Use Of Novel IL-1 Receptor Inhibitor (EBI-005) In The Treatment Of Patients with Moderate To Severe Dry Eye Disease
Poster #29
Michael Goldstein1,2, Jennifer Agahigian1, Gregory Zarbis-Papastoitsis1, Kathryn Golden1, Joseph Kovalchin1, Cameron Wheeler1, Siddhartha Chowdury1, Abbie Celniker1, Eric Furfine1
1
Eleven Biotherapeutics, Cambridge, MA, United States; 2Ophthalmology, New England Eye Center/Tufts Medical Center, Boston, MA, United States
BACKGROUND
Purpose: To describe the results of a
recently
completed
multi-center,
double-masked, environmental trial in
patients with moderate to severe dry
eye disease (DED) using a novel,
topically applied, IL-1 receptor inhibitor.
DED affects 20-25 million Americans (Market Scope, 2011). Although it is more common in
women and the elderly, it affects all ages and races. Symptoms of DED are variable and include
a sensation of dryness, presence of a foreign body, irritation, burning, tearing, pain, and
itching.
Methods:
In a double-masked,
placebo-controlled study, 74 subjects
were randomized to receive vehicle,
EBI-005 5 mg/mL or 20 mg/mL. The
study was powered to show a statistical
trend (P=0.2). Subjects were dosed
3x/day
for
six
weeks.
Safety
assessments included: adverse event
reporting,
complete
ophthalmic
examination, corneal esthesiometry,
corneal pachymetry, ocular surface
microbiology, and serum laboratory
testing. Assessments of biological
activity included: corneal fluorescein
staining (CFS), OSDI, SANDE, patient
individual symptom assessments,
global assessments (patients and
investigators) and rescue tear use.
Exploratory biomarker assessments
included impression cytology and tear
collection.
Results: Topical EBI-005 was safe and
well tolerated. There were no patient
drop-outs and no serious ocular or
non-ocular adverse events. EBI-005
significantly improved signs and
symptoms of DED compared to
baseline at week six by up to 30%
(p<0.001)
and
36%
(p<0.001)
respectively. In addition, there was a
statistical trend in improvement of
signs (CFS) and symptoms (OSDI,
individual
patient
symptom
assessments,
investigator
global
assessments) in the EBI-005 treated
group compared to the vehicle control.
Subjects who received vehicle control
used significantly more rescue tears
than those receiving EBI-005 (p=0.032).
Conclusions: Topical EBI-005 treatment
is a promising therapy for patients with
moderate to severe dry eye disease.
These results further validate the
importance of IL-1 blockade in DED and
support continued development of the
drug in a planned 12-week study
designed to further characterize the
safety and efficacy of EBI-005 in
patients with DED.
Commercial Relationships: Dr. Goldstein is a
consultant to Eleven Biotherapeutics. Mr. Chowdury is
a contractor to Eleven Biotherapeutics. All other
authors are employees of Eleven Biotherapeutics.
CONCLUSIONS
RESULTS
EBI-005:
Development of a novel,
topical blocker of IL-1 to treat ocular
surface disease
IL-1 is the master regulator of
ocular inflammation:
• IL-1 is elevated in multiple
ocular clinical conditions: dry
eye,
retinal
angiogenesis,
uveitis, ocular allergy, corneal
transplant rejection.
• IL-1 promotes the transcription
of
a
wide
array
of
pro-inflammatory
factors
including LFA-1 and VEGF.
IL-1Ra
site A
• IL-1 receptor blockers effect inflammation at two critical points in DED: initiation and maintenance of the
TH17 inflammatory response (Chauhan and Dana
2009).
• IL-1 receptors are found on neurons. IL-1 activation of
neurons induces hyperalgesia, a form of neuropathic
pain (nociception) (Bletsa 2009).
• In a clinical study reported by Amparo et. al., a topical
IL-1 blocker improved the signs and symptoms of dry
eye in human subjects (Amparo 2013).
• IL-1α and IL-1β are upregulated
in the human disease and
mouse models (Solomon, et al
2001; Zhu, et al. 2009).
Figure 1
EBI-005 Targeted Therapy for DED
Lachrymal gland
dysfunction
• IL-1 receptor KO mice show
reduced disease (Chen, 2010).
• An IL-1 receptor antagonist
blocked corneal fluorescein
staining in mouse models
(Okanobo et al. 2010).
Environment
Meibomian gland
dysfunction
Desiccating stress
Inflammatory
response
Neural
response
Local
IL-1
Chronic inflammation
SIGN
(CFS by NEI
0-15)
Magnitude
of Response
Chronic hyperalgesia
(mean)
33%
Improvement
(3 points)
SIGN
(CFS by NEI
0-15)
BL OSDI<50
SYMPTOM
(OSDI Total,
0-100)
39%
36%
Improvement
(3.5 points)
Improvement
(18 points)
SYMPTOM
(OSDI Total,
0-100)
BL OSDI <50
• EBI-005 showed a large magnitude of effect with rapid therapeutic onset.
SYMPTOM SYMPTOM
(OSDI Pain, (OSDI Pain,
0-4)
0-4)
BL OSDI <50
46%
41%
Improvement
(13 points)
61%
Improvement
(0.9 points)
Improvement
(0.9 points)
IL-1β
site B
Corneal Fluorescein Staining in subjects with
starting baseline OSDI “symptom scores” of <50
Maximum Potency
Topical EBI-005 was shown in an earlier
study to be safe and well tolerated when
administered
to
healthy
human
volunteers.
EBI-005 demonstrated a strong
effect on Total CFS compared with
vehicle control both for the entire
study group and for the population
with a baseline OSDI less than 50.
This effect was seen as early as
week 2 and continued to increase
until the end of dosing at week 6.
• EBI-005 reduced the need for rescue artificial tears.
• EBI-005 is efficacious in patients across the full range of disease severity.
• EBI-005 has been safe and well tolerated in all studies conducted to date.
These results support the upcoming twelve-week multi-center pivotal study designed to assess
the safety and biological activity of EBI-005 in patients with DED. They also provide
encouraging data to support investigation of EBI-005 for additional ocular surface conditions
mediated or promoted by IL-1 such as ocular allergy.
Rescue artificial tear use was significantly lower in the
drug treated group than in those subject who received
vehicle control.
CFS BL OSDI <50
To address the needs of patients with
DED, Eleven Biotherapeutics, Inc. has
developed
EBI-005,
a
genetically
engineered blocker of the IL-1 receptor
that is a chimera of sequences of IL-1B
and IL-1Ra (Figure 2). EBI-005 is a pure
antagonist. EBI-005 has been formulated
in a proprietary, preservative free vehicle
with optimal properties for the treatment
of ocular surface diseases. EBI-005 is
much more potent than anakinra, has
optimal dosing properties and room
temperature stability for ease of
handling.
• EBI-005 has a DUAL action to treat the inflammation and pain/discomfort associated
with DED.
• Mechanism has been validated in two independent clinical dry eye studies.
Summary of magnitude of effect of EBI-005 on signs and
symptoms in efficacy evaluable (EE) population (n=67)
• Blocking IL-1 has a DUAL effect on inhibiting
inflammation (signs & symptoms) and suppressing
discomfort and pain (symptoms) [Figure 1].
IL-1α and IL-1β are key mediators
of inflammation in DED:
Topical EBI-005 demonstrated a strong effect on improving the signs and symptoms of subjects with DED.
EBI-005
Validation of IL-1 blockade in DED:
• IL-1 is the most extensively
implicated biological pathway
in the pathogenesis of both
acute and chronic eye disease.
Biological Activity
Figure 2
Patients with DED are commonly stratified by clinical severity into mild, moderate, and severe
groups. Therapy begins with artificial tear replacement and punctal occlusion, expanding to
topical anti-inflammatory therapy (DEWS Report, 2007). There is a large unmet clinical need,
for improved therapeutic options for DED for patients with moderate to severe disease.
• EBI-005 is a targeted therapy for highly selective blockade of a central driver for signs and
symptoms of DED.
EBI-005 Treated Group used Significantly less Rescue Tears
* p-value - 0.18 (t-test)
Mean Vials used in the study
NEI CBL
ABSTRACT
*
Week
Chauhan SK, Dana R. Role of TH1 7 cells in the immunopathogenesis of dry
eye disease. Mucosal Immunol (2009) 2(4): 375-6.
EBI-005 demonstrated a strong effect on Total OSDI
compared with vehicle control at week 6 particularly
for the population with a baseline OSDI less than 50.
EBI-005 demonstrated a strong effect on the ocular
pain question from the OSDI compared with vehicle
control at week 4 and week 6 particularly for the
population with a baseline OSDI less than 50.
OSDI Score in the study population of subjects
with baseline starting “OSDI scores” of <50
Pain Score in the study population of subjects
with baseline starting “OSDI scores” of <50
Total OSDI BL OSDI <50
Pain BL OSDI <50
Median Vial usage: Vehicle: 10.5
Treated: 1
Patients who used ≥50 rescue tears
Evans RJ, Bray J, et al. Mapping receptor binding sites in interleukin (IL) 1
receptor antagonist and IL β by site-directed mutagenesis. J Biol Chem,
(1995) 270:11477-11483.
1 Week
Vehicle (Placebo) 3x/day
30 pts
1 week run-in
Vehicle
(Placebo)
EBI-005 (20 mg/mL) 3x/day
22 pts
Design
International Dry Eye Workshop (DEWS) Report. The Ocular Surface (2007)
5:65-204.
• Multi-center (8 centers in United States), randomized, double-masked,
vehicle-controlled, environmental study.
* p- value=0.17 (ANCOVA)
• Key inclusion criteria: minimum OSDI score of 23 and CFS score of 6.
• Key exclusion criteria: maximum OSDI score of 90, CFS score of 15 and
Schirmer's (no anesthesia)=0.
Safety
Follow-up
Visit:
7 Days after
Last Dose
• Adverse event monitoring and general systemic safety monitoring.
• Ophthalmic safety assessments.
• Serum PK and immunogenicity.
Biological Activity
• Signs assessed by evaluating CFS in five sections of the cornea.
• Symptoms assessed using PRO’s.
• Use of rescue preservative free artificial tears monitored.
Presenting and corresponding author: Michael Goldstein, Eleven Biotherapeutics, michael.goldstein@elevenbio.com
Dana R, Dastjerdi M, Amparo F, Okanobo A, Smaga L, Witkin D, Howe W,
Schaumberg D. Randomized phase II trial of safety and efficacy of topical
interleukin-1 receptor antagonist (IL-1 Ra) for treatment of meibomian gland
dysfunction (MGD) —associated ocular surface disease. 10th Annual
Meeting of the Federation of Clinical Immunology Societies. Poster and
Abstract F.107 (2010).
Dinarello CA. A clinical perspective of IL-1B as the gatekeeper of
inflammation. Eur J Immunol (2011) 41(5): 1203-17.
* p-values
• Investigator Global Assessment- showed statistical trend compared with vehicle
control at 4 weeks and 6 weeks (p<0.23; t-test).
Safety and Tolerability Summary
• No tolerability issues or patient drop outs.
• AE’s were mostly mild, transient and
self-resolving.
• No SAEs.
• Of the 8 ocular AE’s: 2 were in the vehicle
treated eyes, 4 were in the 5 mg/mL
treated eyes and 2 were in the 20 mg/mL
treated eyes.
Investigator Brochure, Edition No. 1.0, Dated 1 August 2012
@ 4 weeks is 0.007 (t-test)
@ 6 weeks is 0.10 (t-test)
• Subjects were allowed to use rescue preservative free artificial tears.
EBI-005 (5 mg/mL) 3x/day
22 pts
Chen Y-T, Nikulina K, Lazarev S, Bahrami AF, Noble LB, Gallup M, McNamara
NA. lnterleukin-1 as a phenotypic immunomodulator in keratinizing
squamous metaplasia of the ocular surface in Sjögren’s syndrome. Am J
Pathology (2010) 177:1333-1343.
Dursun D, Wang M, Monroy D, Li D-Q, Lokeshwar BL, Stern ME, Pflugfelder
SC. A mouse model of keratoconjunctivitis sicca. Invest Ophthalmol Vis Sci
(2002) 43:632- 638.
Herein we describe a phase 1b/2a study in patients with
moderate to severe DED that demonstrates the safety,
tolerability and efficacy of the drug for administration in DED.
Phase
1b/2a
package
insert.
Issue
date
12/15/2009.
Anakinra
(Kineret®)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/anakamgO627O
3LB. pdf
Bletsa A, Fristad I, Berggreen E. Sensory pulpal nerve fibers and trigeminal
ganglion neurons express IL-1RI: A potential mechanism for the development
of inflammatory hyperalgesia. International Endodontic Journal (2009) 42:
978–986.
CLINICAL STUDY DESIGN
6 Week
Amparo F, Dastjerdi MH, Okanobo A, Ferrari G, Smega L Hamrah P, Jurkunas
U, Schaumberg D, Dana R. Topical Interleukin 1 Receptor Antagonist for
Treatment of Dry Eye Disease, JAMA Ophthalmol. Published online April 18,
2013. doi:10.1001/jamaophthalmol.2013.195.
Barabino S, Shen LL, Chen L, Rashid S, Rolando M, Dana MR. The controlledenvironment chamber: a new mouse model of dry eye. Invest Ophthalmol
Vis Sci (2005) 46:2766-2771.
Dry Eye Disease
1 Week
REFERENCES
• Of the 25 non-ocular AE’s: 10 were in
vehicle group, 4 were in the 5 mg/mL
group, and 11 were in the 20 mg/mL group.
• Systemic plasma levels of EBI-005
remained undetectable (less than 2.5
ng/mL) at all time points following topical
administration after 6 weeks of dosing.
• 3/44 (6.8%) had low antibody levels that
were not clinically relevant.
• Safety findings for ocular and non-ocular
safety were equivalent at both dose levels.
Of the 10 heaviest rescue tear users
70% were in the vehicle control group
Lemp MA. Epidemiology and classification of dry eyes. In: Sullivan DA, et al,
ed. Lacrimal gland, tear film and dry eye syndromes 2. New York: Plenum
Press, 1998:791–803.
Market Scope. 2011 Comprehensive Report on the Global Dry Eye Products
Market. St Louis, MO: Market Scope, November, 2011.
Okanobo A, Dastjerdi M, et al. New anti-inflammatory strategy to treat
murine dry-eye disease. World Cornea Congress VI, 2010.
Okanobo A, Chauhan SK, Dastjerdi MH, Kodati 5, Dana R. Efficacy of Topical
Blockade of Interleukin-1 in Experimental Dry Eye Disease. Am J Ophthalmol
(2012) Jul;154(1):63-71.
Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC. Pro- and
anti-inflammatory forms of interleukin 1 in the tear and conjunctiva of
patients with dry eye disease. Investigative Ophthalmology and Visual
Science (2001) 42(10): 2283-2292.
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.