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A Phase 3 Multi-Center, Randomized Controlled Evaluation of the Efficacy, Safety
and Tolerability of Isunakinra in Subjects with Moderate to Severe Dry Eye Disease
Poster #2874-A0083
Karen L. Tubridy, PharmD 1, Michael H. Goldstein, MD1,2, Marianne Magill1
Eleven Biotherapeutics, Cambridge, MA, United States, 2Ophthalmology, New England Eye Center/Tufts Medical Center, Boston, MA, United States.
1
ABSTRACT
Purpose: Isunakinra (EBI-005) is a novel topical
interleukin-1 receptor inhibitor optimized for
topical treatment of ocular surface diseases such
as dry eye disease (DED) and allergic
conjunctivitis (AC). The purpose of this Phase 3
study was to evaluate the efficacy, safety, and
tolerability of isunakinra in subjects with
moderate to severe dry eye.
Results: Of the 669 subjects, 334 received
vehicle-control and 335 received isunakinra;
92% completed the study. There were 33 drop
outs in the isunakinra group and 20 in the
vehicle control group. Baseline demographics of
the two groups were similar. Isunakinra was
generally safe and well tolerated in this study.
No treatment related serious adverse events
were reported. There was no statistically
significant difference between the isunakinra
treated group and the vehicle control group for
the co-primary endpoints. Subjects in both the
isunakinra and vehicle treatment groups
showed statistically significant improvement
from baseline on the co-primary endpoints as
early as one week.
Conclusions: In this study, isunakinra was
generally safe and well tolerated and had a
similar adverse event profile to vehicle and to
earlier studies conducted with isunakinra.
Isunakinra showed a statistically significant
improvement compared to baseline for signs
and symptoms of DED over the 12 week
treatment period, however there was no
statistically significant difference between the
isunakinra and vehicle-control subjects for the
study endpoints.
5 to 7 Days
Prior to Day 1
Screening
•
•
•
•
•
•
Week 6
Week 9
Week 12
Have a history of dry eye disease (DED) in
both eyes for at least 6 months
Subjects randomized
•
Subjects who completed study
314 (94)
Reason for subject discontinuation
At randomization (Visit 2):
– Have a total OSDI score of ≥19 and <50
669 (100)
302 (90)
Parameter
Vehicle
(N=334)
Isunakinra
(N=335)
Age (years), Mean (SD)
60 (13.64)
60 (13.22)
274 (82%)
277 (83%)
Female
616 (92)
– Have complied with the 1-week run-in period
No prior use of an IL-1 blocker
20 (6)
33 (10)
53 (8)
Withdrawal by subject
8 (2)
16 (5)
24 (4)
Adverse event
7 (2)
11 (3)
18 (3)
Protocol violation
– Have a total corneal fluorescein staining score of ≥5
(NEI scale) in the same qualifying eye as in Visit 1
and CFS <15 in at least one eye
•
335 (100)
Total
N (%)
Male
– Continue to meet inclusion/exclusion criteria
Objectives:
• Co-Primary: CFS; pain or
soreness by OSDI
• Secondary: Total OSDI;
CFS regions
• Safety, tolerability, and
immunogenicity
334 (100)
Isunakinra
N (%)
Interleukin-1 (IL-1) is a key mediator of
inflammation in many organ systems in
animal and human studies (Dinarello 2001)
and critical in ocular surface inflammation
(Barbarino 2005; Chen 2010; Okanobo
2012; Zhu 2009; Bletsa 2009).
•
There was a statistically significant difference from
baseline to week 12 within each treatment group for
the co-primary endpoints of CFS and the OSDI pain
question
•
Isunakinra was safe and well tolerated in this study
and had a similar adverse event profile to prior
studies in dry eye.
1 (0.3)
0 (0)
1 (0.1)
Physician decision
0 (0)
1 (0.3)
1 (0.1)
Lost to follow-up
4 (1)
3 (1)
7 (1)
Other
0 (0)
2 (1)
60 (18%)
58 (17%)
•
The majority of patients improved from baseline
while on treatment and were able to remain on
treatment over the 12 weeks regardless of which
treatment arm they participated in.
2 (0.3)
White
271 (81%)
279 (83%)
Black or African American
34 (10%)
30 (9%)
Asian
17 (5%)
16 (5%)
•
We believe there may be an opportunity to look at
longer term treatment with isunakinra to better
understand how the disease severity changes and
responds to treatment over time. In addition, we
believe that looking at specific patient populations
and different metrics will continue to be important in
the treatment of dry eye because of the
heterogeneity of the disease.
Other
12 (4%)
10 (10%)
OSDI painful or sore eye score,
Mean (SD)
1.3 (0.8)
1.2 (0.8)
Total OSDI score,
Mean (SD)
35 (8.9)
35 (8.6)
Total CFS (NEI score, study eye),
Mean (SD)
8.6 (2.3)
8.5 (2.4)
REFERENCES
Barbarino S, Shen LL, Chen L, Rashid S, Rolando M, Dana MR. The
controlled-environment chamber: a new mouse model of dry eye. Invest
Ophthalmol Vis Sci 2005 46:2766-2771.
Assessment of Genotyping
Summary of Subjects with Treatment Emergent
Adverse Events (TEAE)
92% of subjects completed the study
•
96% overall compliance with study treatment
Vehicle
(N=334)
Isunakinra showed no statistically significant difference from placebo in the
co-primary endpoints of total CFS and the pain or sore eye question of the OSDI at
Week 12
Any TEAE
Severe TEAE
There was a statistically significant difference (p<0.001) in the change from baseline to
week 12 for the co-primary endpoints within treatment groups
•
Isunakinra
(N=335)
Ocular
Non-ocular
Ocular
Non-ocular
58 (17%)
82 (25%)
68 (20)
77 (23%)
3 (1%)
5 (2%)
0 (0%)
5 (2%)
Any study drug
related TEAE
23 (7%)
11 (3%)
38 (11%)
7 (2%)
Isunakinra was safe and well tolerated and the frequency of events was similar
between the two treatment groups
TEAE leading to study
drug discontinuation
1 (0.3%)
1 (0.3%)
4 (1%)
0 (0%)
•
The most frequently reported ocular adverse event was eye irritation (4.5%
placebo/4.5% isunakinra)
TEAE leading to study
termination
3 (1%)
3 (1%)
5 (2%)
1 (0.3%)
•
The most frequently reported non-ocular adverse event was pruritus (1.5%
placebo/2.7% isunakinra)
Any TESAE
0 (0%)
4 (1%)
0 (0%)
2 (0.6%)
Any study drug related
TESAE
0 (0%)
0 (0%)
0 (0%)
0 (0%)
Outcome of death
0 (0%)
•
No difference was seen compared to vehicle-control
in the co-primary endpoints of mean change from
baseline at week 12 for total corneal fluorescein
staining score (CFS, sign) or the OSDI pain question
(symptom).
Race
CFS= Corneal Fluorescein Staining
OSDI= Ocular Surface Disease Index
•
•
•
Gender
Have ongoing DED, in the same eye or both eyes, as
defined by the following criteria at screening (Visit 1):
– A Total Corneal Fluorescein Staining Score of ≥6
(NEI scale) and <15
Off Treatment
Baseline Demographics
Vehicle
N (%)
– An OSDI score of ≥23 and ≤75 and have responded
to the painful or sore eye question of the OSDI
21 Days
Follow Up
Week 15
FOLLOW UP
Randomization
18 years of age and older that have given written
voluntary consent
Results
Symptoms of DED are variable and include
a dry eye sensation, foreign body
sensation, irritation, burning, tearing,
ocular pain, and itching among others.
•
•
•
0 (0%)
0 (0%)
•
Bletsa A, Fristad I, Berggreen E. Sensory pulpal nerve fibres and trigeminal
ganglion neurons express IL-1RI: A potential mechanism for development of
inflammatory hyperalgesia. Int Endod J 2009; 42(11): 978-86.
An exploration of genotyping was done to assess clinical
relevance of IL-1 genotyping in ocular surface diseases.
Chen YT, Nikulina K, Lazarev S, et al.
Interluekin-1 as a Phenotypic
immunomodulator in keratinizing squamous metaplasia of the ocular surface in
Sjögren’s Syndrome. Am J Pathol 2010 177:1333-1343.
Interleukin Genetics (ILG) has developed a DNA based
assay system to identify genetic haplotype pairs associated
with the levels of IL-1β that are produced in response to
certain stimuli.
Haplotype pairs defined by SNPs in the IL-1 α and IL-1 β are
grouped into predefined patterns that reflect IL-1 expression
(Groups A, B, and C).
Genotyping performed in CLIA certified laboratory at
Interleukin Genetics, Inc. (Waltham, MA) using pre-defined
proprietary patterns of IL-1 gene variations.
There are distinct groupings that could be explored further
based on these genoptype findings.
Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory
diseases. Blood 2001 117:3720-3732.
International Dry Eye Workshop (DEWS) Report. Ocular surface 2007; 5: 65-204.
Okanobo A, Chauhan S, Dastjerdi M, et al. Efficacy of topical blockade of
Interleukin-1 in experimental dry eye disease. Am J Ophthalmol 2012; 154:
63-71.
Zhu L, Shen J, Shang C, Park CY, Kohanim S, Yew M, Parker JS, Chuck RS.
Inflammatory cytokine expression on the ocular surface in the botulism toxin B
induced murine dry eye model. Molecular Vision 2009 15:250-258.
ACKNOWLEDGMENTS
Arkansas – Laurie Barber
Arizona – Michael Depenbusch, Tariq Qamar
California – John Bacharach, Damian Goldberg, Barry Katzman,
Joseph Martel, Steven Rauchman, Kenneth Sall
0 (0%)
Colorado – Lance Forstot
Connecticut – Mark Milner
Change from Baseline for Total CFS at
each Visit (Standard Deviation)
A Phase 2 study of isunakinra in moderate
to severe dry eye subjects given 3x/day for
6 weeks demonstrated a benefit in the
signs and symptoms of dry eye particularly
those with a baseline OSDI<50.
0
1
3
6
9
12
Change from Baseline for OSDI Pain/Sore
Eye at each Visit (Standard Deviation)
15
0
-2
-3
-4
-5
-6
1
3
6
9
12
Florida – Victor Perez
Vehicle
EBI-005
Time (Weeks)
Differences between EBI-005 and vehicle were not statistically significant
Study Endpoints Based on Genotype Category
Ocular Treatment Emergent Adverse Events
15
Vehicle
(N=334)
EBI-005
(N=335)
Subjects with at least one TEAE
58 (17.4%)
68 (20.3%)
-0.6
Eye Irritation
15 (4.5%)
15 (4.5%)
-0.8
Eye Pain
8 (2.4%)
9 (2.7%)
Conjunctival Hyperemia
5 (1.5%)
9 (2.7%)
Eyelid Itching
5 (1.5%)
9 (2.7%)
0
0
-1
Proposed MOA:
EBI-005 BLOCKS
IL-1αand IL-1β
signaling on
inflammatory,
epithelial and
nerve cells
•
EVALUATION VISITS
•
Isunakinra: Designed and
Engineered to Block IL-1
•
Subject Disposition
STUDY RESULTS
Dry eye is a common clinical problem
affecting >7 million people (DEWS Report
2007).
Elevated levels of IL-1
α and IL-1β drive
ocular surface
cellular signaling
Week 3
Natural environmental study
Double masked, vehicle controlled
U.S. study, 650 subjects planned
Inclusion criteria
– CFS: Screen moderate-to-severe
– OSDI: Screen moderate-to-severe
• <50 at randomization
Rescue tear use restricted
CFS Change from Baseline
•
Week 1
RUN IN
BACKGROUND
•
Vehicle Control — 3 times daily
(~325 Subjects)
Day 1
•
3
Week
Follow
Up
Change from Baseline Pain Score of OSDI
Methods:
In
this
double-masked,
vehicle-controlled study, 669 subjects at 46 sites
in the USA with moderate to severe dry eye
disease (DED) were randomized to topical
isunakinra or vehicle control 1:1. Subjects were
treated 3x/day for 12 weeks. Co-primary efficacy
assessments were mean change from baseline
at week 12 for total corneal fluorescein staining
score (CFS, sign), and the OSDI pain question
(symptom). Safety and tolerability of isunakinra
were assessed.
Subject Population – Key Eligibility Criteria
Isunakinra 5 mg/ml — 3 times daily
(~325 Subjects)
1
Week
Run In
CONCLUSIONS/KEY MESSAGES
PATIENT DEMOGRAPHICS
STUDY DESIGN
-0.2
-0.4
-1
-1.2
-1.4
-1.6
Endpoint
Total CFS
Eye Pain
Vehicle
EBI-005
All other ocular AE’s below 2%
Time (Weeks)
Differences between EBI-005 and vehicle were not statistically significant
Presentation #2874 /Poster #A0083, ARVO Annual Meeting, Session #: 310, Session Title: Dry Eye II. The poster presentation describes a Phase 3 efficacy trial of isunakinra in moderate to severe dry eye disease., Tuesday, May 3, 2016 08:30 AM to 10:15 AM
OSDI
Group
N
Vehicle
CBL
Isunakinra
N
CBL
Georgia – Douglas Day
Indiana – Kathleen Kelley, Clark Springs, Steve Wilson
P-value
Illinois – Lisa Wohl
Kentucky – Paul Karpecki, John Meyer, Gregory Sulkowski
ITT
334
-2.7
335
-2.4
0.237
A
47
-2.6
54
-2.4
0.691
Massachusetts – Jack Greiner, Jason Rothman
B
28
-2.8
32
-3.6
0.325
Missouri – Gregg Berdy, Joseph Gira, Michael Korenfeld,
Mujitaba Qazi, Joseph Tauber
C
64
-3.3
46
-1.9
0.026
Nevada – Jack Abrams
ITT
334
-0.5
335
-0.3
0.173
New York – Paul Hartman, Jodi Luchs, Kathryn Richdale
A
47
-0.4
54
-0.5
0.495
North Carolina – Robert DaVanzo
Maine – Jean Tibbetts
Ohio – Marc Abrams
B
28
-0.5
32
-0.4
0.739
C
64
-0.6
46
-0.4
0.337
South Dakota – Monte Dirks
ITT
334
-7.9
335
-5.9
0.128
Tennessee – David Evans,
A
47
-4.1
54
-4.7
0.855
Texas – William Lipsky, Robert Rice, Jay Rubin, Da-Thuy Van,
Jeffrey Whisett
B
28
-7.7
32
-8.0
0.929
Virginia – John Sheppard
C
64
-10.5
46
-6.8
0.251
Presenting and corresponding author: Karen Tubridy, Pharm.D., Eleven Biotherapeutics
Pennsylvania – Deepinder Dhaliwal, David Silbert, Daniel Zimmer