Study of the Pharmacodynamic Activity of P-321 Ophthalmic Solution Compared to Placebo in Subjects With Dry Eye Disease

This is a single-center, randomized, cross-over placebo controlled study to evaluate the
changes in tear volume by P-321 Ophthalmic Solution and Placebo. The study will enroll
subjects with tear deficient dry eye disease to receive sequentially one of two treatment
sequences: P-321 Ophthalmic Solution then Placebo or Placebo then P-321. The study will
consist of two Phases: In each Phase, subjects will be treated with P-321 Ophthalmic Solution
under the same study design.

Approximately twenty-four eligible subjects will complete the study with approximately 8
subjects participating in Phase 1 and the remainder of the 24 subjects participating in the
phase 2. Decisions on the dose to be used in Phase 2 will be made based on Phase 1 data.

The study will consist of three study visits: a Screening Visit (Visit 1), and two treatment
visits (Visit 2 and Visit 3). The primary and secondary outcome measures will be assessed at
each treatment visit. Safety assessments include adverse events (AEs).

Inclusion Criteria:

1. Provide written informed consent

2. Male or female subjects aged 18 to 80 years

3. Have a history of predominantly tear-deficient dry eye of mild to moderate severity,
supported by a previous clinical diagnosis

4. Have normal lid anatomy

5. Subjects must:

1. Remain on current medications for the duration of the study and have been on the
current medication regimen at least during the past 28 days

Exclusion Criteria:

1. Have undergone refractive eye surgery in either eye during the past 12 months

2. Have undergone uncomplicated cataract surgery in either eye during the past 3 months

3. Have undergone previous eyelid surgery in either eye (External blepharoplasty, not
resulting in exposure or abnormal blinking is allowed)

4. Have undergone botulinum toxin (BotoxTh1 or equivalent) injection in the periocular
area within 3 months prior to Visit 1

5. Subjects that have a systemic, multi-organ disease requiring active medical or
surgical treatment are excluded with the exception of subjects with SS or GVHD

6. Have punctal plugs, punctal occlusion, history of nasolacrimal duct obstruction or
wear scleral lens.

7. Past or present exposure keratopathy, neurotrophic keratopathy, lagophthalmos, or
trichiasis