A Phase I Single Ascending Dose Study of the Intravitreal Plasma Kallikrein Inhibitor KVD001 in Subjects With DME

The plasma kallikrein-kinin system has long been recognized as a key player in inflammatory
processes, capillary leakage and angiogenesis in various organs. Recent work suggests that
plasma kallikrein is central to the pathogenesis of Diabetic Macular Edema (DME) and that
activation of the enzyme contributes to the excessive retinal vascular permeability leading
to DME. Among different persons with DME, plasma kallikrein contributes both independently
in some, and in association with Vascular Endothelial Growth Factor (VEGF) in others.
However, the effect of plasma kallikrein appears to be independent of VEGF. Thus, growing
scientific evidence points to plasma kallikrein inhibitors as an exciting potential new
therapeutic opportunity directed at a novel VEGF-independent pathway that may reduce retinal
vascular permeability and treat DME, in patients whose disease process is, at least in part,
driven by the plasma kallikrein pathway.

This is an open label, single ascending dose study to investigate the safety, tolerability
and pharmacodynamics of a novel plasma kallikrein inhibitor administered by intravitreal
(IVT) injection in subjects with central involved diabetic macular edema and reduced vision.

Inclusion Criteria:

1. Male or female adult subjects 18 years of age and older

2. Confirmed diagnosis of Type I or Type II diabetes mellitus

3. Best corrected visual acuity, using Early Treatment Diabetic Retinopathy Study
(ETDRS) electronic visual acuity (EVA) testing, of between 20/40 and 20/400 (Snellen
equivalent) in the study eye

4. Fellow eye acuity 20/80 or better measured as above with no expectation of
requirement for anti-VEGF treatment in fellow eye within 2 months of study drug
administration

5. Presence of central involved DME in the study eye defined as Optical Coherence
Tomography (OCT) Central Subfold Thickness (CST) ≥305 µm in women and ≥320 µm in men
in the study eye

6. Subjects who fulfil one of the following criteria:

1. Subjects who have not previously received an anti-VEGF treatment and who, in the
view of the Investigator, can have initiation of anti-VEGF treatment in the
study eye deferred for at least 2 months following the date of anticipated study
drug administration

2. Subjects who are receiving regular anti-VEGF intravitreal injections who:

- Have received at least 3 intravitreal injections of an anti-VEGF treatment
within the last 5 months (study drug administration will be at least 6
weeks after the most recent intravitreal administration of anti-VEGF) and

- In the view of the Investigator, can have continuation of anti-VEGF
treatment in the study eye deferred for at least 2 months following the
date of anticipated study drug administration

3. Subjects who have received anti-VEGF in the past (>3 months prior to study
inclusion) but are not actively receiving treatment and who in the view of the
Investigator, can have resumption of anti-VEGF or alternative treatment in the
study eye deferred for at least 2 months following anticipated study drug
administration

7. Subjects, who in the view of the Investigator, are not expected to require panretinal
laser photocoagulation or intravitreal steroids or intraocular surgery in the study
eye for at least 2 months following anticipated study drug administration

8. No prior treatment with panretinal photocoagulation or intravitreal steroid in the
study eye within the previous 3 months

9. No prior treatment with systemic corticosteroids or systemic anti-VEGF therapy within
the previous 3 months

10. Study participant voluntarily agrees to participate in this study and signs the
Institutional Review Board (IRB) approved informed consent prior to performing any
procedure

Exclusion Criteria:

1. Females who are pregnant or lactating, or expecting to become pregnant during the
course of the study

2. Poorly controlled diabetes mellitus

3. Uncontrolled hypertension

4. Significant co-existing disease

5. Participation in an investigational intervention clinical study within 2 months prior
to study inclusion

6. History of alcohol and/or drug abuse in the last 2 years

7. Men not willing to use appropriate birth control methods

8. Media clarity or pupillary dilation inadequate to obtain reasonable quality OCT
and/or fundus image

9. Subjects employed by the Sponsor or in any relationship of dependence with the
Sponsor and/or Investigator