Abstract
Background
While anti-vascular endothelial growth factor (VEGF) therapies are effective for macular oedema secondary to retinal vein occlusion (RVO), there remains a need for additional treatment options. This study evaluated the novel anti-VEGF agent 601 versus ranibizumab in patients with branch RVO (BRVO) or central RVO (CRVO).
Methods
In two multicentre, randomised, double-masked, active-controlled phase IIa trials (NCT04667897, NCT04667910) conducted at 12 Chinese sites (2021–2022), 120 patients were assigned 1:1 to receive intravitreal 1.25 mg 601 or 0.5 mg ranibizumab every 4 weeks until week 20, followed by pro re nata dosing through week 48. Eligible patients had best-corrected visual acuity (BCVA) of 78–19 Early Treatment Diabetic Retinopathy Study letters and central subfield thickness ≥250 µm. The primary endpoint was change in BCVA at week 24.
Results
At week 24, the adjusted mean BCVA change from baseline was +16.52 letters for 601 versus +17.79 letters for ranibizumab (adjusted mean difference: −1.27 letters (95% CI −5.439 to 2.891 letters)) in BRVO, and +13.81 letters versus +16.79 letters (adjusted mean difference: −2.97 letters (95% CI −10.488 to 4.540 letters)) in CRVO. Central retina thickness (CST) reduction was similar for both treatments. Both groups showed sustained improvements from week 24 to 52 with similar adverse event profiles.
Conclusions
These trials demonstrate that 601 is as effective and safe as ranibizumab for improving vision and reducing CST in RVO-related macular oedema. Phase III trials are warranted.
Keywords: Clinical Trial, Intraretinal Fluid, Treatment Medical
WHAT IS ALREADY KNOWN ON THIS TOPIC
The advent of intravitreal anti-vascular endothelial growth factor (VEGF) therapy has revolutionised the management of macular oedema secondary to retinal vein occlusion (RVO), establishing it as the current first-line treatment. Despite its off-label status for ocular use, bevacizumab is widely employed worldwide owing to its demonstrated efficacy and favourable cost-effectiveness profile.
WHAT THIS STUDY ADDS
In these randomised clinical trials including patients with macular oedema caused by branch RVO and central RVO, 601, an intravitreal injection solution of bevacizumab, provided robust and similar vision and anatomic improvement to ranibizumab throughout 52 weeks, as well as a favourable safety profile.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These results provide evidence that 601 is a promising management for patients with RVO.
Introduction
Retinal vein occlusion (RVO), a partial or complete obstruction of normal venous system of the retina, is the second most common retinal vascular disease following diabetic retinopathy.1 2 The global prevalence of RVO in people aged 30–89 years was 0.77%, translating to a total of 28.06 million affected individuals, respectively.3 According to the site of occlusion, RVO can be classified as branch RVO (BRVO) and central RVO (CRVO).4 5 RVO is usually presented as acute painless loss of vision in one eye.6 7 Macular oedema, driven by vascular endothelial growth factor (VEGF) upregulation due to retinal ischaemia, represents the principal cause of visual impairment in RVO.8,10
The advent of intravitreal anti-VEGF therapy has revolutionised the management of macular oedema secondary to RVO,11 12 and now it has been established as the first line of treatment. Ranibizumab and aflibercept are approved by the US Food and Drug Administration (FDA) and China’s National Medical Products Administration (NMPA) for RVO, demonstrating superior efficacy over sham injections or photocoagulation.13,20 State-of-the-art comparative randomised controlled trials (RCTs) have established the non-inferiority of bevacizumab to these agents,21 22 supporting its widespread off-label use as a cost-effective option.23,25
601 (Sunshine Guojian Pharmaceutical), a recombined humanised anti-VEGF monoclonal antibody, shares identical amino acid sequences and highly similar structural and functional characteristics with bevacizumab. Here we reported two identically designed phase II trials evaluating 601 for the treatment of macular oedema resulting from BRVO and CRVO, respectively.
Methods
Study design
Both studies were multicentre, randomised, double-blinded, active comparator-controlled phase IIa trials evaluating the safety and efficacy of 601 versus ranibizumab administered by intravitreal injection in patients with macular oedema secondary to BRVO (NCT04667897) or CRVO (NCT04667910), respectively. Details and statistical analysis plans (SAPs) are provided in online supplemental 2.
The trials were conducted in accordance with International Conference on Harmonisation E6 Guideline, the Declaration of Helsinki and Chinese regulatory requirements. Written informed consent was obtained before initiation of study procedures. Both trials followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Participants
Eligible patients were aged ≥18 years with foveal centre-involved macular oedema following RVO diagnosis within 12 months. Study eyes had a best-corrected visual acuity (BCVA) of 78–19 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and central retina thickness (CST) of ≥250 µm. Patients were excluded for any of the following: (1) concomitant conditions or ocular disorders that may confound outcomes; (2) any prior or current treatment for macular oedema (eg, anti-VEGF within 3 months, intraocular/periocular corticosteroids within 3 months or dexamethasone implant within 6 months) or laser photocoagulation; (3) vitreoretinal or other intraocular surgery within 3 months; and (4) systemic therapy of anti-VEGF within 6 months.
Randomisation and treatment
Participants were randomised 1:1 to receive 601 (1.25 mg/eye) or ranibizumab (0.5 mg/eye) every 4 weeks up to week 20 (core treatment period) in BRVO and CRVO trials. During week 24–week 52 (extend treatment period), eyes in both treatment groups could receive monthly injection. To minimise the regional practice variations across trial sites, standardised retreatment criteria required repeat treatment if any of the following were met: (1) ≥50 µm CST increase from the lowest previous value; (2) ≥5-letter BCVA loss from the best previous value due to RVO; (3) ≥5-letter BCVA increase from the last measurement; and (4) presence of new or persistent macular oedema, intraretinal or subretinal fluid.
Study end points and assessments
The primary endpoint was the change in BCVA from baseline at week 24. Secondary endpoints include change in BCVA and CST at week 12 and 52; proportion of patients gaining or losing ≥15/10/5 letters at week 12, 24 and 52; and mean injections through week 52. Safety outcomes included the incidence and severity of ocular and non-ocular adverse events (AEs). Pharmacokinetic (plasma concentration), pharmacodynamic (plasma VEGF) and immunogenicity (anti-drug and neutralising antibodies) were assessed at prespecified visits from week 0 to 52.
Statistical analysis
Given the exploratory nature of phase II design, the sample size was determined per Chinese regulatory guidelines and analogous trials rather than statistical hypothesis. Efficacy was analysed in the full analysis set, which comprised all randomised eyes that received ≥1 dose with postbaseline efficacy data. The primary endpoint (BCVA change at week 24) was assessed using a covariance model with baseline BCVA and treatment groups as covariates. The missing BCVA data at week 24 were handled via multiple imputation (MI) followed by covariance analysis (ANCOVA), with robustness verified by mixed-effects model for repeated measures (MMRM). Treatment differences were expressed as least-squares means with 95% CI. Safety was analysed in all treated patients with AEs coded by MedDRA and summarised by System Organ Class. All statistical analyses were performed per a prespecified SAP (online supplemental 2) using SAS V.9.4.
Results
Patient disposition
In the BRVO trial, 60 patients were randomised in a 1:1 ratio to the 601 group (n=31) or ranibizumab group (n=29) between January 2021 and July 2022. In the CRVO trial, 60 patients were randomised to the 601 group (n=29) or ranibizumab group (n=31) between January 2021 and November 2022. Sixty (100.0%) patients with BRVO and 59 (98.3%) patients with CRVO received ≥1 dose of study treatment and were included in the full analysis and safety sets. Up to week 52, 25 (80.6%) and 28 (96.6%) patients in the 601 and ranibizumab groups completed the BRVO study, while 24 (82.8%) and 26 (83.9%) patients completed the CRVO study (figure 1). Six participants withdrew prior to week 24: four (6.7%) from 601 groups (three consent withdrawals and one investigator-initiated discontinuation due to safety concerns) and two (3.4%) from ranibizumab groups.
Figure 1. Study participant disposition for (A) branch retinal vein occlusion and (B) central retinal vein occlusion.
Baseline characteristics
Baseline demographics and disease characteristics were similar across treatment groups in both trials (table 1). The study population consisted entirely of Chinese participants with a mean age of 54.5–59.1 years. The mean time from RVO diagnosis to screening was 1.0–1.6 months. Mean BCVA at baseline was 58.1 letters in the BRVO trial and 50.7 letters in the CRVO trial, while mean CST measured 557.1 µm and 715.2 µm, respectively.
Table 1. Baseline patient characteristics in BRVO and CRVO trials.
| Characteristics | BRVO (n=60) | CRVO (n=59) | ||
|---|---|---|---|---|
| 601 1.25 mg (n=31) |
Ranibizumab 0.5 mg (n=29) |
601 1.25 mg (n=29) |
Ranibizumab 0.5 mg (n=30) |
|
| Age, mean (SD), years | 58.9±8.9 | 59.1±8.1 | 54.5 (15.0) | 54.9 (15.1) |
| Sex, no. (%) | ||||
| Female | 19 (61) | 15 (52) | 17 (59) | 10 (33) |
| Male | 12 (39) | 14 (48) | 12 (41) | 20 (67) |
| Ethnic group, no. (%) | ||||
| Han Chinese | 28 (90) | 29 (100) | 28 (97) | 27 (90) |
| Others | 3 (10) | 0 | 1 (3) | 3 (10) |
| Study eye | ||||
| Right, no. (%) | 16 (52) | 18 (62) | 18 (62) | 12 (40) |
| Left, no. (%) | 15 (48) | 11 (38) | 11 (38) | 18 (60) |
| BCVA letter score, mean (SD) | 55.7 (15.9) | 60.6 (10.4) | 51.9 (14.9) | 49.5 (17.4) |
| CST, mean (SD), μm | 569.4 (221.1) | 544.0 (183.4) | 684.5 (214.1) | 744.9 (235.9) |
| Time since RVO diagnosis, mean (SD), months | 1.0 (1.6) | 1.1 (2.2) | 1.6 (2.6) | 1.0 (2.2) |
BCVA, best-corrected visual acuity; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; CST, central subfield thickness; no, number of cases; RVO, retinal vein occlusion.
Vision outcomes
An improvement in BCVA compared with baseline was observed in both treatment groups in BRVO and CRVO trials (figure 2). In the BRVO trial, vision gains at week 24 were 16.52 letters in the 601 group versus 17.79 letters in the ranibizumab group (adjusted mean difference: −1.27 letters by MI+ANCOVA (−5.439 to 2.891 letters; p=0.549); 0.47 letters by MMRM (−3.192 to 4.127 letters; p=0.802)). In the CRVO trial, vision gains at week 24 were 13.81 letters versus 16.79 letters (adjusted mean difference: −2.97 letters by MI+ANCOVA (−10.488 to 4.540 letters; p=0.438); −2.53 letters by MMRM (−8.459 to 3.391 letters; p=0.802)). The visual gains with 601 were maintained through week 24–week 52 using pro re nata (PRN) regimen and were comparable between treatments.
Figure 2. Graphs showing mean change in BCVA from baseline over 52 weeks in (A) BRVO and (B) CRVO. BCVA, best-corrected visual acuity; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; ETDRS, Early Treatment Diabetic Retinopathy Study.
Consistent with the primary endpoint, similar proportions of patients in each group of BRVO and CRVO trials gained or avoided a loss of ≥15/10/5 letters from baseline at week 12, 24 and 52 (online supplemental eTable 1 and eTable 2). A 50%–60% of 601-treated patients gained ≥15 letters compared with 52%–58% in the ranibizumab group at primary endpoint visits. Over 96% of 601-treated patients in both studies avoided ≥15-letter loss from baseline at week 24 (figure 3).
Figure 3. Bar graphs showing the proportion of patients gaining or avoiding a loss of vision at week 24 and 52 in BRVO and CRVO. BCVA, best-corrected visual acuity; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion.
Anatomical outcomes
In both trials, patients experienced robust CST reductions after the initial dose that were sustained through week 52 (figure 4). The adjusted mean CST change from baseline at week 24 was −300.11 µm with 601 versus −311.96 µm with ranibizumab in BRVO (adjusted mean difference: 11.86 µm (−15.171 to 38.884 µm)), and −418.12 µm versus −475.48 µm in CRVO (adjusted mean difference: 57.36 µm (19.772 to 94.954 µm)). The reduction in CST persisted at week 52 with adjusted mean differences of −48.03 µm (−115.975 to 19.909 µm) in BRVO, and −26.72 µm (19.772 to 94.954 µm) in CRVO.
Figure 4. Line graphs showing adjusted mean change in CST from baseline over 6 months in (A) BRVO and (B) CRVO. Central subfield thickness was measured as internal limiting membrane to Bruch’s membrane. BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; CST, central subfield thickness.
During weeks 24–52, there was no difference in the number of repeated treatment injections in the 601 group or ranibizumab group (2.4 vs 2.6 injections in BRVO, 2.9 vs 3.6 injections in CRVO).
Safety outcomes
Through week 52, 601 demonstrated an acceptable safety profile comparable with that of ranibizumab in both BRVO and CRVO trials (online supplemental eTable 3). The incidence of ocular AEs in the study eye was similar between patients receiving 601 (45% and 62% in BRVO and CRVO, respectively) and ranibizumab (35% and 63%, respectively). Most events were mild or moderate in severity. The most frequent (≥2 patients in any treatment group) ocular AEs for 601 were conjunctival haemorrhage (13%), dry eye (10%), intraocular pressure increased (7%) and visual acuity reduced (7%) in BRVO, and intraocular pressure increased (28%), visual acuity reduced (14%), cataract (14%), RVO (10%), epiretinal membrane (10%) and conjunctival hyperaemia (10%) in CRVO. Three 601-treated patients (one in BRVO and two in CRVO) and one ranibizumab-treated patient (CRVO) experienced ocular serious AEs, and only the ranibizumab event was considered treatment-related. No intraocular inflammation events were reported in either trial.
The overall incidence of non-ocular AEs was comparable between 601 and ranibizumab, with no non-ocular serious adverse events (SAEs) reported in 601 groups.
Pharmacokinetics, pharmacodynamics and immunogenicity outcome
Following intravitreal administration of 601, the mean plasma concentrations of free drug and total drug reached steady state by week 12. The trough concentrations of free drug on week 12 were comparable between BRVO (124.3 ng/mL) and CRVO (116.5 ng/mL) trials and to those of total drug.
Mean plasma VEGF concentrations decreased from 35.6 pg/mL(baseline) to 29.4 pg/mL (week 4) and 24.2 pg/mL (week 8) in BRVO, and from 39.0 pg/mL to 26.2 pg/mL and 20.7 pg/mL in CRVO. These suppressed levels were maintained throughout the core treatment period and returned to near baseline by the end of the extend treatment Period.
All patients were anti-drug antibodies negative after administration in BRVO and CRVO trials.
Discussion
The BRVO and CRVO studies were designed as exploratory phase IIa trials to evaluate the efficacy and safety of monthly administration of 1.25 mg 601 vers 0.5 mg ranibizumab in participants with macular oedema resulting from RVO. Both trials met their primary efficacy endpoints of the change in BCVA from baseline to week 24 and all the secondary efficacy endpoints with 601 treatments with no significant safety differences.
Ranibizumab was selected as the active control based on established non-inferiority of bevacizumab to ranibizumab in both BRVO and CRVO populations,22 unlike aflibercept which has limited BRVO data.21 The SCORE2 study confirmed comparable efficacy between ranibizumab and aflibercept in CRVO, with BCVA improvement of 18.6 letters (bevacizumab) versus 18.9 letters (aflibercept) at month 6, meeting prespecified non-inferiority margin of −5. Concurrently, central subfield thickness decreased by 387 µm versus 425 µm, indicating no statistically significant disparity.
Treatment with fixed monthly over 6 months resulted in rapid and sustained improvements in visual acuity. After the first 601 injection, BCVA increased by 10.2 letters and 7.7 letters, followed with continued gains at each visit point. The mean BCVA increases in BRVO and CRVO trials at week 24 were 16.5 letters and 13.8 letters for 601, and 17.8 letters and 16.8 letters for ranibizumab. The overall trend of change in BCVA letters was comparable between 601 and ranibizumab groups. These results are consistent with those of the BRAVO and CRUISE studies, phase III clinical trials of ranibizumab, which compared 0.5 mg of ranibizumab with sham injections and observed mean visual acuity improvements of 18.3 letters and 14.9 letters after 6 months in patients with BRVO and CRVO, respectively.13 15 In our studies, the proportion of patients who gained ≥15 letters after 6 months was 52%–58% in the ranibizumab group and 50%–60% in the 601 group, also consistent with BRAVO and CRUISE studies (61% and 48%). Supporting the primary endpoint, patients in the 601 arms experienced rapid and sustained meaningful reductions in CST that were similar to those seen with ranibizumab, corroborating findings from previous trials13 15 and a direct comparison between bevacizumab and ranibizumab.22 Although the sample sizes of the current studies were limited, the above data confirmed the reliability of the trial designs and results, supporting 601 to continue with a phase III clinical study.
It should be noticed that 601 treatment groups also exhibited robust vision gains which were similar to the outcomes in comparative RCTs of bevacizumab. The BRVO22 trial compared 1.25 mg bevacizumab with 0.5 mg ranibizumab in patients with BRVO and CRVO, demonstrating a mean increase in visual acuity of 15.5 letters and 15.3 letters after 6 months, respectively. The proportion of gainers (improvement of ≥15 letters after 6 months) was 49.6% in the bevacizumab arm and 46.4% in the ranibizumab arm. The SCORE221 trial included patients with higher baseline visual acuity (BCVA of 24–79 letters) than our trials, which could explain the slightly lower visual outcome after 6 months.
During the extend treatment period, the mean number of PRN injections among all randomised patients was 2.4 and 2.9 for 601, and 2.6 and 3.6 ranibizumab, which was comparable to that in BRAVO14 and CRUISE16 studies (2.7 and 3.3). PRN regimen maintained visual acuity outcomes at week 24 and led to additional gain of 2.0 (18.3–20.3) letters and 5.1 (15.4–19.5) letters in BCVA at week 52 for 601 (figure 2). A similar gain was only found in patients with BRVO for ranibizumab. Meanwhile, the visual acuity benefits in the BRAVO and CRUISE studies remained unchanged and even showed a decrease at week 52 (−1.0 letters in the CRUISE study). Although with a higher mean CST at baseline, the 601 group experienced much smaller fluctuation of visual acuity and anatomic change from baseline than the ranibizumab group and reached comparable BCVA (+19.5 vs +14.8 letters) and CST (−387.8 and −418.20 µm) improvement at the end of the extend treatment period in patients with CRVO. These results preliminarily confirmed that after receiving 601 for 6+ PRN doses, the optimal visual acuity and CST outcomes could be maintained with fewer intravitreal injections in patients with BRVO and CRVO (figures2 4).
It was worth noting that no patient with BRVO experienced a loss of ≥15 letters at any point during the study in the 601 group, and a comparable patient with CRVO experienced a loss of ≥15 letters at the end of the study (one patient each). Whereas, the BRAVO and CRUISE studies reported that three patients (2.3%) receiving 6+ PRN injections of 0.5 mg ranibizumab experienced a visual acuity loss from baseline of ≥15 letters at month 12.14 16 These findings may be limited to the sample sizes of the current studies.
Intravitreal 601 was generally well tolerated and there were no significant differences between the treatment groups in terms of frequency or pattern of ocular and non-ocular SAEs, which is consistent with the safety outcomes in other comparative trials of anti-VEGF agents.14 16 18 20 22 26 27 Subjects in both BRVO and CRVO studies experienced visual acuity reduced AEs, which were mainly associated with the recurrent macular oedema. At the same time, the incidence of visual acuity reduced AEs was not higher in the 601 group than in the control group. We also noticed that more patients with CRVO experienced ocular AEs, which may be due to the complexity and severity of CRVO itself. No unexpected safety findings were reported. The key AEs were either because of the injection procedure or the result of the underlying disease. The further phase III trials will evaluate overall safety in a larger sample population and focus on common AEs observed in current studies.
Caution is required in extrapolating these findings to ethnically diverse populations, given the exclusively Chinese enrolment in our BRVO and CRVO trials. This limits the generalisability of our results to other regions, such as Europe or North America, where genetic backgrounds, environmental exposures and clinical practices may differ. Nevertheless, this homogeneous cohort design enhanced control over genetic confounders in effect and safety assessments and provided population-specific evidence for East Asian patients. These data meaningfully complement existing data from predominantly Caucasian trials such as BRVO and SCORE2 studies.
Additionally, this study has limitations inherent to its phase IIa design. Primarily, the predefined sample size was exploratory and was not statistically powered to establish formal non-inferiority of 601 versus ranibizumab. Furthermore, the limited number of participants reduces the precision of safety estimates and was not sufficient to robustly detect rare safety events (eg, endophthalmitis with an incidence <0.5%) or to conduct robust subgroup analyses. The limited number of participants reduces the precision of safety estimates for uncommon adverse reactions. Future pooled analyses incorporating data from phase III trials may enhance detection sensitivity for infrequent safety signals and validate these findings across broader populations.
Conclusion
The BRVO and CRVO studies demonstrated efficacy of 601 under 6+ PRN regimen in the treatment of macular oedema secondary to RVO and was generally well tolerated. Intravitreal injection of 601 shows potential as an additional therapeutic option for managing macular oedema secondary to RVO, pending confirmation in larger phase III trials. The results of the current studies are promising and certainly merit further study in patients with RVO.
Supplementary material
Footnotes
Funding: Financial support was provided by Sunshine Guojian Pharmaceutical Co Ltd. Role of the funder/sponsor: Sunshine Guojian Pharmaceutical Co Ltd was involved in the design of the study; management, analysis and interpretation of the data; preparation, review and approval of the manuscript; and decision to submit the manuscript for publication but had no role in the conduct of the study or collection of the data.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: These studies involve human participants and were conducted in accordance with the ethical principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice (ICH-GCP) guidelines. Participants gave informed consent to participate in the study before taking part. For the BRVO study, IRB approvals were obtained from the following institutions: Beijing Hospital (2020BJYYEC-182-02), Tianjin Medical University Eye Hospital (202010), Henan Eye Hospital (HNEEC-2020-32-01), The First Affiliated Hospital of Jinan University (2021-003), Shanghai General Hospital (2020-115), West China Hospital of Sichuan University (2020-271), Tianjin Eye Hospital (TJYYLCSYSCLL-2021-02), Zhejiang Provincial People’s Hospital (2020YW133), The Second Xiangya Hospital of Central South University (2020-101), Jiangsu Province Hospital (2021-MD-045), The Southwest Hospital of Army Medical University ((BA)YW202122), and The Second Affiliated Hospital of Xi’an Jiaotong University (2021-006), Tianjin Medical University Eye Hospital (202011), Beijing Hospital (2020BJYYEC-244-01), Henan Eye Hospital (HNEEC-2020-36-01), The First Affiliated Hospital of Jinan University (2021-004), Shanghai General Hospital (2020-114), West China Hospital of Sichuan University (2020-273), Tianjin Eye Hospital (TJYYLCSYSCLL-2021-01), Zhejiang Provincial People’s Hospital (2020YW126), The Second Xiangya Hospital of Central South University (2020-102), The Affiliated Eye Hospital of Nanjing Medical University (2021-2021003), Jiangsu Province Hospital (2021-MD-064), and Peking University People’s Hospital (2021PHA017-001). Full IRB names, cities/provinces and approval reference numbers are listed in online supplemental material. Participants gave informed consent to participate in the study before taking part.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Supplementary Materials
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.