Efficacy and Safety of Intravitreal Injection of Conbercept for Moderate to Severe Nonproliferative Diabetic Retinopathy

doi:10.21203/rs.3.rs-3808640/v1

Purpose: To evaluate the efficacy and safety of intravitreal injection of conbercept (IVC) for moderate to severe nonproliferative diabetic retinopathy (NPDR) with or without diabetic macular edema.

Methods: This longitudinal retrospective study enrolled 35 patients (50 eyes) with moderate to severe NPDR and a Diabetic Retinopathy Severity Scale (DRSS) score of 43–53 treated in October 2018–January 2023 at the Department of Ophthalmology, First Affiliated Hospital of Kunming Medical University. The patients underwent three monthly IVC treatments, followed by a pro re nata regimen (3+PRN), and a 2-year follow-up period. Outcomes included best-corrected visual acuity (BCVA), intraocular pressure, central macular thickness (CMT), area of hard exudute (HE), and DRSS scores. The DRSS scores were compared using the Wilcoxon rank-sum test before and after treatment. Systemic and ocular adverse events were recorded to evaluate safety.

Results: From baseline to last follow-up, the mean BCVA increased from 0.41 ± 0.39 to 0.23 ± 0.20 logMAR. The mean CMT decreased from 306.22 ± 77.40 to 297.97 ± 88.15 μm. At 24 months, DRSS scores regressed ≥ 1 stage in 40 eyes (80%), ≥ 2 stages in 28 eyes (56%), ≥3 stages in 10 eyes (20%), and remained unchanged in 6 eyes (12%). In 15 of 27 eyes (55.56%) with DME, the mean area of HE decreased significantly from baseline. No serious systemic adverse events were observed.

Conclusions: IVC is effective and safe for treating moderate to severe NPDR, resulting in a robust regression of DRSS scores.

moderate to severe nonproliferative diabetic retinopathy

Diabetic Retinopathy Severity Scale

conbercept

Diabetes mellitus (DM) will affect 592 million people worldwide by 2035, and about 34.6% of patients with DM will develop ocular microvascular complications, specifically, diabetic retinopathy (DR), which is one of the main causes of vision loss in working-age people[1]. DR can be divided into two clinical stages, nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) according to whether retinal neovascularization occurs. NPDR is the early stage of DR, which is characterized by the tortuous hemorrhage of retinal vessels, microaneurysms, hard exudates, and cotton wool spots. NPDR progresses to PDR, which can lead to severe and irreversible vision loss or even complete blindness secondary to vitreous hemorrhage, traction retinal detachment, and neovascular glaucoma.

Panretinal laser photocoagulation (PRP) is the most commonly used treatment for severe late-stage NPDR. However, this treatment can only maintain visual acuity, which means limited long-term vision improvement, and is associated with significant side effects, including permanent peripheral visual field loss, nyctalopia, macular edema, and worsening of pre-existing edema. Moreover, PRP treatment can lead to the thinning of the retinal nerve fiber layer [2] and to long-term complications, such as laser scar enlargement, secondary choroidal neovascularization, subretinal fibrosis, and reduction of the subfoveal choroidal thickness and blood flow [3]. These complications should be considered to better protect visual function in NPDR treatment. Thus, far no research has shown that PRP treatment can improve the Diabetic Retinopathy Severity Scale (DRSS) score in patients with NPDR without diabetic macular edema (DME).

Intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs is the current first-line treatment for DME[4]. Conbercept (Lumitin, Chengdu Kanghong Biotech Co., Ltd, P. R. China) is a 141-kDa recombinant anti-VEGF fusion protein engineered from a full human cDNA sequence in Chinese hamster ovary cells. It has been developed and used in clinical treatment[5-7]. Several studies have demonstrated the efficacy of conbercept for the treatment of DME [8, 9] and PDR [10, 11]. Improvement in the DRSS score after anti-VEGF injection was first reported in clinical trials evaluating the role of anti-VEGF in DME. In a post hoc analysis of the RIDE (ClinicalTrials.gov identifier NCT00473382) and RISE (ClinicalTrials.gov identifier NCT00473330) trials [12], patients with moderate to severe NPDR (baseline DRSS score 47–53) showed a 78% improvement rate in DRSS scores 2 steps or more. The greatest benefit in DR severity improvement was observed in patients with moderate to severe NPDR at baseline; the improvement was rapid, clinically significant, and sustainable for up to 36 months. Furthermore, mounting evidence has shown that anti-VEGF therapy can improve the DRSS in patients with NPDR without DME. The PANORAMA study is a large prospective trial in the anti-VEGF era targeting eyes with NPDR (DRSS 47–53) without DME[13]. Protocol W is an ongoing phase III study that examines the use of aflibercept versus sham for the prevention of PDR or center-involving DME in eyes with DRSS 47–53 NPDR without DME[14]. Based on these data, anti-VEGF therapy has been suggested for early-stage DR. With the potential of reversing DR grading and improving visual acuity without significant destruction to the retina, anti-VEGF therapy may be more suitable than PRP for treating NPDR. However, the efficacy of conbercept on inducing the regression of NPDR has not been well studied. In this retrospective clinical study, we evaluated the safety, efficacy, and degree of DR regression, as indicated by the DRSS score, of the intravitreal injection of conbercept in patients with early-stage moderate to severe NPDR. The findings are greatly significant in preventing long-term vision impairment, preventing serious blindness complications, and reducing the social and economic burdens of DR treatment.

Patients

Patients were recruited from the clinical centers of the First Affiliated Hospital of Kunming Medical University (Kunming, Yunnan Province, China) between October 2018 and January 2022. This study adhered to the tenets of the Declaration of Helsinki. The retrospective study protocol was approved by the Ethics Review Committee of the First Affiliated Hospital of Kunming Medical University. Because of the retrospective nature of the study, the requirement for informed consent was waived by the Ethics Review Committee.

The study recruited adults (age ≥18 years) with type 1 or 2 diabetes, moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study severity level, 43–53) [15], and with or without DME, as determined by the investigator. In these patients, the glucose level was managed at stable levels, which means that the glycosylated hemoglobin level was＜10% throughout the follow-up period. Patients underwent a complete monthly ophthalmic examination for 1 year. This included a best-correct visual acuity (BCVA) assessment; slit-lamp biomicroscopy; intraocular pressure (IOP) measurement; optical coherence tomography (OCT) imaging using the 6 × 6 mm Retina Angio procedure (RTVue XRAvanti, Optovue, Inc., Fremont, CA, USA) to automatically analyze the central macular thickness (CMT) by macular linear scanning; and ultrawide-field fundus photography using Optomap Panoramic Daytona device (Daytona, Optos, UK). The DRSS levels were defined as follows: DR absent, level 10; minimal DR (microaneurysms only), level 20; mild NPDR, level 35; moderate NPDR, level 43; moderately severe NPDR, level 47; severe NPDR, level 53; mild PDR, level 61; moderate PDR, level 65; and high-risk PDR, level 71/75. The DRSS scores were evaluated by the same specialist (L.Y.). Automatic threshold functions and manual adjustments on the Image J software (Rasband, W.S., ImageJ, U. S. National Institutes of Health, Bethesda, Maryland, USA) were used to generate binary segmentation images. The hard exudation (HE) lesion area within the macular vascular arch in fundus images taken before and during follow-up was measured semi-automatically. The above data were recorded before treatment and at 1, 2, 3, 6, 9, 12, 18 and 24 months after initial treatment.

Patients were excluded if they had a history of vitreoretinal surgery or panretinal photocoagulation or if they previously had vitreoretinal traction, vitreous hemorrhage, uveitis, uncontrolled glaucoma, macular fibrovascular proliferation, or significant media opacities. Patients with other retinal pathological features, such as high myopia, age-related macular degeneration, or other systemic diseases, such as untreated or uncontrolled hypertension, were also excluded. Safety was evaluated during the study by recording the occurrence of severe diseases (e.g., endophthalmitis, vitreous hemorrhage, or cerebrovascular disease).

Treatment

All included patients were treated by intravitreal injection of conbercept in a 3+pro re nata (PRN) [16-18] regimen under aseptic conditions: They received one intravitreal injection per month for 3 months and then continued or stopped treatment based on their clinical progression. PRN criteria: (1) Patients with DME: Conbercept was initiated for DME if CMT increased by 10% or more from baseline with a 5- to 9-letter decrease at two consecutive visits with vision loss presumably due to DME; (2) Patients without DME: exacerbation ≥ 1 DRSS level, the conbercept drugs should be considered for re-injection. Rescue therapy: If retinal non-perfusion areas were noted, treatment with focal retinal laser photocoagulation was implemented. Furthermore, 25G vitrectomy combined with PRP and IVC was implemented if PDR occurred at any follow-up time point, as indicated by the development of vitreous hemorrhage, traction retinal detachment, or other serious complications. The primary outcome measures were changes in DRSS levels. Changes in BCVA, CMT, and HE were also monitored.

Statistical analysis

SPSS Statistics for Windows version 27.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism software version 9.0 (GraphPad Software,Inc., SanDiego, California, USA) were used for data analyses. The distributions of measurement data are expressed as mean ± standard deviation. The paired-sample t-test was performed to compare changes in BCVA and CMT during the follow-up period. The Wilcoxon signed-rank test was performed to compare ranked data. A P value ≤ 0.05 was considered statistically significant.

Patient clinical characteristics and baseline statistics

Fifty eyes of 35 patients with NPDR were evaluated in the study (16 male and 19 female; 24 right eyes and 26 left eyes). The baseline characteristics are described in Table 1. At baseline, the mean age of the entire cohort was 56.56 ± 11.72 years, with a mean DM duration of 18.33 ± 6.62 years. Twenty-seven eyes had DME, whereas 23 eyes had no DME (15 moderate NPDR, 18 moderately severe NPDR, and 17 severe NPDR). The mean baseline BCVA was 0.41 ± 0.39 logarithm of the minimum angle of resolution (logMAR), whereas the mean baseline CMT was 306.22 ± 77.40 μm. The mean number of injections during the follow-up period was 8.15 ± 2.97.

Changes in BCVA

The mean BCVA at each follow-up time point significantly differed from the baseline value except for the 18-month follow-up (P < 0.05; Figure 1 and Table 2). These findings suggest that BCVA significantly improved at the 1-, 2-, 3-, 6-, 9-, 12-, and 24-month follow-up time points compared with the baseline value.

Changes in CMT

The mean CMT decreased markedly from the baseline value in the first 3 months of follow-up (P < 0.05; Figure 2 and Table 3). However, CMT showed a slight increase from the 6-month to the 24-month follow-up. Notably, no significant difference was found between the baseline CMT value and the 6-month CMT value.

Improvement in DRSS scores

At baseline, the DRSS scores were 43, 47, and 53 in 15 patients (30%), 18 patients (36%), and 17 patients (34%), respectively (Figure 3). Compared with baseline, DRSS scores at month 12 regressed by 1 step or more in 41 eyes (82%), 2 steps or more in 25 eyes (50%), and 3 steps or more in 6 eyes (12%). However, the DRSS score remained stable in 8 eyes (16%). Only one eye demonstrated worsening at month 12, which developed vitreous hemorrhage. At month 24, DRSS scores regressed by 1 step or more in 40 eyes (80%), 2 steps or more in 28 patients (56%), and by 3 steps or more in 10 eyes (20%) (Figure 4), whereas they remained stable in 6 eyes (12%). However, 4 eyes showed worsening at month 24. The DRSS scores at each follow-up time point showed a statistically significant regression from the baseline value (Table 4).

Changes in HE

Analysis of the lesion characteristics of eyes with NPDR revealed 15 eyes with HE in the macular vascular arch area before treatment, accounting for 30% of the study sample. Furthermore, 15 of the 27 eyes (55.56%) with DME showed varying degrees of HE within the macular vascular arch. Compared with the HE area in the first month, the mean HE area at each follow-up time point demonstrated statistically significant differences (Table 5 and Figure 5). We speculated that the persistence of HE within the macular vascular arch was correlated with DME recurrence. These results indicate that early intensive intravitreal injection of conbercept significantly reduced the HE area.

Adverse events

Severe ocular adverse events are listed in Table 6. Twelve eyes (24%) with NPDR progressed to PDR, whereas 16 eyes (69.57%) showed new-onset DME. All 12 eyes with severe DR progression were treated with PRP, 6 of which developed vitreous hemorrhage, requiring treatment with PRP during the pars plana vitrectomy (PPV) period and intravitreal injection of conbercept (IVC) immediately after surgery. As for the eyes with new-onset DME, monthly IVC regimen therapy was continued. One eye underwent local retinal laser photocoagulation due to non-perfusion areas revealed on fundus fluorescent angiography examination. PPV and internal limiting membrane (ILM) peeling were performed for 1 eye with macular epiretinal membranes, respectively. No cases of iatrogenic cataract, endophthalmitis, or persistent ocular hypertension developed after injection.

When NPDR progresses to PDR, several serious complications caused by neovascularization develop, including vitreous hemorrhage, tractional retinal detachment, and neovascular glaucoma. These cause serious damage to visual acuity and severely affect the quality of life. Even though PPV combined with PRP is effective in treating PDR, retinal damage from fibrosis and contraction may be irreversible, even with intervention, and has been associated with permanent vision loss and increased management burden. Therefore, treatment options for DR in the early stage and the prevention or delay of the progression of NPDR into PDR must be explored.

Compared with VEGF-trap (e.g., aflibercept), conbercept is a new type of anti-VEGF drug which was added with the fourth binding domain of VEGFR-2, which stabilizes the receptor–ligand complex and further extends the half-life [19]. Therefore, conbercept exhibits high affinity and strong durability. Our findings indicate that IVC treatment for patients with NPDR was effective, based on improvements in BCVA and DRSS levels at the 24-month visit, as well as the decrease in CMT and HE areas.

Although NPDR has significant pathological features, patients without DME rarely have chief complaint symptoms. The risk of progression from severe NPDR to PDR within 1 year was 15%, whereas the risk of progression within 3 years was 60%. Patients with very severe NPDR have a 45% chance of progressing to PDR within 1 year [20]. The cumulative probability of developing PDR within 2 years from randomization was 13.5% in the aflibercept group vs 33.2% in the sham group in the PROTOCOL W study [13]. Although our study showed that 24% of patients with moderate to severe NPDR who received IVC treatment within 2 year still developed PDR, a slightly higher rate than in previous studies, we considered that this might be related to the faster progression of DR caused by chronic renal insufficiency in 6 patients. Excluding these patients with chronic renal insufficiency, the proportion of patients who developed PDR during the observation period was 10%. To prevent irreversible visual impairment, patients with NPDR should be closely monitored. A post hoc analysis of 748 DME eyes in the VIVID and VISTA studies showed that patients treated with intravitreal aflibercept showed better BCVA outcomes than those treated with laser photocoagulation. DRSS level improvement ≥ 2 steps was observed in 13% of eyes with baseline DRSS score ≤ 43, 25.8% with baseline DRSS score 47, and 64.5% with baseline DRSS score ≥ 53 [21]. In the PANORAMA study, aflibercept was used to treat NPDR without DME with a DRSS score of 47–53. With continued intravitreal aflibercept treatment at a fixed interval of every 16 weeks, the proportion of patients with DRSS level improvement ≥ 2 steps at week 52 (65.2%) was maintained through week 100 (62.2%) [13]. In the present study, 56% of participants with NPDR achieved DRSS score regression grade ≥ 2 at the 24^th month of follow-up after IVC therapy, suggesting that the severity of DR was significantly reduced after early enhanced IVC treatment in most NPDR eyes, which was substantially consistent with the results of previous studies. PROTOCOL W investigated aflibercept therapy every 16 weeks vs sham treatment for the prevention of PDR and DME in a similar NPDR population (DRSS level of 43–53 and BCVA ≥ 0.8) [14]. The study found that the proportion of eyes with DRSS level improvement ≥ 2 steps was also significantly higher with aflibercept than with sham treatment. Furthermore, the proportion of eyes that developed PDR or central involved-DME with vision loss was significantly lower with aflibercept than with sham treatment, at least until up to 2 years after treatment.

HE manifests as yellow and white deposits in the retina composed of lipid and protein substances, such as fibrinogen and albumin, and are mainly formed in the outer plexus layer. A histopathological evaluation showed that diffuse lipid and cholesterol esterification, apolipoprotein B, and macrophages were distributed around the diseased blood vessels in the retinal HE lesions [22]. Although HE occasionally resolves spontaneously, it can form fibrotic lesions, leading to severe vision loss, especially when it develops in the macular fovea [23]. In the Phase III trial of the RISE and RIDE studies, the monthly injection of ramizumab significantly reduced intraretinal HE in DME eyes compared with sham injection. However, the reduction in the HE area was more gradual than the rapid response to DME [24]. Our findings indicate that the HE area in patients with NPDR decreased significantly across all follow-up time points. However, further long-term studies involving a larger sample group on the pathological mechanism of the efficacy of IVC therapy on HE are needed.

Our study has some limitations. First, the reliability of the results needs to be supported by more cases, especially those focusing on the influence of well-controlled systemic diseases on the statistical results. Second, the observation time was not long enough. The long-term results and the duration of adherence to anti-VEGF therapy for eyes with NPDR have not yet been established, and the cost–ratio is also a challenge that needs to be addressed. Third, we could not establish whether anti-VEGF–induced improvement in DRSS is related to retinal reperfusion.

In conclusion, our findings demonstrated that early intensive intravitreal injection of conbercept can induce a robust regression in the DRSS scores of patients with moderate to severe NPDR, improve BCVA, and reduce the CMT values and HE areas, suggesting that conbercept slows the progression of NPDR to PDR. Nevertheless, further follow-up studies are needed on the disease progression in this NPDR population for 5 years or even longer to determine whether early anti-VEGF therapy can produce long-term visual benefits.

Data Availability Statement

The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. While the data that support the findings of this study are available from the corresponding author, Ling Yuan, upon reasonable request.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Funding Statement

This study was supported by the Applied Basic Research Foundation of the Department of Science and Technology of Yunnan Province, Yunnan, China (grant no 202201AY070001-036); National Natural Science Foundation Project (grant no 82260207).

Acknowledgments

The authors would like to thank the help of all their colleagues.

Author contributions

The following authors were involved in the design of the study (Ling Yuan, Yijun Hu); collection (Lu Shen, Yuxiang Zheng, Wenchang Yang), analysis (Qiying Zhang), and interpretation(Lu Shen, Zelan Gao) of the data; and preparation (Lu Shen, Qirui Li, Min Dai), revision (Dongli Li), and approval of the manuscript (Ling Yuan, Yijun Hu). All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

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Table 1. Baseline patient demographics and ocular characteristics.

Parameters Patients/eyes (n) Sex (n, male/female) Eyes (n, right/left) Mean age (years, mean ± standard deviation) Mean duration of diabetes (years, mean ± standard deviation) DME (n, with/without)	35/50 16/19 24/26 56.56 ± 11.72 18.33 ± 6.62 27/23
Kidney insufficiency (n)	6
Stage of DR (n)
Moderate NPDR	15
Moderately severe NPDR	18
Severe NPDR	17
Baseline BCVA (logMAR, mean ± standard deviation)	0.41 ± 0.39
Baseline CMT (μm, mean ± standard deviation)	306.22 ± 77.40
Number of injections (mean ± standard deviation)	8.15 ± 2.97

Abbreviations: DME, diabetic macular edema; DR, diabetic retinopathy; NPDR, nonproliferative diabetic retinopathy; BCVA, best-corrected visual acuity; CMT, central macular thickness; logMAR, logarithm of the minimum angle of resolution.

Table 2. Best-corrected visual acuity (logMAR) values over time in patients with nonproliferative diabetic retinopathy who received intravitreal injections of conbercept.

	Before treatment		1 month	2 months	3 months	6 months	9 months	12 months		18 months	24 months
n=50	0.41±0.39		0.25±0.26	0.24±0.16	0.24±0.24	0.28±0.15	0.27±0.20		0.26±0.22	0.30±0.25		0.23±0.20
t	-		2.931	3.200	3.611	2.201	2.598		2.394	1.784		3.137
P	-	0.006		0.003	0.001	0.035	0.014		0.022	0.083		0.004

Values are shown as mean ± standard deviation.

P value vs. before treatment.

Abbreviations: logMAR, logarithm of the minimum angle of resolution.

Table 3. Central macular thickness (μm) values over time in patients with nonproliferative diabetic retinopathy who received intravitreal injections of conbercept.

	Before treatment		1 month	2 months	3 months	6 months	9 months	12 months		18 months	24 months
n=50	306.22±77.40		261.24±42.19	262.69±46.44	262.54±50.48	296.14±112.20	297.75±95.98		288.39±87.54	270.60±68.07		297.97±88.15
t	-		4.655	3.373	3.668	0.477	0.423		1.076	2.870		0.881
P	-	<0.001		0.002	<0.001	0.636	0.675		0.289	0.007		0.385

Values are shown as mean ± standard deviation.

P value vs. before treatment.

Table 4. Diabetic Retinopathy Severity Scale scores over time in patients with nonproliferative diabetic retinopathy who received intravitreal injections of conbercept.

	Before treatment		1 month	2 months	3 months	6 months	9 months	12 months	18 months	24 months
Z		-	−3.223	−4.003	−4.224	−5.051	−4.878	−4.522	−3.579	−3.646
P		-	0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001

P value vs. before treatment.

Table 5. Hard exudate areas over time among patients with nonproliferative diabetic retinopathy who received intravitreal injections of conbercept.

	Area of HE (pixels)	Mean range	t	P
1 month	3554.50±1927.24	-	-	-
2 months	2906.70±1590.50	647.80±769.76	2.661	0.026
3 months	2163.00±1445.04	1391.50±1525.90	2.884	0.018
6 months	1779.50±1401.78	1775.00±1361.79	4.122	0.003
9 months	1369.78±832.61	2413.00±1475.46	4.906	0.001
12 months	1005.33±570.58	2777.44±1496.90	5.566	<0.001
18 months	664.22±229.88	3118.56±1798.83	5.201	<0.001
24 months	385.11±148.61	3397.67±1880.74	5.420	<0.001

Values are shown as mean ± standard deviation

P value vs. 1st month.

Table 6. Severe ocular adverse events and treatment.

Characteristic	n (%)
Characteristic	Total	Therapy
PDR progression
Vitreous hemorrhage	6 (12)	PPV + PRP + IVC
Proliferative diabetic retinopathy	6 (12)	PRP
Neovascular glaucoma	0	-
New-onset DME in eyes without DME at baseline	16 (69.57)	IVC
Non-perfusion area (FFA)	1 (2)	Local laser photocoagulation
Macular epiretinal membranes	1 (2)	PPV + ILM peeling
Iatrogenic cataract	0	-
Endophthalmitis	0	-
Persistent ocular hypertension	0	-

Abbreviations: DR, diabetic retinopathy; DME, diabetic macular edema; FFA, fundus fluorescent angiography; PPV, pars plana vitrectomy; PRP, panretinal laser photocoagulation; IVC, intravitreal injection of conbercept; ILM, internal limiting membrane.

No competing interests reported.

Efficacy and Safety of Intravitreal Injection of Conbercept for Moderate to Severe Nonproliferative Diabetic Retinopathy

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Abstract

Figures

Introduction

Patients and methods

Results

Discussion

Conclusions

Declarations

References

Tables

Additional Declarations

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