A First in Human trial to study safety and tolerability of single rising intravitreal doses (oPen label, non-randomized, uncontrolled) and in Addition the early biological Response of mulTiple intravitreal doses (double-masked, RandomIzed, shamcontrolleD) of BI 765128 in panretinal photocoaGulation (PRP) treated diabetic rEtinopathy (DR) patients with diabetic macular ischemia (DMI) - the PARTRIDGE Study

Diabetic retinopathy (DR) can cause visual loss in a number of ways.
Microvascular changes due to hyperglycemia lead to increases in permeability,
and thus extravascular exudation and fluid accumulation in the macula (diabetic
macular edema, DME). Similarly, alterations of micro-vessels can lead to
retinal non-perfusion and ischemia. Consequently, a dramatic increase of
vascular endothelial growth factor (VEGF) drives the formation of retinal new
vessels (proliferative diabetic retinopathy, PDR), which eventually bleed, and
cause a sudden decrease in vision (vitreous hemorrhage). In both conditions,
VEGF plays a fundamental role, and anti-VEGF agents are effective in improving
both DME and DR. For patients with PDR, panretinal photocoagulation (PRP) is
the current standard of care. Patients with severe non- proliferative diabetic
retinopathy (NPDR) and a high risk of developing PDR can also benefit from PRP
to prevent progression of retinopathy. PRP destroys the ischemic retina, (the
major source of VEGF), and thus prevents the formation of new vessels, or
promotes their regression.

In some patients, however, in the absence of DME, after successful treatment
with PRP, with no evidence of active new vessels, the visual acuity continues
to decrease.

Some reports have suggested increasing ischemia in the central part of the
retina, the macula, as a possible explanation. In this condition, called
diabetic macular ischemia (DMI), the retinal tissue may not receive enough
nutrients leading to retinal tissue loss and permanent and irreversible vision
loss. In DMI, anti-VEGF therapy is not effective, and destructive laser
photocoagulation cannot be applied.

Previously, DMI was observed and diagnosed by means of fluorescein angiography
(FA) using an intravenous dye. It was defined as an abnormal enlargement of the
foveal avascular zone (FAZ). In patients with diabetic retinopathy, FA may show
an abnormal enlargement of the FAZ, which is the most common definition of DMI.
Recently, optical coherence tomography angiography (OCTA) has emerged which can
visualize the retinal blood vessels and hence ischemia in greater detail. OCTA
is non-invasive and multiple levels of the capillary plexus can be visualised.
OCTA can measure the area of the FAZ. Moreover, the FAZ measured by FA
corresponds well with the FAZ measured by OCTA (R17-3317). For these reasons
OCTA is likely to become the gold standard in the diagnosis and monitoring of
DMI.

There are many unknowns related to DMI. Since this condition is associated with
a progressive loss of neural tissue, it can be hypothesized that restoration of
the macular vasculature before retinal degeneration occurs could be a key
objective for these patients and prevent permanent vision loss. There are
currently no treatments available for DMI making it an urgent unmet need.

Diabetic Macular Ischemia (DMI) is a complication of diabetic retinopathy (DR)
and can lead to vision loss. Currently, there are no approved or effective
treatments to prevent either onset or progression of DMI in DR patients.

As a transition from preclinical investigations to clinical development in this
first-in human trial, the safety, tolerability, pharmacokinetics and early
biological response of BI 765128 will be investigated in volunteer subjects
with DMI.

This trial will include subjects affected by DMI with significant visual loss
since intravitreal injections in subjects without the condition would not be
considered ethically justifiable.

This trial will consist of two parts, A and B. Part A will be nonrandomized,
open-label and uncontrolled. Part B will be doublemasked, randomized and
sham-controlled (ratio 2:1). The Netherlands will participate in part B.

This trial will consist of two parts, Part A and Part B.

Cohorts of subjects will receive escalating doses of BI 765128, with the
starting dose of 0.5 mg. The other dose level is 1 mg and the maximum planned
dose is 2.5 mg.

For any dose-escalation cohort, at least 3 evaluable subjects will be required.
Each cohort will
consist of newly enrolled subjects.

Dosing of subjects will be done in the following order:
- Cohort 1, 0.5 mg (number=3)
- Cohort 2, 1 mg (number=3)
- Cohort 3, 2.5 mg (number=6)

Part B of the study will only start if the highest dose is tolerated. Once the
last subject in the highest dose cohort of Part A has attended visit 5 (day15)
the SMC will meet and evaluate all DLE data as well as available systemic and
ophthalmological safety data. The decision on whether to proceed to Part B will
be taken based on the occurrence of DLEs.

In Part B, the highest dose will be used (2.5mg). Thirty subjects will be
recruited, 2:1 ratio of active treatment versus sham. Subjects dosed in Part A
of the trial will not be included.

Subjects will be randomized to receive either active treatment or sham
injection. In Part B, subjects will receive three consecutive doses/sham
injections over a 3-month period (once every 4 weeks). All subjects included in
the part B of the trial, will be observed for safety and efficacy for 12 weeks
after the last injection.

Part B will provide information about the early biological response of BI
765128 by comparing the treated group to the sham group.

Burden/ possible risk:
- Worsening of the disease
- Patient may experience side effects or adverse events of the study drug
- Patient may experience discomfort due to the procedures and measurements
during the study
- Additional procedures and measurements will be performed (outside SoC), as
described in the protocol
- Participating in the study will take extra time
- Patient needs to adhere to the study schedule

The procedures that will be performed in this study are described in section
E4, E5 and E6 of this ABR.

Possible benefit:
- The study medication may improve the symptoms associated with DMI
- Participation in the study helps researchers gain a better understanding of
the disease.
See section 1.4 of the protocol for the benefit-risk assessment.