Study to Assess Safety and Tolerability of PMC-403 in Subjects With Neovascular Age-related Macular Degeneration

Study Overview
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Brief Summary
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This is a Phase 1 study, first-in-human (FIH), open label study to evaluate the safety, tolerability and identify the maximum tolerated dose (MTD) of PMC-403 and determine the recommended phase 2 dose (RP2D).

Detailed Description
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In this study, Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) will be carried out in a sequential manner. - PART 1- SAD The SAD part of the study will be conducted in a step-wise manner for a total of 4 dose levels (0.7 mg, 2 mg, 3 mg, 4 mg). To each dose group, 3 subjects at minimum or 6 subjects at maximum will be recruited. In the SAD part, dose escalation will be performed up to 4 mg/eye (50 uL/eye) until the MTD is identified. In the SAD part, a maximum of 24 participants are to be enrolled. - PART 2- MAD Upon the end of the SAD part of the study, the MAD part is planned to be conducted in a step-wise manner for a total of 2 dose levels (3 mg, 4 mg). In the MAD part will begin with dose level 1 (3 mg). Subjects will be given a total of 3 doses of IP at 4-week intervals over a total period of 12 weeks and will be assessed for safety and tolerability according to study procedures. While a total of 6 subjects are to be recruited per dose group in the MAD part. Dose escalation will be performed up to 4 mg/eye (50 uL/eye) until the MTD is identified. In the MAD part, a maximum of 12 participants are to be enrolled.

Official Title
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A Multi-center, Open-Label, Phase 1, Single- and Multiple Ascending Dose Study to Assess Safety and Tolerability of PMC-403 in Subjects With Neovascular Age-related Macular Degeneration (nAMD).

Conditions
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Neovascular Age-related Macular Degeneration

Intervention / Treatment
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* Drug: PMC-403


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for study participation, subjects must meet all of the following inclusion criteria. * Criteria for the selection of the study eye If both eyes meet the criteria, the study eye will be selected according to the following criteria: The eye with lower (severer) best corrected visual acuity (BCVA) at baseline will be selected as the study eye. If both eyes have the same BCVA, the right eye will be selected as the study. Male and female ≥50 years of age at the time of written informed consent. Treatment required, based on the judgment of the investigator, due to insufficient therapeutic efficacy despite ≥ 3 repeated doses of anti-vascular endothelial growth factor (anti-VEGF) intravitreal injection (IVT) for nAMD in the study eye, and the subject's agreement to receive the study drug instead of conventional standard therapy >12 weeks must have elapsed since the last dose of anti-VEGF IVT at the time of screening. Active subfoveal or parafoveal choroidal neovascularization (CNV)* confirmed by fundus fluorescein angiography (FFA), spectral domain-optical coherence tomography (SD-OCT), and IndoCyanine Green (ICG) angiography. *Active CNV (confirmed by the central reading center) is defined as the presence of subretinal fluid (SRF) or intraretinal fluid (IRF) in consequence of vascular leakage. The size of the entire lesion in the study eye (including blood, atrophy, fibrosis, and neovascularization) must be ≤ 9-disc areas, and the area of CNV in the study eye must account for ≥ 50% of the total area of the lesion, as confirmed by FFA and ICG angiography. BCVA measured in the study eye must be between ≥ 23 letters and ≤ 78 letters based on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart (Snellen visual acuity 20/25 - 20/320). Voluntary written informed consent to study participation. Exclusion Criteria: Subjects who meet any of the following exclusion criteria are not eligible for study participation. At the screening visit: Uncontrolled ocular hypertension (≥ 25 mmHg) despite drug therapy; Retinal pigment epithelium (RPE) tears involving the macula; Improvement in visual acuity is not expected due to scars, fibrosis, or atrophy involving the fovea; Presence of vitreous hemorrhage; Aphakia or absence of posterior capsule (with the exception of pseudophakic eyes treated with laser posterior capsulotomy); Presence of any causes of CNV other than nAMD, such as ocular histoplasmosis, trauma, pathological myopia, angioid streak, choroidal rupture, or uveitis; or Macular pathology that is unrelated to nAMD, but may affect visual acuity or study drug treatment (e.g., macular hole, epiretinal membrane, vitreomacular traction, macular telangiectasia, central serous chorioretinopathy, retinal vascular occlusion, etc.). Any of the following conditions or medical history in either eye: Current or known history of at least moderate diabetic retinopathy or diabetic macular edema; Active intraocular or periocular infections or inflammations (e.g., infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, etc.); or History of idiopathic or autoimmune uveitis. Any of the following systemic diseases: Unstable or serious cardiovascular disorders such as congestive heart failure (New York Heart Association Functional Class III or IV), ventricular tachycardia requiring continuous treatment, unstable angina pectoris, or critical limb ischemia; Uncontrolled hypertension with systolic or diastolic blood pressure > 160/100 mmHg; Stroke or myocardial infarction within 24 weeks prior to screening; Dementia or neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease) that might affect study results during the study period; History of malignant tumors within 5 years prior to screening; or Weakened immunity or requiring immunotherapy. Clinically significant liver/kidney disease or any of the following hematologic test results: Serum creatinine ≥1.5 x upper limit of normal Aspartate transaminase (AST) or alanine transaminase (ALT) ≥2 x upper limit of normal Treatment with any of the following systemic drug therapy: Systemic anti-VEGF therapy within 12 weeks prior to baseline; Systemic corticosteroids for ≥2 consecutive weeks ≤ 10 mg/day prednisolone or equivalent for less than 2 consecutive weeks will be allowed Inhaled, nasal, and topical steroids will also be allowed Ongoing treatment with any drugs with potential toxicity to the lens, retina, and optic nerves (e.g., deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines, vigabatrin, or ethambutol). Any of the following medical history (surgical or procedural): Intraocular or periocular injection of corticosteroids (e.g., triamcinolone acetonide, etc.) to the study eye within 24 weeks prior to screening; Intraocular surgery or laser therapy (e.g., cataract surgery, laser posterior capsulotomy, etc.) to the study eye within 12 weeks prior to screening; Eyelid surgery within 4 weeks prior to screening; History of vitrectomy, glaucoma surgery, macular laser treatment, keratoplasty, or retinal detachment surgery; or History of treatment with radiotherapy around the study eye including radiation retinopathy Any concurrent ophthalmic abnormalities that, based on the judgment of the investigator, may affect the assessment of safety and therapeutic efficacy or may need medical or surgical treatment during the study period (e.g., cloudy ocular media, optic neuropathy, amblyopia, etc.). Hypersensitivity to any of the components of IP or to contrast agents used for FFA and ICG angiography. Pregnant and/or breastfeeding women. Men and women of childbearing potential who are unwilling to use adequate methods of contraception* or who are planning a pregnancy during the study period and for 12 weeks from the last dose of IP -Methods of contraception: hormone contraceptives (oral contraceptives, contraceptive patch, etc.), intrauterine device (IUD) (copper IUD, hormonal intrauterine system), double barrier method (both male [condom] and female [diaphragm, vaginal sponge, or cervical cap]), surgical sterilization (tubal sterilization, vasectomy, etc.) Having participated in another clinical trial and treated with an IP within 12 weeks prior to screening Distance vision test result of <0.1 for the fellow eye Other reasons based on which individuals are determined by the investigator to be ineligible for study participation.

Ages Eligible for Study
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Minimum Age: 50 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PART 1- SAD<br>The SAD part of the study will be conducted in a step-wise manner for a total of 4 dose levels of PMC-403. Dose level 1: 0.7 mg/eye, baseline(Day 0) Dose level 2: 2 mg/eye, baseline(Day 0) Dose level 3: 3 mg/eye, baseline(Day 0) Dose level 4: 4 mg/eye, baseline(Day 0) | Drug: PMC-403<br>* PMC-403 will be administered Intravitreal.<br>* Other names: Monotherapy;|
| Experimental: PART 2- MAD<br>Upon the end of the SAD part of the study, the MAD part is planned to be conducted in a step-wise manner for a total of 2 dose levels. Dose level 1: 3 mg/eye, baseline(Day 0), Week 4(Day 28), Week 8(Day 56) Dose level 2: 4 mg/eye, baseline(Day 0), Week 4(Day 28), Week 8(Day 56) | Drug: PMC-403<br>* PMC-403 will be administered Intravitreal.<br>* Other names: Monotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | To identify the maximum tolerated dose (MTD), and determine the recommended phase 2 dose (RP2D) of PMC-403 in patients with nAMD. MTD of PMC-403 will be calculated by incidence of DLT at 4 weeks from the first dosing of PMC-403. | Baseline upto 4 weeks | 
| Adverse events | For Treatment-emergent adverse events (TEAEs), Adverse Drug Reactions (ADRs), Serious Adverse Events (SAEs), Serious Adverse Drug Reactions (SADRs), and Adverse Events (AEs) leading to study withdrawal, number of subjects, incidence, number of events, and 95% two-sided confidence interval will be presented by dose group. | Baseline upto 5 months | 
| Vital Signs - Pulse Rate (beats/min) | At each visit, pulse rate will be measured. Vital signs collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings. By dose group, values at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum. | Baseline upto 5 months | 
| Vital Signs - body temperature | At each visit, body temperature will be measured. Vital signs collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings. By dose group, values at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum. | Baseline upto 5 months | 
| Vital Signs - systolic/diastolic blood pressure (mmHg) | At each visit, systolic/diastolic blood pressure will be measured. Vital signs collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings. By dose group, values at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented with number of subjects, mean, standard deviation, median, minimum, and maximum. | Baseline upto 5 months | 
| Laboratory tests - Hematology | Hematology will be performed at Visits 1, 2, 5, and 7 and at Follow-up Visits 8 and 9 in the SAD groups and at each visit in the MAD groups. The following Hematology parameters will be recorded: white blood cell (WBC), red blood cell (RBC), hemoglobin, hematocrit, platelet, WBC differential count (neutrophil, lymphocyte, monocyte, eosinophil, basophil) Test results collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings. | Baseline upto 5 months | 
| Laboratory tests - Blood chemistry | Blood chemistry will be performed at Visits 1, 2, 5, and 7 and at Follow-up Visits 8 and 9 in the SAD groups and at each visit in the MAD groups. The following Blood chemistry parameters will be recorded: glucose, aspartate transaminase (AST; SGOT), alanine transaminase (ALT; SGPT), total bilirubin, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein, albumin, blood urea nitrogen (BUN), creatinine, uric acid, sodium, potassium, chloride, calcium, phosphorus, C-reactive protein (CRP), HbA1c (to be tested at the screening visit only) Test results collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings. | Baseline upto 5 months | 
| Laboratory tests - Urinalysis | Urinalysis will be performed at Visits 1, 2, 5, and 7 and at Follow-up Visits 8 and 9 in the SAD groups and at each visit in the MAD groups. For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. Additionally, test results collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings. | Baseline upto 5 months | 
| Laboratory tests - Blood coagulation | Blood coagulation will be performed at Visits 1, 2, 5, and 7 and at Follow-up Visits 8 and 9 in the SAD groups and at each visit in the MAD groups. For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. Additionally, test results collected will be assessed for change before and after IP dosing and/or change in normal/abnormal findings. | Baseline upto 5 months | 
| Electrocardiogram (ECG) | Test results will be classified into normal/NCS and CS, and change from baseline at each time point and at the last visit will be presented with frequency and percentage in a shift table by dose group. The following ECG parameters will be recorded: heart rate, RR interval, HR interval, QTc interval and QRS interval. | Baseline upto 5 months | 
| Ophthalmologic examination - Slit lamp examination | Slit lamp examination measuring will be performed according to Schedule of Events. For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. The ophthalmologic examination results will be assessed for change in normal/abnormal status before and after IP dosing. | Baseline upto 5 months | 
| Ophthalmologic examination - fundus examination | fundus examination measuring will be performed according to Schedule of Events. For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. The ophthalmologic examination results will be assessed for change in normal/abnormal status before and after IP dosing. | Baseline upto 5 months | 
| Ophthalmologic examination - spectral domain-optical coherence tomography (SD-OCT) | SD-OCT will be performed according to Schedule of Events. For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. The ophthalmologic examination results will be assessed for change in normal/abnormal status before and after IP dosing. | Baseline upto 5 months | 
| Ophthalmologic examination - intraocular pressure (IOP) | IOP will be performed according to Schedule of Events. During the study visits involving IP dosing (SAD: Visits 2, MAD: Visits 2, 5, 7), IOP will be measured a total of 3 times (once before dosing and twice after dosing). For continuous variables, values at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. The ophthalmologic examination results will be assessed for change in normal/abnormal status before and after IP dosing. | Baseline upto 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in best corrected visual acuity (BCVA) | It is measured by early treatment of diabetic retinopathy study (ETDRS) chart at each point of visit. For BCVA will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. | Baseline upto 5 months | 
| Change in central retinal thickness (CRT) | It is measured by SD-OCT at each point of visit. For CRT will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. | Baseline upto 5 months | 
| Presence of intraretinal fluid (IRF) | It is measured by SD-OCT at each point of visit. For presence of IRF frequency, percentage, and 95% confidence interval will be presented by dose group. | Baseline upto 5 months | 
| Presence of subretinal fluid (SRF) | It is measured by SD-OCT at each point of visit. For presence of SRF frequency, percentage, and 95% confidence interval will be presented by dose group. | Baseline upto 5 months | 
| Presence of sub-RPE fluid | It is measured by SD-OCT at each point of visit. For presence of sub-RPE fluid frequency, percentage, and 95% confidence interval will be presented by dose group. | Baseline upto 5 months | 
| Change from baseline in choroidal neovascularization (CNV) lesion size as measured by Fundus Fluorescein Angiography (FFA) | FFA will be performed to measure the size of CNV lesions and to assess vascular leakage. For CNV lesion size will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. | Baseline upto 5 months | 
| Change from baseline in CNV lesion size as measured by ICG angiography | ICG angiography will be performed to measure the size of CNV lesions and to assess vascular leakage. For CNV lesion size will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum; and change from baseline at each time point will be presented by dose group with number of subjects, mean, standard deviation, median, minimum, and maximum. | Baseline upto 5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PMC-403