2. Note Regarding Forward-Looking Statements
The presentations set forth herein contain forward-looking statements within the meaning of Section
27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of
1934, as amended. The forward-looking statements including, among others, statements regarding
expectations as to regulatory approvals, market opportunity for the Company’s product candidates,
goals as to product candidate development and timing of our clinical trials, are based on the
Company s current intent, belief and expectations. These statements are not guarantees of future
performance and are subject to certain risks and uncertainties that are difficult to predict. Actual
results may differ materially from these forward-looking statements because of the Company s
unproven business model, its dependence on new technologies, the uncertainty and timing of clinical
trials, the Company s ability to develop and commercialize products, its dependence on collaborators
for services and revenue, its substantial indebtedness and lease obligations, its changing
requirements and costs associated with planned facilities, intense competition, the uncertainty of
patent and intellectual property protection, dependence on key management and key suppliers, the
uncertainty of regulation of products, the impact of future alliances or transactions and other risks
described in the Company s filings with the Securities and Exchange Commission. Existing and
prospective investors are cautioned not to place undue reliance on these forward-looking statements,
which speak only as of today s date. The Company undertakes no obligation to update or revise the
information contained in this presentation whether as a result of new information, future events or
circumstances or otherwise.
3. Agenda & Speakers
Supply and Technology Transfer Agreement in Brazil
Dr. David Aviezer, President and CEO, Protalix Biotherapeutics
Commercial Update on Elelyso / Uplyso for Gaucher Disease
Vera Wu, Global Asset Lead, Elelyso/Uplyso, Pfizer
PRX-102 for Fabry Disease
Dr. Gregory Pastores, Associate Professor, Neurology and Pediatrics, NYU School of Medicine
Dr. Einat Almon, Senior Vice President, Product Development, Protalix Biotherapeutics
Oral GCD for Gaucher Disease
Dr. Yoseph Shaaltiel, Executive Vice President, Research and Development, Protalix Biotherapeutics
Prof. Ari Zimran, Director, Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem
Preclinical Pipeline Candidates PRX-106, PRX-110 & PRX-107
Prof. Yaron Ilan, Director, Department of Medicine, Hebrew University Hadassah Medical Center
Dr. Yoseph Shaaltiel, Executive Vice President, Research and Development, Protalix Biotherapeutics
Q&A Session
4. Supply and Technology Transfer
Agreement in Brazil
Dr. David Aviezer, President and CEO, Protalix
Biotherapeutics
5. Gaucher Market in Brazil
!
~600 patients treated
!
~US$65M market per year
!
Additional untreated patients
!
Enzyme therapy is fully paid for by the Brazilian Ministry of Health
!
Currently two enzymes are available:
!
!
Cerezyme
Uplyso
6. Supply and Technology Transfer: Deal Description
Stage 1
!
Protalix sells fully packaged vials to Fiocruz
Stage 2
!
!
Protalix sells naked vials to Fiocruz which will be labeled and packed in Brazil
Fiocruz set-ups and gets approval for a fill and finish facility
Stage 3
!
!
Protalix sells drug substance to Fiocruz, which they will lyophilize, label and
package into vials
Fiocruz builds a validated manufacturing facility for UPLYSO
Stage 4
!
!
!
!
Protalix establishes cell technology for Uplyso in Brazil
Fiocruz conducts clinical trials with drug produced in their facility
Fiocruz applies for approval of the facility and drug with ANVISA
Protalix establishes cell bank for Uplyso in Brazil
7. Deal Description Cont…
!
Throughout the entire agreement, Fiocruz will support and
distribute Uplyso in Brazil
!
Upon completing all four stages, Fiocruz will be able to
produce Uplyso for the Brazil market on its own
!
After the technology transfer is complete, Protalix will receive
mid-single digit royalties on net sales by Fiocruz
8. Financial Benefits of the Deal
!
Creates partnership with one of worlds growing economies
!
Lucrative economics and steady cash flow for Protalix
!
Ability to generate visible, meaningful revenues on limited
operational expenses
!
Relatively short penetration period into the market
!
Eliminates the need to participate in bids
!
Secures prices over a long period
18. Kaplan-Meier analysis:
Probability of developing chronic renal insufficiency,
analyzed by residual α-Gal A activity
Branton M et al. JASN 13:S139, 2007
19. ΔGFR on ERT in male FD patients,
stratified according to baseline GFR.
West M et al. JASN 20:1132,2009
25. Fabry disease :
Age adjusting severity scores
Predicted FOS-MSSI Score
Predicted FOS-MSSI Score
Hughes DA, et al. Mol Genet Metab. 101(2-3):219,2010
26. Fabry disease
Summary
• Fabry disease is a complex multi-systemic disorder, associated with
significant disease burden and shortened lifespan; affecting both males
and female, and with symptom onset in childhood
• There are currently two enzyme formulations, which indicate clinical
benefit for certain patient groups, using different regimens
• Interestingly, time on therapy appears to have a greater influence on mid
term outcome (up to 10 years), rather than enzyme dose; although this
needs to be examined in larger cohorts. Moreover, there is a need to
stratify patients in according to disease severity at baseline, which
appears to be a major determinant of outcome
• Cardiac and cerebrovascular disease continue to be major drivers of
morbidity, and renal insufficiency is progressive for those with advanced
stages and significant proteinuria
• Antibodies against the infused enzyme, appears to be neutralizing in some
cases; based on increased substrate (GL3) excretion,; athough there is no
evidence at this time of an adverse influence on outcome
27. PRX-102 for Fabry Disease
Dr. Einat Almon, Senior Vice President, Product
Development, Protalix Biotherapeutics
28. PRX-102 - A Plant Cell Expressed,
Chemically Modified, Human
α-Galactosidase for the Treatment of
Fabry Disease
29. Fabry Disease
Accumulation of Gb3 (α-Galactosidase-A substrate) in lysosomes
Increased risk of stroke
Hypertension and
cardiomyopathy
Renal insufficiency and renal failure
Outcome: Poor quality of life - Death
Source: Adopted from Najafian et al., Kidney Int. 2011
30. α-Galactosidase-A
! A non-covalently linked homo-dimer of 398aa each (~96 KDa)
! A lysosomal hydrolase that cleaves a terminal galactose from
glycolipids/glycoproteins
Gb3
α-Galactosidase-A
32. Product Rationale
Currently available treatment:
! Fabrazyme® (Genzyme)
! Replagal® (Shire) - Not approved in the US
! Both mimic the natural non-covalently bound homo-dimer
! Marketed products' half-life is a few minutes long
! Not all clinical parameters sufficiently addressed
Protalix approach:
Objective:
! Develop a Bio-Better enzyme with superior clinical effect
Method:
! Generation of a stable dimer via covalent cross-linking
33. PRX-102 Product Description
The chemical modification:
!
Both protein sub-units are PEGylated , resulting in a covalently
bound active and stable dimer
Advantages:
!
!
!
Improved stability
Longer circulatory half life
Enhanced uptake and activity in target organs
PRX-102 properties can potentially lead to:
!
!
Better clinical efficacy
Different regimen
41. Bio-Distribution and Efficacy of PRX-102 in
Fabry Mice Following Repeat Dosing
Experiment
Four injections, once every two weeks with 2mg/kg
of either PRX-102 or placebo
Gb3 clearance from target tissues following
repeated administration of PRX-102
42. Improved In-vivo Activity
PRX-102 Vs. Replagal
Experiment
Single injection of 2mg/kg of either PRX-102 or Replagal
PRX-102 exhibits higher activity levels in target
organs over time in Fabry mice
43. PRX-102 Toxicology Studies
Design:
! Six month studies in two animal species : mice and cynomolgus monkeys
! GLP Tox and TK studies in both species:
- Three doses (1X (2mg/kg), 5X and 20X of maximal clinical dose)
- IV every two weeks
Tox results:
! No systemic toxicity was observed in either species
! No safety concerns in monkeys at 20x dose "doses up to 2 mg/kg in
patients should be well tolerated
! The data support long term clinical trials
45. Proposed Clinical Development Plan
Phase 1/2 study
Open Label, Dose Ranging
! Patients who complete the study will be offered the opportunity to
enroll in an extension study
Phase 3 Pivotal Study
Double Blind, Active Controlled
! Patients who complete the study will be offered the opportunity to
enroll in an extension study
46. Phase 1/2:
!
!
18 adult men and women patients (6/group),
IV infusion once every two weeks
!
Three doses (0.2mg/Kg,1mg/Kg, 2mg/Kg)
!
Duration - 12 weeks (7 infusions, 3 months)
Extension study:
!
!
18 patients, IV infusion once every two weeks, at same doses as in
Phase 1/2
Duration - 38 weeks (20 infusions, 9 months)
Study evaluation
!
Gb3 in urine and blood, lyso-Gb3 in blood, pain, cardiac MRI
!
Skin and kidney biopsies (after 6 months)
Month = 0
3
Phase 1/2
12
6
Extension study
47. PRX-102 Clinical Development Status
! Ongoing phase I/II trial in Fabry patients (under IND)
! Current recruiting sites:
!
Three sites in the United States
!
One site in South America
!
One site in the United Kingdom
!
One site in Australia
! Additional sites pending
48. Oral GCD for Gaucher Disease
Dr. Yoseph Shaaltiel, Executive Vice President,
Research and Development, Protalix
Biotherapeutics
49. PRX-112 - Oral Delivery of Plant
Glucocerebrosidase (prGCD) for
the Treatment of Gaucher Disease
50. Oral Delivery of Therapeutic Proteins
The plant cell advantage:
! The concept: Plant cell wall (cellulose) serves as protective agent
against the gastric environment
! Can serve as a natural vehicle for oral administration
Three requirements for oral delivery of protein therapeutics:
! Protein must survive the gastric environment
! Protein must be released into the intestine from the cells
! Protein must be able to cross the intestinal wall and remain active
51. Ability to Survive the Gastric Environment
Various proteins naturally encapsulated in plant cells
were incubated in a “simulated gastric fluid” to asses the
protective nature of the plant cell wall
High
pH!gradient!
Low
!
!!
Time!(min)!
!!!1!!!!!!!10!!!!30!!!!!!!1!!!!!!10!!!!30!!!!!!1!!!!!10!!!!!30!!!!!!!!!!!!!1!!!!!10!!!!30!!!!!!!1!!!!!10!!!30!!!!!1!!!!10!!!!!!30!!!!!!!!standard!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
!
!
!!!!!!!!!
!
!
!!!!!!!!!!!!!!!!50!25!12.5
Standards!(ng/ml)
Protein!!
in!cells
Purified!!
protein
52. Cellular Assay That Mimics Crossing the Epithelial Barrier
Protein is added to upper chamber
Upper chamber medium:
Simulated intestinal fluid
CaCo-2 epithelial cells on membrane
Lower chamber medium:
HBSS pH 7.4 + 4% BSA
Protein absorption is tested
53. Crossing the Epithelial Barrier (Caco-2 cell model)
2. Time lapse:
Protein added to chamber.
Transcytosis is measured after the
indicated times at 37°C
1. Dose response:
Protein added to chamber at different
concentrations. Transcytosis is
measured after 2 hours at 37°C
6
Protein activity in the
basolateral chamber
Protein activity in the
basolateral chamber
7
5
4
3
2
1
0
X
2.5X
5X
Protein added to the apical chamber
16
14
12
10
8
6
4
2
0
0
1
2
3
4
5
time (hours)
6
7
8
54. Timeline of Food Passing the Stomach
Open stomach
4.5(
4(
stomach!content!(gr)!
Stomach
3.5(
3(
2.5(
2(
1.5(
1(
0.5(
0(
0(
5(
10(
15(
@me!post!feeding!
20(
25(
57. PK Experiments in Rodents
Rats
% addition of GCD activity
Over baseline
60
50
40
30
20
10
0
0
2
4
6
8
10
12
Time post feeding (hours)
! Rats were fed lyophilized plant cells expressing prGCD
! Animals were assayed for the presence of prGCD in their plasma
58. % addition of GCD activity
Over baseline
PK experiments in Large Animals
Pigs
60
50
40
30
20
10
0
0
1
2
3
4
5
6
Time post feeding (hours)
7
8
9
! Animals were fed lyophilized plant cells expressing prGCD
! Animals were assayed for the presence of prGCD in the plasma
for several hours post feeding
59. prGCD Feeding Experiment in Rats
GCD activity mg/gr tissue
Experiment plan:
# Rats were fed with lyophilized carrot cells +/- prGCD;
# Amounts of cell consumption were recorded
# Feeding duration: twice with a six-hour interval
# 2 hours following 2nd feeding, prGCD activity was measured in extracted organs
4(
liver(
4(
3(
spleen(
3(
2(
2(
1(
1(
0(
$1(
Control!(K)!
(K)!AC!
prGCD
Active prGCD is found in target organs after feeding
60. prGCD Activity in Target Organs
Rats liver
70
60
50
40
30
20
10
0
-10
-20
80
control
feeding
% GCD activity addition over the control
% GCD activity addition over the control
80
Pigs liver
70
60
50
40
30
20
10
0
-10
-20
control
feeding
61. Summary
Animal studies of Oral prGCD demonstrate the following:
# Absorbance
# Active
of GCD in the plasma (PK)
prGCD detected in Gaucher target organs in-vivo
63. Disclosure!
!
Receives consultancy fees and has options in Protalix
Biotherapeutics and member of the Scientific Advisory Board;
receives support from Genzyme/Sanofi for participation in the
ICGG registry & from SHGT for GOS; honoraria; Pfizer and SHGT.
(
(
101. PRX-110 & PRX-107
Dr. Yoseph Shaaltiel, Executive Vice President,
Research and Development, Protalix
102.
103. DNase I
!
!
!
Protein: Recombinant human deoxyribonuclease
Indication: Cystic Fibrosis (CF)
Protein function: Break down of excessive DNA in the accumulated
mucus (sputum) in lungs of CF patients decreases viscosity of airway
secretions
!
Market (2012): 572M$
!
!
Marketed Product: Pulmozyme (Roche; Genentech)
IP- Product patents expiration date: 2013
104. PRX-110 Product Description
PRX-110 Advantages:
! Improved enzyme kinetics
! Less sensitive to inhibition by actin
! Improved ex-vivo efficacy
PRX-110 properties can potentially lead to:
! Different regimen
! Lower cost
110. In Vivo Study - Inhalation of PRX-110 in Rats
! Nose-only aerosol inhalation exposure
! PRX-110 enzyme activity in animal lung after
inhalation maintained substantial enzymatic activity
112. PRX-107 – Plant Cell Recombinant Human
Alpha1-antitrypsin (AAT) for the
Treatment of Pulmonary Disorders
AAT
Trypsin
113. ! Main function: regulates AAT-dependent inflammatory response
in the lungs
! Single-chain protein: 394aa, 52kDa
! Indication: Emphysema due to Hereditary AAT deficiency
(AATD)
! Market (2012): est. ~$600M
! Marketed products are purified from plasma and administered
IV
! No recombinant AAT approved
114. All marketed AAT products are plasma-derived
!
!
Limited plasma supply
Potential adventitious agents
Protalix benefit: Recombinant AAT
!
!
!
Easy scale up to meet demand
No potential adventitious agents
Lower production cost
All marketed products are for IV use
!
IV delivery results in only ~2% of the protein reaching the lungs
PRX-107 goal: Inhalation delivery
!
!
Directly to the lungs
Better patient quality of life
115. Biological Activity – IC50
% of control activity
100
PRX-107
Commercial
80
60
40
20
0
0.01
0.1
1
10
100
[AAT] (ug/ml)
Similar amounts of PRX-107 and commercial AAT reagent
needed to achieve 50% inhibition of Elastase
116. In vivo Induced Emphysema Model
Lm(
healthy(
Lm(–(mean(linear(intercept((diameter)(
VL(–(lung(volume(
Sa(–(alveolar(surface(
Lm(
emphysematous(
117. PRX-107 In-vivo Efficacy Study in Rats
Group ID
(10 rats/group)
AAT
(10mg/kg)
Elastase dose
(U/g BW)
1
2
3
4
5
mock
PRX-107
mock
PRX-107
Commercial
0
0
0.25
0.25
0.25
Post-mortem analyses:
Lung
collection and
fixation
Lung slide
preparation
Stereometry
(quantitative
histology)
118. Efficacy In-vivo Study Results
!
!
!
Experiment - AAT Ability to rescue Elastase induced lung damage
Comparison between PRX-107 and AAT (plasma derived reagent)
The extent of the damage is measured by the mean alveolar volume
p < 0.0001 (n=10)
4.5
p"<"0.0001"(n=10)"
4.0
mean alveolar volume
p < 0.0001 (n=10)
p < 0.0001 (n=10)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Induced Damage
-
-
elastase
elastase
elastase
Treatment
-
PRX-107
-
PRX-107
Commercial
