Study summary
This study aims to preliminarily evaluate the efficacy and safety of GB10 intravitreal (IVT) injection for the treatment of patients with neovascular age-related macular degeneration (nAMD). It consists of two parts, single-ascending-dose escalation (SAD) and multiple-ascending-dose escalation (MAD).
In SAD, a single IVT of up to 6 doses will be administered to up to 36 treatment-naïve or previously treated patients with nAMD. If the lowest dose is considered safe without dose-limiting toxicity, escalation will proceed to the next higher dose level. At the end of SAD, the two doses that best balance efficacy and safety will be selected and entered into MAD.
In MAD, a single IVT of 2 doses will be administered to 12 treatment-naïve or previously treated patients with nAMD, who will be enrolled across the low- to high-dose levels.
After GB10 intervention, the participants will undergo tests to evaluate the PK/PD characteristics of GB10 and ocular and non-ocular safety.
Eligibility
Key Inclusion Criteria:
1. Diagnosed with choroidal neovascularization (CNV) secondary to AMD (nAMD); For the study eye, either no prior IVT anti-VEGF treatment (treatment-naïve patients) or the last injection of the prior IVT anti-VEGF treatment occurred \> 3 months before the first dose, with investigator-assessed effectiveness of prior anti-VEGF therapy (previously treated patients).
2. The study eye must have either subfoveal CNV or juxtafoveal CNV with a subfoveal component related to the CNV activity (as evidenced by subretinal fluid, subretinal hyper-reflective material, leakage, or hemorrhage);
3. CNV lesion of all types (CNV lesion types in the study eye include predominantly classic, minimally classic, or occult \[including polypoidal choroidal vasculopathy (PCV)\]) with:
1. Total lesion size (including blood, atrophy, fibrosis, and neovascularization) of ≤ 9 disc areas by FFA;
2. CNV component area of ≥ 50% of total lesion size by FFA;
3. Active CNV confirmed by FFA (evidence of leakage);
4. CNV exudation confirmed by SD-OCT (presence of fluid).
4. BCVA letter score in the study eye of 78-24 letters (inclusive) in ETDRS-like charts (20/32-20/320 Snellen equivalent) before the first dose;
5. Willingness to participate in the study, to comply with the study protocol, and to provide signed informed consent.
Key Exclusion Criteria:
1. CNV in the study eye due to causes other than AMD, such as ocular histoplasmosis, trauma, pathological myopia, angioid streaks, choroidal rupture, or uveitis;
2. The study eye on FFA:
1. Subretinal hemorrhage of \> 50% of the total lesion area and/or that involves the fovea; or
2. Fibrosis or atrophy of \> 50% of the total lesion area and/or that involves the fovea;
3. Any concurrent intraocular condition in the study eye (e.g., central serous chorioretinopathy \[CSC\], retinal pigment epithelial tear involving the macula, amblyopia, aphakia, retinal detachment, cataract, diabetic retinopathy or maculopathy, epiretinal membrane with traction, retinal vein occlusion, etc.) that, in the opinion of the investigator, may either reduce the potential for visual improvement or require medical or surgical intervention;
4. Spherical equivalent of the refractive error demonstrating more than 8 diopters of myopia in the study eye (for study eye with prior refractive surgery or cataract surgery, preoperative refractive error demonstrating more than 8 diopters), or axial length \>26.5 mm when reliable refractive assessment is unavailable;
5. Uncontrolled glaucoma (e.g., progressive loss of visual fields or defined as IOP≥25 mmHg despite treatment with anti-glaucoma medication) in the study eye;
6. Current or prior receipt of any treatment for the study eye, including but not limited to:
1. IVT implantation or injection other than anti-VEGF drugs within 6 months before screening (e.g., steroids, transplasminogen activator, ocriplasmin, C₃F₈ gas, air filling);
2. Periocular pharmacological interventions for retinal diseases within 6 months before screening (including subconjunctival, sub-tenon's, peribulbar, or retrobulbar injections);
3. Laser/photodynamic therapies within 6 months before screening (including laser photocoagulation, verteporfin PDT, diode laser, or transpupillary thermotherapy);
4. Cataract surgery within 3 months before screening, or corticosteroid treatment for complications of cataract surgery, or YAG (yttrium aluminum garnet) laser posterior capsulotomy;
5. Prior other intraocular surgery (e.g., pars plana vitrectomy \[PPV\], glaucoma surgery \[except YAG peripheral iridotomy \>3 months prior\], corneal transplant, or radiotherapy).
7. Active intraocular inflammation (grade trace or above) in the study eye before the first dose;
8. Current vitreous hemorrhage (grade trace or above) in the study eye before the first dose;
9. Monocular vision or non-study eye BCVA \< 24 letters before the first dose;
10. History of any cardiovascular/cerebrovascular events within 6 months before the first dose, including but not limited to: stroke (cerebrovascular accident), myocardial infarction, unstable angina, ventricular arrhythmias, and heart failure ≥ NYHA Class II;
11. History of major surgery within 6 months before the first dose or plan to undergo surgery during the study;
12. History of other disease, metabolic dysfunction, abnormal physical examination finding, or clinical laboratory finding prompting reasonable suspicion of a condition that might affect interpretation of the results of the study or render the patient at high risk for treatment complications in the opinion of the investigator, including but not limited to:
1. Hepatic/renal dysfunction (ALT/AST\>2.5×ULN; Cr/BUN\>2×ULN);
2. Uncontrolled diabetes (HbA1c≥7.5%);
3. Uncontrolled hypertension (resting SBP ≥160 mmHg and/or DBP ≥100 mmHg);
4. Platelets\<100×10⁹/L; or coagulation dysfunction (PT\>3 sec above ULN; APTT \>10 sec above ULN);
13. Pregnant or nursing (lactating) women;
14. Any other conditions deemed by the investigator to render the participant unsuitable for trial participation.