Use Of Novel IL-1 Receptor Inhibitor (EBI-005) In The Treatment Of Patients with Moderate To Severe Dry Eye DiseaseMichael Goldstein1,2, Jennifer Agahigian1, Gregory Zarbis-Papastoitsis1, Kathryn Golden1, Joseph Kovalchin1, Cameron Wheeler1, Siddhartha Chowdury1, Abbie Celniker1, Eric Furfine1

1Eleven Biotherapeutics, Cambridge, MA, United States; 2Ophthalmology, New England Eye Center/Tufts Medical Center, Boston, MA, United States

Poster #29

ABSTRACT

Presenting and corresponding author: Michael Goldstein, Eleven Biotherapeutics, michael.goldstein@elevenbio.com

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.

Anakinra (Kineret®) package insert. Issue date 12/15/2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/anakamgO627O3LB. pdf

Barabino 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.

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.

Chauhan SK, Dana R. Role of TH1 7 cells in the immunopathogenesis of dry eye disease. Mucosal Immunol (2009) 2(4): 375-6.

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.

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.

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.

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.

International Dry Eye Workshop (DEWS) Report. The Ocular Surface (2007) 5:65-204.

Investigator Brochure, Edition No. 1.0, Dated 1 August 2012

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.

• EBI-005 is a targeted therapy for highly selective blockade of a central driver for signs and symptoms of DED.

• 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.

• EBI-005 showed a large magnitude of effect with rapid therapeutic onset.

• 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.

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.

RESULTS

CLINICAL STUDY DESIGN

CONCLUSIONS

REFERENCESCorneal Fluorescein Staining in subjects with starting baseline OSDI “symptom scores” of <50

*

Week

NE

I CB

L

CFS BL OSDI <50

*

OSDI Score in the study population of subjects with baseline starting “OSDI scores” of <50

* p-value=0.17 (ANCOVA)

Biological Activity

Topical EBI-005 demonstrated a strong effect on improving the signs and symptoms of subjects with DED.

Total OSDI BL OSDI <50

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.

* p-values @ 4 weeks is 0.007 (t-test)@ 6 weeks is 0.10 (t-test)

Pain BL OSDI <50

Pain Score in the study population of subjects�with baseline starting “OSDI scores” of <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.

• Investigator Global Assessment- showed statistical trend compared with vehicle control at 4 weeks and 6 weeks (p<0.23; t-test).

Rescue artificial tear use was significantly lower in the drug treated group than in those subject who received vehicle control.

Summary of magnitude of effect of EBI-005 on signs and symptoms in efficacy evaluable (EE) population (n=67)

SIGN (CFS by NEI 0-15)

SIGN(CFS by NEI 0-15)BL OSDI<50

SYMPTOM (OSDI Total, 0-100)

SYMPTOM(OSDI Total, 0-100)BL OSDI <50

SYMPTOM (OSDI Pain, 0-4)

SYMPTOM(OSDI Pain, 0-4)BL OSDI <50

Magnitude of Response

(mean)

33%Improvement

(3 points)

39%Improvement(3.5 points)

36%Improvement(18 points)

41%Improvement(13 points)

46%Improvement(0.9 points)

61%Improvement(0.9 points)

EBI-005 Treated Group used Significantly less Rescue Tears

Median Vial usage: Vehicle: 10.5 Treated: 1

Of the 10 heaviest rescue tear users 70% were in the vehicle control group

Mean Vials used in the study

Patients who used ≥50 rescue tears

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.

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.

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.

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.

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.

BACKGROUND

Validation of IL-1 blockade in DED:

• Blocking IL-1 has a DUAL effect on inhibiting inflammation (signs & symptoms) and suppressing discomfort and pain (symptoms) [Figure 1].

• IL-1 receptor blockers effect inflammation at two criti-cal 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-1 is the master regulator of ocular inflammation:

• IL-1 is the most extensively implicated biological pathway in the pathogenesis of both acute and chronic eye disease.

• 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-1α and IL-1β are key mediators of inflammation in DED:

• IL-1α and IL-1β are upregulated in the human disease and mouse models (Solomon, et al 2001; Zhu, et al. 2009).

• 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).

EBI-005: Development of a novel, topical blocker of IL-1 to treat ocular surface disease

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.

Topical EBI-005 was shown in an earlier study to be safe and well tolerated when administered to healthy human volunteers.

EnvironmentMeibomian glanddysfunction

Lachrymal glanddysfunction

Desiccating stress

Inflammatoryresponse

Neuralresponse

aiseglarepyh cinorhCnoitammalfni cinorhC IL-1Local

Dry Eye Disease

EBI-005 Targeted Therapy for DED

Figure 1

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.

Design

• Multi-center (8 centers in United States), randomized, double-masked, vehicle-controlled, environmental study.

• 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.

• Subjects were allowed to use rescue preservative free artificial tears.

Safety

• 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.

Vehicle (Placebo) 3x/day30 pts

Follow-up Visit:

7 Days after Last Dose

EBI-005 (5 mg/mL) 3x/day22 pts

Phase 1b/2a

1 week run-in Vehicle

(Placebo)

1 Week 6 Week 1 Week

EBI-005 (20 mg/mL) 3x/day22 pts

p-value - 0.18 (t-test)

Maximum Potency

EBI-005

Figure 2

IL-1βsite B

IL-1Rasite A

• 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.