Phase 2/3 Dose-Ranging Study of the Safety and Efficacy of OTX-101 in the Treatment of Keratoconjunctivitis Sicca

Keratoconjunctivitis sicca (KCS) is a common multifactorial ophthalmologic disorder of the
tears and ocular surface characterized by symptoms of burning, stinging, itching, grittiness,
scratchiness, foreign body sensation, dryness, stickiness and tired eye sensation.

This study is the first clinical safety and efficacy study with OTX-101 and is designed to
compare two dose concentrations of OTX-101 against vehicle (placebo) in reducing the signs
and symptoms of KCS and evaluate safety when dosed twice a day in both eyes over an 84 day
period.

Inclusion Criteria:

1. Subjects age 18 years or older on the date of informed consent.

2. All subjects must provide signed written consent prior to participation in any
study-related procedures.

3. Patient-reported history of KCS for a period of at least 6 months.

4. Clinical diagnosis of bilateral KCS supported by OTX-101-2014-001 study assessments.

5. Lissamine green conjunctival staining sum score of ≥ 3 to ≤ 9 out of a total possible
score of 12 (scoring excludes superior zones 2 and 4) in the same eye at Screening and
Baseline.

6. Global symptom score ≥ 40 at both Screening and Baseline.

7. Corrected Snellen VA of better than 20/200 in each eye.

8. Willing to discontinue use of current dry eye therapy (including artificial tears or
ocular lubricants) during the study as of the run-in period.

9. Female subjects of childbearing potential must have a negative urine pregnancy test at
Screening. Women of childbearing potential (ie, women who are not either
postmenopausal for one year or surgically sterile) must use an acceptable form of
contraception throughout the study.

Exclusion Criteria:

1. Use of cyclosporine ophthalmic emulsion 0.05% (Restasis®) within 3 months prior to
Screening.

2. Previous treatment failure (lack of efficacy) on cyclosporine ophthalmic emulsion
0.05% (Restasis).

3. Diagnosed with Sjögren's disease ˃5 years prior to Screening.

4. Clinical diagnosis of seasonal and perennial allergic conjunctivitis.

5. Use of systemic and topical medications that are known to cause dry eye within 7 days
prior to Screening and throughout the study period. These include the following
medications:

- Immunomodulators (permitted if dose is stable for 3 months prior to screening and
does not change during the study period)

- Antihistamines (including over-the counter (OTC))

- Cholinergics

- Antimuscarinics

- Tricyclic antidepressants

- Phenothiazines

- Retinoids

6. Oral omega-3 fatty acids (permitted if dose is stable for 3 months prior to Screening
and does not change during the study period)

7. Use of any topical ophthalmic medications, prescription (including antiglaucoma
medications) or OTC (including artificial tears), other than the assigned study
medication during the study period.

8. Current active eye disease other than KCS (i.e., any disease for which topical or
systemic ophthalmic medication is necessary).

9. History of herpes keratitis.

10. Unstable macular disease (e.g., age-related macular degeneration, diabetic
maculopathy). Stable macular disease is defined as no reduction in central VA within 6
months prior to Screening.

11. Diagnosis of chronic uveitis.

12. Corneal transplant (e.g., penetrating keratoplasty, lamellar keratoplasty, Descemet's
stripping endothelial keratoplasty (DSEK) ).

13. Corneal refractive surgery (e.g., laser-assisted in situ keratomileusis (LASIK]) photo
refractive keratectomy (PRK), limbal relaxing incision (LRI) ) within 6 months prior
to screening or postoperative refractive surgery symptoms of dryness that have not
resolved.

14. Cataract surgery within 3 months prior to Screening.

15. Non-laser glaucoma surgery at any time; glaucoma laser procedures within 3 months
prior to Screening.

16. Presence of punctal plugs or past history of permanent punctal occlusion (e.g.,
cautery).

17. Lagophthalmos or clinically significant eyelid margin irregularity of the study eye
whether congenital or acquired.

18. Presence of conjunctivochalasis (i.e., mechanical blockage of the lower lid punctum by
redundant conjunctiva).

19. Presence of pterygium in the study eye.

20. Unwilling to discontinue use of contact lenses during the duration of the study.

21. Preplanned elective surgery or hospitalization during the study period.

22. HIV-positive.

23. Unable to reliably report symptoms and history.

24. Has known hypersensitivity or contraindication to the study medication(s) or their
components.

25. Has a history or presence of chronic generalized systemic disease that the
Investigator feels might increase the risk to the subject or confound the result(s) of
the study.

26. Has a severe/serious ocular condition, or any other unstable medical condition that,
in the Investigator's opinion, may preclude study treatment or follow-up.

27. Women who are pregnant or breastfeeding.

28. Participation in any drug or device clinical investigation within 30 days prior to
entry into this study and/or during the period of study participation.

29. Previous randomization into this study.