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

Phase I/II Study to Assess Safety and Efficacy of PRL3-zumab in Patients With Neovascular Age-related Macular Degeneration (nAMD)

Study Design This is a Single-center, Phase I/II placebo-controlled study to assess the safety and efficacy of PRL3-zumab in patients with Neovascular Age-related Macular Degeneration (nAMD).

PRL3-zumab will be administered intravenously in 2-week interval for 3 doses. Normal saline (0.9% Sodium Chloride w/v) will be used in placebo treatment. The study will consist of 3 arms.

Arm-1: PRL3-zumab 3mg/kg intravenously will be administered in 2 week interval followed by 20 weeks of monitoring (n=6) Arm-2: PRL3-zumab 6mg/kg intravenously will be administered in 2 week interval followed by 20 weeks of monitoring (n=6) Arm-3: Placebo (normal saline 0.9% sodium chloride w/v) intravenously will be administered in 2 week interval followed by 20 weeks of monitoring (n=3)

Initial 3 arms will be conducted on patients who failed Standard-of-Care (SOC) therapy. Response assessment will be done at every 4 weeks from last dose of treatment till 24-week.

Randomization:

Randomization will be done in 2:2:1 manner on PRL3-zumab (Arm 1), 3mg/kg (n=6); PRL3-zumab (Arm 2), 6mg/kg (n=6); and placebo group (Arm 3) (n=3). Randomization can be achieved using random number table which will be prepared before the commencement of clinical trial.

The allocation of participants will be done by Investigator and will be concealed from the participants.

Blinding:

Single blinding will be done for this trial in which all participants are unaware of their treatment assignment. No blinding will be done on Investigator.

Primary Endpoints:

1. Safety:

   • Adverse Events: Frequency and severity of adverse events throughout the primary outcome assessment period will be assessed by the Investigator for severity according to Common Terminology Criteria for Adverse Events (CTCAE) version 5 or later

2. RP2D:

   • This study will confirm Recommended Phase 2 DOse (RP2D) established from Phase I Clinical Trial in Cancer patients conducted in National University Hospital Singapore (MC/03/0616).

3. Efficacy:

   • Change From Baseline in Best Corrected Visual Acuity (BCVA) Measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score. Change in BCVA letter gain of 0-4 will be considered as primary end point.
   • Change From Baseline in Central Subfield Retinal Thickness (CST) measured by Optical Coherence Tomography (OCT).

[Assessment Time Frame: 4 weekly through 24 weeks]

Secondary endpoints:

• Change in visual Acuity (Best Corrected Visual Acuity) of 5 or more letters.
• Proportion of patients gaining ≥15, ≥10, ≥5, or ≥0 ETDRS letters in BCVA from baseline over time
• Proportion of patients avoiding a loss of ≥15, ≥10, or ≥5 ETDRS letters in BCVA from baseline over time
• Proportion of patients with absence of intraretinal fluid measured by OCT
• Proportion of patients with absence of subretinal fluid measured by OCT [Assessment Time Frame: 4 weekly through 24 weeks]

Criteria for additional Therapy:

Once the treatment is stopped after the third dose, patients from all groups are eligible for additional therapy as open-label treatment if there is recurrence of disease activity, as defined by presence of any of the following criteria:

1. Decrease of ≥5 letters in BCVA compared with average BCVA value over the previous two scheduled visits, owing to nAMD disease activity (as determined by the investigator).
2. Increase of >50 µm in OCT-measured CST compared with the average CST value over the previous two scheduled visits.
3. Recurrence of intra-retinal or sub-retinal fluid (if resolved previously)
4. New macular hemorrhage

Patients in the placebo group will be given PRL3-zumab (6mg/kg) if they fulfil the criteria for additional therapy. Additional therapy will be continued in subsequent monitoring visit until the progression of disease, or end of the trial. If patients show clinical benefit from the treatment, additional doses could be given based on investigators' judgment.

Criteria for progression of disease:

1. BCVA decreases by 15 letters or more from best recorded BCVA because of nAMD disease activity.
2. an increase in OCT central retinal thickness 150 µm or more from lowest recorded measurement after 2 consecutive additional therapy occurring 1 month apart.

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.

1. . 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.

2. . 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

1. . Visual Acuity (Best Corrected Visual Acuity) by ETDRS letter score
2. . Central retinal thickness by OCT
3. . 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:

1. Patients with Neovascular Age-related Macular Degeneration (nAMD).

2. Willing to provide written informed consent for the study.

3. 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.

4. 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.

   1. Ranibizumab (half-life: 9 days) requires a wash-out period of 45 days (7 weeks)
   2. Aflibercept (half-life: 11 days) requires a wash-out period of 55 days (8 weeks)
   3. Faricimab (half-life: 7.5 days) requires a wash-out period of 37.5 days (5 weeks)
   4. Bevacizumab (half-life: 6 days) requires a wash-out period of 30 days (4weeks)

5. 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).

6. BCVA ETDRS letter score of 78 to 24 (corresponding to a Snellen equivalent of approximately 20/32 to 20/320) in the study eye.

7. Decrease in BCVA determined to be primarily the result of nAMD or DR/DME in the study eye.

8. Presence of pigment epithelium detachment (PED), intraretinal fluid (IRF) and/or subretinal fluid (SRF) affecting the central subfield of the study eye on OCT.

9. 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:

1. Scar, fibrosis, atrophy, or retinal pigment epithelial tears involving the central fovea in the study eye.
2. Uncontrolled glaucoma (defined as IOP >25 mmHg despite treatment with antiglaucoma medication) in the study eye.
3. History of idiopathic or autoimmune uveitis in the study eye.
4. Myopia of a spherical equivalent of at least 8 diopters in the study eye prior to any refractive or cataract surgery.
5. Evidence of extraocular or periocular infection or inflammation (including infectious blepharitis, keratitis, scleritis, or conjunctivitis) in either eye at the time of screening/randomization.
6. Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg).
7. 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.