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 C-1

Rejena
(Sodium Hyaluronate
Ophthalmic Solution, 0.18%)
United States Food and Drug Administration
Dermatologic and Ophthalmic Drugs
Advisory Committee
June 26, 2009
 C-2

Rejena
(Sodium Hyaluronate
Ophthalmic Solution, 0.18%)
Safety and Efficacy Review
River Plate Biotechnology, Inc.
Presenters:
Russell Ellison, MD
Roger Vogel, MD
 C-3

Sponsor Attendees
y Russell Ellison, MD, MS - Chairman
y Luis Molina, PhD - President/CSO
y Terry W. Laliberte, BS - Director of Development
y Roger Vogel, MD - Medical Monitor, Consultant
y Christine Miller, PharmD - Regulatory, Consultant
y Gary Koch, PhD - Statistics, Consultant
y Steve Crockett, PhD - Statistics, Consultant
 C-4

River Plate Biotechnology Presentation

Introduction Russell Ellison, MD

Rejena Efficacy Roger Vogel, MD

and Safety
 C-5

Dry Eye Disease Affects

5 Million Patients
In the United States, an estimated 3.2 million
women and 1.7 million men, a total of 4.9
million people are affected by dry eye disease.
(Tsubota, 1992; Craig, 1997)

Dry eye symptoms (dry-, gritty-, or scratchy-

feeling eyes, itching, redness, blurred vision,
and sensation of foreign body in the eye) are
the leading cause of ophthalmology visits.
 C-6

Efficacy Criteria for the

Treatment of Dry Eye Disease
y Significant improvement in an objective sign of dry eye
disease (ie, does drug have an effect on the disease)
For example:
Corneal erosion (fluorescein or lissamine green
staining)
Tear break up time (TBUT)
Tear production (Schirmers test)
and
y Significant improvement in a symptom of dry eye (PRO)
(ie, does drug have a clinical benefit perceived by patient)

Reasonable, pragmatic, and rational criteria but very hard to meet

 C-7

Dry Eye Study Challenges

y Variability of assessments
y Effectiveness of placebo or vehicle
y Signs and symptoms are poorly correlated
y Time course of signs and symptoms
resolution can be different
 C-8

Current Therapies
Many products have been tested in clinical trials, but
y No prescription product is currently approved for the treatment of
the signs and symptoms of dry eye disease
y Artificial tears (OTC)
Provide only transient relief and are formulated with
preservatives, which are irritants
Certain products can aggravate the condition; tears with
decongestants/antihistamines can decrease production of the
tear film
y Cyclosporine ophthalmic emulsion (Restasis)
Topical immunosuppressant approved to increase tear
production in patients whose tear production is presumed to be
suppressed due to ocular inflammation associated with KCS
Slow onset of action (months)
 C-9

Rejena - Sodium Hyaluronate

Ophthalmic Solution, 0.18%
y Preservative free
y Marketed in Europe and parts of Asia since
January 1998 in 27 countries
Vismed
Vislube
Hylovis
y ~ 9.5 million boxes (20 units/box) sold
through Dec 31, 2008
 C-10

Rejena Clinical Development

Overview
y 967 subjects in 10 clinical trials with Rejenaa
8 supportive clinical studies
5 studies against artificial tear products,
all showing improvement over
comparator
3 open label studies
2 adequate and well-controlled studies
Baudouin 2005 study
RP-001 study
a There are several earlier studies using different formulations.
 C-11

Baudouin 2005 Clinical Study

Report Errata
y Sponsor recalculated all endpoints presented in briefing
document resolving inconsistencies identified by FDA analysis
y Transcription errors from analysis files into summary tables
appear in CSR and were carried forward into briefing document
Primary endpoint: VAS summed score
Descriptive statistics transcribed from PP population
instead of ITT/LOCF
P-value generated from ITT/LOCF as specified
Secondary endpoints: Lissamine green staining and
symptom frequency score
P-values actually transcribed from analysis of absolute
change from baseline whereas protocol specified
percent change from baseline
 Rejena Clinical Development C-12

Hypothesis Generation and Confirmation,

and Replication
Hypothesis generation
y Early studies positive for signs and/or symptoms vs
artificial tears
Rolando 1994
Rapisarda 1994
Baudouin 2001
y Adequate and well-controlled study: Baudouin 2005
Did not meet primary endpoints
2 secondary endpoints showed an effect - selected for
the design and powering of confirmatory study (RP-001)
Lissamine green staining (sign)
Symptom frequency score (symptom)
 C-13

Rejena Clinical Development

y Hypothesis: Rejena is superior to vehicle (gold
standard for comparator) for improvement in a
sign (lissamine green staining) and a symptom
(global symptom frequency score) in the same
study
y Hypothesis confirmation: RP-001
Rejena was statistically significantly
superior to vehicle for these 2 co-primary
endpoints
y Replication: analysis of Baudouin 2005 using
RP-001 analytical methodology
 C-14

Efficacy and Safety of Rejena

(Sodium Hyaluronate
Ophthalmic Solution 0.18%)
Roger Vogel, MD
 C-15

Efficacy and Safety of Rejena

y Sodium hyaluronate
y Efficacy endpoints
y Dose selection rationale
y Baudouin 2005
y RP-001
y Integrated analysis
y Safety results
y Summary and conclusions
 C-16

Sodium Hyaluronate
y Ubiquitous molecule
Occurs naturally in all vertebrates in the
vitreous body of the eye, the extracellular
matrix of the skin, and synovial fluid
y Viscoelastic properties similar to natural tears
y Rejena sodium hyaluronate is obtained by
bacterial fermentation
High degree of purity
No appreciable toxicity or
immunosensitizing activity
 C-17

Sodium Hyaluronate
y Extremely wide safety margin
y Sodium hyaluronate (SH) used
Intraocularly as a viscoelastic during
cataract extraction to protect corneal
endothelium
Intra-articularly as injections for synovial
fluid replacement
As a dermal filler
 C-18

Sodium Hyaluronate
Ophthalmic Solution 0.18%

Under shear stress (during blinks) At rest between blinks

Solution is elastic, nonviscous, Solution is less elastic,

and spreads easily over the more viscous
ocular surface
 C-19

Actions of Sodium Hyaluronate

Ophthalmic Solution 0.18%
y Stabilizes the precorneal tear film
y Restores tear film and ocular surface
homeostatic states
y Allows recovery of goblet cells
y Entraps water and hydrates and lubricates
the ocular surface
As a result improves ocular comfort
and quality of life
 C-20

Efficacy and Safety of Rejena

y Sodium hyaluronate
y Efficacy endpoints
y Dose selection rationale
y Baudouin 2005
y RP-001
y Integrated analysis
y Safety results
y Summary and conclusions
 6/19 3:30 pm
C-21

Dry Eye Efficacy Endpoints - Signs

y Tear film break-up time
Decreased tear production
(TBUT)
Tear film instability
Hyperosmolarity
y Time required for the
eye to lose its wet
surface after a blink
Inflammatory Conjunctival
suppression & corneal y Normal eye: 10 to 12
of tear epithelial
secretion damage seconds
y Dry eye: Less than
10 seconds
Decreased
Loss of
mucin
goblet cells
production
 C-22

Dry Eye Efficacy Endpoints - Signs

y Corneal and conjunctival
staining
Decreased tear production
Tear film instability Fluorescein (corneal)
Hyperosmolarity stains the area between
surface cells (extent to
which epithelial cells are
Inflammatory Conjunctival drying and shrinking)
suppression & corneal
of tear epithelial Lissamine green (corneal
secretion damage and conjunctival) stains
keratinized and
devitalized epithelial
Decreased cells, goblet cells,
Loss of
mucin
goblet cells mucous, and epithelial
production
filaments (more sensitive
dye than fluorescein)
 C-23

Rejena Clinical Studies

Efficacy Endpoints - Signs
y 3 dose-finding studies used TBUT
y Baudouin 2005
Primary endpoint: fluorescein staining
Secondary endpoints: lissamine green
staining (also TBUT, Schirmers test, tear
prism height)
y RP-001
Primary endpoint: lissamine green staining
 C-24

Rejena Clinical Studies

Efficacy Endpoints - Symptoms

Symptoms assessed Scoring

y Dryness y Symptom intensity
y Soreness y Symptom frequency
y Scratchiness y Composite symptom
y Grittiness y Global symptom
y Burning frequency
 C-25

Efficacy and Safety of Rejena

y Sodium hyaluronate
y Efficacy endpoints
y Dose selection rationale
y Baudouin 2005
y RP-001
y Integrated analysis
y Safety results
y Summary and conclusions
 C-26

Dose Selection Rationale: Concentration

y 3 clinical dose-finding studies
Effects of sodium hyaluronate in solutions
ranging from 0% (vehicle/placebo) to 0.3%
on the prolongation of TBUT
Higher concentrations more effective than
lower concentrations
y 0.18% concentration was highest
concentration that could be feasibly
formulated
 C-27

Clinical Program Objective

y Demonstrate that sodium hyaluronate
ophthalmic solution 0.18% is safe and
effective for the treatment of the signs and
symptoms of dry eye disease
 C-28

Rejena Clinical Development

y Hypothesis generating
Early studiesa
Rapisarda 1994, Rolando 1994, and
Baudouin 2001 all showed differences in
signs and symptoms vs artificial tears
Baudouin 2005

a2 additional phase 4 studies with similar results,

Prabhasawat 2007 and Johnson 2008.
 C-29

Efficacy and Safety of Rejena

y Sodium hyaluronate
y Efficacy endpoints
y Dose selection rationale
y Baudouin 2005
y RP-001
y Integrated analysis
y Safety results
y Summary and conclusions
 C-30

Hypothesis Generating:
Baudouin 2005
y Rejena (n = 74) vs 0.9% saline (n = 77)
y Subjects with 3 months history of bilateral
moderate dry eye disease or moderate dry eye
disease due to Sjgrens syndrome
y Primary endpoints
Objective endpoint: Percent change from baseline of
the fluorescein staining summed score (average of the
sum of the total scores over both eyes) at Day 28
Subjective endpoint: Percent change from baseline of
the VAS summed intensity score (average of the sum
of five VAS symptom scales for soreness,
scratchiness, dryness, grittiness, and burning) at
Day 28
 C-31

Baudouin 2005
Study Conduct
y Sponsored by TRB Chemedica, SA
(manufacturer in Europe)
y Study management and monitoring by
Clirophtha, an experienced CRO in Europe
100% source document validation
Study conducted under GCP according to ICH
y Experienced, well-published, principal
investigator (who served as a principal
investigator for Restasis development)
 C-32

Baudouin 2005
Data Management & Statistical Analysis

y Data entry and management and statistical

analysis performed by MD Research (CRO in
Germany)
y Data listings and statistical tables and figures
were forwarded to the EU sponsor, TRB
Chemedica, SA, who prepared the clinical study
report
y Abstract and poster authored by Dr. Baudouin,
based on the CSR, presented in ARVO 2004
 C-33

Baudouin 2005 - Primary Endpoints

(% Change From Baseline)
Measure Visit Study drug Mean (SD) 1-sided P-value
Fluorescein Day 7 Active 27.03 (38.36) 0.0546
staining of Saline 20.19 (38.26)
cornea
Day 28 Active 43.44 (47.21) 0.0279
Saline 30.21 (44.75)
VAS summed Day 7 Active 21.41 (32.75) 0.0295a
score Saline 12.34 (33.55)
Day 28 Active 35.95 (31.68) 0.1333a
Saline 26.80 (43.17)

ITT = Intent to treat; SD = Standard deviation; VAS = Visual analogue scale

a
Calculated in ITT population, LOCF (correct analysis).
 C-34
Hypothesis Generating: Baudouin 2005
Secondary Endpoints
(% Change from Baseline, 1-sided P-values)
P-value per
P-value SAP (recalculated
Measure Visit Study drug Mean (SD)b CSRa by Sponsor)b
Lissamine Day 7 Rejena 28.32 (34.48) 0.0013 0.0059
green Saline 13.62 (41.81)
staining
Day 28 Rejena 41.18 (31.24) 0.0007 0.0031
Saline 22.97 (39.60)
Symptom Day 7 Rejena 23.28 (33.03) 0.0117 0.0141
frequency Saline 13.50 (30.60)
score
Day 28 Rejena 34.86 (26.38) 0.0035 0.0093
Saline 22.83 (34.68)

a
Calculated from absolute change from baseline (transcription error).
b
Calculated from percent change from baseline.
 C-35

Baudouin 2005
Summary
y Baudouin 2005 showed positive results in
secondary endpoint for sign (lissamine green
staining) and symptom (symptom frequency
score) at Days 7 and 28
y On agreement with FDA, Study RP-001
adopted a similar study design and these
2 endpoints as co-primary
 C-36

Efficacy and Safety of Rejena

y Sodium hyaluronate
y Efficacy endpoints
y Dose selection rationale
y Baudouin 2005
y RP-001
y Integrated analysis
y Safety results
y Summary and conclusions
 C-37

Hypothesis Confirmation:
RP-001
y Hypothesis: Rejena is significantly superior to
vehicle for improvement in a sign and a symptom
in the same study
y Agreed with FDA under a Special Protocol
Assessment (SPA)
Sign: absolute change from baseline in lissamine
green staining (co-primary endpoint)
Symptom: absolute change from baseline in global
symptom frequency score (co-primary endpoint)
Wilcoxon rank sum test primary analysis method:
t-test secondary
= 0.025 1-sided ( = 0.05 2-sided)
 C-38

Hypothesis Confirmation: RP-001

Sample Size Calculation
y Rejena (n = 221) vs vehicle (n = 223)
RP-001 sample size based on 2-sided = 0.05
Used difference in means and SD based upon
subjects in Baudouin 2005 matching the entry
criteria for RP-001 to determine the sample size
for a power of 80%
Prespecified masked interim analysis showed
increased variance requiring sample size
increase from 300 to 440
 C-39

Inclusion Criteria
RP-001
y Subjects with 3 months history of diagnosed KCS
or dry eye due to Sjgrens syndrome
y Experienced in the same eye:
At least 2 symptoms of dry eye
Rated as 2 (often)
Scored as 50 mm on VAS intensity
Objective parameters of dry eye:
Corneal fluorescein staining total score of 3
Lissamine green staining total score of 3
 RP-001 C-40

Change From Baseline at Day 7

Primary Endpoints (ITT, LOCF)
2-sided P-values
Wilcoxon
Primary rank sum Students
endpoint Visit Study drug Mean (SD) testa van Elteren t-test
Lissamine Day 0 Rejena 5.71 (2.42)
green Vehicle 5.52 (2.36)
staining
Day 7 Rejena 1.1 (2.01) 0.0502 0.0354 0.0291
Vehicle 0.7 (1.79)
Global Day 0 Rejena 8.33 (2.23)
symptom Vehicle 8.22 (2.47)
frequency
Day 7 Rejena 1.7 (2.78) 0.0497 0.0451 0.0173
Vehicle 1.1 (2.62)

a Primary analytical method.

 C-41

RP-001
Global Impact of Dry Eye on Daily Life

% reporting improvement by
Study drug 1 or more grades at Day 7
Rejena 40.3%
Vehicle 30.4%

Scale is 0 to 3, absent to severe

 C-42

Efficacy and Safety of Rejena

y Sodium hyaluronate
y Efficacy endpoints
y Dose selection rationale
y Baudouin 2005
y RP-001
y Integrated analysis
y Safety results
y Summary and conclusions
 C-43

Replication: Steps
1. Baudouin 2005 is supportive of efficacy
y Results suitable for integrated analysis (side-by-side
comparison)
2. RP-001 confirmed results from Baudouin 2005
y Efficacy demonstrated for same selected sign and symptom
as those achieved in Baudouin 2005
3. Replication
y Side-by-side comparative analysis was conducted to
evaluate how Baudouin 2005 and RP-001 replicate each
other using RP-001 analytical methodology agreed upon
with FDA
 C-44

RP-001 Endpoints Used for

Comparative Analysis
y Absolute change from baseline in lissamine
green staining score
y Absolute change from baseline in global
symptom frequency score
y Primary endpoint: Day 7
RP-001 time points: Days 7 and 14
Baudouin 2005 time points: Days 7 and 28
 C-45

RP-001 Statistical Methodology for

Comparative Analysis
Reanalysis of Baudouin 2005 using analytical
methodology for RP-001 that was agreed upon with FDA
y Selected study eye for lissamine green staining score
Eye with lower baseline Schirmers I test score
y ITT population (LOCF) defined as all randomized
subjects: baseline observation carried forward
y Wilcoxon rank sum test (primary)
y Students t-test (supportive)
 C-46

Efficacy: Lissamine Green Staining Score

Change from Baseline (ITT, LOCF)
Baudouin 2005 Study RP-001
2-sided P-values 2-sided P-values
Wilcoxon Wilcoxon
Visit Study drug Mean (SD) rank sum t-test Mean (SD) rank sum t-test
Day 0 Rejena 4.03 (2.12) 5.71 (2.42)
Control 3.83 (2.28) 5.52 (2.36)

Day 7 Rejena 1.1 (1.51) 0.0157 0.0237 1.1 (2.01) 0.0502 0.0291
Control 0.6 (1.38) 0.7 (1.79)
 C-47

Efficacy: Global Symptom Frequency

Scores Change from Baseline (ITT, LOCF)
Baudouin 2005 Study RP-001
2-sided P-values 2-sided P-values
Wilcoxon Wilcoxon
Visit Study drug Mean (SD) rank sum t-test Mean (SD) rank sum t-test
Day 0 Rejena 8.35 (2.27) 8.33 (2.23)
Control 8.04 (1.76) 8.22 (2.47)

Day 7 Rejena 2.0 (2.44) 0.0372 0.0470 1.7 (2.78) 0.0497 0.0173
Control 1.2 (2.58) 1.1 (2.62)
 C-48

Phase 3 Efficacy Analysis

Conclusion
y Hypothesis generated: early studies and
Baudouin 2005 provided basis for generating
hypothesis that Rejena was superior to
vehicle in reducing lissamine green staining
and global symptom frequency score
y Hypothesis confirmed: RP-001 statistically
significant for these 2 co-primary endpoints
y Replication achieved: analysis of Baudouin
2005 with RP-001 analytical methodology
 C-49

Summary of Efficacy
y 10 clinical studies assessed efficacy (957 subjects)
for up to 2 months and were consistently positive
5 studies showed improvement over artificial tears
3 exploratory studies show improvement in ocular
surface disease
2 Phase 3 studies: reduction in lissamine green
staining and improvement in global symptom
frequency score versus both saline and vehicle

Rejena is effective for the treatment of the

signs and symptoms of dry eye
 C-50

Efficacy and Safety of Rejena

y Sodium hyaluronate
y Efficacy endpoints
y Dose selection rationale
y Baudouin 2005
y RP-001
y Integrated analysis
y Safety results
y Summary and conclusions
 C-51

Safety Results
y 3 studies form basis of safety profile (n = 305)
Phase 3 studies (Baudouin 2005, RP-001)
Phase 2 study (Baudouin 2001)
y Safety evaluations included
Slit lamp examination
Best-corrected visual acuity (BCVA)
Ophthalmic examination
Collection of AEs
Intraocular pressure (RP-001)
 C-52

Safety Studies

Baudouin 2001 Baudouin 2005 RP-001

SH ophthalmic Carboxymethyl- Saline 0.9% Vehicle
solution 0.18% cellulose 1%
compared with
Dose regimen 1 drop 3 times/ 1 drop at least 3 1 to 2 drops at
day or as and up to 8 least 3 and up to
needed, for up to times/day or as 6 times/day or as
56 days needed, for up to needed, for up to
28 days 14 days
Average 3.8 daily 3.7 daily 3.7 units used
exposure instillations instillations daily
 C-53

Adverse Events Overview

Patients, n (%)
Baudouin 2005 RP-001
Rejena Saline Rejena Vehicle
N = 74 N = 77 N = 221 N = 222
Any AE 10 (13.5) 9 (11.7) 57 (25.8) 48 (21.6)
Any SAE 0 0 1 (0.5) 1 (0.5)
AE leading to 1 (1.4) 2 (2.6) 2 (0.9) 1 (0.5)
withdrawal
Death 0 0 0 0

y No AEs were reported in Baudouin 2001 (N = 10)

y No ocular SAEs reported in the 3 safety studies
 C-54

Ocular Treatment-Emergent AEs in

1% of Subjects
Patients, n (%)
Baudouin 2005 RP-001
Rejena Saline Rejena Vehicle
Adverse event N = 74 N = 77 N = 221 N = 222
Dry eyea 0 0 18 (8.1) 14 (6.3)
Eye paina 0 0 13 (5.9) 7 (3.2)
Eye irritationa 2 (2.7) 0 4 (1.8) 5 (2.3)
Foreign body sensation in eyes 0 0 5 (2.3) 7 (3.2)
Visual acuity reduced 0 0 4 (1.8) 6 (2.7)
Eye pruritis 0 0 4 (1.8) 4 (1.8)
Vision blurreda 0 0 4 (1.8) 0
Ocular hyperaemia 0 0 3 (1.4) 3 (1.4)
Eyelid margin crustinga 0 0 3 (1.4) 1 (0.5)

a
TEAEs that occurred at a greater frequency in Rejena-treated subjects.
 C-55

Worldwide Marketing Experience

y Approximately 9.5 million boxes (20 units
each) sold (Jan 1998 to Dec 31, 2008)
Estimated 2.8 million patients have used
Rejena
y 39 reports of post-marketing medical
complaints reported (through 30 April 2009)
 C-56

Spontaneous Complaint Reports

Marketed Product Surveillance
Adverse event Total complaints, n
Burning sensation 16
Hypersensitivity/intolerance 13
Eye reddening 5
Foreign body sensation 1
Eye injurya 1
Local swelling 1
Blurred vision 1
Other 1
Total 39
a
This complaint was due to incorrect handling of the delivery device.
 C-57

Summary of Clinical Safety

Rejena has an acceptable safety profile for the
treatment of the signs and symptoms of dry eye
y No ocular SAEs
y Low incidence of AEs
14.4% of subjects experienced 1 AE
Most were mild in intensity
y Ocular TEAEs
No ocular AE occurred at a frequency greater
than 8.1%
Only 3 Rejena-treated subjects withdrew due
to an ocular adverse event
 C-58

Efficacy and Safety of Rejena

y Sodium hyaluronate
y Efficacy endpoints
y Dose selection rationale
y Baudouin 2005
y RP-001
y Integrated analysis
y Safety results
y Summary and conclusions
 C-59

Summary and Conclusions

y RP-001 (Rejena/vehicle) confirms and
replicates positive endpoints in Baudouin 2005
(Rejena/saline)
y Rejena is currently widely marketed outside the
US; the safety profile is well established
y Clinical trial data demonstrate that Rejena is
safe and well tolerated

Clinical data demonstrate that Rejena is safe and

effective for the treatment of dry eye disease