including multi-drug resistant strains) and have undergone preclinical monotherapy study for the treatment

of oral bacterial infections at UTHSC.

formulations are undergoing preclinical monotherapy study for the treatment of fungal infections at UTHSC.

formulations have undergone preclinical monotherapy study for the treatment of fungal infections at UTHSC.

Regeneration and Repair :

Different formulations are undergoing preclinical monotherapy study for vertebrate development, wound

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.

January, preclinical research on a formulation of the Company’s pharmaceutical-grade rose bengal against Gram-positive bacteria

was published in Molecules, an open-access journal of chemistry by UTHSC:

“ Antibacterial Activity of Pharmaceutical-Grade Rose

An Application of a Synthetic Dye in Antibacterial Therapies .”

USPTO published the Company’s patent application entitled “Halogenated Xanthenes as Vaccine Adjuvants” (publication

17/488,430) that contained, among other things, in vitro data that showed PV-10 was able to significantly increase numbers

of interferon gamma-producing CD8 cells (compared to controls) for peptides representing various antigenic regions of the Hepatitis B

virus (“HBV”) core protein (HBcAg).

These peptides were selected for their capability to raise CD4 and CD8 T cells against

March, data from an ongoing clinical trial of PV-10 for the treatment of neuroendocrine tumors metastatic to the liver refractory to

somatostatin analogs and peptide receptor radionuclide therapy (NCT02693067) were presented as an oral presentation at the annual conference

of the European Neuroendocrine Tumor Society (ENETS), held from March 10-11, 2022 in a hybrid setting of Barcelona, Spain and online:

“A phase 1 study of percutaneous autolytic rose bengal disodium for metastatic uveal melanoma patients with hepatic metastases.”

Company successfully developed and manufactured a second HX.

The molecular name of the newly synthesized HX is 4,5,6,7-tetrabromo-3′,6′-dihydroxy-2′,4′,5′,7′-tetraiodo-3H-spiro[isobenz-

ofuran-1,9′-xanthen]-3-one.

April, preclinical research on systemic administration of PV-10 for the treatment of high-risk and refractory adult solid tumor cancers

is being presented at the annual meeting of the American Association for Cancer Research (AACR), held April 8-13, 2022 in New Orleans,

“ Identification and In Vivo Validation of Unique Anti-Oncogenic Properties and Mechanisms Involving Protein

Kinase Signaling and Autophagy Mediated by the Investigational New Agent PV-10 .”

Narendran, MD, PhD was added to the Company’s Scientific Advisory Board.

Narendran is a professor in the departments of Pediatrics,

Oncology, and Biochemistry & Molecular Biology at UCal, and holds the Kids Cancer Care Foundation Endowed Chair in Clinical and Translational

Research in pediatric oncology.

USPTO allowed US patent application 16/688,319 (Patent No.

11,419,844), “Composition and Method for Treating Hematologic Cancers,” covering the

use of PV-10 for the treatment of hematologic diseases.

In vivo data of mice with acute lymphoblastic leukemia receiving oral

PV-10 showed increased survival compared to controls.

This allowed patent application was the first patent awarded to the Company in

hematology from the USPTO.

May, the USPTO allowed US patent application 17/466,600 (Patent No.

11,426,379), “Combination of local and systemic therapies for enhanced treatment of

dermatologic conditions,” covering the use of topical PH-10 in combination with one or more systemic therapies for the treatment

of various inflammatory dermatoses, such as psoriasis and atopic dermatitis, and various epithelial diseases.

This allowed patent application

was the first patent awarded to the Company in dermatology from the USPTO.

June, updated data from the Company’s initial expansion cohort of patients with uveal melanoma metastatic to the liver in its cancers-of-the-liver

Phase 1 trial of PV-10 (NCT00986661) were presented at the 2022 American Society of Clinical Oncology (ASCO) annual meeting, held June

3-7 in Chicago, Illinois and online:

“ Metabolic complete responses (mCR) in metastatic uveal melanoma (mUM) patients treated

with image-guided injection (IGI) of PV-10 .”

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.”

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.

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.

data from the Company’s initial expansion cohort of patients with uveal melanoma metastatic to the liver in its cancers-of-the-liver

Phase 1 trial of PV-10 (NCT00986661) were part of two oral presentations at the 20 th Congress of the International Society

of Ocular Oncology (ISOO), held June 17-21, 2022 in Leiden, The Netherlands:

“ A phase 1 study of percutaneous autolytic rose

bengal disodium for metastatic uveal melanoma patients with hepatic metastases ” and “ Metabolic complete responses

(mCR) in metastatic uveal melanoma (mUM) patients treated with image-guided injection of PV-10 .”

July, the Company initiated a new sponsored research program with Kelly Tseng, PhD, Associate Professor of Pathology and Lab Medicine,

School of Life Sciences at UNLV to characterize the effects of the Company’s pharmaceutical-grade RBS on vertebrate tissue regeneration

The Tseng Lab at UNLV will assess the effects of RBS on animal development and tissue repair using the African clawed frog

( Xenopus laevis ), an established vertebrate model organism, and in vivo assays to evaluate key biological processes:

embryo development,

wound healing, and tissue regeneration.

August, the Company expanded its sponsored research program with Dr.

Narendran at UCal to investigate systemic administration of Provectus’

pharmaceutical-grade rose bengal for the treatment of pediatric leukemia.

The Company’s innovatively-assembled and proprietary

rose bengal is the lead member of a class of small molecules called halogenated xanthenes.

As part of this new sponsored research, the

Narendran team plans to identify clinically-feasible drug combinations and synthetic lethality that have synergistic activity with Provectus’

rose bengal, evaluate systemic drug administration routes for maximal tolerability, evaluate the modulation of WNK1 (lysine deficient

protein kinase 1) and other related pathways induced by the Company’s rose bengal, and complete demonstration of STING (stimulator

of interferon genes) dimerization in leukemia cells.

Company expanded its sponsored research program with Michio Kurosu, PhD, Professor, Department of Pharmaceutical Sciences at the College

of Pharmacy of UTHSC to investigate the Company’s pharmaceutical-grade RBS for the treatment of anti-fungal and anti-oral bacterial

As part of this new sponsored research, the Kurosu team plans to evaluate the in vitro activity of Provectus’ rose

bengal against different fungal strains and to conduct susceptibility tests against fungal and bacterial mouth microbes.

September, the Company entered into an option agreement with UM for an exclusive worldwide license of intellectual property developed

by the Ophthalmic Biophysics Center (“OBC”) of BPEI, which is part of the UM Health System, for the use of OBC’s photodynamic

antimicrobial therapy (PDAT) medical device in combination with Provectus’ proprietary pharmaceutical-grade rose bengal for the

treatment of bacterial, fungal, and viral infections of the eye.

The Company also initiated a sponsored research program with OBC to

investigate the Company’s pharmaceutical-grade RBS for the treatment of infectious keratitis.

Company initiated a new sponsored research program with Amina El Ayadi, PhD, Assistant Professor, Surgical Sciences Division and Jayson

Jay, PhD, Postdoctoral Research Fellow and Jeane B.

Kempner Scholar of the Burn, Trauma, and Critical Care Research Laboratory in the

Department of Surgery at UTMB to characterize the effects of Provectus’ proprietary pharmaceutical-grade RBS on full-thickness

cutaneous wounds and during the subsequent phases of wound healing.

October, the Company expanded its sponsored research program with James G.

Krueger, MD, PhD, Co-director, Center for Clinical and Translational

Martin Carter Professor in Clinical Investigation, Senior Attending Physician, and head of the Laboratory of Investigative

Dermatology at TRU to investigate the potential for PH-10 to directly alter the growth and differentiation of human keratinocytes, and

to block cytokine-mediated signaling that creates different inflammatory skin diseases and may also be important in skin neoplasms.

November, the International Nonproprietary Names (“INN”) Expert Committee of the World Health Organization (“WHO”)

selected “rose bengal sodium” (RBS) for the nonproprietary name of the Company’s API.

The RBS name was selected by

the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, reached the status of recommended INN

after a period of public consultation, and was included in INN Recommended List 88 published with the No.

3 issue of the WHO Drug Information,

Volume 36 in October 2022.

data from the Company’s ongoing, multi-cohort, Phase 1b/2 study of the combination of PV-10 and anti-PD-1 therapy Keytruda (pembrolizumab)

for the treatment of immune checkpoint blockade-naïve Stage III cutaneous melanoma (NCT01223415) were presented as a poster presentation

and an oral video communication at Melanoma Bridge 2022 in Naples, Italy and online from December 1-3, 2022:

“ Response for combination

of PV-10 autolytic immunotherapy and immune checkpoint blockade in stage III cutaneous melanoma ,”

On November 29, 2022, the Company’s Board decided to not undertake the reverse stock split and authorized share reduction, which Company stockholders

approved at the Company’s 2022 Annual Meeting of Stockholders, by the expiration date of December 31, 2022.

July, the USPTO published the Company’s patent application entitled “Photodynamic Anti-Gram-Positive Bacterial Activity of

Pharmaceutical-Grade Rose Bengal” (publication no.

August, the USPTO published the Company’s patent application entitled “Halogenated Xanthene-Containing Topical Anti-Gram-Positive

Bacterial Ophthalmic Composition and Method” (publication no.

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.”

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).

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).

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.

general, the pharmaceutical and biotechnology industries are competitive, characterized by steady and sometimes disruptive advances in

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and may be further along in their respective product cycles.

2022, many companies across a variety of sectors were still having disruptions, shortages, and other supply chain-related issues.

the biopharmaceutical sector, delays and interruptions in the supply chain have been particularly pronounced.

During 2022, we were able

to effectively manage our supply of prescription drug candidates in a manner that avoided any significant interruptions to our clinical

2023, we undertook extensive validation testing of our supply of prescription drug candidate PV-10.

Regulation of Therapeutic Products

of the prescription drug candidates we currently contemplate developing will require approval by the U.S.

the prescription drug candidates that we currently contemplate developing will require approval by the U.S.

Food and Drug Administration

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process, and providing input into the design and site selection of human clinical studies.

testing and approval process require substantial time, effort, and financial resources, and we may not obtain FDA approval on a timely

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.

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We also engage independent contractors,

who currently serve as COO, director of clinical operations, clinical research associates, information technology manager, and patient

advocacy manager.

who currently serve as chief operations consultant, director of clinical operations, clinical research associates, and information technology manager.

believe the Company’s success depends on its ability to attract, develop, and retain key personnel.

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The Company’s Board of Directors and management oversee various employee and contractor initiatives.

health and safety in the workplace is one of the Company’s core values.

The COVID-19 pandemic has underscored for us the importance

of keeping our employees and contractors safe and healthy.

In response to the pandemic, the Company has taken actions aligned with the

WHO and the Centers for Disease Control and Prevention to protect its workforce so they can more safely and effectively perform their

During the past three years, employees have worked remotely to ensure their safety, while continuing to perform their duties as

they would have.

website is located at www.provectusbio.com .

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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.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business