A Study of PRL3-zumab in Neovascular Age-related Macular Degeneration (nAMD)

ASSESSMENTS:

Safety:

All adverse events (AEs) will be classified according to Common Terminology Criteria for Adverse Events (CTCAE) version 5 or the latest version.

Treatment-emergent adverse events (TEAEs), Treatment-related TRAEs, serious TEAEs, TEAE of Grade 2 or greater, TEAEs leading to treatment discontinuation, and TEAEs leading to dose modification will be summarized respectively. Physical examination findings, Clinical laboratory data, vital signs will be summarized descriptively.

• . Ocular adverse event:

Ocular adverse events will be identified at every drug administration visit followed by every 4 weeks (28 days) eye examination. Any ocular adverse events will be recorded and determined for possible or probable relation to study treatment. Post-injection complications including worsening visual acuity, change in vision, worsening macular oedema, vitreous hemorrhage, retinal pigment epithelium tears, retinal tear or detachments, inflammation and intra ocular pressure (IOP) alterations will be identified.

• . Non-ocular adverse events Patient safety will be evaluated based on physical examination, vital signs (blood pressure [systolic and diastolic], heart rate, respiratory rate, and temperature), clinical laboratory tests (hematology, liver and renal function). Patient safety will be assessed on an ongoing basis at every drug administration visit followed by 4 weeks after the last dose of treatment.

Efficacy:

Efficacy assessment will be performed 4 weeks from the first dose of treatment by

• . Visual Acuity (Best Corrected Visual Acuity) by ETDRS letter score
• . Central retinal thickness by OCT
• . Intraretinal fluid (IRF) and/ or subretinal fluid (SRF) by OCT

DURATION OF THE STUDY:

The duration of study treatment is 4 weeks and monitoring is 20 weeks. Total duration of study will be 24 weeks.

Treatment Period:

PRL3-zumab will be administered 3 times in 2-week interval within the first 4 weeks of study period. Treatment with be terminated in case of intolerable toxicity, patients meet the criteria for end-of-trial or withdrawal of consent.

Monitoring Period:

Monitoring will be done every 4 weeks, starting from 4 weeks after the 3rd dose of study medication. The total duration of Monitoring period will be 20 weeks (All 3 arms). The trial will be terminated in case of intolerable toxicity, patients meet criteria for end of trial or withdrawal of consent.

Sample Size Determination PRL3-zumab was administered intravenously with the dose of 6mg/kg in > 155 advanced cancer patients to date (14 Dec 2023) with no safety issue. No drug-related Serious Adverse Event was reported so far. This clinical trial is for extended indication of PRL3-zumab in nAMD disease.

Primary endpoint is adverse events, visual acuity, central retinal thickness and IRF and/or SRF. No. of evaluable patients for primary endpoint (minimum) in each cohort = 3 -6 Only patients who have received PRL3-ZUMAB are evaluable, patients who did not receive PRL3-ZUMAB may be replaced to achieve the total sample size.

Arm 1: PRL3-zumab 3mg/kg (n=6) Arm 2: PRL3-zumab 6mg/kg (n=6) Arm 3: Placebo (normal saline) (n=3)

Once the Recommended Phase 2 Dose (RP2D) is confirmed and endpoints have been assessed in this trial, this protocol will be amended to include a detailed design of a Phase II expanded study.

Inclusion criteria

• Patients with Neovascular Age-related Macular Degeneration (nAMD).
• Willing to provide written informed consent for the study.
• Patients undergoing intravitreal treatment having failed at least two Standard-of care treatments and be receiving ongoing intravitreal treatment at intervals of ≤ 8 weeks including Ranibizumab, Aflibercept, or Faricimab.
• Participants receiving intravitreal treatment at screening must complete a wash-out period before enrolment. This wash-out period should be calculated based on five half-lives of the specific intravitreal treatment the participant is receiving.

Below is the washing out period for some standard of care treatments.

• Ranibizumab (half-life: 9 days) requires a wash-out period of 45 days (7 weeks)
• Aflibercept (half-life: 11 days) requires a wash-out period of 55 days (8 weeks)
• Faricimab (half-life: 7.5 days) requires a wash-out period of 37.5 days (5 weeks)
• Bevacizumab (half-life: 6 days) requires a wash-out period of 30 days (4weeks)
• Subfoveal CNV or juxtafoveal/extrafoveal CNV with a subfoveal component related to the CNV activity identified by FFA or OCT (where CNV activity is defined as showing evidence of subretinal fluid, subretinal hyperreflective material, or leakage).
• BCVA ETDRS letter score of 78 to 24 (corresponding to a Snellen equivalent of approximately 20/32 to 20/320) in the study eye.
• Decrease in BCVA determined to be primarily the result of nAMD or DR/DME in the study eye.
• Presence of pigment epithelium detachment (PED), intraretinal fluid (IRF) and/or subretinal fluid (SRF) affecting the central subfield of the study eye on OCT.
• Adequate organ (liver and renal) and hematological functions as evidenced by the laboratory results obtained within 7 days of treatment which are within the normal range for the study population, or with abnormalities deemed not clinically significant by the investigators.

Exclusion criteria

• Scar, fibrosis, atrophy, or retinal pigment epithelial tears involving the central fovea in the study eye.
• Uncontrolled glaucoma (defined as IOP >25 mmHg despite treatment with antiglaucoma medication) in the study eye.
• History of idiopathic or autoimmune uveitis in the study eye.
• Myopia of a spherical equivalent of at least 8 diopters in the study eye prior to any refractive or cataract surgery.
• Evidence of extraocular or periocular infection or inflammation (including infectious blepharitis, keratitis, scleritis, or conjunctivitis) in either eye at the time of screening/randomization.
• Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg).
• Patient is receiving systemic glucocorticoids (only if higher than 10mg or equivalent of prednisolone daily) or other immunosuppressive treatment for autoimmune disease or any other medical condition.