ARTICLE

A Phase 2 Exploratory Study of a Novel Interleukin-1 Receptor Inhibitor (EBI-005) in the Treatment of Moderate-to-Severe Allergic Conjunctivitis Michael H. Goldstein, M.D., Karen L. Tubridy, Pharm.D., Jennifer Agahigian, B.S., Eric Furfine, Ph.D., Marianne Magill, M.S., Joseph Kovalchin, Ph.D., Kathryn Golden, M.Eng., Gregory Zarbis-Papastoitsis, Ph.D., Fiona Soong, O.D., Anne Marie Salapatek, Ph.D., Gary Sternberg, M.D., and Abbie Celniker, Ph.D.

Objectives: Many allergic conjunctivitis (AC) patients are inadequately treated with conventional therapies or require steroids. EBI-005 was developed to address the late phase allergic response. This study’s objectives were to evaluate two adapted clinical models for this indication and to assess safety and biological activity of EBI-005 in AC. Methods: In this randomized, double-masked, vehicle-controlled study, 159 subjects with moderate-to-severe AC were randomized to topical EBI005 (5 mg/mL) or vehicle control given 3 times per day and repeatedly challenged with allergen using an adaptation of 2 clinical models of AC. Subjects were assigned to repetitive aerosolized challenge in an allergy chamber (Environmental Exposure Chamber, EEC), or repetitive challenges with a direct conjunctival allergen challenge (Conjunctival Allergen Provocation Test, CAPT). Results: In the EEC, the prespecified primary endpoint of ocular itching was not met. In the CAPT, EBI-005–treated subjects showed clinically meaningful, statistically significant improvements in ocular itching compared with vehicle control at the final 2 efficacy time points, visit 6 (P¼0.033) and visit 7 (P¼0.046). EBI-005–treated subjects showed statistically significant improvement compared with vehicle control for ocular tearing (P¼0.027 and P¼0.044) and nasal symptoms (P¼0.004 and P¼0.011) at visit 6 and visit 7. EBI-005 was well tolerated. Conclusions: These results support use of an adapted, multiple-challenge, direct conjunctival allergen model to assess efficacy of EBI-005 in late phase AC. In the CAPT, EBI-005 showed statistically significant improvements in clinically meaningful symptoms (ocular itching, tearing, and nasal symptoms) at multiple time points for moderate-to-severe AC subjects. Key Words: Allergic conjunctivitis—Late phase—Interleukin-1— Interleukin-1 receptor—Cytokines—Inflammation—Clinical trials. (Eye & Contact Lens 2015;41: 145–155)

From the Eleven Biotherapeutics (M.H.G., K.L.T., J.A., E.F., M.M., J.K., K.G., G.Z.-P., G.S., A.C.), Cambridge, MA; New England Eye Center, Department of Ophthalmology (M.H.G.), Tufts Medical Center, Boston, MA; and Inflamax Research, Inc. (F.S., A.M.S.), Mississauga, Canada. M. H. Goldstein, K. L. Tubridy, J. Agahigian, E. Furfine, J. Kovalchin, K. Golden, G. Zarbis-Papastoitsis, and A. Celniker are employees of Eleven Biotherapeutics. F. Soong and A. M. Salapatek are employees of Inflamax Research. M. Magill is a consultant to Eleven Biotherapeutics. Supported by Eleven Biotherapeutics. Address correspondence to Michael H. Goldstein, M.D., Eleven Biotherapeutics, 215 First Avenue, Cambridge, MA 02142; e-mail: [email protected] Accepted February 9, 2015. DOI: 10.1097/ICL.0000000000000152

Eye & Contact Lens  Volume 41, Number 3, May 2015

A

llergic eye diseases involve inflammation of the conjunctiva from a reaction to allergy-causing substances (e.g., pollen, dander) with type 1 hypersensitivity reaction.1–3 Allergic conjunctivitis (AC) affects between 15% and 40% of the population worldwide.3,4 Although many patients with acute AC are well controlled with current standard of care therapy (antihistamine/mast cell stabilizers), many patients experience symptoms because of late phase allergic inflammatory response and are inadequately treated with these medications or require topical steroids, which can be associated with serious side effects. A significant challenge in testing therapeutics to meet the needs of these patients is to develop appropriate clinical models that mimic the late phase allergic response seen in these patients. One model for studying AC is to use an allergy chamber model or Environmental Exposure Chamber (EEC). The EEC is a clinical model that has been used over the past 20 years primarily to assess anti-allergy medications such as nasal sprays and oral formulations of mainstay allergy treatments, including antihistamines and corticosteroids,5,6 and biologic treatments such as T-cell modulators, immunotherapies, and anti-IgE medications such as Xolair. The EEC has not been used for registration studies in AC. The main advantage of the EEC model is the ability to control environmental factors such as humidity and temperature while delivering a steady and consistent level of airborne allergen.7,8 One potential limitation of this model for the development of treatments for moderate-to-severe AC is that subjects are exposed to the allergen through multiple mucous membranes: the eyes, nose, and respiratory tract. Many acute acting AC drugs in the United States have been evaluated using a different model, the direct conjunctival allergen challenge model, where allergen is placed directly onto the conjunctival surface. The advantage of this model is that the ocular response is isolated and not affected by systemic exposure of the allergen. In addition, unlike environmental allergy studies where results can be confounded by various factors such as environmental conditions and allergen levels, this model offers a well-controlled approach to study specific allergens. This model has been demonstrated to be particularly useful for testing the effect of ocular anti-allergy medications on the early phase of the ocular immune response.9–13 This study was designed to evaluate the utility of both of these models in evaluating EBI-005 in the late phase allergic response. Patients with IgE against specific allergens can mount an ocular allergic response that is characterized by ocular itching, conjunctival redness and chemosis, ocular burning, ocular discomfort, tearing, lid

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M. H. Goldstein et al. swelling, and associated nasal symptoms (Fig. 1). Initial exposure to allergen first generates an immediate “early phase” response that is primarily mediated by preformed histamine from mast cells. In most patients, this is followed by a “late phase” response mediated by cytokines induced by the allergen exposure. The severity of both the early phase and the late phase responses may vary among patients. Interleukin 1 (IL-1) is a key cytokine for mediation of the late phase allergic response. Virtually, every aspect of the pathobiology and pathophysiology of allergic eye disease can be mediated or amplified by IL-1. These pathobiological aspects include antigenpresenting (dendritic) cell maturation and recruitment,14,15 gene transcription for critical chemokines that direct pathogenic white blood cells to the ocular surface,16 and activation and amplification of T-cell–mediated responses.17 Pathophysiological aspects reduced by IL-1 blockade include photosensitivity, chemosis, edema, itching, and corneal neovascularization. EBI-005 is a new molecule being developed for the topical treatment of diseases associated with ocular surface inflammation, including moderate-to-severe AC and moderate-to-severe dry eye disease. EBI-005 is an IL-1 receptor inhibitor.18 It is a protein chimera of IL-1b and IL-1 receptor antagonist (IL-1Ra). The 17.7-kDa protein contains entirely human amino acid sequences and was designed to merge the best binding characteristics of IL-1b and IL-1Ra into one molecule. Despite being a chimera of an agonist and an antagonist, the drug only inhibits IL-1 signaling and is devoid of agonist activity. The chimera is also more thermally stable than either parental molecule.19

Eye & Contact Lens  Volume 41, Number 3, May 2015 Two clinical studies with EBI-005 have demonstrated that EBI005 is safe and well tolerated in both healthy subjects and subjects with moderate-to-severe dry eye disease at doses of 5 and 20 mg/mL as compared with a vehicle control.20,21 In one study, EBI-005 demonstrated a strong biological effect on both the signs and symptoms of DED after 6 weeks of treatment compared with pretreatment baseline assessments.21 In this randomized, double-masked, vehicle-controlled study, subjects with moderate-to-severe AC were randomized to topical EBI-005 or vehicle and repeatedly challenged with allergen using an adaptation of these two clinical models for studying AC. The objectives of this study were as follows: 1. To assess an adaptation of two models of AC in evaluating the late phase allergic ocular response, 2. To assess biological activity of EBI-005 (5 mg/mL) ophthalmic solution compared with vehicle control in the treatment of subjects with moderate-to-severe AC, and 3. To assess the safety and tolerability of EBI-005 (5 mg/mL) ophthalmic solution in subjects with moderate-to-severe AC.

METHODS This study was conducted in accordance with Good Clinical Practices and the tenets of the Declaration of Helsinki. All subjects received appropriate informed consent after explanation of the nature and possible consequences of the study and before enrolling in the trial. The research was approved by the appropriate institutional

FIG. 1. Schematic diagram of interleukin-1 (IL-1) involvement in ocular allergy. An IgE-mediated immune response is generated toward a particular antigen, which stimulates mast degranulation and IL-1 release by FcE receptor activation. Degranulation of mast cells is responsible for the early phase response through release of preformed mediators (primarily histamine) that leads to itching, redness, and ocular swelling. Interleukin-1 release from mast cells stimulates eosinophils, T cells, and macrophages to release more IL-1 and drive an inflammatory response. This late stage inflammatory response leads to itching, redness, fibrosis, and epithelial breakdown. Histamine release and other degranulation factors stimulate additional IL-1 production, which further drives the inflammatory process.

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Eye & Contact Lens  Volume 41, Number 3, May 2015

Phase 2 EBI-005 AC Study

FIG. 2. Schematic diagram of the phase 2 trial design. At visit 1a (V1a), subjects underwent medical screen and signed informed consent. At visit 1b (V1b), all subjects were screened for allergen reactivity using the Environmental Exposure Chamber (EEC). Qualifying subjects were assigned to EEC or Conjunctival Allergen Provocation Test (CAPT) challenges for future visits. “:” indicates allergen challenge by EEC or CAPT (depending on group assignment) on the visits in which the challenge occurred. At visit 2, subjects received a second allergen challenge. At visit 3 (V3 also known as baseline), subjects received a third allergen challenge after which subjects were randomized to EBI-005 or vehicle control treatment arms. At visit 4 (V4), subjects underwent safety assessment 24 hr after the third allergen challenge. At visits 5, 6, and 7 (V5, V6, and V7, respectively), subjects received 3 additional allergen challenges (depending on group assignment) while still receiving treatment 3 times daily. At visit 8 (V8), subjects came back 24 hr after the allergen challenge for safety evaluation, and at visit 9 (V9), subjects came back (approximately 42 days after V3) for safety visit and exit from the study.

review board. This trial was registered with clinicaltrials.gov (NCT 02082899). It was conducted between January 2014 and June 2014. This was a single-center, randomized, double-masked, vehiclecontrolled, parallel group study evaluating the biological activity and safety of topical EBI-005 ophthalmic solution (5 mg/mL) compared with vehicle control. The study involved 10 clinic visits using an adaptation of 2 different allergen challenge models, the direct conjunctival allergen challenge model (Conjunctival Allergen Provocation Test, CAPT) and the allergy chamber model (EEC) (Fig. 2). All subjects were exposed to six different allergen challenges over the course of the study in two series of three challenges. The initial three challenges were before treatment with study medication and served to determine sensitivity to the allergen and to prime the allergic response for future challenges. After the initial 3 challenges, subjects were randomized 1:1 to receive study medication (EBI-005 or vehicle control) topically 3 times per day for 2 weeks and then received 3 additional allergen challenges. Treatment with study medication continued during the second series of 3 challenges and for 1 day after the second series of 3 challenges, for a total of 18 days on study medication. The final study visit was conducted 6 weeks after initiating study medication. © 2015 Contact Lens Association of Ophthalmologists

Before, during, and after allergen challenge, subjects assessed their ocular itching, ocular tearing, and associated nasal symptoms of AC. Ocular itching was rated using a 4-point descriptive scale from 0 (no symptoms) to 3 (symptoms hard to tolerate, causes interference with activities of daily living). Ocular tearing was assessed using a 4-point descriptive scale from 0 (None) to 3 (severe). Associated total nasal symptoms were evaluated by summing three different related questions (nasal itching, runny/ stuffy nose, and sneezing) using a 4-point descriptive scale for each from 0 (none) to 3 (severe). Trained investigators also evaluated signs of AC before, during, and after allergen challenge including: conjunctival redness on a 5-point scale from 0 (normal, quiet eye) to 4 (extremely severe conjunctival redness),22–24 conjunctival chemosis and mucus discharge scored 0 (absent) or 1 (present), follicular/papillary response on a 4-point scale from 0 (none) to 3 (severe), and lid swelling scored on 5-point scale from 0 (none) to 4 (extremely severe). EBI-005 was supplied as a clear and colorless preservative-free topical ophthalmic solution in low-density polyethylene (LDPE) blow fill units containing 0.3 mL of 5 mg/mL concentration. The vehicle control (placebo) was supplied as a clear and colorless topical ophthalmic solution in LDPE blow fill units containing 0.3 mL. 147

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M. H. Goldstein et al. Subjects were consented at the initial study visit and underwent the required examinations to ensure the subjects met inclusion/ exclusion criteria. Key inclusion criteria were at least a 2-year history of moderate-to-severe AC, a positive skin prick test to grass or ragweed within the past 12 months, and the use of more than one anti-allergy pharmaceutical treatment in the past 2 years to treat ocular symptoms (including oral, topical, nasal treatments). In addition, at least 50% of the subjects randomized must have failed antihistamine/mast cell stabilizer therapy or required topical steroids for their signs and symptoms of AC. Atopic keratoconjunctivitis patients were not excluded from this study. Subjects who met the study entry criteria were exposed to the EEC allergen challenge at the next visit. Signs and symptoms of AC were collected at specified time points throughout the visit. Those who passed the inclusion criteria of $2 in conjunctival redness and $2 in ocular itchiness at any time point within 3.5 hr of exposure were eligible to continue on in the study and remained in the EEC for an additional 1.5 hr to collect signs and symptoms at specified time points throughout the visit. After exit from the EEC, subjects remained in the clinic for 60 min to collect signs and symptoms at specified time points. Those who did not meet the criteria within 3.5 hr of exposure were deemed ineligible and excluded from the study. Eligible subjects were assigned to participate in the EEC or the CAPT arm at the conclusion of this visit.

Environmental Exposure Chamber Arms Subjects in the EEC arm returned at visit 2 that consisted of 5 hr in the EEC and 1 hr in the clinic after exiting the EEC. Signs and symptoms of AC were collected at 2.5, 5, 15, and 30 min and then every 30 min thereafter up to 5 hr after receiving allergen challenge. Subjects returned the next day (visit 3) that consisted of the same EEC procedures as visit 2. After exiting the EEC, participants remained for 5 hr in the medical clinic for further collection of signs and symptoms of AC at specified time points for a total of 10 hr. Scores at visit 3 were used to establish the baseline ocular allergic response. At the conclusion of visit 3, subjects were randomized 1:1 to topical study drug (EBI-005 or vehicle control) to be used 3 times per day for 2 weeks. Subjects were given at-home diary cards (for recording of dosing and any adverse effects) and an appointment to return 1 day after for visit 4 for a safety visit. Following visit 4, subjects returned to the clinic 13 days later for visit 5 for repeat EEC. Subjects were again exposed to a 5-hr allergen challenge in the EEC, and after exiting the EEC, subjects remained for 1 hr in the clinic. Subjects were scheduled to return on the next two consecutive days for visit 6 and visit 7, which mimicked visit 5. Visit 6 consisted of a 5-hr EEC allergen challenge, followed by 1 hr in the clinic, whereas visit 7 consisted of a 5-hr EEC allergen challenge, followed by 5 hr in the medical clinic with signs and symptoms being scored at specified time points throughout the visit. Dosing of the randomized ophthalmic medication (three times per day) continued through these days.

Conjunctival Allergen Provocation Test Arms Subjects in the CAPT arm returned at visit 2 for a titrating CAPT that began with the administration of allergen at the lowest concentration in the conjunctival sac. A positive reaction was defined as a symptom score of $2 for ocular itching and a score of $2 for conjunctival redness at any time point. If this initial CAPT 148

Eye & Contact Lens  Volume 41, Number 3, May 2015 did not elicit a positive response, CAPT was repeated with the next higher concentration of allergen until a positive reaction was elicited or the maximum dose was reached with the same evaluation of allergic response at the time points specified above. Ocular allergy signs and symptoms were followed up for 5 hr in the clinic following a positive response. The concentration eliciting the positive reaction was used as the allergen provocation concentration for visit 3. Ocular allergy signs and symptoms were followed up for 5 hr in the clinic following allergen challenge. Signs and symptom scores at visit 3 were used to establish the baseline ocular allergic response. At the conclusion of visit 3, subjects were randomized 1:1 to topical study drug (EBI-005 or vehicle control) with 3 times per day dosing for 2 weeks. Subjects were given at-home diary cards (for recording of dosing and any adverse effects) and an appointment to return 1 day later (visit 4) for a safety visit. At visits 5, 6, and 7, subjects were again exposed to CAPT with the same allergen concentration used in visit 3 that elicited a positive reaction. Signs and symptoms of AC were collected at the same time points assessed at visits 2 and 3. Dosing of the randomized ophthalmic medication (three times per day) continued through these days.

Conjunctival Allergen Provocation Test and Environmental Exposure Chamber All subjects (EEC and CAPT arms) returned at visit 8, approximately 1 day after visit 7 for a safety visit. Drug treatment terminated after the completion of visit 8. All subjects (EEC and CAPT arms) returned at visit 9, approximately 42 days after completion of visit 3 (initiation of study medication) for a safety ophthalmic examination, scoring of signs and symptoms, and a final blood draw for immunogenicity before study exit. Any changes in health were recorded.

Statistical Analysis The planned sample size was 120 EEC subjects and 30 CAPT subjects equally allocated between treatment groups. It was assumed that 60 subjects per treatment arm would be needed in the EEC arm to detect a mean difference in the primary endpoint of area under the curve (AUC0–5hr) ocular symptom itching scores with 80% power at the a level of 0.05. No formal sample size calculations were performed for the CAPT arm. The intention-to-treat population was defined as all randomized subjects who received at least one drop of study medication and completed at least one post-baseline efficacy assessment during the treatment phase. Subjects were analyzed by the treatment received, and all efficacy and safety assessments were performed using this population. The AUC0–5hr of the mean symptom score was defined using the scores reported by subjects at posttreatment visits at 2.5, 5, 15, and 30 min and then every 30 min thereafter up to 5 hr after receiving allergen challenge in the CAPT and EEC arms. The AUC0–5hr was calculated using the trapezoidal rule for discrete time points. Missing efficacy data were imputed using last observation carried forward methodology. Changes from baseline (visit 3 pretreatment) to each visit were calculated. An analysis of covariance using the baseline AUC as a covariate and treatment as a fixed effect was used to test for treatment group differences. The least square mean (LSM) for each Eye & Contact Lens  Volume 41, Number 3, May 2015

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Eye & Contact Lens  Volume 41, Number 3, May 2015 TABLE 1.

Phase 2 EBI-005 AC Study Demographics Challenge Arm/Treatment Group

EEC

Race, N (%) White Black or African American Asian Other Gender, N (%) Female Male Age, y Mean6SD Median Min, max Allergen challenge, N (%) Ragweed Grass Previous AC Tx,a N (%) Failed SOC No failure

CAPT

Vehicle (N¼62)

EBI-005 (5 mg/mL) (N¼61)

35 (56.5) 16 (25.8) 9 (14.5) 2 (3.2)

40 (65.6) 12 (19.7) 8 (13.1) 1 (1.6)

75 28 17 3

(61.0) (22.8) (13.8) (2.4)

10 (55.6) 6 (33.3) 2 (11.1) 0 (0)

6 5 4 3

(33.3) (27.8) (22.2) (16.7)

16 (44.4) 11 (30.6) 6 (16.7) 3 (8.3)

29 (46.8) 33 (53.2)

29 (47.5) 32 (52.5)

58 (47.2) 65 (52.8)

10 (55.6) 8 (44.4)

8 (44.4) 10 (55.6)

18 (50.0) 18 (50.0)

43.1610.1 42.5 23, 61

46.3612.8 46.0 22, 70

44.7611.5 45.0 22, 70

37.9612.2 39.0 18, 60

38.369.9 37.5 25, 62

38.1610.9 37.5 18, 62

43 (69.4) 19 (30.6)

43 (70.5) 18 (29.5)

86 (69.9) 37 (30.1)

10 (55.6) 8 (44.4)

10 (55.6) 8 (44.4)

20 (55.6) 16 (44.4)

29 (46.8) 33 (53.2)

35 (57.4) 26 (42.6)

64 (52.0) 59 (48.0)

7 (38.9) 11 (61.1)

5 (27.8) 13 (72.2)

12 (33.3) 24 (66.7)

Total (N¼123)

EBI-005 (5 mg/mL) (N¼18)

Vehicle (N¼18)

Total (N¼36)

a

Failed standard of care includes those subjects who failed standard of care antihistamine/mast cell stabilizers.

AC, allergic conjunctivitis; CAPT, Conjunctival Allergen Provocation Test; EEC, Environmental Exposure Chamber; SD, standard deviation; SOC, standard of care.

treatment, the LSM of the treatment difference and the corresponding 95% confidence interval, and the P-value were calculated. No adjustments of the significance level for multiple comparisons were made. The investigator evaluation of signs before, during, and after allergen challenge was analyzed similarly. Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities coding dictionary (Version 16.1). Each AE was evaluated for date/time of onset, duration, ocular versus nonocular, frequency, severity, casual relationship with the study drug, action taken related to the study drug, outcome, and other actions taken. To examine the clinical magnitude of effect, the percentage change from baseline to each posttreatment visit in subject symptom scores was calculated. Data are presented with medians and ranges. The median is presented because it is less sensitive to the appearance of a few extreme outlier values than the mean.

RESULTS

conjunctival redness, and follicular/papillary response scores generally improved posttreatment with topical EBI-005, there was no statistically significant difference between EBI-005–treated groups and vehicle control–treated groups (Table 2). There were too few subjects with presence of lid edema, conjunctival chemosis, or mucous discharge at any visit to make any meaningful conclusions between the two treatment groups for these metrics.

Conjunctival Allergen Provocation Test Ocular Itching The CAPT subjects treated with EBI-005 improved compared with vehicle in mean ocular itching (AUC0–5hr, change from baseline) at each posttreatment visit. This improvement was statistically significant at the final 2 efficacy time points, visit 6 (P¼0 0.033) TABLE 2.

Environmental Exposure Chamber, Allergic Conjunctivitis Differences Between EBI-005 and Vehicle Control

Demographics This study randomized 159 subjects, 123 in the EEC arms and 36 in the CAPT (Table 1). Only one subject (EEC group, EBI-005 treatment) failed to complete the study (99% completion rate). Gender was evenly distributed (male: 52.8% in EEC and 50% in CAPT, female: 47.2% in EEC and 50% in CAPT). Age ranged from 22 to 70 years (median 45) for EEC and 18 to 62 years (median 38) for CAPT. The EEC subjects were exposed to ragweed (69.9%) and grass (30.1%). In the CAPT, 55.6% of the subjects were exposed to ragweed and 44.4% were exposed to grass. Demographics and type of allergen exposure were equally distributed between study treatment groups.

Environmental Exposure Chamber In the EEC model, although ocular itching (the prespecified primary endpoint), ocular tearing, associated total nasal symptom, © 2015 Contact Lens Association of Ophthalmologists

Ocular itching 95% confidence interval P Tearing 95% confidence interval P Total nasal symptoms 95% confidence interval P

V5

V6

V7

231 292 to 30 0.3140 226 287 to 35 0.3962 286 2225 to 53 0.2225

216 283 to 51 0.6400 25 266 to 56 0.8767 232 2170 to 106 0.6469

7 265 to 79 0.8461 17 250 to 84 0.6140 77 286 to 239 0.3529

All values are mean difference between EBI-005 and vehicle control for change in AUC0–5hr from V3 (analysis of covariance). The more negative the value for difference between drug and vehicle control, the greater the subject improvement. AUC, area under the curve; V3, visit 3 (study day 3, pretreatment, baseline); V5, visit 5 (study day 17); V6, visit 6 (study day 18); V7, visit 7 (study day 19).

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FIG. 3. Mean6standard error of the change from baseline area under the curve (AUC0–5hr) for ocular itching from 0 min to 5 hr postallergen challenge for each study visit (where baseline is V3, study day 3). Improvement in patient symptoms is represented by a negative value. The more negative the value, the greater the improvement. A comparison between the EBI-005 (5 mg/mL) treatment (d) group and vehicle control (■) shows a reduction in ocular itching at V5 (study day 17), V6 (study day 18, P¼0.0330), and V7 (study day 19, P¼0.0458) in which subjects were treated 3 times daily for 2 weeks starting at V3.

and visit 7 (P¼0.046), respectively (Fig. 3; Table 3). The median improvement in ocular itching from baseline was 32% for EBI-005 at visit 6 (compared with 8% for vehicle control) and 49% at visit 7 (compared with 8% for vehicle control) (Table 4). Mean change from baseline for individual time points over the 5 hr subjects were evaluated at visit 7 (after direct conjunctival allergen challenge) is shown in Figure 4. The EBI-005–treated group had a greater improvement than the vehicle control group at all time points during the 5 hr observation period and was most robust starting approximately 30 min after challenge.

TABLE 3. Conjunctival Allergen Provocation Test, Allergic Conjunctivitis Differences Between EBI-005 and Vehicle Control

Ocular itching 95% confidence interval P Tearing 95% confidence interval P Total nasal symptoms 95% confidence interval P

V5

V6

V7

254 2144 to 36 0.2300 233 2119 to 53 0.4424 2148 2383 to 86 0.2071

2115 2220 to 210 0.0330 299 2186 to 212 0.0268 2351 2582 to 2120 0.0040

2120 2238 to 2 0.0458 2110 2217 to 23 0.0441 2347 2610 to 284 0.0113

All values are mean difference between EBI-005 and vehicle control for change in AUC0–5hr from V3 (analysis of covariance). The more negative the value for difference between drug and vehicle control, the greater the subject improvement. AUC, area under the curve; V3, visit 3 (study day 3, pretreatment, baseline); V5, visit 5 (study day 17); V6, visit 6 (study day 18); V7, visit 7 (study day 19).

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FIG. 4. Mean6standard error for the change in baseline for ocular itching for each time point (from 0 min to 5 hr postallergen challenge) for study visit 7. Improvement in patient symptoms is represented by a negative value. The more negative the value, the greater the improvement.

Ocular Tearing The CAPT subjects treated with EBI-005 improved compared with vehicle in mean ocular tearing (AUC0–5hr, change from baseline) at each posttreatment visit. This improvement was statistically significant at the final 2 efficacy timepoints, visit 6 (P¼0.027) and visit 7 (P¼0.044), respectively (Fig. 5; Table 3). There was a 32% median improvement in tearing from baseline in the EBI-005– treated group at visit 6 (compared with 6% for vehicle control– treated subjects) and a 65% improvement in the EBI-005–treated group at visit 7 (compared with 22% for vehicle control–treated subjects) (Table 5). Mean change from baseline for the individual time points over the 5 hr subjects were evaluated at visit 7 (Fig. 6). The EBI-005–treated subjects had a greater improvement compared with vehicle-treated subjects at all time points during the 5-hr observation period and was most robust starting approximately 30 min after challenge and continuing for over 3 hr after challenge.

Associated Total Nasal Symptoms The CAPT subjects treated with EBI-005 improved compared with vehicle in mean associated total nasal symptoms (AUC0–5hr, change from baseline) at each posttreatment visit. This improvement was statistically significant at the final 2 efficacy time points, visit 6 (P¼0.004) and visit 7 (P¼0.011), respectively (Fig. 7; Table 3). The EBI-005–treated subjects had a 31% median improvement in total nasal symptoms from baseline at visit 6 (compared with 5% for vehicle control subjects) and 40% improvement at visit 7 (compared with 8% for vehicle control subjects) (Table 6). Mean change from baseline for the individual time points over the 5 hr subjects were evaluated at visit 7 (Fig. 8). The EBI-005– treated group had a greater improvement than the vehicle control Eye & Contact Lens  Volume 41, Number 3, May 2015

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Conjunctival Allergen Provocation Test, Ocular Itching Scores, and AUC0–5hr EBI-005 (5 mg/mL) Treatment Group (N¼18)

Mean AUC0–5hr itching score Mean change (range) in AUC0–5hr itching score from V3 Median percentage change (range) in AUC0–5hr itching score from V3

Vehicle Control Group (N¼18)

V3

V5

V6

V7

V3

V5

V6

534 NA

345 2189 (2499 to 83)

380 2154 (2458 to 263)

346 2188 (2530 to 308)

492 374 462 440 NA 2118 (2291 to 139) 230 (2216 to 196) 252 (2211 to 149)

NA

236% (297 to 25)

232% (296 to 318)

249% (285 to 373)

NA

222% (278 to 45)

28% (248 to 57)

V7

28% (267 to 54)

The more negative the value for difference between study drug and baseline, the greater the subject improvement. AUC, area under the curve; V3, visit 3 (study day 3, pre-treatment, baseline); V5, visit 5 (study day 17); V6, visit 6 (study day 18); V7, visit 7 (study day 19); NA, not applicable.

TABLE 5.

Conjunctival Allergen Provocation Test, Tearing Scores, and AUC0–5hr

EBI-005 (5 mg/mL) Treatment Group (N¼18)

Mean AUC0–5hr tearing score Mean change (range) in AUC0–5hr tearing score from V3 Median percentage change (range) in AUC0–5hr tearing score from V3

Vehicle Control Group (N¼18)

V3

V5

V6

V7

V3

V5

V6

V7

344 NA

231 2113 (2408 to 163)

241 2103 (2323 to 175)

200 2144 (2390 to 275)

384 NA

295 289 (2275 to 68)

369 216 (2175 to 278)

340 244 (2303 to 168)

NA

237% (2100 to 50)

232% (2100 to 338)

265% (2100 to 225)

NA

211% (291 to 500)

26% (263 to 200)

222% (2100 to 73)

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TABLE 4.

The more negative the value for difference between study drug and baseline, the greater the subject improvement. AUC, area under the curve; V3, visit 3 (study day 3, pretreatment, baseline); V5, visit 5 (study day 17); V6, visit 6 (study day 18); V7, visit 7 (study day 19); NA, not applicable.

TABLE 6.

Conjunctival Allergen Provocation Test, Associated Total Nasal Symptoms Scores, and AUC0–5hr EBI-005 (5 mg/mL) Treatment Group (N¼18)

V3

V5

V6

V7

V3

V5

V6

V7

1,096 NA

733 2362 (21,300 to 353)

725 2371 (21,448 to 328)

673 2422 (21,585 to 468)

1,187 NA

943 2244 (2628 to 688)

1,128 259 (2543 to 688)

1,085 2102 (2603 to 738)

NA

230% (285 to 33)

231% (2100 to 354)

240% (298 to 44)

NA

218% (270 to 382)

25% (236 to 382)

28% (2100 to 410)

The more negative the value for difference between study drug and baseline, the greater the subject improvement. AUC, area under the curve; NA, not applicable; TNSS, total nasal symptoms scores; V3, visit 3 (study day 3, pretreatment, baseline); V5, visit 5 (study day 17); V6, visit 6 (study day 18); V7, visit 7 (study day 19).

151

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Phase 2 EBI-005 AC Study

Mean AUC0–5hr TNSS score Mean change (range) in AUC0–5hr TNSS from V3 Median percentage change (range) in AUC0–5hr TNSS from V3

Vehicle Control Group (N¼18)

M. H. Goldstein et al.

FIG. 5. Mean6standard error of the change from baseline (V3, study day 3) in AUC0–5hr for ocular tearing from for each study visit. Improvement in patient symptoms is represented by a negative value. The more negative the value, the greater the improvement. A comparison between the EBI-005 (5 mg/mL) treatment (d) group and vehicle control (■) shows a reduction in ocular tearing at V5 (study day 17), V6 (study day 18, P¼0.0268), and V7 (study day 19, P¼0.0441) in which subjects were treated 3 times daily for 2 weeks starting at V3. AUC, area under the curve.

group at all time points after the first 30 min postchallenge and was most robust starting approximately 30 min after challenge.

Other Endpoints Conjunctival redness and follicular/papillary response scores generally improved posttreatment with EBI-005 compared with pretreatment. There were, however, no observed statistically significant differences between the two treatment groups. There were too few subjects with presence of lid edema, conjunctival chemosis, or mucous discharge at any visit to make any meaningful conclusions between the two treatment groups for these metrics.

Safety Of the 159 subjects, 43 (27%) reported an AE (71 total) (Table 7). There was no difference in AEs between EBI-005–treated and vehicle control–treated subjects. There was no difference in AEs between the two models of AC. The most frequent AE noted was headache, which was reported in approximately 15% of all subjects. No other AE had a frequency of greater than 1.5%. Only 2 subjects reported ocular AEs (Table 8). One subject reported ocular irritation, which did not require discontinuation of the study medication, and one subject who failed to disclose a history of glaucoma was noted to have elevated intraocular pressure (IOP). There were no treatment-related serious adverse events (SAE) in this study. There was one non–treatment-related SAE in a subject hospitalized for a broken leg suffered at an athletic event during the safety follow-up period (several weeks after stopping study medication). No subject in this study developed antibodies to EBI-005. Visual acuity, slitlamp examination, fundus examination, and IOP evaluations revealed no safety concerns. 152

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FIG. 6. Mean6standard error for the change in baseline for ocular tearing for each time point (from 0 min to 5 hr postallergen challenge) for study visit 7. Improvement in patient symptoms is represented by a negative value. The more negative the value, the greater the improvement.

DISCUSSION This study evaluated the late phase AC response in moderate-tosevere subjects by adapting two allergen challenge models currently used to evaluate drugs for this purpose. The adaptation involved repetitive daily allergen challenges. To our knowledge, this is the first time data have been reported in the peer-reviewed literature on using multiple allergen challenges to specifically study the late phase AC response. In addition, to our knowledge, this is the first time that these two different models for evaluating AC have been directly compared in the same study. The results of this study demonstrate that adapting the CAPT model by including multiple allergen challenges seems to be an appropriate model to evaluate late phase drugs in AC based on the understanding of the role that mediators other than histamine play in driving this response. Unlike many other reported studies in AC, we specifically screened for and enrolled subjects with more severe AC in this study. Subjects had to have symptoms of AC for at least 2 years versus 1 year in most studies, subjects had to use at least two antiallergy medications, and at least 50% of subjects had to have failed standard of care therapy with anti-histamines/mast cell stabilizers or required topical steroid use. In addition, atopic patients who are often excluded from AC studies were allowed to participate in this study. This study found a statistically significant improvement in the prespecified endpoint of ocular itching in the CAPT, at visit 6 (P¼0.023) and visit 7 (P¼0.046), resulting in a median improvement from baseline of 32% to 49%, respectively. Although there are no definitive guidelines on clinically meaningful changes, it is generally accepted by clinicians that a treatment effect of at least 25% is clinically meaningful. The beneficial effect of EBI-005 treatment was also seen with clinically meaningful, statistically significant improvements in ocular tearing at visits 6 and 7 and associated total nasal symptoms at visits 6 and 7. Eye & Contact Lens  Volume 41, Number 3, May 2015

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Phase 2 EBI-005 AC Study TABLE 7.

Systemic, Treatment Emergent Adverse Events

System Organ Class

Preferred Term

Vehicle

EBI-005 (5 mg/mL)

Total

(N¼80)

(N¼79)

(N¼159)

N (%)

N (%)

N (%)

21 (26.6)

43 (27.0)

2 (2.5) 1 (1.3)

3 (1.9) 3 (1.9)

1 (1.3) 4 (5.1) 2 (2.5)

1 (0.6) 6 (3.8) 3 (1.9)

1 (1.3) 4 (5.1)

1 (0.6) 6 (3.8)

10 (12.7) 1 (1.3)

24 (15.1) 1 (0.6)

2 (2.5)

5 (3.1)

Subjects with at least one adverse 22 (27.5) event Gastrointestinal disorders 1 (1.3) General disorders and administration 2 (2.5) site conditions Immune system disorders 0 (0) Infections and infestations 2 (2.5) Injury, poisoning and procedural 1 (1.3) complications Investigations 0 (0) Musculoskeletal and connective tissue 2 (2.5) disorders Nervous system disorders 14 (17.5) Reproductive system and breast 0 (0) disorders Respiratory, thoracic and mediastinal 3 (3.8) disorders

FIG. 7. Mean6standard error of the change from baseline (V3, study day 3) in AUC0–5hr for total nasal symptoms score from for each study visit. Improvement in patient symptoms is represented by a negative value. The more negative the value, the greater the improvement. A comparison between the EBI-005 (5 mg/mL) treatment (d) group and vehicle control (■) shows a reduction in total nasal symptoms score at V5 (study day 17), V6 (study day 18, P¼0.0040), and V7 (study day 19, P¼0.0113) in which subjects were treated 3 times daily for 2 weeks starting at V3. AUC, area under the curve.

Most studies in AC evaluate ocular symptoms only up to 15 to 20 min postchallenge because anti-histamines are really targeted to the early phase allergic response.9–13 This study, however, used an AUC analysis from 0 to 5 hr postchallenge (AUC0–5hr) to capture the effect of treatment on the late phase allergic response where an IL-1 blocker is considered to be most relevant. The durability of the clinical response demonstrated in this study over multiple time points out to 5 hr postchallenge has not been previously demonstrated with any other AC drugs that we are aware of. The repetitive EEC model was not able to show any separation between the EBI-005–treated group and vehicle control group. When the data from the EEC were analyzed, a few interesting trends emerged: (1) the maximum symptom score in the EEC were below what was achieved using the CAPT and (2) with each successive EEC challenge, the prechallenge value (at time 0 min) seemed to slowly increase (worsen) but the maximum value achieved during the EEC consistently decreased from visit to visit. The reasons for these interesting trends are unclear but may be because of compensatory feedback loops inherent in the immune system caused by chronic exposure of multiple mucous membranes simultaneously (eyes, nose, respiratory system) over a prolonged period. The CAPT, however, results in direct ocular surface exposure, which focuses on the ocular allergic response. The most clinically meaningful endpoint for AC studies is improvement in ocular itching, and this symptom has been the basis for approval for all AC drugs in the United States. Ocular TABLE 8.

Ocular, Treatment Emergent Adverse Events

System Organ Class

FIG. 8. Mean6standard error for the change in baseline for total nasal symptoms score for each time point (from 0 min to 5 hr postallergen challenge) for study visit 7. Improvement in patient symptoms is represented by a negative value. The more negative the value, the greater the improvement.

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Vehicle

EBI-005 (5 mg/mL)

Total

(N¼80)

(N¼79)

(N¼159)

Preferred Term

N (%)

N (%)

N (%)

Subject with at least one adverse events Eye irritation Intraocular pressure increased

0 (0) 0 (0) 0 (0)

2 (2.5) 1 (1.3) 1 (1.3)

2 (1.3) 1 (0.6) 1 (0.6)

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M. H. Goldstein et al. itching has typically been considered an early phase allergic response, but newer evidence indicates that itching is also important in the late phase allergic response. Ocular itch in the early phase response of AC is believed to be mediated primarily by histamine release from mast cells.25,26 Not surprisingly, anti-histamines are often effective therapies for treatment of AC. The late phase response in AC is driven by infiltration of a broader array of inflammatory cells beyond the mast cells, such as eosinophils, neutrophils, and T cells. This more pronounced inflammatory response in late phase AC results in a recurrence and prolongation of the symptoms in the acute phase.26 Although histamine production continues in this late phase,25 other factors probably play a major role in driving the ocular itching. In fact, many patients with more severe forms of AC become refractory to anti-histamines and require other anti-inflammatory therapy to control symptoms. One plausible mechanism for a loss in histamine-driven itch symptoms in the late phase is that cells can become desensitized to histamine signaling after continued exposure, partially because of receptor downregulation.27 Numerous factors beyond histamine can elicit an itch response, including but not limited to IL-31, leukotrienes, and proteases, such as tryptase.28 Interleukin-1 is known to be upstream of many of these mediators. These itch mediators are produced by some of the inflammatory cells involved in sustaining the AC late response. For example, IL-31 is produced by mast cells and Th2 T cells.28 In addition, nasal IL-31 levels are correlated with nasal symptoms (itching, obstruction, secretion) in allergic rhinitis.29 Leukotrienes mediate intradermal itch30 and are produced by eosinophils,31 suggesting that these mediators may also drive ocular itch. Finally, tryptase is produced by mast cells that are sustained in the late phase. Tryptase activates protease-activated receptors, such as PAR2, which mediate itch responses.32 Interleukin-1 mediates the production of all these mediators by activating the cells that produce them. Steroids are currently used to treat the late phase allergic response. Steroids are well known to have ocular side effects. Approximately 33% of the population is considered at risk of being a steroid responder.33 If patients are treated with steroids for 4 to 6 weeks, 30% of patients may experience an IOP elevation of 6 to 15 mm Hg and 5% of patients may see IOP elevation of greater than 15 mm Hg.34 The risk of elevated IOP with steroid use is even higher (up to 90%) for patients with primary open-angle glaucoma.34 In addition to elevation of IOP, steroids are also associated with worsening of cataracts and increased risk of infection. None of these steroid-associated liabilities have been found to date to be attributed to treatment with topical EBI-005. Limitations of this study are that it is a single-center study with a relatively few subjects. Additional studies need to be performed to confirm these results in a multi-center study with more subjects.

CONCLUSIONS There is a substantial unmet medical need to treat the late phase allergic response seen in patients with moderate-to-severe AC. Adapting the direct conjunctival allergen challenge model by incorporating multiple challenges seems to be an appropriate model to evaluate the late phase AC response. EBI-005, an IL-1 receptor blocker, is a promising potential future therapy for patients with moderate-to-severe AC. In this study of subjects 154

with moderate-to-severe AC, EBI-005 demonstrated clinically meaningful, statistically significant biological activity in improving patient symptoms (ocular itching, tearing, and total nasal symptoms) over a longer duration than has previously been shown and over multiple time points postchallenge. EBI-005 was generally safe and well tolerated in this study. EBI-005 may provide a clinically meaningful anti-inflammatory effect without the side effects seen with steroids. Further studies are warranted to confirm these findings. REFERENCES 1. Ono SJ, Abelson MB. Allergic conjunctivitis: Update on pathophysiology and prospects for future treatment. J Allergy Clin Immunol 2005;115:118–122. 2. Offiah I, Calder VL. Immune mechanisms in allergic eye diseases: What is new? Curr Opin Allergy Clin Immunol 2009;9:477–481. 3. Bielory L, Friedlaender MH. Allergic conjunctivitis. Immunol Allergy Clin North Am 2008;28:43–58. 4. Rosario N, Bielory L. Epidemiology of allergic conjunctivitis, Curr Opin Allergy Clin Immunol 2011;11:471–476. 5. Day JH, Briscoe MP, Rafeiro E, et al. Onset of action of intranasal budesonide (Rhinocort Aqua) in seasonal allergic rhinitis studied in a controlled exposure model. J Allergy Clin Immunol 2000;105:489–494. 6. Patel P, Roland PS, Marple BF, et al. An assessment of the onset and duration of action of olopatadine nasal spray. Otolaryngol Head Neck Surg 2007;137:918–924. 7. Day JH, Horak F, Briscoe MP, et al. The role of allergen challenge chambers in the evaluation of anti-allergic medication: An international consensus paper. Clin Exp Allergy Rev 2006;6:31–59. 8. Salzano FA, D’Angelo L, Motta S, et al. Allergic rhinoconjunctivitis: Diagnostic and clinical assessment. Rhinology 1992;30:265–275. 9. Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge: A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol 1990;108:84–88. 10. Abelson MB, Gomes P, Crampton HJ, et al. Efficacy and tolerability of ophthalmic epinastine assessed using the conjunctival allergen challenge model in patients with a history of allergic conjunctivitis. Clin Ther 2004;26:35–47. 11. Abelson MB, Torkildsen GL, Williams JI, et al; Bepotastine Besilate Ophthalmic Solutions Clinical Study Group. Time to onset and duration of action of the antihistamine bepotastine besilate ophthalmic solutions 1.0% and 1.5% in allergic conjunctivitis: A phase III, single-center, prospective, randomized, double-masked, placebo-controlled, conjunctival allergen challenge assessment in adults and children. Clin Ther 2009;31:1908–1921. 12. Spangler DL, Abelson MB, Ober A, et al. Randomized, double-masked comparison of olopatadine ophthalmic solution, mometasone furoate monohydrate nasal spray, and fexofenadine hydrochloride tablets using the conjunctival and nasal allergy challenge models. Clin Ther 2003;25:2245–2267. 13. Torkildsen G, Shedden A. The safety and efficacy of alcaftadine 0.25% ophthalmic solution for the prevention of itching associated with allergic conjunctivitis. Curr Med Res Opin 2011;27:623–631. 14. Guo Z, Zhang M, An H, et al. Fas ligation induces IL-1beta-dependent maturation and IL-1beta-independent survival of dendritic cells: Different roles of ERK and NF-kappaB signaling pathways. Blood 2003;102:4441–4447. 15. Saban DR, Calder V, Kuo CH, et al. New twists to an old story: Novel concepts in the pathogenesis of allergic eye disease. Curr Eye Res 2013;38: 317–330. 16. Keane–Myers AM, Miyazaki D, Liu G, et al. Prevention of allergic eye disease by treatment with IL-1 receptor antagonist. Invest Ophthalmol Vis Sci 1999;40:3041–3046. 17. Ben-Sasson SZ, Hu-Li J, Quiel J, et al. IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci USA 2009;106:7119–7124. 18. Hou J, Townson SA, Kovalchin JT, et al. Design of a superior cytokine antagonist for topical ophthalmic use. Proc Natl Acad Sci U S A 2013;110: 3913–3918. 19. Furfine ES. IL-1 blockade for the topical treatment of ocular surface inflammatory disorders and the discovery of EBI-005, a novel IL-1 receptor inhibitor. Expert Rev Ophthalmol 2014;9:71–79. 20. Goldstein MH, Zarbis-Papastoitsis G, Golden K, et al. Association for Research in Vision and Ophthalmology Annual Meeting. Scientific Poster,

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Phase 2 EBI-005 AC Study 27. Bielkiewicz B, Cook DA. The mechanism of the histamine-induced desensitization of guinea-pig ileum. Gen Pharmacol 1984;15:51–54. 28. Potenzieri C, Undem BJ. Basic mechanisms of itch. Clin Exp Allergy 2012; 42:8–19. 29. Baumann R, Rabaszowski M, Stenin I, et al. The release of IL-31 and IL-13 after nasal allergen challenge and their relation to nasal symptoms. Clin Transl Allergy 2012;2:13. 30. Camp RD, Coutts AA, Greaves MW, et al. Responses of human skin to intradermal injection of leukotrienes C4, D4 and B4. Br J Pharmacol 1983;80:497–502. 31. Nagata M, Saito K. The roles of cysteinyl leukotrienes in eosinophilic inflammation of asthmatic airways. Int Arch Allergy Immunol 2003;131 (Suppl 1):7–10. 32. Barry GD, Le GT, Fairlie DP. Agonists and antagonists of protease activated receptors (PARs). Curr Med Chem 2006;13:243–265. 33. Cohen A. Steroid induced glaucoma. In: Rumelt S, ed. Glaucoma—Basic and Clinical Concepts 2011. Available at: http://www.intechopen.com/ books/glaucoma-basic-and-clinical-concepts/steroid-induced-glaucoma. Accessed November 12, 2014. 34. Jones R, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: A brief review and update of the literature. Curr Opin Ophthalmol 2006;17:163–167.

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A Phase 2 Exploratory Study of a Novel Interleukin-1 Receptor Inhibitor (EBI-005) in the Treatment of Moderate-to-Severe Allergic Conjunctivitis.

Many allergic conjunctivitis (AC) patients are inadequately treated with conventional therapies or require steroids. EBI-005 was developed to address ...
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