Safety and Proof of Concept Study of ANXV (Annexin A5) in Patients With Diabetic Retinopathy or Retinal Vein Occlusion

The study is an open label, prospective, dose evaluation study to investigate the safety, tolerability and efficacy in patients with Non-Proliferative Diabetic Retinopathy (NPDR) or Retinal Rein Occlusion with recent onset (within 28 days from symptoms onset or diagnosis (whichever is first) to first treatment).

The study consists of 11 visits, whereof one screening visit, five treatment visits and five follow up visits, during a 4 months period.

Intervention is intravenous infusion (30 minutes) with the investigational medicinal product ANXV, a recombinant Annexin A5 protein. The intended dose levels are 4 mg, 1 mg and 6 mg, daily administration for five days.

Safety will be regularly evaluated by the Medical Monitors on a per need basis, as data become available. In case of safety concerns within one indication subset (NPDR and RVO), a lower dose will be initiated within the concerned indication subset (for each subset, independently).

The following assessments will be performed:

Ocular assessments:

• BCVA
• OCT and OCTA
• ERG
• UWF-retinal imaging
• UWF-FFA
• Ocular examination - Slit Lamp biomicroscopy examination, Intraocular Pressure (IOP), RAPD
• Dilated indirect ophthalmoscopy

Non-ocular assessments:

• Vital signs
• ECG
• Safety labs (blood and urine)
• Study labs (blood)

Inclusion criteria

To be eligible to participate in this trial, an individual must meet all the following criteria:

• Must have given written informed consent (signed and dated), and any authorizations required by local law and be able to comply with all study requirements
• Male or female, ≥18 years of age at the time of informed consent
• Females should have no childbearing potential according to Clinical Trial Facilitation Group (CTFG) definition.
• Clear ocular media and adequate pupillary dilation in the Study Eye to permit high quality retinal imaging
• Willing to refrain from unusually strenuous exercise/activity (for example heavy lifting, weight training, intense aerobics classes etc.) for at least 72 hours prior to study visits

Additionally, NPDR participants must meet the following criteria to be eligible:

• Diagnosed with moderately severe or severe non-proliferative Diabetic Retinopathy defined as having a DRSS score of 47 and 53 respectively, and no CI-DMO
• Found to have an ETDRS BCVA score in the study eye (SE) of ≥69 ETDRS (equivalent to Snellen 6/12 or 20/40)

Additionally, RVO participants must meet the following criteria to be eligible:

• Diagnosed with Retinal Vein Occlusion with onset of symptoms within 28 days prior to first administration of ANXV

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this trial:

General:

• Unwillingness or inability to attend all study visits and/or perform all procedures/tests/examinations, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
• Any major medical or surgical procedure or trauma within 4 weeks prior to the day of trial intervention Treatment 1 (ANXV administration), or planned major surgery within the duration of the study through Day 120
• History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study
• Prior exposure to a recombinant Annexin A5 protein
• History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to biologics (for example systemically administered recombinant proteins/peptides; a similar drug class to ANXV)
• Uncontrolled hypertension (systolic > 180 mmHg or diastolic > 110 mmHg)
• Current use of any systemically administered anti-angiogenic agent (e.g., bevacizumab, sunitinib, cetuximab, sorafenib, pazopanib) or corticosteroids
• Diagnosed untreated systemic metastasis malignancy
• A current systemic infection or inflammation that may require antiviral or antimicrobial therapy that will not be completed prior to Screening Visit, or that in the opinion of the Investigator and with concurrence of the Medical Monitor may either put the participant at risk or may influence the results of the study, or the participant's ability to participate in the study
• Treatment with another investigational drug, biological agent, or device within 3 months of Screening Visit, or 5 half-lives of investigational agent, whichever is longer or planned participation in an interventional trial from signing Informed Consent Form (ICF) through Day 120
• History of thromboembolic events or deep venous thrombosis within 3 months of Screening Visit
• Current use of anticoagulant medication (any medications that might have effect on coagulation, haemostasis, and platelets); low dose aspirin allowed prior to informed consent but must be stopped at the time of consent; may begin again 1 day post Treatment 5 infusion
• Current daily use of benzodiazepines
• Clinically significant abnormal coagulation parameters at baseline
• History of autoimmune disease with anticipated presence of persistent Annexin A5 antibodies, e.g., antiphospholipid syndrome, systemic lupus erythematosus, rheumatoid arthritis, Behcet disease or systemic sclerosis
• Inherited blood disorder (e.g. sickle cell disease, thalassemia)
• History of unstable coronary artery disease or cerebrovascular accident within the last 3 months
• Current known kidney disease or evidence of kidney disease and eGFR below 60 mL/min/1.73m2 at baseline
• Current drug or alcohol abuse as per the opinion of the Investigator, or current excessive nicotine intake (e.g. ≥ 20 cigarettes/day, or equivalent, as per the opinion of the Investigator)
• Known history of or positive test for chronic infection that affect the immune system (e.g. hepatitis C (HCV), chronic hepatitis B (HBV) and HIV)
• Class III obesity (Body Mass Index ≥ 40kg/m2), at the time of informed consent
• Within 6 months prior to the Screening Visit, use of medications known to be toxic to the retina, lens, or optic nerve (e.g., deferoxamine, chloroquine/hydrochloroquine, chlorpromazine, phenothiazines, tamoxifen, and ethambutol)
• Known hypersensitivity or allergy to fluorescein (e.g., bronchospasm, rash, etc.) or to any component of the study products or a contraindication to dilation of the pupil or fixed pupils; mild allergies without angio-oedema or treatment need may be acceptable if deemed not to be of clinical significance (including but not limited to allergy to animals or mild seasonal hay fever)

Either or both eyes:

• A severe (≥0.9 log, Grade 3+ or worse) Relative Afferent Pupillary Defect (RAPD)
• An IOP greater than 24 mmHg that is not controlled with medication or surgery at the time of the Screening Visit
• Recent (6 months) history of, or presence of uveitis, presence of intraocular inflammation (history of blepharitis is not exclusionary), current ocular infection
• Evidence of neovascularization
• ETDRS BCVA score in the Fellow eye of ≤54 (equivalent to Snellen 6/24 or 20/80)
• Ocular disorders/additional eye disease, which in the opinion of the Investigator may confound interpretation of study results, compromise protocol assessments or are likely to require intervention during the study, including, but not limited to, atrophy of the retinal pigment epithelium, sub-retinal fibrosis, organized hard exudate plaque, retinal detachment, macular hole, vitreomacular traction, macular epiretinal membrane, clinically significant cataract, vitreous opacities or haemorrhage, glaucoma with documented visual field loss, ischemic optic neuropathy, retinitis pigmentosa or choroidal neovascularization of any cause (e.g., AMD, ocular histoplasmosis, toxoplasmosis, or pathologic myopia)
• Receipt within the past 6 months or ongoing intravitreal injection of anti-VEGF treatment in either eye

Study Eye only:

• Evidence of deep intraretinal haemorrhage involving the centre 1mm of the macula
• Laser photocoagulation in the study eye within the preceding 6 months prior to the Screening Visit, or likely to receive during the study period
• Intraocular surgery (including refractive surgery, cataract surgery), or intravitreal (IVT) injection within the preceding 6 months prior to the Screening Visit, or cataract surgery within the preceding 3 months prior to the Screening Visit, or planned intraocular surgery or procedure during the study
• Recent (6 months) history, or current evidence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus)

NPDR participants will not be eligible if they meet any of the following criteria (only NPDR participants):

• CI-DMO in either eye which, in the opinion of the Investigator, qualifies for anti-VEGF or laser treatment