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Item 1. Business

2021-03-02 compared with 2020-03-05 · 209 added, 505 removed, 72 unchanged (91% of the section changed)

Biopharmaceuticals, Inc.

(“Provectus”, the “Company,”

or “we”) is a clinical-stage

biotechnology company developing a new class of drugs for oncology, hematology, and dermatology based on an entire, wholly-owned,

family of chemical small molecules called halogenated xanthenes.

Intratumoral (aka intralesional) PV-10®, the first small

molecule autolytic immunotherapy, which can induce immunogenic cell death, is undergoing clinical study for adult solid tumor

cancers, such as melanoma and GI tumors (e.g., hepatocellular carcinoma, metastatic colorectal cancer, metastatic neuroendocrine

tumors, metastatic uveal melanoma), and preclinical study for pediatric solid tumor cancers (e.g., neuroblastoma, Ewing sarcoma,

rhabdomyosarcoma, osteosarcoma) and blood cancers (e.g., acute myeloid leukemia).

Topical PH-10®

is undergoing clinical study

for inflammatory dermatoses (e.g., psoriasis, atopic dermatitis).

Provectus is a Delaware corporation formed in 2002.

PV-10 drug product is an injectable formulation of rose bengal disodium (4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein

disodium salt) (“RB”) drug substance (i.e., active pharmaceutical ingredient).

PV-10 is a bright rose red solution

containing 10% w/v RB in 0.9% saline for injection, which is supplied in single-use glass vials containing 5 mL (to deliver) of

PV-10 is administered directly to superficial disease (e.g., cutaneous melanoma) via injection and to visceral disease

(e.g., GI tumors) via image-guided percutaneous injection.

PV-10 selectively accumulates in the lysosomes of cancer cells.

cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning ( Piao et al., Ann N Y Acad

Cancer progression and metastasis are associated with lysosomal compartment changes ( Nishimura et al., Pathol

Oncol Res 1998;

Gocheva et al., Genes Dev 2006 ), which are closely correlated with, among other things, invasive

growth, angiogenesis, and drug resistance ( Fahrenbacher et al., Cancer Res 2005 ).

Physicochemical properties of

lysosomes trap PV-10.

Lumenal pH of 4.5 to 5 is ideal for the conversion of soluble rose bengal disodium into insoluble rose bengal

are the central organelles for intracellular degradation of biological macromolecules and organelles.

Discovered by Christian

de Duve, M.D.

in 1955, lysosomes have been linked with a number of biological processes like cell death, inflammasome activation,

and immune response.

de Duve described lysosomes as “suicide bags,”

because their rupture led to cell

death and tissue autolysis.

Lysosomes have been shown to play a role in each of the primary pathways of cell death, which are

apoptosis, autophagy, and necrosis.

He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes.

showed that PV-10 selectively accumulates in the lysosomes of cancer cells and disrupts them, causing the cancer cells to die.

PV-10 (RB) has also been shown by Provectus and independent researchers to trigger each major, distinct form of lysosomal cell

that is, apoptosis, autophagy, and necrosis.

PV-10’s

lysosomal targeting comprises:

Transiting the plasmalemma

(i.e., the cell membrane) of cancer cells.

PV-10 penetrates the cell membrane of cancerous cells which normally

protects the cancer cell from its surrounding environment.

PV-10, however, is excluded from normal cells;

in the lysosomes of cancer cells.

As noted above, the physicochemical properties of lysosomes trap PV-10;

the release of lysosomal contents.

Acute autolysis can occur within 60 minutes.

Early preclinical work by Provectus on PV-10’s

lysosomal targeting showed identical responses in different disease models, such as Hepa1-6 murine hepatocellular carcinoma,

HTB-133 human breast carcinoma , and H96Ar human multi-drug resistant small cell lung carcinoma;

the rapid cell death of cancer cells.

Early trypan blue exclusion work by Provectus confirmed cell death within hours;

Intracellular

pH consistency with the release of acidic lysosomal contents.

Early seminaphthorhodafluor-1 (“SNARF-1”) staining

work by Provectus confirmed lower intracellular pH upon exposure to PV-10 (RB).

For psoriasis, pathways significantly improved include published psoriasis transcriptomes and cellular responses mediated

by IL-17, IL-22, and interferons.

Clinical work has shown that more than 500 disease-related genes were down-regulated after four

weeks of PH-10 application and expression of a wide-range of central “psoriasis related”

genes including IL-23, IL-17,

IL-22, S100A7, IL-19, IL-36, and CXCL1 were effectively normalized;

that is, treated lesional skin had values in the same range

as baseline non-lesional skin.

Drug Development Strategy for Oncology

Company’s strategy is to (i) demonstrate the independent action of single-agent PV-10;

that is, safety and activity in T

cell and non-T cell inflamed tumor types, in high and low tumor mutation burden tumor types, and in other tumor type categories,

such as gene mutations, (ii) demonstrate the coordinated induction of multiple immune signaling pathways (i.e., functional immunogenic

cell death [“ICD”];

Snyder et al., Sci Immunol 2019 ) by PV-10 treatment, (iii) demonstrate the functional

T cell response generated by PV-10 treatment, and (iii) contrast and compare PV-10 treatment –

safety, activity, and induced

immune response –

with that of immune checkpoint inhibition (“CI”) and other drug classes in single-agent and

PV-10-based combination therapy settings.

strategy may quicken the advancement of single-agent PV-10 along a pathway-to-approval in solid tumor cancer indications where

there is high unmet need, limited activity from other therapies, and the opportunity to display the immune response from PV-10

treatment, such as neuroendocrine tumors (“NET”) metastatic to the liver (“mNET”) ( NCT02693067 ).

This strategy may also permit the Company to develop and advance a cancer combination therapy involving one or more CI and/or

other drug classes along a pathway-to-approval in a disease indication where there is high unmet need, limited activity from standard

of care (“SOC”) treatment, and the opportunity to display how PV-10 augments clinical response to existing or emerging

SOCs, such as uveal melanoma metastatic to the liver (“mUM”) (i.e., combination therapy with an anti-CTLA-4 agent

and an anti-PD-1 agent) ( NCT00986661 ).

Drug Development Strategy for Dermatology

Company’s strategy is to (i) demonstrate 12-week single-agent administration proof-of-concept (“POC”) for PH-10

that includes (a) a preclinical safety study of extended 12-week administration (compared to, previously, four weeks), (b) a clinical

mechanism of action study in atopic dermatitis, which would be a “book-end”

trial to the already completed clinical

mechanism study in psoriasis, (c) Phase 2 randomized controlled trials of PH-10 for the treatment of psoriasis and atopic dermatitis

that may potentially utilize SOC comparators, and (d) end-of-Phase 2 meetings with the FDA upon the completion of the abovementioned

Phase 2 trials, and (ii) expand POC PH-10 treatment to include dermatology combination therapy.

Our goal for this POC work is

to achieve Phase 3 trial-ready status for PH-10 in both psoriasis and atopic dermatitis.

(single-agent)

Phase 1 and 2 studies ( NCT00219843 and NCT0052105 3, respectively).

drug designation (“ODD”) status was granted by the U.S.

Food and Drug Administration (the “FDA”) for

metastatic melanoma .

2019, terminated a Phase 3 study ( NCT02288897 ).

2019, results from an investigator-conceived and led, single-center study of in-transit melanoma (“ITM”) patients

receiving either regionally-administered isolated limb infusion (“ILI”) or PV-10 to assess and compare the effect

of these treatments on survival by principal investigators at the Princess Alexandra Hospital in Brisbane, Australia (where

isolated limb infusion represents the historical standard of care for ITM and PV-10 was used to treat the disease under expanded

access) was published:

Patients with in-transit melanoma metastases have comparable survival outcomes following

isolated limb infusion or intralesional PV-10—A propensity score matched, single center study.

J Surg Oncol .

and Non-Melanoma Cancers of the Skin (combination therapy)

CI drug KEYTRUDA®

(pembrolizumab) –

Ongoing Phase 1b/2 study for metastatic melanoma (Stage III-IV) ( NCT02557321 );

updated data from the Main Cohort of CI-naïve patients at the annual meetings of the American Society of Clinical

Oncology (“ASCO”), including preliminary progression-free survival (PFS) and changes in T cell populations

( Agarwala et al., ASCO 2019 ), and Society for Melanoma Research (“SMR”), including 12-month overall

survival (“OS”) and disease-specific survival (“DSS”) rates, and median OS and DSS ( Agarwala et

al., SMR 2019 ),

to enroll patients in an Expansion Cohort of CI-refractory patients,

preliminary data from the Expansion Cohort of CI-refractory patients at SMR, including objective response and disease control

rates (“ORR”

and “DCR,”

respectively), and changes in immune system activation biomarkers ( Zager

et al., SMR 2019 ), and

to enroll patients in an Expansion Cohort of patients with satellite or in-transit disease.

These patients are typically CI-naïve.

Gastrointestinal

Cancers (single-agent)

Phase 1 basket study of hepatocellular carcinoma (“HCC”) and other solid tumors metastatic to the liver ( NCT00986661 );

to date, patients have received PV-10 via percutaneous administration into several different hepatic tumor types, including

HCC, colorectal cancer, lung cancer, cutaneous melanoma, uveal melanoma, breast cancer, ovarian cancer, and pancreatic cancer.

ODD status was granted for HCC .

2019, FDA ODD status was granted for ocular melanoma (including uveal melanoma) .

Phase 1 study of symptomatic mNET ( NCT02693067 );

to enroll in the Second Cohort, and

preliminary data from the First Cohort at ASCO, including lesion-level ORR and DCR, and Chromogranin A responses and quality

of life scores ( Price et al., ASCO 2019 ).

Gastrointestinal

Cancers (combination therapy)

CI combination of YERVOY®

(ipilimumab) and OPDIVO®

(nivolumab) –

Ongoing Phase 1 basket study of HCC and

other solid tumors metastatic to the liver ( NCT00986661 );

to enroll patients in the single-site cohort of mUM patients treated with single-agent PV-10, the combination therapies of

PV-10+KEYTRUDA or PV-10+OPDIVO, or the combination therapy of PV-10, YERVOY, and OPDIVO, and

updated uveal melanoma single-agent PV-10 and PV-10 based combination therapy data at the 2019 European Society for Medical

Oncology (“ESMO”) Immuno-Oncology Congress (“ESMO I-O”), including lesion-level ORR and DCR ( Patel

et al., ESMO I-O 2019 ), and patient-level ORR and PFS ( Carter et al., ESMO I-O 2019 ).

Cancers (single-agent and combination therapy)

non-clinical assessment of pediatric cancer tumor cell lines by the Pediatric Oncology Experimental Therapeutics Investigators’

Consortium (“POETIC”);

from POETIC’s preclinical work on in vitro and animal tumor model studies of PV-10 for the treatment of relapsed

and refractory neuroblastoma was published:

Potent in vitro and xenograft antitumor activity of a novel agent,

PV-10, against relapsed and refractory neuroblastoma .

Onco Targets Ther .

ODD was granted for neuroblastoma .

non-clinical, single-administration studies to demonstrate lack of systemic uptake,

as part of toxicology work to support extended 12-week administration.

Phase 2c randomized study of mild-to-moderate psoriasis ( NCT01247818 ).

Phase 2d mechanism of action study of mild-to-moderate psoriasis ( NCT02322086 ).

Phase 2 study of mild, moderate or severe atopic dermatitis ( NCT00690807 ).

We are developing PV-10 for direct injection

into tumors as an autolytic immunotherapy, where (a) cancer cells in injected tumors die from self-digestion (i.e., autolytic

death), which activate the innate immune system, and (b) a tumor-specific immune response can result via downstream

activation of the adaptive immune system (i.e., immunotherapy).

Advanced and Widely Metastatic Melanoma

pivotal Phase 3 randomized controlled trial of PV-10 as single-agent treatment for locally advanced cutaneous melanoma (Stage

IIIB-IV M1a), compared to standard therapy (i.e., investigator’s choice of oncolytic viral therapy or systemic chemotherapy),

opened to enrollment in 2015 ( NCT02288897 ).

The primary outcome measure of the study was progression-free survival (“PFS”)

assessed every 12 weeks for up to 18 months.

Secondary outcome measures include complete response (“CR”) rate and

its duration, and OS, all also assessed every 12 weeks up to 18 months.

In October 2019, we terminated the trial due to an inadequate

enrollment rate, which was due in large part to systemic therapy with CI being recommended in the U.S.

for Stage III melanoma

patients with satellite or in-transit disease.

of action and other work previously reported by our research collaborators at Moffitt Cancer Center ( Toomey et al., PLOS

ONE 2013 , Liu et al., Oncotarget 2016, and Pilon-Thomas et al., J Immunother Cancer 2016 )

and the University of Illinois at Chicago ( Qin et al., Cell Death Dis 2017 ) indicate that PV-10 functions as an

autolytic immunotherapy in laboratory models of multiple tumor types, such as melanoma, breast cancer, colon cancer, and

pancreatic cancer.

These collaborators definitively classify PV-10 as an autolytic immunotherapy capable of yielding ICD, a primer

for adaptive immunity, functioning via multiple immune effector cells, including CD8+ T cells, dendritic cells, and natural killer

By the end of 2019, additional mechanism work was underway to assess the potential breadth of this immunotherapy capability

in other tumor types.

January 2019, principal investigators at the Princess Alexandra Hospital published results from an investigator-conceived and

led, single-center study of ITM patients receiving either regionally-administered ILI or intratumoral PV-10 to assess and compare

the effect of these treatments on survival, including:

and disease characteristics:

matched for key covariates:

Age, gender, primary disease site, and Breslow thickness,

median age of 76.5 years (interquartile range 69-83);

100% Stage IIB/IIIC, and

median age of 74.5 years (65-81);

89% Stage IIV/IIIC (11% Stage IV).

response (patient-level best overall response [“BORR”]):

22% CR and 50% ORR, and

25% CR and 83% ORR.

survival outcomes:

PFS of 5.0 months (interquartile range 2.7-10.7),

disease-free survival (“DFS”) of 16.5 months (8.9-48.4),

OS of 29.7 months (12.3-88.5), and

melanoma-specific survival (“MSS”) of 74.4 months (24.3-NA);

12-,24-,36-, and 60-month MSS rates of 85%, 75%,

and 60%, respectively.

survival outcomes:

PFS of 3.9 months (9.6-47.9),

DFS of 14.1 months (4.5-20.9),

OS of 27.1 months (14.3-48.6),

MSS of 36.4 months (16.6-65.3);

12-, 24-, 36-, and 60-month MSS rates of 83%, 70%, 54%, and 36%, respectively, and

in PFS, DFS, and MSS comparing ILI with PV-10 were not statistically significant.

those patients with more advanced melanoma that is not fully accessible to injection (Stage IV), we are assessing PV-10 in combination

with CI in a Phase 1b/2 clinical study.

This study is the result of mechanism of action work on PV-10 showing that it may be complementary

Updated data from the fully-enrolled Phase 1b study portion of 21 CI-naïve patients were reported at the SMR annual

meeting in November 2019, including:

characteristic:

Median age of 69 years (range 28-82),

characteristics:

52% Stage IV M1b-c;

median of 2 injectable lesions (range 1-15);

most patients had substantial non-injected

systemic disease burden,

Patients received a median of 5 cycles of PV-10 (mean 3.8, range 1-5) and a median of 5 total injections of PV-10

(mean 11.7, range 1-82);

PV-10 was not administered after week 12,

Adverse events were consistent with the established patterns for the single-agent use of each drug;

principally Grade 1-2

injection site reactions to PV-10;

principally Grade 1-3 immune-mediated reactions to KEYTRUDA,

target lesion efficacy (BORR):

75% CR, 79% ORR, and 86% DCR for 28 injected lesions in 21 patients;

85% CR and 92% DCR for

13 injected lesions in 11 M1b-c patients,

patient efficacy (BORR, RECIST 1.1):

10% CR and 67% ORR for 21 patients;

9% CR and 82% ORR for M1b-c patients, and

95% 12-month OS rate;

100% 12-month DSS rate;

median OS and DSS were not reached;

median PFS of 11.7 months.

expanded the Phase 1b study in 2018 to include a First Expansion Cohort of up to 24 patients with advanced melanoma (Stage III-IV)

who are CI-refractory and a Second Expansion Cohort of up to 24 patients who have satellite or in-transit disease.

Both expansion

cohorts continue to enroll patients.

Preliminary data from 10 CI-refractory patients were reported at the same SMR annual meeting,

characteristic:

Median age of 77 years (range 54-90);

compared to the median age of 69 years (range 28-62) of the CI-naive

characteristics:

50% Stage IV M1b-d;

50% of patients were refractory to single-agent and dual-agent checkpoint inhibition

treatment (KEYTRUDA, YERVOY, or OPDIVO and YERVOY),

PV-10 was limited to 5 cycles,

Adverse events were consistent with the established patterns for the single-agent use of each drug;

1 patient withdrew due

to an adverse reaction to KEYTRUDA,

patient efficacy (BORR, RECIST 1.1):

20% ORR and 40% DCR;

2 of 10 patients were not evaluated (“NEV”),

Median OS and DSS were not reached;

median PFS of 4.9 months, and

in peripheral blood biomarkers:

Initial correlative results for these highly checkpoint inhibition-refractory patients were

consistent with prior evidence of immune activation by PV-10 in checkpoint inhibition-naïve patients, both as a single-agent

and in combination with KEYTRUDA;

PV-10-based combination therapy-treated CI-refractory patients exhibited a damage-associated

molecular pattern (“DAMP”) profile similar to the DAMP profile of CI-naïve patients receiving single-agent

PV-10 ( NCT01760499 ).

collaborators published results from a study investigating cancer combination therapy with PV-10 and checkpoint inhibition (anti-CTLA-4,

anti-PD-1 and anti-PD-L1 antibodies) in murine melanoma models ( Liu et al., PLOS ONE 2018 ), and also examined the

role of specific immune cell populations in eliciting and controlling tumor-specific response.

The authors showed the impact of

combining checkpoint inhibition with the tumor-specific immune response induced by PV-10.

Treatment with PV-10 and anti-PD-1 antibody

resulted in a delay in tumor growth and enhanced T cell activation in an M05 melanoma tumor model.

Similar effects were observed

with PV-10 and anti-PD-L1 antibody in a B16 tumor model.

The effect of combination therapy with PV-10 and PD-1 blockade is mediated

by CD8+ T cells, and depletion of either CD4+ T cells or CD4+CD25+ Tregs enhanced anti-tumor immunity in the M05 melanoma model.

Similar effects were also observed with PV-10 and anti-CTLA-4 antibody in the B16 tumor model.

Gastrointestinal

During 2019, we continued our exploratory

Phase 1 study of cancers of the liver.

This “basket study”

enrolls patients with HCC and other tumor types that have

metastasized to the liver.

Patients are treated using percutaneous injection of PV-10 under image guidance into one or move

liver lesions.

To date patients with HCC and liver metastases, including colorectal, lung, breast, cutaneous melanoma,

uveal melanoma, ovarian, and pancreatic, have been treated at the five centers.

The non-clinical mechanism of action work reported

by Qin et al.

was consistent with clinical observations reported for patients with metastatic colorectal cancer participating

in our Phase 1 basket study.

In 2018, we announced that the Phase 1 study

had expanded to include a single-site cohort of mUM patients.

Eligible mUM patients may also receive standard of care checkpoint

blockade during and after treatment with PV-10.

Updated data from this cohort were reported at the ESMO I-O meeting

in December 2019, including:

characteristics:

median age of 61 years;

46% elevated LDH,

characteristics:

100% Stage IV M1a-b;

38% of patients were refractory to one or more prior lines of treatment, with 31% having

received prior immunotherapy,

7 patients received 1 cycle of PV-10;

6 patients received 2 cycles;

26 tumors were injected with PV-10,

9 patients received concomitant standard of care checkpoint blockade (i.e., maintenance anti-PD-1, anti-PD-1 subsequent

to PV-10 treatment, or anti-CTLA-4+anti-PD-1 subsequent to PV-10 treatment),

3 cases of Grade 3/4 transaminitis that resolved to Grade 1 or better within 72 hours;

additional Grade 1 PV-10 related events

seen in 1 patient each included pink stool, pink urine, photosensitivity, injection site pain, and hyperbilirubinemia;

adverse events, such as nausea, headache, myalgias, blurry vision, decreased white blood cells, and fatigue, were attributed

to concomitant checkpoint blockade, and

injected target lesion efficacy:

32% ORR and 82% DCR.

In February 2019, the Company was granted

FDA ODD for PV-10 for the treatment of for the treatment of ocular melanoma (to include all melanoma disease including that

affecting the eye and orbit).

The FDA grants ODD status to medicines intended for the treatment, diagnosis or prevention of

rare diseases or disorders that affect fewer than 200,000 people in the US.

ODD status qualifies companies for benefits that include

seven years of market exclusivity following marketing approval, tax credits on U.S.

clinical trials, eligibility for orphan drug

grants, and waiver of certain administrative fees.

In 2017, we initiated clinical activity

in a Phase 1 study to assess PV-10 as an autolytic immunotherapy for patients with symptomatic mNET at The Queen Elizabeth

Hospital in Adelaide, Australia.

This study uses a treatment protocol comparable to that employed in the Phase 1 liver

cancer basket study.

Because the NET study is focused on a single tumor type, it includes radiologic (medical imaging), blood

biomarker, and quality of life assessments specific to NET.

Updated data were reported at the ASCO annual meeting in June 2019,

characteristics:

median age of 65 years (range 47-72),

characteristics:

primary tumor site –

50% small intestine, 33% pancreas, and 17% caecal;

87% Grade 2 (well differentiated,

intermediate);

all patients were refractory to systemic somatostatin analogues and peptide receptor radionuclide therapy,

treatment summary:

Median of 1 cycle (mean 1.7, range 1-4) and median dose per cycle of 2.1 mL (range 1.0-5.8 mL),

Acceptable toxicity (e.g., post-procedure pain, carcinoid flare, nausea);

liver function tests have remained stable,

target lesion efficacy:

50% objective response and 87% disease control;

response follow-up in 3 patients (50%) is ongoing,

clinical and biomarker outcomes:

overall quality of life scores were stable in 5 patients (87%);

Chromogranin A responses

were stable in 5 patients (87%).

December 2016, we announced a joint research agreement with POETIC to investigate the potential of PV-10 for pediatric cancers.

This collaboration involves National Cancer Institute-Designated Cancer Centers that are part of the POETIC group such as Memorial

Sloan Kettering Cancer Center, Alberta Children’s Hospital, and other cancer centers.

In February 2019, POETIC researchers

published preclinical work on in vitro and animal tumor model studies of PV-10 for the treatment of relapsed and refractory neuroblastoma:

Potent in vitro and xenograft antitumor activity of a novel agent, PV-10, against relapsed and refractory

neuroblastoma.

Onco Targets Ther .

According to the POETIC authors,

“Our studies provide preclinical proof-of-concept data on the efficacy of PV-10 in neuroblastoma.

Mechanistically,

we have found that PV-10 acts by disrupting lysosomes, inducing cell cycle changes and initiating cell death by apoptosis.

have also identified several commonly used treatments with which PV-10 shows synergistic anti-tumor activity.

Furthermore, we

have validated the efficacy of PV-10 in vivo, using neuroblastoma xenograft mouse experiments.

Our experiments, carried out in

representative cell lines and in tumor bearing mice, provide evidence for the direct cytotoxic potential of PV-10, as well as

mechanisms by which this agent may induce target modulatory effects in cancer cells.

We have also identified agents that can be

combined to generate treatment synergy, providing the framework for the formulation of early phase clinical trials.

This, in addition

to the expected immunostimulatory effect of PV-10 described previously, provides support for a potential approach where a PV-10

backbone regimen can be combined with agents such as immune checkpoint inhibitors to further enhance its activity in patients

with relapsed or refractory neuroblastoma.”

Among the authors’

results, PV-10 was

shown to be cytotoxic to neuroblastoma cell lines, to disrupt tumor lysosomes, to induce both apoptosis

and necrosis in neuroblastoma, to be synergistic with multiple standard anticancer agents, to induce radiosensitivity

in neuroblastoma cell lines, and to lead to tumor regression in vivo .

are developing PH-10, an aqueous hydrogel formulation of rose bengal disodium, for topical administration to the skin for inflammatory

dermatoses such as psoriasis and atopic dermatitis.

In January 2015, we commenced a mechanism

of action study of PH-10 to characterize its immunologic signaling aspects, safety, and efficacy.

The clinical portion of this

study was completed in January 2016.

Advanced immunologic profiling of clinical samples obtained from that work was completed

in June 2017 and data were reported at Psoriasis Gene to Clinic in London, England in November 2017 (Krueger et al.).

data demonstrated downregulation of more than 500 disease-related genes, including central “psoriasis-related”

that were normalized to levels consistent with non-lesional skin, and established that PH-10 has a novel mechanism of action in

inflammatory dermatoses.

Work began in support of extended 12-week

administration (proof-of-concept or POC) for PH-10.

In 2018, we finished two toxicology-focused, non-clinical, single administration

studies using 14C-labeled Rose Bengal to demonstrate lack of systemic uptake.

Radio-labeled Rose Bengal is easier to detect in

plasma and tissues at very low levels than Rose Bengal itself.

These data suggest there is minimal potential of systemic, distant

target organ effects from topical application of PH-10.

The goal of a planned, non-clinical, toxicology-focused, 12-week administration

study is to demonstrate local effects in the skin from the extended use of PH-10 and identify any potential systemic toxicities.

When completed, the 12-week POC program may allow for direct comparison of PH-10 to approved topical treatments for psoriasis

and atopic dermatitis.

and Development

Our approach to drug development in oncology

comprises two related, complementary, clinical program paths based on the features of our respective investigational drugs

and their clinically-rational applicability to different patient populations.

In solid tumor cancers for adults, for example,

we believe PV-10 has important implications as a single-agent for earlier states of disease (e.g., locally advanced disease;

III or earlier), while the combination of PV-10 with other classes of therapy (e.g., immunotherapy, chemotherapy, radiotherapy,

targeted therapy) is more appropriate for advanced disease states (e.g., widely metastatic disease;

In both paths,

direct delivery of PV-10 to cancerous tumor (i.e., intratumoral delivery) maximizes local therapeutic potential while minimizing

potential for toxicity in normal tissue.

Our approach to drug development in dermatology

comprises a similar approach, where direct delivery of PH-10 to diseased tissue (i.e., topical delivery) maximizes local therapeutic

potential while minimizing potential for toxicity in normal tissue.

We believe these approaches optimize potential

value in the single-agent setting while providing favorable pharmacologic properties for the use of PV-10 or PH-10, respectively,

in combination with other systemic therapies.

Property (“IP”)

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, with the aims of maximizing

the curative impact of these medicines and achieving immunity from treated disease.

These investigational drugs are based on an

entire, wholly-owned, family of small molecules called halogenated xanthenes (“HXs”);

our lead HX molecule

is named rose bengal disodium (“RBD”).

Former scientists from the U.S.

Department of Energy’s Oak Ridge

National Laboratory founded Provectus in 2002, identifying and advancing RBD’s dark-effect therapeutic potential

and developing RBD and HXs into proprietary molecules.

Starting in 2017, new science and business leadership pivoted and then

expanded drug discovery and development, targeting global patient populations in a number of disease areas and indications made

viable by RBD’s immunotherapeutic potential and new routes of administration.

RBD possesses an

innovative physical chemistry science with broad-spectrum prophylactic and therapeutic medical applications.

The prerequisite

mechanistic step for these immunotherapies is direct contact between RBD and disease that may lead to disease death repair, RBD

treatment-specific innate immune activation, and disease-specific functional adaptive immune response.

consistent mechanistic behavior across different indications of a disease and across different disease areas, with the

potential to be a multi-disease treatment platform and a universal contributor to different medical treatments.

Discovery and Development Strategy

New company leadership has

a compelling vision of accessible and affordable, safe, broad-spectrum small molecule immunotherapies.

Provectus’

intralesional (IL) oncology clinical program was pivoted and enhanced to pursue U.S.

Food and Drug Administration (“FDA”)

and/or Australia’s Therapeutics Good Administration (“TGA”) regulatory advancement for rare or refractory cancers

of the skin and cancers of the liver in both single-agent and combination therapy settings.

Drug development was expanded to pursue

proof-of-concept of systemic RBD administration.

Routes of administration and target diseases being developed

include oral (“PO”) hematology in relapsed and refractory adult and pediatric leukemias, and PO

oncology for prophylactic and/or therapeutic RBD in high-risk adult solid tumor cancers.

Drug discovery into RBD

treatment has also been deepened to explore different disease areas.

Target diseases include virology, such as SARS-CoV-2

microbiology, such as antibiotic-resistant gram-negative bacteria;

ophthalmology, such as diseases of the cornea;

and dermatology, such as combination therapy with systemic biologics for psoriasis and atopic dermatitis.

and HX Intellectual Property (“IP”)

RBD, the active pharmaceutical ingredient

(API) in our current investigational immunotherapy medicines, is a systemically-active, environmentally-adaptive stable,

and selective small molecule.

RBD has a nominal formula of 4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein

Rose bengal drug substance (“RB DS”) is produced by Provectus’

Quality-by-Design (“QbD”)

manufacturing process, which avoids the formation of uncontrolled impurities generally (and also proprietarily) known to be present

in commercial-grade rose bengal, and follows International Council for Harmonisation of Technical Requirements for Pharmaceuticals

for Human Use (“ICH”) Guidelines for pharmaceutical ingredients and current Good Manufacturing Practices (“cGMP”)

Multiple Provectus cGMP RB DS lots have surpassed multi-year stability testing.

Company’s science and molecules are currently protected by global intellectual property that includes composition of matter,

manufacturing methods and techniques, pharmaceutical synthesis standards, trade secrets, and concomitant combination therapy use

for different disease areas.

We hold a number of patents covering the technologies

we have developed and are continuing to develop for the production of investigational drugs and other technologies.

material to an understanding of the Company are included below, and a cross reference to a discussion that explains the patent

technologies and products is identified for certain patents in the following table:

and Cross Reference

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

antiperspirant and antimicrobial compositions

see discussion under Over-the-Counter Pharmaceuticals in Description of Business

intracorporeal medicaments for high energy photodynamic treatment of disease

see discussion under Dermatology in Description

for the synthesis of rose bengal and related xanthenes

see discussion under Oncology in Description of Business

therapy for cancer

see discussion under Oncology in Description of Business

for the synthesis of rose bengal and related xanthenes

see discussion under Oncology in Description of Business

for the synthesis of rose bengal and related xanthenes

see discussion under Oncology in Description of Business

of local and systematic immunomodulative therapies for melanoma and liver cancer

of rose bengal and systemic immunomodulative therapies for enhanced treatment

of rose bengal and systemic immunomodulative therapies for enhanced treatment of cancer

of ex vivo enhancement of immune cell activity for cancer immunotherapy with a small molecule ablative compound

of local rose bengal and systemic immunomodulative therapies for enhanced treatment of cancer

2019, we received U.S.

10,471,144, entitled “Combination of local rose bengal and systemic immunomodulative therapies

for enhanced treatment of cancer.”

In general, the pharmaceutical and biotechnology

industries are competitive, characterized by steady and sometimes disruptive advances in products and technology.

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.

International

Indian Patent Office granted the Company’s patent application on May 29, 2020 for the combination of investigational

autolytic cancer immunotherapy PV-10 and systemic immunomodulatory therapy, such as immune checkpoint blockade.

a co-assignee on this patent.

The Japan Patent Office granted the

Company’s patent application on October 5, 2020 for ex vivo enhancement of immune cell activity for cancer immunotherapy

with small molecule ablative compound.

Lee Moffitt Cancer Center is a co-assignee on this patent.

Product Pipeline

is an injectable pharmaceutical formulation of RBD and registration study-ready investigational drug product (“PV-10

Multiple lots of PV-10 DP have surpassed multi-year stability testing, respectively.

PV-10 DP is shipped,

stored, and used at room temperature.

Provectus has developed two clinical-stage formulations of PV-10:

an IL administration for

oncology (10% RBD) for the treatment of cancers of the skin and cancers of the liver, and topical (“top.”) application

for dermatology (0.01% RBD) for the treatment of inflammatory dermatoses (psoriasis, atopic dermatitis, and actinic keratosis).

A third formulation is under development for a currently proprietary disease area.

Research into new routes of RBD administration

and formulations of PV-10 is ongoing, including PO, intranasal (“IN”), top., and/or intravenous (“IV”)

for hematology, oncology, virology, microbiology, and/or ophthalmology.

from the Company’s clinical trial of PV-10 as a single-agent and in combination with immune checkpoint blockade for the

treatment of primary or metastatic tumors of the liver (NCT00986661) was uploaded to the SIR 2020 ePoster Gallery of the canceled

Society of Interventional Radiology (“SIR”) 2020 Annual Scientific Meeting, held March 28-April 2, 2020 in Seattle,

“Oncolytic immunotherapy of hepatic tumors with intralesional rose bengal disodium.”

from ongoing preclinical study of PV-10 was presented at the American Association for Cancer Research (“AACR”) 2020

Virtual Annual Meeting II, held online June 22-24, 2020:

“Association of heat shock proteins as chaperone for STING:

A potential link in a key immune activation mechanism revealed by the novel anti-cancer agent PV-10.”

data from the first cohort of the Company’s autolytic cancer immunotherapy PV-10 were published as an abstract as part of

the American Society of Clinical Oncology (“ASCO”) 2020 Virtual Scientific Program, held online May 29-31, 2020:

1 results of a phase I study of autolytic immunotherapy of metastatic neuroendocrine neoplasms using intralesional rose bengal

disodium.”

data from the Company’s expansion cohort of patients with uveal melanoma metastatic to the liver (“mUM”) in

its Phase 1 cancers of the liver “basket study”

of PV-10 were presented at ASCO:

“Percutaneous hepatic injection

of rose bengal disodium (PV-10) in metastatic uveal melanoma.”

Company expanded its sponsored research program with Aru Narendran, MD, PhD, Professor, Departments of Pediatrics, Oncology, Biochemistry

& Molecular Biology, and Physiology & Pharmacology at the Cumming School of Medicine of the University of Calgary in Calgary,

Alberta, Canada.

Under ongoing collaboration with Provectus, the Narendran research team has produced preliminary findings that

show oral dosing of RBD is effective and well tolerated in an in vivo pediatric leukemia murine model.

Data from this work

are currently being prepared for publication.

As part of the sponsored research expansion, the Narendran team would investigate

oral dosing of RBD in in vivo murine models for the treatment of refractory adult solid tumors that are high-risk phenotypes

and have high metastatic potential.

These cancer types will include head and neck, breast, pancreatic, liver, and colorectal.

Company initiated a new sponsored research program with Michio Kurosu, PhD, Professor, Department of Pharmaceutical Sciences at

the College of Pharmacy of the University of Tennessee Health Science Center (“UTHSC”) in Memphis, Tennessee to investigate

RBD targeting of multi-drug resistant (“MDR”) bacteria.

Kurosu’s team would undertake in vitro studies

on the spectrum of RBD activity against drug-susceptible and drug-resistant bacterial strains, synergistic activity of combinations

of RBD and FDA-approved antibiotics for Gram-negative bacteria, the mutation frequency of

RBD against bacterial strains, measuring spontaneous bacterial mutations for RBD and these combinations, and gene analyses of

mutant bacterial strains to understand resistance mechanisms.

landmark survival, response, and safety data from the Company’s Phase 1b/2 study of PV-10 in combination with KEYTRUDA (pembrolizumab)

for the treatment of advanced cutaneous melanoma in patients naive to immune checkpoint blockade (CB) was presented at the European

Society for Medical Oncology (“ESMO”) Virtual Congress 2020, held online from September 19-21, 2020:

“A phase

1b study of rose bengal disodium and anti-PD-1 in metastatic cutaneous melanoma:

results in patients naïve to immune checkpoint

blockade.”

response, safety, and immune correlative data from the Company’s Phase 1b/2 study of PV-10 in combination with KEYTRUDA for the treatment of advanced cutaneous melanoma in patients refractory to immune checkpoint blockade was also

presented at ESMO:

“A phase 1b study of rose bengal disodium and anti-PD-1 in metastatic cutaneous melanoma:

results in patients refractory to checkpoint blockade.”

October, the Company announced completion of enrollment

of 12 patients into Provectus’

Phase 1 study of PV-10 for the treatment of symptomatic mNET refractory to somatostatin analogs

(“SSAs”) and peptide receptor radionuclide therapy (“PRRT”).

data from ongoing research on PV-10 as a single-agent and in combination with gemcitabine chemotherapy for the treatment of pancreatic

cancer at the Society for Immunotherapy of Cancer’s (“SITC”) 35 th Anniversary Annual Meeting &

Pre-Conference Programs (“SITC 2020”), held online from November 9-14, 2020:

“Intralesional injection of

rose bengal augments the efficacy of gemcitabine chemotherapy against pancreatic tumors.”

preliminary patient response, safety, and immune correlative data, as well as new preliminary PV-10-treated lesion response data,

from the Company’s ongoing Phase 1b/2 study of PV-10 in combination with KEYTRUDA for the treatment of advanced

cutaneous melanoma in patients refractory to CB was presented at Melanoma Bridge 2020, held online from December 3-5, 2020.

oral presentation, entitled “Response for combination of PV-10 autolytic immunotherapy and immune checkpoint blockade

in checkpoint-refractory patients,”

was presented by Dr.

Jonathan Zager, Chief Academic Officer at Moffitt Cancer Center,

and a surgical oncologist and Senior Member in Moffitt’s Departments of Cutaneous Oncology and Sarcoma.

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

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.

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.

Regulation of Therapeutic Products

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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 Council on Harmonisation

(“ICH”) Good Clinical Practice (“GCP”) standards.

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 ICH Good Clinical

Practice (“GCP”) standards.

the FDA is satisfied with the results and data from pre-clinical tests, it will authorize human clinical trials.

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tolerance, side effects, absorption, metabolism, distribution, excretion, and clinical efficacy.

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.

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

1 studies also evaluate drug metabolism, structure-activity relationships, and the mechanism of action in humans.

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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.

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.

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.

have established a core clinical development team and have been working with external and FDA-experienced consultants to assist

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development data is maximally applicable for potential global approval.

March 25, 2019, the Company’s Board of Directors (the “Board”) named Heather Raines, CPA as Chief Financial

Officer (“CFO”).

On May 9, 2019, the Board named Bruce Horowitz as Chief Operating Officer (“COO”).

of Director Change

July 11, 2020, the Company announced that Jan Koe had resigned from the Board of Directors (the “Board”).

His resignation

was not due to any disagreement with the Company on any matter relating to the Company’s operations, policies or practices.

Koe’s resignation was contemplated by the Amended and Restated Definitive Financing Commitment Term Sheet effective

as of March 19, 2017, entered into between the Company and a group of the Company’s stockholders (the “PRH Group”),

which set forth the terms on which the PRH Group would provide financing to the Company (the “2017 Term Sheet”).

July 20, 2020, the Company added Webster Bailey to fill this vacant spot on the Board.

Capital Resources

have two full-time employees.

2 unchanged sentences

manager, and database manager.

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

The skills, experience

and industry knowledge of key employees and contractors significantly benefit our operations and performance.

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 World Health Organization and the Centers for Disease Control and Prevention to protect its workforce so they

can more safely and effectively perform their work.

website is located at www.provectusbio.com .

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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