DELIVERING THE FIRST LYSOSOME-TARGETING CANCER IMMUNOTHERAPY
Small Molecule, Halogenated Xanthene-derived Medicine
10025 Investment Drive, Suite 250, Knoxville, Tennessee, USA 37932 www.provectusbio.com © 2019, Provectus Biopharmaceuticals, Inc.
This presentation may contain forward-looking statements as defined under U.S. federal securities laws. These
statements reflect Company management’s current knowledge, assumptions, beliefs, estimates, and expectations,
and express Provectus management’s current views of future performance, results, and trends. These forward-
looking statements may also be identified by their use of terms, such as anticipate, believe, could, estimate,
expect, intend, may, plan, predict, project, will, and other similar words. Forward-looking statements are subject to
a number of risks and uncertainties that could cause the Company’s actual results to materially differ from those
described during this presentation. Readers of this presentation should not place undue reliance on forward-
looking statements. Such statements are made as of the date hereof, and Provectus undertakes no obligation to
update such statements after this date. Risks and uncertainties that could cause the Company’s actual results to
materially differ from those described in these forward-looking statements include those discussed in Provectus’
filings with the U.S. Securities and Exchange Commission (the “SEC”) and those described in item 1A of the
Company’s Annual Report in its Form 10-K for the year ended December 31, 2018. Provectus Biopharmaceuticals,
Inc. (“Provectus” or the “Company”) assumes no obligation to update any forward-looking statements or
information that speaks as to their respective dates. No claims with respect to PV-10, Provectus’ investigational
drug for oncology, or PH-10, the Companys investigational drug for dermatology, are intended regarding safety or
efficacy in the context of any forward-looking statements made in this presentation.
© 2019, Provectus Biopharmaceuticals, Inc. 2
Forward-Looking Statements
© 2019, Provectus Biopharmaceuticals, Inc.
Provectus Biopharmaceuticals: An Overview
Developing medicines based on a class of small molecules called halogenated xanthenes
An entire class of molecules wholly-owned by Provectus
Clinical-stage, lysosomal-targeting cancer immunotherapy (PV-10), based on lead molecule rose
bengal disodium (RB)
Clinical-stage immuno-dermatology agent (PH-10), also based on RB
New leadership team (board of directors, executive management) in place since 2017
3
o Business Model
Small molecule immunotherapies
400+ patients treated for a number of different tumor types in multiple clinical settings
Multiple cell death pathways and multiple signaling pathways elucidated in different cancers
Demonstrating activity of PV-10 in T cell- & non-T cell-inflamed and high & low TMB tumor types
Demonstrating T cell responses generated by PV-10 treatment
Contrasting and comparing PV-10 with checkpoint inhibitor (CI) and other drug classes (chemotherapy,
radiotherapy, targeted therapy) in monotherapy and combination therapy settings
o Immuno-Oncology
PV-10, intralesional/intratumoral injection
Tumor-specific and tumor-agnostic
Platform science for oncology and
hematology
200+ patients treated for a number of dermatological diseases (4-week administration)
Demonstrating 12-week monotherapy administration proof-of-concept for inflammatory dermatoses
Expanding PH-10 treatment to include combination therapy
Goal: Achieve Phase 3 trial-ready status for PH-10 in both psoriasis and atopic dermatitis
o Immuno-Dermatology
PH-10, topical gel
Platform science for conventional, onco-,
orphan, and pediatric dermatology
© 2019, Provectus Biopharmaceuticals, Inc.
PV-10: Lysosomal-Targeting Cancer Immunotherapy
4
o Outside of ‘hot’ tumors, checkpoint inhibitor (CI) drugs struggle to overcome the
inadequate recognition of most solid tumor cancers by the immune system; they are
constrained by several factors, such as:
Low tumor mutation burden (low TMB tumors)
Insufficient T cell inflammation (‘cold’ tumors)
o Better drugging of the druggable and effective drugging of the undruggable starts
with the cancer cell and continues with the activation of the immune system in the
tumor microenvironment (TME)
PV-10 may unlock any TME because it is the first lysosomal-targeting drug, which
ruptures lysosomes of diseased cells and leads to all major, distinct pathways of cell
death; nearly all types of eukaryotic cells, normal and diseased, possess a lysosome
It is also the first drug that may facilitate multiple, temporally-distinct, immune system
signaling pathways
PV-10 can overcome the constraints of the TME, irrespective of tumor type, because it:
Has acute oncolytic activity potentially across the spectrum of tumor types
May allow CI drugs to recognize low TMB/cold tumor types; CI drugs augment
the functional immune response generated by PV-10 treatment
Has potential safety and efficacy in combination with CI drugs in multiple tumor
types
Has potential superior activity and/or broader applicability over most-to-all
pairings explored by biopharma for CI drugs, including but not limited to
cytokines, TLR and STING agonists, and oncolytic viruses
Clinical/preclinical PV-10 data in tumor types
1
Green shaded arrows, and red (hot), blue (cold), and purple (lukewarm)
ovals are illustrative and not part of the original journal article
© 2019, Provectus Biopharmaceuticals, Inc.
For Cancer, a New ”Drug Target” Class: Lysosomal Cell Death
o Lysosomes are the central organelles for intracellular degradation of biological
materials (e.g., the ‘stomach of the cell,’ the ‘trash bin,’ etc.)
Nearly all types of animal-like, eukaryotic cells have lysosomes
o Discovered by Christian de Duve, MD in 1955, lysosomes are linked with a
number of biological processes, including cell death, inflammasome activation,
and immune response
5
o In 1959, Dr. de Duve described lysosomes as ‘suicide bags’ because their
rupture causes cell death and tissue autolysis
Lysosomes are linked with each of the three major and distinct pathways of cell
death: apoptosis, autophagy, and necrosis
o Dr. de Duve was awarded the Nobel Prize in 1974 for discovering and
characterizing lysosomes
*
[LEFT IMAGE] Source. [RIGHT IMAGE] Source.
© 2019, Provectus Biopharmaceuticals, Inc.
Cell Death Pathways Lead to Signaling Pathways (MOAs)
6
o Lysosomes have been
linked to each of the three
major distinct pathways of
cell death
Apoptosis
Autophagy
Necrosis
o PV-10 treatment, leading
to cell death, mediates the
following signaling
pathways (mechanisms of
action)
1. Release of damage
associated molecular
patterns (DAMPs)
2. Poly-ADP ribose
polymerase (PARP)
cleavage
3. Current hypothesis of
a further signaling
pathway
4. n.
*
[LEFT IMAGE] Source.
*
[RIGHT IMAGE] Source.
*
MOA = mechanism of action.
o Provectus has shown that PV-10 selectively accumulates in the lysosomes of only cancer cells upon contact, disrupts them,
and causes the cancer cells to die
o Provectus and independent researchers have also shown that PV-10 (RB) can trigger all major, distinct forms of lysosomal
cell death: apoptosis, autophagy, and necrosis
© 2019, Provectus Biopharmaceuticals, Inc.
Triggering the Release of Lysosomal Contents
7
o Acute autolysis occurs within 30 to 60 minutes
*
Wachter et al., SPIE Proceedings 2002; 4620: 143-147. Liu et al., AACR 2014.
Identical responses in Hepa1-6 murine hepatocellular carcinoma (HCC), HTB-133 human breast carcinoma, and H96Ar human multi-drug
resistant small cell lung carcinoma
The chronology is consistent with pharmacodynamics observed in murine models
Lysosomal release
© 2019, Provectus Biopharmaceuticals, Inc.
MORE REPRODUCIBILITY: Treatment with PV-10 Disrupts Lysosomes
8
o Work conducted on relapsed and refractory neuroblastoma
*
A collaboration with POETIC,the Pediatric Oncology Experimental Therapeutics Investigators' Consortium. [ABOVE] Swift et al., Journal of Clinical Oncology 36, no. 15_suppl, 10557, 2018.
Figure 3 (left). PV-10 disrupts lysosomes.
Notes: Live cells were stained with the nucleic acid stain Hoechst 33342 and LysoTracker green DND-
26, which concentrates and fluoresces in acidic organelles, and observed by fluorescence microscopy.
(A) Neuroblastoma cell lines IMR5 and SK-N-AS were treated with either PBS (vehicle control) or 100
µM PV-10 for 6 hours. (B) Neuroblastoma cell line SK-N-AS was treated with either PBS (vehicle
control) or 200 µM PV-10 for 6 hours. Scale bars = 20 µm. Data presented are representative of three
separate experiments.
SK-N-AS and IMR5 cells were treated with either PBS (vehicle control) or 100 µM PV-10 for 6
hours, stained live cells with the nucleic acid stain Hoechst 33342 and LysoTracker Green DND-26
(which concentrates and fluoresces in acidic organelles) and observed cells by fluorescence
microscopy (Figure 3A)
In PBS-treated SK-N-AS and IMR5 cells and in SK-N-AS PV-10-treated cells, lysosomes were
visible as specific foci
By contrast, lysosomal foci were no longer visible in PV-10-treated IMR5 cells
As SK-N-AS cells were less sensitive to PV-10 than IMR5 cells, we next observed lysosomes in SK-
N-AS cells treated for 6 hours with an increased concentration of PV-10 (200 µM) (Figure 3B)
As observed in IMR5 cells treated with 100 µM PV-10, lysosomal foci were not visible in 200 µM
PV-10 SK-N-AS cells, indicating that PV-10 disrupts lysosomes in both the cell lines tested
© 2019, Provectus Biopharmaceuticals, Inc.
Lysosome-based Cell Death Leads to Several Different MOAs: e.g., Release of DAMPs
9
Hours
Lysosomal
Accumulation
Immunogenic
Cell Death (ICD)
Lysosomal
Disruption
Intralesional
Injection
Primary Oncolysis
Secondary Adaptive Immunity
DAMP and Antigen
Release
APC Recruitment
and Antigen Uptake
T-cell
Activation
Functional T-cell
Activity
Weeks
Hours
Lysosomal
Accumulation
Immunogenic
Cell Death (ICD)
Lysosomal
Disruption
Intralesional
Injection
Primary Oncolysis
Secondary Adaptive Immunity
DAMP and Antigen
Release
APC Recruitment
and Antigen Uptake
T-cell
Activation
Functional T-cell
Activity
Weeks
o Lysosomal accumulation and disruption in tissue culture
(HCC: murine) (refractory pediatric solid tumor: human)
Wachter et al., SPIE 4620, 143, 2002; Swift et al., Journal of Clinical Oncology 36, no. 15_suppl, 10557, 2018
o Oncolysis of injected tumors and bystander regression in recurrent patients
(melanoma: human)
Thompson et al., Melanoma Res 18, 405, 2008
o Tumor-specific immune response
(breast cancer, melanoma: murine)
Toomey et al., PLOS One 8, e68561, 2013
o DAMPs, DC recruitment & activation, T-cell activation
(melanoma: murine, human)
Liu et al., Oncotarget 7, 37893, 2016
o Immunogenic cell death
(colon cancer: murine)
Qin et al., Cell Death and Disease 8, e2584, 2017
o Confirmation of oncolytic activity in multi-drug resistant cell lines
(refractory pediatric solid tumor: human)
Swift et al., 2018
*
DC = dendritic cell.
1
Panzarini et al., Cell Death Dis 2011: 2 : e169.
PV-10 treatment, leading to cell death, thus far mediates the following signaling pathways: release of DAMPs, PARP cleavage, and a third signaling pathway currently being
investigated
In cancer, RB (PV-10) triggers several different pathways in regards to the mechanism of death of cancer; however, independent temporal activation ensures cell death even when one
or several of these pathways are inactivated
1
© 2019, Provectus Biopharmaceuticals, Inc.
PV-10 Monotherapy Drug Development Strategy
o Demonstrate PV-10’s activity in cold/hot, low/high TMB, and other categories/labels of tumor types where CI
drugs show activity or modest-to-no activity
o Demonstrate the T cell response generated by PV-10 treatment, which may be tumor-specific
o Contrast and compare PV-10 treatment (e.g., activity, safety, induced immune response) with that of CI and other
drug classes (e.g., chemotherapy, radiotherapy, targeted therapy) in monotherapy and combination therapy
settings
This strategy may:
Advance PV-10 along a monotherapy-based pathway-to-approval in solid tumor cancer indications where
there is high unmet need, limited activity from other therapies, and the opportunity to further display a
functional immune response from PV-10 treatment, such as for metastatic neuroendocrine tumors (mNET)
(NCT02693067) (ASCO 2019)
10
© 2019, Provectus Biopharmaceuticals, Inc.
PV-10 Ablation Experience: Cell Lines & Murine Models
11
Tumor Type Cell Line Murine Model Notes
Murine bladder carcinoma
MB49
C57BL/6 flank
proprietary
Murine breast carcinoma
MT
-901
BALB/c bilateral flank
Toomey et al., PLOS One 2013
MCF
-7 [ER+ / ER-], HTB-133, T-47D
BALB/c flank
proprietary
Murine breast carcinoma (spontaneous)
n/a
Neu+/+
proprietary
Murine colon carcinoma
CT26
BALB/c flank
Qin et al., Cell Death Dis 2017
Murine HCC
Hepa1
-6
C57BL/6 bilateral flank
Dees et al. AACR 2013
Hepa1
-6
C57BL/6 bilateral flank
Dees et al. SITC 2012
Hepa1
-6
C57BL/6 bilateral flank
proprietary
Hepa1
-6
BALB/c bilateral flank
proprietary
Hepa1
-6
BALB/c flank
proprietary
Hepa1
-6
C57BL/6 flank and bilateral flank
BALB/c flank and bilateral flank
proprietary
Murine melanoma
B16
C57BL/6 flank and lung
Toomey et al. 2013
B16, M05
C57BL/6 bilateral flank
Liu et al., PLOS One 2018
B16
C57BL/6 flank and lung
Liu et al., Oncotarget 2016
M05
C57BL/6 flank
Liu et al. 2016
B16
C57BL/6 flank and lung
Dees et al. AACR 2013
B16/F10
C57BL/6 flank
proprietary
A375
BALB/c flank
proprietary
Murine pancreatic adenocarcinoma
Panc02
C57BL/6 bilateral flank
Pilon-Thomas et al. SITC 2016
Human neuroblastoma
IMR5, SK
-N-AS
CB17 SCID flank
Swift et al., Onco Targets Ther 2019
Human prostate adenocarcinoma
PC
-3
nu/nu flank
proprietary
Human small cell lung carcinoma (multi
-drug resistant)
H69Ar
nu/nu flank
proprietary
© 2019, Provectus Biopharmaceuticals, Inc.
PV-10 Ablation Experience: Companion Animals
12
Tumor Type Delivery Method Resolution Notes
Mast cell Intratumoral injection Mostly
Dog (Golden retriever, age 13 years) with >20 superficial (grade 2) tumors
Squamous cell carcinoma Intratumoral injection Partial
Cat (DSH, age 14 years) with tumor on ventral tongue
Melanoma (oral) Intratumoral injection No
Dog (Chow, age 18 years) with 2 cm tumor on tongue, possible lymph node involvement
Transitional cell carcinoma Bladder instillation Yes
Dog (West highland terrier, age 10 years) with mass in ventral bladder
Fibrous histiocytoma Intratumoral injection Yes
Dog (German shepherd, age 3.5 years) with recurrent 5x2x2 cm mass in roof of mouth/sinus (below)
Hepatic safety study Intrahepatic injection N/A
Dog (Beagle, adult, male and female); single injection to establish hepatic depot in healthy canines
Prostatic safety study Intraprostatic injection N/A
Dog (Beagle, adult male); single injection to establish depot in prostate of healthy canine
© 2019, Provectus Biopharmaceuticals, Inc.
PV-10 Ablation Experience: Clinical, Lesion-Level Treatment
13
Tumor Type Clinical Setting CR PR OR # of Patients
# of Injected
Lesions
Most Recent Paper or Presentation
Cutaneous Melanoma
Phase 1 single-agent
(1 injection/lesion, Stage IIIB-IVM1a)
16 (15%) 5 (5%) 21 (19%) 20 110 Thompson et al., Mel Res 2018
Phase 2 single-agent
(1-4 injections/lesion, Stage IIIB-IVM1c)
224 (46%) 36 (7%) 260 (53%) 80 491 Agarwala et al., Melanoma Bridge 2018
Expanded access single-agent
(1 or more injections/lesion, Stage IIIB-
IVM1a)
5 (26%)
5 (26%)
10 (53%)
19 190
Lippey et al., JSO 2016
(
patient level data shown, lesion level data not reported;
estimated)
Expanded access single-agent
(1 or more injections/lesion, Stage IIIB-
IIIC)
19 (42%)
20 (44%)
39 (87%)
45 401
Read et al., JSO 2018
(
patient-level data shown, lesion-level data not reported)
Phase 2 neo-adjuvant to XRT
(1 injection/lesion, Stage IIIB-IV)
66 (64%) 22 (21%) 88 (84%) 15 103 Foote et al., JSO 2017
Phase 1b combination
(1-5 injections/lesion combined with anti-
PD-1, Stage IIIB-IVM1c)
23 (77%) 1 (3%) 24 (80%) 23 30 Agarwala et al., Melanoma Bridge 2018
Scalp Sarcoma
Expanded access single-agent
(1 or more injections/lesion, refractory
disease)
7 (100%) 0 (0%) 7 (100%) 2 7 Tan and Neuhaus, ANZ J Surg 2013
Metastatic
neuroendocrine tumors
Phase 1 single-agent/combination
(1 injection/lesion to hepatic metastases
w/wo CI, Stage IV)
0 (0%) 4 (50%) 4 (50%) 5 8 Price et al., ASCO 2019
Metastatic uveal
melanoma
Phase 1 single-agent
(1 injection/lesion to hepatic metastases,
Stage IV)
0 (0%) 5 (50%) 5 (50%) 6 10 Patel et al., ISOO 2019 (also OOG 2019)
Key enhancements were implemented for Phase 2 vs Phase 1 in cutaneous melanoma (Clinical Setting row 1 vs row 2): repeat injections and a
minimum injection volume. Note the improvement in complete response (CR).
© 2019, Provectus Biopharmaceuticals, Inc.
Achieving a Complete Response of a PV-10-injected Lesion/Tumor
14
o Clinical data to date suggest favorable outcomes are possible in a broad range of solid tumor types
o Potential, prognostic, clinical factors
1
for achieving a CR of a PV-10-injected lesion or tumor thus far include:
Younger age
Earlier disease stage/Smaller lesion size (or volume)
Lower number of lesions present/Lower total disease burden
Greater proportion of total disease burden treated
o CR may be achieved with minimal PV-10 intervention (e.g., 1-2 injections, depending on certain lesion factors)
Data to date may represent PV-10’s ‘performance’ floor for achieving a CR of an injected lesion or tumor
May also indicate an immunotherapeutic outcome and benefit for a cancer patient (i.e., systemic)
1
Statistically significant. Age (the younger the better): 61 (median, range 42-82) vs. 85 (71-94), 26% patient CR (J Surg Oncol 2016). Lesion size/diameter (the smaller the better): <10 mm, 74% lesion CR
(J Surg Oncol 2017), 3 mm (median, range 3-5) vs. 7 mm (5-25), 26% patient CR (J Surg Oncol 2016). Number of lesions (the fewer the better): <15, 29% episodic patient-treatment CR (J Surg Oncol
2018). Amount of total tumor burden/volume (the lower the better): Low-to-moderate disease burden. Proportion of disease treated (the higher the better): All disease treated (Ann Surg Oncol 2014).
Disease stage (the earlier the better): Stage III, 50% target lesion CR vs Stage IV, 0% (Ann Surg Oncol 2014).
© 2019, Provectus Biopharmaceuticals, Inc.
Cutaneous Melanoma Clinical Example (PV-10 Monotherapy)
15
Agarwala et al., ASCO 2010
*
Cutaneous/subcutaneous intralesional/intratumoral administration of PV-10.
© 2019, Provectus Biopharmaceuticals, Inc.
HCC Clinical Example (PV-10 Monotherapy)
16
*
Percutaneous intralesional/intratumoral administration of PV-10.
© 2019, Provectus Biopharmaceuticals, Inc.
Metastatic Colorectal Cancer Clinical Example (PV-10 Monotherapy)
17
*
Percutaneous intralesional/intratumoral administration of PV-10.
© 2019, Provectus Biopharmaceuticals, Inc.
mNET Tumors Clinical Example (PV-10 Monotherapy)
18
!"#$%&'()*+,-+./0+-,+-,-,1 !"#$%&'%()*+(, -./012!2!23(+32
*
Percutaneous intralesional/intratumoral administration of PV-10.
© 2019, Provectus Biopharmaceuticals, Inc.
Tumor Types: T cell & Non-T cell Inflamed, Low & High TMB, Etc.
19
Figure 1, Yarchoan et al., NEJM 2017: 377: 2500 (objective response rates of CI drugs)
1
Vareki et al., JITC 2018: 6: 157
1
1
Red (‘hot’), blue (‘cold’), and purple (‘lukewarm’) ovals (size, positioning) are illustrative, and are not part of the original journal articles.
2
Arrows are meant to indicate areas or quadrants, and not specific indications.
Clinical/preclinical PV-10 single-agent and combination therapy data
2
CI drug failure, lack of sufficient activity, or resistance (illustrative disease indication results)
Better drugging of the druggable and effective drugging of the undruggable starts with the cancer cell and, thus, efficient, effective, and timely
ablation of the TME
CI drug
20% ORR
© 2019, Provectus Biopharmaceuticals, Inc.
PV-10-based Cancer Combination Therapy Drug Development
o Demonstrate PV-10’s agnosticism to tumor type, and how CI and other drug classes may augment the functional immune
response from PV-10 treatment
This strategy may:
Advance a PV-10-based combination therapy involving a CI or other drug class along a pathway-to-approval in an
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/emerging SOCs
o Clinical examples to date include (but are not limited to):
1. Cutaneous melanoma
1
; +radiotherapy (J Surg Oncol 2017)
2. CI drug-naïve cutaneous melanoma
1
; +pembrolizumab (NCT02557321) (ASCO 2019)
3. CI drug-refractory cutaneous melanoma
1
; +pembrolizumab (NCT02557321 expansion cohort)
4. In-transit melanoma
1
; +pembrolizumab (NCT02557321 expansion cohort)
5. Metastatic uveal melanoma (mUM)
2
; +ipilimumab & nivolumab (this CI combination is an emerging SOC) (NCT00986661
expansion cohort) (SMR 2018)
6. Mucosal melanoma of the vagina
1
(+pembrolizumab; refractory to CTLA-4+PD-1), breast cancer
1
(+nivolumab; refractory to
PD-1), Merkel cell carcinoma
1
(+avelumab; refractory to PD-L1): single-patient expanded access
7. Metastatic pancreatic cancer
2
; +chemotherapy (gemcitabine/nab-paclitaxel) (planned)
8. mNET
2
; +pembrolizumab (contemplated) (awarded AGITG ASM Best of New Concepts 2019 award)
20
1
Cutaneous/subcutaneous intralesional/intratumoral administration of PV-10.
2
Percutaneous intralesional/intratumoral administration of PV-10.
© 2019, Provectus Biopharmaceuticals, Inc.
mUM Clinical Example (PV-10 Monotherapy & Combination Therapy)
21
*
Percutaneous intralesional/intratumoral administration of PV-10. Patel et al., SMR 2018. Contemplated triplet therapy of PV-10+CTLA-4+PD-1.
© 2019, Provectus Biopharmaceuticals, Inc.
PV-10: The Ideal Cancer Immunotherapy to Pair with any CI Drug
22
Monotherapy
Product
Combination
therapy
Corporate
partner
Established safety profile
Activity (CR)
Immunologic up-regulation
Multi-indication viability
Orthogonality (non-overlapping AEs)
Synergy (complementary activity)
Multi-indication viability
CI market expansion
Minimal intervention
Provider ease-of-use
Outpatient setting
Flexible dosing for paired CI drug
Wholly-owned asset
Global CTA experience
Robust API & drug supply chain
Global IP (synthesis, combination)
CI Drug
*
The cancer combination therapy of PV-10 with a CI drug (or a CI combination of drugs) may be interchangeable (e.g., PV-10+CTLA-4, PV-10+PD-1, PV-10+PD-L1, PV-10+CTLA-4+PD-1, etc.). AE = adverse events. CTA = clinical
trial authorization. API = active pharmaceutical ingredient. IP = intellectual property.