Age-related macular degeneration (AMD), a chronic macular disease that affects the central retina, is the third leading cause of irreversible blindness and the first cause of visual impairment in developed countries (1–3). The total number of patients with AMD was estimated to be 196 million in 2020 and might rise to 288 million by 2040 (4). Global burden of disease in 2010 showed that vision-related quality-adjusted life-years (QALYs) caused by AMD increased at an exponential rate of 160% (5). Diabetic retinopathy is the leading blinding eye disease for working-aged people and diabetic macular edema (DME) secondary to diabetic retinopathy is the direct cause of visual impairment (6). Epidemiological surveys in China show that the incidence of DME in diabetic patients is 5% (7, 8). Pathological myopia (PM) is one of the three most common causes of blindness in the world. As many as 3% of the population of the world suffer from PM, especially in Asian countries, and the global prevalence is generally increasing (9). Thus, the visual impairment caused by fundus diseases related to pathological neovascularization, including AMD, DME, and PM, has brought a heavy economic burden to the society.

In China, with the advent of an aging society, AMD, DME, and PM have become an increasingly serious medical and health problems, for which intravitreal injection of antivascular endothelial growth factor (VEGF) drugs is an effective method. Until now, the main anti-VEGF drugs in clinical use are ranibizumab, aflibercept, bevacizumab, and conbercept, which have been proven to be superior to conventional treatments (10).

Ranibizumab, the first drug proven to improve eyesight, has been confirmed that it has good effects through randomized controlled trials (RCTs) (11–13). Conbercept (Lumitin, Chengdu Kanghong Biotech Corporation Ltd., Chengdu, Sichuan, China), a genetically engineered fusion protein, is an anti-VEGF drug independently developed by China in the recent years. It can effectively combine with VEGF in blood vessels and tissues to treat a variety of eye diseases related to pathological angiogenesis (14). A recent systematic review demonstrated that conbercept had comparable safety and efficacy profiles rather than ranibizumab (15). Ranibizumab and conbercept have been commonly used and covered by the national basic medical insurance in China, so it is necessary to conduct an economic evaluation of these two drugs, which socioeconomic burden would be fueled soon for their high cost and widespread used. An economic evaluation has concluded previously that conbercept is more cost-effective than aflibercept and ranibizumab for the treatment of AMD in China, but only based on the 2-year medication situation in clinical scenarios (16). Even worse, there is still a lack of studies on the pharmacoeconomic evaluation between conbercept and ranibizumab treatment of DME and PM. Therefore, it is urgent to evaluate the cost-effectiveness between conbercept and ranibizumab in treatment of AMD, DME, and PM from the perspective of Chinese payers in order to optimally allocate and utilize the limited medical resources.

A Markov chain model, the simplest Markov model, was used to estimate the cost-effectiveness of conbercept and ranibizumab in treatment of AMD, DME, and PM. The principle is to simulate the development of the disease according to the transition probability of its natural process, divided into different states (Markov state) in a certain period of time (Markov cycle). Combined with the health utility value of the disease and the consumption of public health resources, the outcome and cost of disease progression were estimated through multiple iterations.

In this study, assuming that the simulated population is patients with AMD, DME, and PM, the baseline characteristics are consistent with that in PHOENIX (identifier NCT01436864), SAILING (identifier NCT02194634), and SHINY (identifier NCT01809223) studies, respectively (Appendix Part A). Health states were represented by different vision conditions of the patients, which were indicated by the number of letters in best corrected visual acuity (BCVA). There are six health states of AMD and five health states of the other two eye diseases. The specific health status classification and baseline visual acuity distribution of the patient are shown in Table 1. The baseline distribution of visual acuity among the patients with AMD, DME, and PM was derived from unpublished data in PHOENIX, SAILING, and SHINY studies, respectively. The average annual number of injections was used to simulate the injection situation within 10 years, assuming that remained the same. The number of injections for conbercept and ranibizumab was set according to the existing literature and research. The difference between the costs of the two drugs has remained approximately the same within 10 years due to focus on the incremental cost-effectiveness ratio (ICER) in this study, which is the ratio of incremental cost to incremental effectiveness. The ICER is used to evaluate the relative economics of two or more alternative treatment options. The Markov transition processes of the eye diseases were shown in Figures 1–3, respectively, and the arrows indicate whole possible transitions between the states 1 year later.

After a cycle, participants in one stage could stay in that stage or move onto the next stage with a certain transition probability. Suppose that after 1 year of the treatment, there were three types of therapeutic effects of AMD and DME: BCVA increased by 15 letters or more, BCVA remained unchanged, BCVA decreased by 10 letters or more, five types of therapeutic effects of PM: BCVA increased or decreased by 30 letters, BCVA increased or decreased by 15 letters, and BCVA remained unchanged. The model structure is shown in Figures 1–3.

To the best of our knowledge, this is the first study to analyze and compare the cost-effectiveness of conbercept and ranibizumab for the treatment of AMD, DME, and PM based on the real-world scenarios. The results of the economic evaluation study suggest that compared with ranibizumab, conbercept has lower cost and more effective in treatment of DME and PM, which indicated that conbercept had significant cost-effectiveness. In treatment of AMD, the total cost and total utility value of conbercept were lower than that of ranibizumab within 10 years, while the ICER was lower than the threshold of three times per capita GDP. The results indicated that conbercept had a certain cost-effectiveness as well relative to ranibizumab in treatment of AMD.

Previous cost-effectiveness study based on the status change of BCVA, using a similar Markov structure, has explored the cost-effectiveness of conbercept and ranibizumab for wet AMD and found that conbercept was a more cost-effective option for the treatment of AMD in a Chinese healthcare setting (16). A meeting abstract from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) also mentioned that compared with ranibizumab, conbercept is a superior cost-saving alternative for the treatment of Chinese AMD (49). Additionally, conbercept also has certain advantages in clinical application. Unlike ranibizumab, a recombinant humanized anti-VEGF monoclonal antibody Fab fragment, which can only neutralize all the active components of VEGF-A, conbercept is a recombinant fusion protein of the extracellular segments of VEGF receptors 1 and 2 and the human immunoglobulin Fc segment, which can target VEGF-A, VEGF-B, and placental growth factor (15, 50). Therefore, among the four anti-VEGF drugs such as ranibizumab, aflibercept, bevacizumab, and conbercept, conbercept is a 100% humanized protein with the highest affinity and the most binding VEGF targets, which avoids the immune risk of murine protein. The high affinity also means a longer active period of the drug, thereby extending the treatment interval, reducing the burden of the patient, and reflecting the therapeutic advantage in AMD, DME, and PM.

Age-related macular degeneration, induced by a variety of factors and closely related to age, can occur in middle age and its incidence shows an exponential increase after the age of 70 years (51). At the same time, it has been estimated that 25% of Asians will be aged over 60 years by 2050 (52). Therefore, with aging global populations, it was anticipated that AMD would continue to be major causes of vision impairment (4). High myopia is particularly prevalent in East Asian populations and the prevalence of high myopia in the Chinese population in Singapore is 9.1%, China is 3.3%, Taiwan is 2.4%, and Japan is 8.2% (53, 54). PM can develop from high myopia, brings severe visual impairment, and its prevalence is relatively high (about 9–21%) in adults in Asian populations (55). DME is a diabetic microvascular complication that occurs in the retina (56) and diabetic retinopathy (DR) is a common diabetic complication and the main cause of moderate-to-severe visual impairment in diabetic patients (57). About one-third of diabetic patients develop DR and about one-third of patients with DR develop DME (58). Until now, diabetes mellitus (DM) remains a major health burden, with ~80% occurring in low- and middle-income countries (59, 60). The number of DM in China is expected to increase to 142.7 million by 2035 (61). Similarly, it was predicted that the diabetic population in Malaysia would continue to rise (62).

In summary, in low- and middle-income countries that have many similarities and comparability with China in terms of national conditions, such as Malaysia and Singapore, the disease burden of AMD, DME, and PM is also heavy. Although the European Society of Retina Specialists recommends anti-VEGF therapy as a first-line treatment, it is unclear which anti-VEGF should be used first (63). Economic evaluation and analysis should be carried out to obtain greater benefits at the minimum cost and then optimize the allocation and utilization of limited medical resources. This study was based on real-world data for long-term evaluation, which is objective, scientific, and authentic, and can reflect the medication and health of the patient under real conditions to the maximum extent. Therefore, the conclusion throws significant light on the treatment of AMD, DME, and PM in low- and middle-income countries such as Malaysia.

Our research findings showed that in order to maximize health within the fixed general healthcare budget, in the case of the equivalence of conbercept and ranibizumab, the preferential price of conbercept enables it to achieve good therapeutic effect and saves the medical cost during treatment, which has certain advantages. Therefore, clinicians could consider using conbercept instead of ranibizumab to treat AMD, DME, and PM.

This analysis has some limitations that need to be considered along with the results. Firstly, this study mainly used parameters extracted from foreign reports and articles, which might cause a certain degree of uncertainty, so we carried out extensive sensitivity analyses to prove the credibility and robustness of our research results. Secondly, there were more or less differences in population characteristics under different research backgrounds, which may cause the results to have a certain orientation and lack the ability to generalize. Moreover, indirect costs such as the loss of productivity and adverse effects of conbercept and ranibizumab were not included in this study, which may cause a heavy socioeconomic burden for the family and society of the patient. According to clinical trials, the incidence of adverse effects of the two treatment options is very low and mild; the cost-effectiveness of conbercept vs. ranibizumab would become more credible, if this study included the indirect costs. Finally, we simply compared the cost-effectiveness of conbercept and ranibizumab. In fact, compared with other potential anti-VEGF therapies (aflibercept and bevacizumab), ranibizumab has not been shown to be cost-effective in treatment of AMD, DME, and PM (64–66). In light of fact that bevacizumab has been admitted to medical insurance in China in 2017, it is necessary to conduct the cost-effectiveness of conbercept vs. aflibercept or bevacizumab in follow-up studies.

In conclusion, from the third-party payer perspective, conbercept was more cost-effective than ranibizumab in treatment of AMD, DME, and PM. Therefore, due to its favorable economic outcomes, conbercept was the most suitable option in the current Chinese healthcare setting, although conbercept and ranibizumab were both licensed for the treatment of the three eye diseases in China.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

ZC and WZ collected data. TZ, HW, and QC designed the entire plan of this study and wrote the manuscript. XM and YL did data analysis and interpretation. ZC, WZ, and HY discussed and supervised this study. All the authors wrote the manuscript and approval the final manuscript.

This study was supported by the National Natural Science Foundation of China (Grant Numbers 82020108007 and 81830026) and the Beijing-Tianjin-Hebei Special Project (Grant Numbers 19JCZDJC64300(Z) and 20JCZXJC00180).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.