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

Prior treatment

• 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.
• 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).
• Any major (complex, invasive medical or surgical procedure or trauma that carries a higher risk of complications and requires a longer recovery period) 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
• 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).
• Either or both eyes: An IOP greater than 24 mmHg that is not controlled with medication or surgery at the time of the Screening Visit.
• Intravitreal treatment in either eye: - Anti-VEGF treatment within 3 months before Visit 1 (e.g. ranibizumab (Lucentis®), aflibercept* (Eylea®), brolucizumab (Beovu®), faricimab (Vabysmo®), bevacizumab (Avastin®) or biosimilar products)(*RVO participants in a cohort designated by the Sponsor for aflibercept pre-treatment, are allowed a single intravitreal injection of aflibercept 2 mg to treat macular oedema caused by the present RVO, 7-14 days prior to first ANXV administration.) - Longer acting anti-VEGF treatment within 6 months before Visit 1 (e.g. 8 mg aflibercept) - Short-acting corticosteroids within 3 months before Visit 1 - Longer-acting corticosteroids within 6 months before Visit 1 (e.g. dexamethasone (Ozurdex®)) - Iluvien® (Flucinolone acetonide intravitreal implant) in the - study eye - within 3 years before Visit 1
• Study Eye only: Intraocular surgery (including refractive surgery, cataract surgery), or cataract surgery within the preceding 3 months prior to the Screening Visit, or planned intraocular surgery or procedure during the study.
• Prior exposure to a recombinant Annexin A5 protein.
• Current use of any systemically administered anti-angiogenic agent (e.g., bevacizumab, sunitinib, cetuximab, sorafenib, pazopanib) or corticosteroids.
• 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.

Other illness

• History of thromboembolic events or deep venous thrombosis within 3 months of Screening Visit.
• 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.
• 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).
• 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: Recent (6 months) history of, or presence of uveitis, presence of intraocular inflammation (history of blepharitis is not exclusionary), current ocular infection.
• Either or both eyes: Ocular disorders/additional eye disease, which in the opinion of the Investigator may confound interpretation of study results for the study eye (SE), compromise patient safety, 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) (N.B. If the study eye (SE) is not affected by any of the above mentioned disorders/disease, the participant may be eligible based on Investigator clinical judgement).
• 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.
• Study Eye only: Evidence of deep intraretinal haemorrhage involving the centre 1mm of the macula.
• Study Eye only: Recent (6 months) history, or current evidence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus).
• 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).
• Diagnosed untreated systemic metastasis malignancy.

Lab values

• Current use of medication that might have effect on coagulation, haemostasis, and platelets); low dose aspirin allowed prior to informed consent but must be discontinued once informed consent has been obtained, after consultation with the treating/prescribing physician, and at least 7 days prior to the first administration of ANXV; may begin again 1 day post last study Treatment infusion.
• Current known kidney disease or evidence of kidney disease and eGFR below 60 mL/min/1.73m2 at baseline.

Other

• 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.
• Current daily use of benzodiazepines.
• Clinically significant abnormal coagulation parameters at baseline.
• Class III obesity (Body Mass Index ≥ 40kg/m2), at the time of informed consent (Medical Monitor or Sponsor may accept eligibility for a participant with higher Body Mass Index based on the participant´s overall health status).
• Either or both eyes: A severe (≥0.9 log, Grade 3+ or worse) Relative Afferent Pupillary Defect (RAPD).
• Either or both eyes: Evidence of neovascularization in the study eye (SE) (this exclusion criterion is only applicable for participants with RVO).
• Either or both eyes: ETDRS BCVA score in the Fellow eye of ≤54 (equivalent to Snellen 6/24 or 20/80).
• Study Eye only: Full 4-quadrant panretinal laser photocoagulation with significant retinal carbonisation or RPE loss on UWF-Fundus autofluorescence which, in the opinion of the Principal Investigator, will affect the assessment of the effects of the IMP ANXV
• DR participants: CI-DMO (i.e. involving the central 1mm subfield) in study eye which, in the opinion of the Investigator, qualifies for immediate anti-VEGF or laser treatment.

• 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.
• DR participants must be diagnosed with mild NPDR (DRSS score of 35) with significant retinal ischemia, or moderately severe or severe NPDR (DRSS score of 47 and 53 respectively), without CI-DMO# that requires immediate treatment*, or mild or moderate PDR without CI-DMO# that requires immediate treatment* defined as having a DRSS score of 61 and 65 respectively. (#DMO not involving the central 1mm subfield will be eligible) (*in the opinion of the Principal Investigator)
• DR participants must be found to have an ETDRS BCVA score in the study eye (SE) of ≥64 ETDRS (equivalent to Snellen 6/15 or 20/50).
• RVO participants must be diagnosed with Retinal Vein Occlusion with onset of symptoms within 45 days prior to first administration of ANXV. For participants enrolled into a cohort designated by the Sponsor for aflibercept pre-treatment, a single intravitreal injection of commercially available aflibercept 2 mg must have been administered as part of routine clinical care (outside the study) 7-14 days prior to the first administration of ANXV.