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

Study Overview
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Brief Summary
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Randomised, double-masked placebo controlled study to evaluate safety and proof of concept with ascending doses of ANXV (human recombinant Annexin A5 protein) during 5 consecutive days treatment in patients recently diagnosed with Retinal Vein Occlusion.

Official Title
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Dose Ascending Safety, Tolerability, and Proof of Concept Double Masked, Placebo Controlled, Randomized Study to Evaluate the Use of ANXV (Human Recombinant Annexin A5) in Treatment of Subjects With Recently Diagnosed Retinal Vein Occlusion

Conditions
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Retinal Vein Occlusion

Intervention / Treatment
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* Biological: ANXV


Participation Criteria
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Eligibility Criteria
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Inclusion 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 must be non-pregnant and non-lactating, and either surgically sterile (e.g., ≥6 weeks post bilateral salpingectomy, bilateral oophorectomy with or without hysterectomy) or post-menopausal (12 months of spontaneous amenorrhea in females > 55years of age or, in females ≤55 years, or 12 months of spontaneous amenorrhea without an alternative medical, or 12 months with an elevated Follicle Stimulating Hormone (FSH) level Males must either be surgically sterile or abstinent*, or if engaged in sexual relations with a female of child-bearing potential, the subject or the subject's non-pregnant female partner must use a highly effective contraception method from the time of signing the Informed Consent Form (ICF) until at least 30 days after the last dose of study drug; Refer to Section 10.3 for acceptable methods *Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods). Declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods of contraception (Section 10.3). Onset of symptoms of Retinal Vein Occlusion within 14 days prior to informed consent BCVA score of less than 69 letters and greater than 34 letters (approx. 20/40 - 20/200 Snellen equivalent) on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart in the Study Eye 8. Clear ocular media and adequate pupillary dilation in the Study Eye to permit high quality retinal imaging 9. Willing to refrain from strenuous exercise/activity (for example heavy lifting, weight training, intense aerobics classes etc.) for at least 72 hours prior to study visits 10. A negative rapid SARS-CoV-2 (COVID) test on Day 1 prior to initiation of study drug infusion Exclusion Criteria: Subjects will not be eligible if they have any of the following criteria: Study Eye only: A Retinal Area of Non-Perfusion (RANP) that is > 30 Disc Areas (DA) on Ultra-Wide Field Fluorescein Angiography (UWF-FA) confirmed by the CRC A Relative Afferent Pupillary Defect (RAPD) Evidence of deep, extensive intraretinal hemorrhage Evidence of neovascularization confirmed by the CRC 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, clinically significant diabetic macular edema, retinal detachment, macular hole, vitreomacular traction, macular epiretinal membrane, clinically significant cataract, vitreal opacities or hemorrhage, glaucoma with documented visual field loss, ischemic optic neuropathy, retinitis pigmentosa or choroidal neovascularization of any cause (e.g., Age-related Macular Degeneration (AMD), ocular histoplasmosis, toxoplasmosis, or pathologic myopia) Laser photocoagulation in the study eye within the preceding 6 months prior to the Screening Visit Receipt within the past 6 months prior to the Screening Visit of any intraocular or periocular surgery (including refractive surgery, cataract surgery), or intravitreal (IVT) injection, or planned intraocular surgery or procedure during the study History of, or current evidence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus) Both Eyes: Within 6 months prior to the Screening Visit, use of medications known to be toxic to the retina, lens, or optic nerve (e.g., desferoxamine, 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-edema 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) History of glaucoma or an IOP greater than 24 mmHg that is not controlled with medication or surgery at the time of the Screening Visit History of, or presence of uveitis, presence of intraocular inflammation (history of blepharitis is not exclusionary), current ocular infection 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 medical or surgical procedure or trauma within 4 weeks prior to Day 1 (study drug administration), or planned major surgery within the duration of the study through Day 43 History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study Prior exposure to a recombinant Annexin A5 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) Prior or current use of any systemically administered anti-angiogenic agent (e.g., bevacizumab, sunitinib, cetuximab, sorafenib, pazopanib) or corticosteroids, approved or investigational History of malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated A history of or 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 subject at risk or may influence the results of the study, or the subject'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 investigational trial from signing ICF through Day 43 History of thromboembolic events or deep venous thrombosis within 6 months of Screening Visit Current use of anticoagulant medication (any medications that might have effect on coagulation, hemostasis, and platelets); 81 mg aspirin allowed prior to informed consent but must be stopped at the time of consent; may begin again 1 day post Day 5 infusion Current daily use of benzodiazepines (intermittent use permissible with MM approval) History of significant bleeding (gross hematuria, hemoptysis, gastrointestinal tract bleeding) Evidence or history of a hypercoagulable state (e.g. shortened APTT) 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 coronary artery disease or cerebrovascular accident within the last 6 months Estimated Glomerular Filtration Rate (eGFR) (based on plasma-creatinine) outside of normal range at screening or known renal impairment (≤70 mL/min) Recent history of, or current drug or alcohol abuse, current excessive smoking (i.e., ≥ 20/day) Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B Body Mass Index ≥ 30 kg/m2 at the time of informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2 mg ANXV - active<br>ANXV (human recombinant Annexin A5), infusion, 2 mg daily during five days. | Biological: ANXV<br>* ANXV (Human recombinant Annexin A5 protein)<br>|
| Placebo Comparator: 2 mg ANXV - placebo<br>Saline, infusion, daily during five days. | Biological: ANXV<br>* ANXV (Human recombinant Annexin A5 protein)<br>|
| Experimental: 4 mg ANXV - active<br>ANXV (human recombinant Annexin A5), infusion, 4 mg daily during five days. | Biological: ANXV<br>* ANXV (Human recombinant Annexin A5 protein)<br>|
| Placebo Comparator: 4 mg ANXV - placebo<br>Saline, infusion, daily during five days. | Biological: ANXV<br>* ANXV (Human recombinant Annexin A5 protein)<br>|
| Experimental: 1 mg ANXV - active<br>ANXV (human recombinant Annexin A5), infusion, 1 mg daily during five days. | Biological: ANXV<br>* ANXV (Human recombinant Annexin A5 protein)<br>|
| Placebo Comparator: 1 mg ANXV - placebo<br>Saline, infusion, daily during five days. | Biological: ANXV<br>* ANXV (Human recombinant Annexin A5 protein)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Treatment Emergent Adverse Events | Incidence and severity of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | 43 days | 
| Safety - Anti-drug antibodies | Incidence and titer of anti-drug antibodies (ADA) to ANXV pre- and post-administration | 43 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Slit lamp | Slit-lamp biomicroscopy including intraocular pressure (IOP) and dilated indirect ophthalmoscopy | 29 days | 
| Safety - Gonioscopy |  | 29 days | 
| Safety - Best Corrected Visual Acuity (BCVA) | Distance BCVA by manifest refraction should be performed utilizing the ETDRS chart at a starting distance of 4 meters | 29 days | 
| Safety - laboratory parameters | Concentration of analytes in Chemistry panel, lipid panel, hematology, coagulation, inflammatory and urinalysis | 43 days | 
| Safety - vital signs Blood Pressure | Blood pressure (BP) | 15 days | 
| Safety - vital signs Heart rate | Heart rate (HR) | 15 days | 
| Safety - vital signs Weight | Weight | 15 days | 
| Safety - vital signs Body Temperature | Body temperature | 15 days | 
| Safety - vital signs Respiratory rate | Respiratory rate (RR) | 15 days | 
| Safety - vital signs Pulse oximetry | Pulse oximetry | 15 days | 
| Safety - ECG | 12-lead ECG | 15 days | 
| Safety - ANXV anti-drug antibodies Persistence | Persistence anti-drug antibodies | 12 months | 
| Safety - ANXV anti-drug antibodies Titer | Titer of anti-drug antibodies | 12 months | 
| Efficacy - Microperimetry Change from baseline | Change from baseline in microperimetry mean retinal sensitivity calculated on all stimulus points ≤20 dB at baseline (MSEff), at Days 8, 15, and 29 | 29 days | 
| Efficacy - Microperimetry Stimulus points | Number of microperimetry stimulus points that improve by ≥7decibels (dB) from baseline to Day 8 and 29 after the first ANXV infusion | 29 days | 
| Efficacy - Microperimetry Improvement over baseline | Number of subjects with an improvement over baseline in MSEff of ≥7dB at Days 8, 15 and 29 (MMP positive responders, MMP-pos) | 29 days | 
| Efficacy - Microperimetry Incremental loss | Number of subjects with an incremental loss over baseline in MSEff of ≥7dB at Days 8, 15 and 29 (MMP negative responders, MMP-neg) | 29 days | 
| Efficacy - Microperimetry Improvement of ≥7dB | Number of subjects with an improvement of ≥7dB over baseline in ≥5 stimulus points at Days 8, 15 and 29 (MMP positive-5 responders, MMP-pos-5) | 29 days | 
| Efficacy - Microperimetry MMP negative-5 responders | Number of MMP negative-5 responders, i.e., subjects with an incremental loss over baseline of ≥7dB in ≥5 stimulus points at Days 8, 15 and 29 (MMP-neg-5) | 29 days | 
| Efficacy - BCVA Improvement | Number of subjects with an improvement of ≥15 ETDRS letters over baseline at Days 8, 15 and 29 | 29 days | 
| Efficacy - BCVA Improvement or letter score ≥78 | Number of subjects with an improvement of ≥15 ETDRS letters over baseline or an ETDRS letters score ≥78 at Days 8, 15 and 29 | 29 days | 
| Efficacy - Spectral Domain Optical Coherence Tomography / Spectral Domain Optical Coherence Tomography Angiography (SD-OCT/OCTA) SD-OCT | Change from baseline in Center Subfield Macular Thickness (CMT), Macular Volume and Outer Nuclear Layer (ONL) thickness on SD-OCT at Days 8, 15 and 29 | 29 days | 
| Efficacy - Spectral Domain Optical Coherence Tomography / Spectral Domain Optical Coherence Tomography Angiography (SD-OCT/OCTA) OCTA | Change from baseline in Foveal Avascular Zone (FAZ) and Vessel Density (VD) on OCTA at Days 8, 15 and 29 | 29 days | 
| Efficacy - Ultra-Wide Field Fluorescein Angiography (UWF-FA) Size of Retinal Area of Non-Perfusion | Change from baseline at Days 8 and 29 in the size of Retinal Area of Non-Perfusion (RANP) for: all the retina captured by UWF-FA in posterior pole | 29 days | 
| Efficacy - Ultra-Wide Field Fluorescein Angiography (UWF-FA) Conversion from non-ischemic RVO to ischemic RVO | Number of subjects at Days 8, and 29 with: RANP ≥30 DA RANP ≥10 DA Rate of conversion from non-ischemic RVO (niRVO) to ischemic RVO (iRVO) by Day 29 | 29 days | 
| Efficacy - Need for rescue treatment with anti Vascular Endothelial Growth Factor (aVEGF) therapy | Number of subjects requiring rescue with an aVEGF by Day 29 | 29 days | 
| Ischemic Index | Change in Ischemic Index (ISI) from baseline at Days 8 and 29 | 29 Days | 
| Pharmacokinetic (PK) profile | ANXV concentration on Days 1 and 5 pre-infusion and at 15, 30, and 40 minutes and 1, 1.5, 2 and 3.5 hours after the start of the infusion | 5 days |