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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Annexin Pharmaceuticals AB (publ)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Eye Diseases [C11]

Decision date (initial)

2026-04-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Annexin Pharmaceuticals AB

External identifiers

EU CT number

2026-525349-65-00

ClinicalTrials.gov

NCT07259928

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

To evaluate the safety and tolerability of recombinant human Annexin A5 (ANXV) in participants with Diabetic Retinopathy (DR) or Retinal Vein Occlusion (RVO).

Secondary objectives 1

1. To explore the proof of concept and to determine pharmacokinetics of ANXV in the treatment of DR and RVO.

Conditions and MedDRA coding

Diabetic Retinopathy

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

Yes

IPD plan description

Following completion of the study, the main study results will be published. De-identified individual participant data may be shared with individual qualified researchers upon reasonable request and in accordance with applicable data protection regulations.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 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.
2. Male or female, ≥18 years of age at the time of informed consent.
3. Females should have no childbearing potential according to Clinical Trial Facilitation Group (CTFG) definition.
4. Clear ocular media and adequate pupillary dilation in the Study Eye to permit high quality retinal imaging.
5. 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.
6. 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)
7. 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).
8. RVO participants must be diagnosed with Retinal Vein Occlusion with onset of symptoms within 28 days prior to first administration of ANXV.

Exclusion criteria 35

1. 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.
2. 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
3. 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.
4. Prior exposure to a recombinant Annexin A5 protein.
5. 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).
6. Uncontrolled hypertension (systolic > 180 mmHg or diastolic > 110 mmHg).
7. Current use of any systemically administered anti-angiogenic agent (e.g., bevacizumab, sunitinib, cetuximab, sorafenib, pazopanib) or corticosteroids.
8. Diagnosed untreated systemic metastasis malignancy.
9. 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.
10. 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.
11. History of thromboembolic events or deep venous thrombosis within 3 months of Screening Visit.
12. 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 last study Treatment infusion.
13. Current daily use of benzodiazepines.
14. Clinically significant abnormal coagulation parameters at baseline.
15. 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.
16. Inherited blood disorder (e.g. sickle cell disease, thalassemia).
17. History of unstable coronary artery disease or cerebrovascular accident within the last 3 months.
18. Current known kidney disease or evidence of kidney disease and eGFR below 60 mL/min/1.73m2 at baseline.
19. 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).
20. 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).
21. 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).
22. 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).
23. 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).
24. Either or both eyes: A severe (≥0.9 log, Grade 3+ or worse) Relative Afferent Pupillary Defect (RAPD).
25. 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.
26. 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.
27. Either or both eyes: Evidence of neovascularization in the study eye (SE) (this exclusion criterion is only applicable for participants with RVO).
28. Either or both eyes: ETDRS BCVA score in the Fellow eye of ≤54 (equivalent to Snellen 6/24 or 20/80).
29. 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).
30. 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) - 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
31. Study Eye only: Evidence of deep intraretinal haemorrhage involving the centre 1mm of the macula.
32. 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
33. 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.
34. Study Eye only: Recent (6 months) history, or current evidence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus).
35. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Incidence and severity of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs).
2. Incidence and titre of anti-drug antibodies (ADA) to ANXV pre- and post-administration.

Secondary endpoints 19

1. Persistence and titre of ADA.
2. OCT (CST, Macular Volume and ONL thickness, areas of oedema and DRIL)
3. OCTA (FAZ, VD, Perfusion Density of the Vascular Complex layers on the macula, and vessel skeleton).
4. BCVA (ETDRS letters).
5. Contrast Sensitivity (letter log contrast sensitivity score).
6. Electroretinogram (ERG) (RETeval: DR Score, amplitude response and implicit time changes from baseline in Flicker ERG, change in PhNR).
7. Ultra-Wide Field Fundus Fluorescein Angiography (UWF-FFA) (DRSS score, RANP, vessel leakage, conversion from niRVO to iRVO, ISI).
8. Ultra-Wide Field Retinal Imaging (resolution of haemorrhages).
9. MMP (changes in Mean Sensitivity).
10. Rescue Treatment.
11. The PK profile of ANXV as determined on the days of Treatment 1, Treatment 4 and Treatment 5 pre-infusion and at 15, 30, and 40 minutes and 1, 1.5, 2 and 4 hours after the start of the infusion.
12. PK parameters after the first dose: AUClast, Cmax, Tmax, λz, T½, CL, Vz.
13. PK parameters after the first dose: Dose proportionality
14. PK parameters after the fourth and fifth dose (or third dose for participants only receiving three doses): Area Under the Curve (AUC) during a dosage interval (tau) (AUCtau).
15. PK parameters after the fourth and fifth dose (or third dose for participants only receiving three doses): Cmax, Tmax, λz, T½, CL, Vz, Vss.
16. PK parameters after the fourth and fifth dose (or third dose for participants only receiving three doses): Dose proportionality after multiple doses, based on AUC over the dose interval (AUCtau) and Cmax.
17. PK parameters after the fourth and fifth dose (or third dose for participants only receiving three doses): Accumulation ratio.
18. PK parameters after the fourth and fifth dose (or third dose for participants only receiving three doses): Minimum plasma concentrations of ANXV prior to dosing on the day of Treatment 4 and Treatment 5 (Cmin).
19. PK parameters after the fourth and fifth dose (or third dose for participants only receiving three doses): Mean plasma concentrations of ANXV on the day of Treatment 4 and Treatment 5 (Cmean).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Annexin Pharmaceuticals AB (publ)

Sponsor organisation

Annexin Pharmaceuticals AB (publ)

Address

Kammakargatan 48, Adolf Fredrik Adolf Fredrik

City

Stockholm

Postcode

111 60

Country

Sweden

Scientific contact point

Organisation

Annexin Pharmaceuticals AB (publ)

Contact name

Chief Operating Officer

Public contact point

Organisation

Annexin Pharmaceuticals AB (publ)

Contact name

Chief Operating Officer

Third parties 2

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications