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).
Overview
- Phase
- Phase 1
- Intervention
- PMC-403
- Conditions
- Neovascular Age-related Macular Degeneration
- Sponsor
- PharmAbcine
- Enrollment
- 17
- Locations
- 4
- Primary Endpoint
- Maximum tolerated dose (MTD)
- Status
- Completed
- Last Updated
- 4 months ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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.
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:
Arms & Interventions
PART 1- SAD
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)
Intervention: PMC-403
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. * 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)
Intervention: PMC-403
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD)
Time Frame: Baseline upto 4 weeks
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.
Laboratory tests - Hematology
Time Frame: Baseline upto 5 months
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.
Laboratory tests - Blood coagulation
Time Frame: Baseline upto 5 months
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.
Vital Signs - body temperature
Time Frame: Baseline upto 5 months
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.
Laboratory tests - Urinalysis
Time Frame: Baseline upto 5 months
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.
Ophthalmologic examination - fundus examination
Time Frame: Baseline upto 5 months
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.
Ophthalmologic examination - spectral domain-optical coherence tomography (SD-OCT)
Time Frame: Baseline upto 5 months
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.
Vital Signs - Pulse Rate (beats/min)
Time Frame: Baseline upto 5 months
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.
Laboratory tests - Blood chemistry
Time Frame: Baseline upto 5 months
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.
Ophthalmologic examination - Slit lamp examination
Time Frame: Baseline upto 5 months
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.
Adverse events
Time Frame: Baseline upto 5 months
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.
Vital Signs - systolic/diastolic blood pressure (mmHg)
Time Frame: Baseline upto 5 months
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.
Electrocardiogram (ECG)
Time Frame: Baseline upto 5 months
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.
Ophthalmologic examination - intraocular pressure (IOP)
Time Frame: Baseline upto 5 months
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.
Secondary Outcomes
- Presence of intraretinal fluid (IRF)(Baseline upto 5 months)
- Presence of subretinal fluid (SRF)(Baseline upto 5 months)
- Change in best corrected visual acuity (BCVA)(Baseline upto 5 months)
- Presence of sub-RPE fluid(Baseline upto 5 months)
- Change from baseline in CNV lesion size as measured by ICG angiography(Baseline upto 5 months)
- Change in central retinal thickness (CRT)(Baseline upto 5 months)
- Change from baseline in choroidal neovascularization (CNV) lesion size as measured by Fundus Fluorescein Angiography (FFA)(Baseline upto 5 months)