A Study of the Safety and Tolerability of Intravitreal LKA651 in Patients With Diabetic Macular Edema

This first-in-human study will be conducted in 2 parts. Part 1 is an ascending dose design
to assess the safety, tolerability, pharmacodynamics and pharmacokinetics of various single
IVT doses of LKA651 in up to 48 subjects with diabetic macular edema. Subjects will be
randomized to receive active or sham injections in a 3:1 ratio. A total of 6 cohorts (8
subjects per cohort) may be enrolled in Part 1. Each subject will participate in a
screening/eligibility period (up to 60 days), a treatment period (single day), and an 84 day
follow up period. A total of up to 11 visits will take place, all on an out-patient basis.
An independent data monitoring committee (DMC) will be chartered to review cumulative safety
data and approve each dose escalation and cohort progression in this first-in-human trial.

Part 2 is a double-masked design to assess the safety/tolerability, pharmacokinetics and
pharmacodynamics of a single IVT dose of LKA651 when co-administered with Lucentis®. A total
of up to 3 cohorts (8 subjects per cohort) may be enrolled in Part 2. Each subject will
participate in a screening/eligibility period (up to 60 days), a treatment period
(combination therapy, single day), and an 84 day follow up period. A total of up to 11
visits will take place, all on an out-patient basis. For the LKA651 vs sham injections, the
unmasked ophthalmologist is not permitted to do any of the assessments except for the
injection (and an inspection of the injection site immediately following). All other ocular
assessments after randomization will be conducted by a second ophthalmologist masked to the
type of injection (active or sham). The Lucentis injection (Part 2) is given open label to
all patients following either the LKA651 or sham injection.

Inclusion Criteria:

- Written informed consent must be obtained.

- Type 1 or type 2 diabetes that is actively managed by a physician and hemoglobin A1C
≤ 12% at screening/eligibility.

- Negative pregnancy test results at screening/eligibility and pre-injection on
treatment day.

- Diabetic macular edema (DME) with center involvement in at least one eye, including
those with focal or diffuse DME.

- ETDRS letter score in the study eye of 55 letters or worse (approximate Snellen
equivalent of 20/80). The non-study eye (fellow eye) should be ≥ 60 letters or better
(approximate Snellen equivalent of 20/63) at Day 1 pre-dose.

- Safe to withhold treatment of the study eye with laser photocoagulation, intravitreal
steroid injection, or intravitreal vascular endothelial growth factor (VEGF)
inhibitor (Part 1) for the duration of the study.

- Other protocol-defined inclusion criteria may apply.

Exclusion Criteria:

- Proliferative diabetic retinopathy in the study eye, with the exception of tufts of
neovascularization less than 1 disc area with no vitreous hemorrhage.

- Any progressive disease of the retina (e.g. uveitis, rod-cone dystrophy) or optic
nerve (e.g. glaucoma) other than diabetic retinopathy.

- Any active infection involving ocular adnexa including infectious conjunctivitis,
keratitis, scleritis, endophthalmitis, as well as idiopathic or autoimmune-associated
uveitis in either eye.

- Ocular disorders in the study eye that may confound interpretation of study results,
including retinal vascular occlusion, retinal detachment, macular hole, or choroidal
neovascularization of any cause (e.g., AMD, ocular histoplasmosis, or pathologic
myopia).

- Cataract surgery in the study eye, Yttrium-Aluminum-Garnet (YAG) laser capsulotomy or
any intraocular surgery within the past 6 months preceding Day 1.

- Use of systemic anticoagulant therapy during the study, e.g., warfarin, heparin, etc.
The use of aspirin is not an exclusion.

- Use of other investigational drugs at the time of enrollment, or within 5 half-lives
of enrollment, whichever is longer; or longer if required by local regulations.

- Pregnant or nursing (lactating) women.

- Women of child-bearing potential, unless using highly effective methods of
contraception during dosing of study treatment.

- Other protocol-defined exclusion criteria may apply.