Exudative age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the population over 50 years of age, and is a common vision-threatening condition dealt with by the vitreoretinal specialist. Despite many efficacious therapies on the market, much interest lies in newer anti-VEGF therapies, with the goal of finding an agent with greater efficacy and durability.
In 2013, Chengdu Kanghong Biotechnology received Chinese Food and Drug Administration approval for the use of conbercept in the treatment of exudative AMD. Currently, there is a worldwide phase 3 clinical development program evaluating conbercept in the treatment of exudative AMD (PANDA), looking at efficacy and safety of 2 different doses and regimens of intravitreal conbercept compared to aflibercept in the treatment of exudative AMD (NCT03577899 and NCT03630952).1 Herein, we will describe conbercept, review the major Chinese conbercept trials for exudative AMD to date, and summarize the PANDA trials.
EXUDATIVE AGE-RELATED MACULAR DEGENERATION
Exudative AMD is defined by the growth of new blood vessels, or neovascularization, and it is apparent that vascular endothelial growth factor (VEGF) plays an important role in the development and leakage of choroidal neovascular membranes (CNVM). Therefore, VEGF has become a fundamental target in the treatment of CNVM due to exudative AMD. There are many forms of VEGF, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PlGF).1 The currently used bevacizumab (Avastin; Genentech) and ranibizumab (Lucentis; Genentech) target VEGF-A, and aflibercept (Eylea; Regeneron) is known to target VEGF-A, VEGF-B, and PlGF. Although these medications have been found to be efficacious, some patients with aggressive disease demonstrate a suboptimal response to these therapies in terms of efficacy or durability, leading to vision loss despite regular treatment.
CONBERCEPT IN CHINA
Conbercept was approved for use in China for the treatment of exudative AMD in November 2013. Conbercept is a recombinant fusion protein composed of the second IgG domain of VEGFR1 and the third and fourth domains of VEGFR2 to the constant region (Fc) of human IgG1 (Figure 1). In vitro experiments have shown that conbercept has a 30 times higher binding affinity for VEGF than ranibizumab or bevacizumab.2-4 Similar to aflibercept, conbercept targets VEGF-A, VEGF-B, and PlGF, although the structure of conbercept is hypothesized to have higher binding capacity and have a longer half-life than aflibercept. Conbercept also binds VEGF-C. The following trials were all conducted in China.
In the AURORA trial, 122 patients with exudative AMD were randomized 1:1 to receive either 0.5 mg or 2.0 mg conbercept for 3 consecutive monthly doses. After the third dose, subjects were again randomized to either monthly or as-needed (PRN) therapy, without changing the dose of conbercept that they were receiving.5
At month 3, mean BCVA improvement was 8.97 letters in the conbercept 0.5 mg group, vs 10.43 in the conbercept 2.0 mg group. Visual changes from baseline were statistically significant (P<.001). At month 12, mean best-corrected visual acuity (BCVA) improvement was 14.31 letters for the 0.5 mg PRN group, 9.31 for the 0.5 mg monthly group, 12.42 for the 2.0 mg PRN group, and 15.43 for the 2.0 mg monthly group. The reduction in central retinal thickness (CRT) was 119.8 µm for the 0.5 mg PRN group, 129.7 µm for the 0.5 mg monthly group, 152.1 µm for the 2.0 mg PRN group, and 170.8 µm for the 2.0 mg monthly group. The difference in CRT compared to baseline in all groups was statistically significant.5
Two ocular serious adverse events were noted in the AURORA trial: cataract development thought to be related to the study drug, and endophthalmitis thought to be related to the injection procedure. There were no related systemic serious adverse events or related thromboembolic events.5
In the PHOENIX trial, 124 patients were randomized 2:1 to receive 1 of 2 conbercept treatment arms. In the treatment arm, patients received monthly injections of conbercept 0.5 mg for 3 months, followed by quarterly injections of conbercept 0.5 mg. In the delayed treatment arm, patients received sham monthly injections for 3 months, followed by conbercept 0.5 mg monthly for 3 months, followed by quarterly therapy of conbercept 0.5 mg. The study ran over a 52-week period.6
At month 3, mean changes in BCVA from baseline were 9.20 letters in the conbercept group and 2.02 letters in the sham group. The conbercept group also experienced a mean reduction in CRT of 125.92 µm, and the reduction of CRT was 40.67 µm in the sham group (P<.001). At month 12, both groups achieved visual improvement, with the normal treatment group achieving a 9.9 letter improvement and the delayed treatment group achieving an 8.8 letter improvement. There was no significant difference in reduction in CRT between the normal treatment group and delayed treatment group at month 12.6
No ocular serious adverse events were noted in the PHOENIX trial. There were no drug-related systemic serious adverse events. There were 2 isolated patients with myocardial infarction and mild cerebral infarction that were thought to be unrelated to the study drug.6
Current Use in China
Since it received Chinese approval in November 2013, conbercept has been used extensively in China for the treatment of exudative AMD and other retinal vascular disorders.7-10 In the treatment of exudative AMD, conbercept has been safe and effective.11,12 In a real-world study looking at the efficacy of conbercept for the treatment-naïve exudative AMD, patients experienced improvement in BCVA and decreased CRT after an initial loading dose of 3 conbercept injections, followed by a PRN approach.13 However, these Chinese studies have relatively small population sizes and therefore larger studies are warranted to support the validity of these data.
The PANDA trials are global multicenter clinical trials created to study conbercept on a larger scale. The PANDA trials (including both the PANDA-1 and PANDA-2 trials) are masked randomized controlled trials that aim to evaluate the efficacy, safety, and durability of 0.5 mg conbercept every 8 weeks and 1.0 mg conbercept every 12 weeks, compared to aflibercept 2.0 mg every 8 weeks for the treatment of exudative AMD, with a 1:1:1 randomization of patients. The primary objective is to prove noninferiority, while secondary objectives are to determine overall improvement in BCVA and mean change in baseline CRT. In both trials, the 3 arms have 3 monthly injections for a loading phase. In PANDA-1, the 0.5 mg conbercept arm and 2.0 mg aflibercept arm receives treatment at day 1, week 4, and week 8, followed by every 8 weeks thereafter for a total of 92 weeks of treatment. The 1.0 mg conbercept arm receives treatment at day 1, week 4, and week 8, followed by every 12 weeks thereafter for a total of 92 weeks of treatment.
In PANDA-2, the arms are dosed similarly to PANDA-1 in the first year. However, at week 40, all 3 arms begin a capped (maximum interval of 16 weeks) criteria-based (VA- and OCT-driven evaluation) PRN treatment until week 92. Approximately 1,140 subjects will be enrolled in each trial, with around 380 study subjects in each arm. The studies will run through 96 weeks for final assessments.
Subjects are eligible for PANDA-1 or PANDA-2 if they have treatment-naïve exudative AMD with an Early Treatment Diabetic Retinopathy Study BCVA letter score of 78 to 25 (approximately 20/32 to 20/320) in the study eye at screening. Patients are excluded who have extensive (>50%) macular scarring, fibrosis, or subretinal hemorrhage. Patients are also excluded if they have a history of retinal pigment epithelium rip, prior vitreoretinal surgery, uncontrolled glaucoma, history of filtering surgery for glaucoma, or active inflammation.
In each study, routine imaging tests will be performed, including spectral domain-optical coherence tomography (SD-OCT), fundus photography, and fluorescein angiography. Optical coherence tomography angiography will be studied at specific sites. A small subset of patients in each treatment arm will undergo specular microscopy. The studies are supported in part by the National Major Scientific and Technological Special Project for “Significant New Drugs Development.”
Conbercept represents a promising new therapy that could prove to be noninferior to aflibercept in the treatment of exudative AMD with the potential for greater durability. While safety and efficacy has been proven in China, the PANDA trials will look at the treatment of conbercept in a global population compared to aflibercept for exudative AMD. Reducing the number of injections and clinic visits while sustaining similar efficacy and safety would be an improvement in current therapeutic options and benefit patients with limited access to health care. RP
- Klettner A, Kauppinen A, Blasiak J, Roider J, Salminen A, Kaarniranta K. Cellular and molecular mechanisms of age-related macular degeneration: from impaired autophagy to neovascularization. Int J Biochem Cell Biol. 2013;45(7):1457-1467.
- Zhang M, Yu D, Yang C, et al. The pharmacology study of a new recombinant human VEGF receptor-fc fusion protein on experimental choroidal neovascularization. Pharm Res. 2009;26(1):204-210.
- Zhang M, Zhang J, Yan M, Li H, Yang C, Yu D. Recombinant anti-vascular endothelial growth factor fusion protein efficiently suppresses choroidal neovascularization in monkeys. Mol Vis. 2008;14:37-49.
- Wang F, Bai Y, Yu W, et al. Anti-angiogenic effect of KH902 on retinal neovascularization. Graefes Arch Clin Exp Ophthalmol. 2013;251(9):2131-2139.
- Li X. Xu G, Wang Y, et al. AURORA study group. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study. Ophthalmology. 2014;121(9):1740-1747.
- Liu K, Song Y, Xu G, et al; PHOENIX study group. Conbercept for treatment of neovascular age-related macular degeneration: Results of the Randomized phase 3 PHOENIX study. Am J Ophthalmol. 2019;197:156-167.
- Huang Z, Ding Q, Yan M, et al. Short-term efficacy of conbercept and ranibizumab for polypoidal choroidal vasculopathy. Retina. 2018. [Epub ahead of print]
- Xu Y, Rong A, Xu W, Niu Y, Wang Z. Comparison of 12-month therapeutic effect of conbercept and ranibizumab for diabetic macular edema: a real-life clinical practice study. BMC Ophthalmol. 2017;17(1):158.
- Jin E, Yin H, Li X, Zhao M. Short-term outcomes after intravitreal injections of conbercept versus ranibizumab for the treatment of retinopathy of prematurity. Retina. 2018;38(8):1595-1604.
- Sun Z, Zhou, H, Lin B, et al. Efficacy and safety of intravitreal conbercept injections in macular edema secondary to retinal vein occlusion. Retina. 2017;37(9):1723-1730.
- Zhang J, Liang Y, Xie J, et al. Conbercept for patients with age-related macular degeneration: a systematic review. BMC Ophthalmol. 2018;18(1):142.
- Li X, Luo H, Zuo C, Zhang Z, Zhang J, Zhang M. Conbercept in patients with treatment-naïve neovascular age-related macular degeneration in real-life setting in China. Retina. 2018. [Epub ahead of print]