The mean change of BCVA from baseline was significantly improved. At Month 3, BCVA changed from 57.83 ± 13.42 to 72.40 ± 10.49 letters (20/63–20/32 Snellen equivalent) in BRVO, a mean increase of 14.57 ± 8.59 letters (t = 9.2892, P = 0.0000). The BCVA changed from 48.73 ± 15.91 to 60.23 ± 17.00 letters (20/100–20/50 Snellen equivalent) in CRVO, an increase of 11.50 ± 11.40 letters (t = 5.5248, P = 0.0000). The change in BCVA was not statistically different between the groups (P = 0.24).
At Month 9, BCVA changed to 75.67 ± 9.08 letters (20/25 Snellen equivalent) in BRVO, an improvement of 17.83 ± 10.89 letters (t = 8.9734, P = 0.0000). The BCVA changed to 62.97 ± 14.98 letters (20/50 Snellen equivalent) in CRVO, which improved to 14.23 ± 11.74 letters (t = 6.6385, P = 0.0000) (Figure 2A). The change in BCVA did not differ between the groups (P = 0.216).
There were 11 patients with baseline BCVA ≤35 letters (20/200 Snellen equivalent), of which three patients had lower baseline BCVA ≤23 letters (20/400 Snellen equivalent). The BCVA of these 11 patients improved to 18.18 ± 13.70 and 22.64 ± 15.33 letters at Month 3 and 9, respectively.
At Month 9, the proportion of patients that gained ≥15 letters from baseline to Month 3 did not differ between the groups: 50% for BRVO and 40% for CRVO (χ2 = 0.6061, P = 0.4363). The proportion of patients that gained ≥15 letters from baseline to Month 9 is 50% in BRVO and 46.67% in CRVO (Figure 2B). There was also no difference between the groups (χ2= 0.0667, P = 0.7961). The BCVA dropped ≥15 letters from baseline to Month 3 in only one patient with CRVO. At Month 9, none of the 60 patients had lost ≥15 letters.
In various kinds of baseline characteristics, the baseline BCVA had the greatest correlation with the change of BCVA from baseline to the last visits in all 60 patients (P < 0.001) (Table 3).
The mean reduction of CRT from baseline to Month 3 was 295.53 ± 155.95 μm in BRVO (t = 10.3796, P = 0.0000) and was 383.63 ± 270.75 μm in CRVO (t = 7.7608, P = 0.0000). There was no difference between BRVO and CRVO (P = 0.129). At Month 9, the mean reduction was 289.97 ± 165.42 μm and 420.47 ± 235.89 μm in BRVO and CRVO, respectively (t = 9.6014, P = 0.0000; t = 9.7631, P = 0.0000) (Figure 3A). There was significant difference between BRVO and CRVO (P = 0.016). It was worth noting that there was a significant increase at Month 4 and Month 7 in CRVO, which corresponded to the decrease of BCVA. It also correlated with the change to PRN therapy at the previous month such as Month 3 and Month 6. The proportion of PRN injection in all 30 CRVO patients was 70.00%, 83.33%, and 56.67% at Months 3, 5, and 6, respectively.
At Month 3, CRT reduced to ≤320 μm in 27 patients (90%) of BRVO and in 18 patients (60%) of CRVO. There was significant difference between BRVO and CRVO (χ2 = 7.20, P = 0.0073). At Month 9, CRT reduced to ≤320 μm in 27 patients (90%) of BRVO and in 20 patients (66.67%) of CRVO with significant difference (χ2 = 4.8118, P = 0.0283) (Figure 3B). That was to say the CRT in three quarter of the patients was thinner than baseline after at least three injections.
At Month 3, CRT reduced to ≤250 μm in 14 patients (46.67%) of BRVO and in 6 patients (20%) of CRVO. There was no significant difference between BRVO and CRVO (P = 0.0539). At Month 9, CRT reduced to ≤250 μm in 14 patients (46.67%) of BRVO and in 8 patients (26.67%) of CRVO. There was also no significant difference between BRVO and CRVO (P = 0.1799) (Figure 3B). That was to say one third of the patients reduced to the normal thickness after at least three injections.
The mean reduction of MV from baseline in BRVO and CRVO was referred to in Figure 4. The trends of the MV changes were similar to that of the CRT changes.
In the per protocol set, the efficacy was similar to the full analysis set analysis (data not shown). In the per protocol set, the mean number of injections was 7.14 ± 1.90 (median = 8; interquartile range = 6–9) in BRVO and 7.59 ± 1.39 (median = 8; interquartile range = 7–9) in CRVO from baseline to Month 9. There was not a significant difference between the groups regarding the mean number of injections (P = 0.4705). In BRVO, there were three patients who received only three injections (the loading phase only) and did not meet re-treatment criteria in the following 6 months. Most patients needed additional injections (Figure 5).
All patients who received ≥1 injection of conbercept were evaluated for safety. From baseline to Month 9, the percentage of patients experiencing at least one ocular AE in the study eye was similar in BRVO and CRVO (90% and 86.67%, respectively). A retinal tear complicated with focal retinal detachment was detected in one patient of CRVO at Month 2 scheduled visit, who had received only one injection before without noted complication. After that, the patient withdrew from the study to accept the laser therapy. The retinal tear complicated with focal retinal detachment was considered possibly related to the injection procedure by the investigator. Retinal neovascularization developed in one patient with BRVO at Month 9; this patient had received only 3 injections in the first 3 months. Almost all the other AEs were common and mild, and were similar to those reported in other papers, such as conjunctival hemorrhage, vitreous opacity, temporary elevated intraocular pressure, and decreased visual sensitivity.2,7,15–18
Form baseline to Month 9, there were 7 SAEs in 5 patients (2 BRVO and 3 CRVO). The percentage was 8.33% in all 60 patients. All the SAEs were nonocular and were not related to the drug or the injection procedure.
The Phase II FALCON study met the primary efficacy end point of the change of BCVA at Month 3 with conbercept treatment and all the secondary efficacy end points, including BCVA improvement and CRT decrease. Treatment with fixed monthly IVC over 3 months resulted in rapid and sustained improvements in visual acuity and anatomic end points. These improvements were largely maintained, and even increased, after PRN dosing with monthly evaluations through Month 9 was initiated. For patients with BRVO, at Month 9, a mean increase of 3.2 letters in BCVA and a mean decrease of 5.5 μm in CRT were gained compared with Month 3. For patients with CRVO, a mean increase of 2.7 letters in BCVA and decrease of 36.9 μm in CRT was gained compared with Month 3. Likewise, the percentage of patients gaining ≥15 letters and ≥30 letters at Month 9 was similar or even slightly higher to that at Month 3. Although the treatment regimen was monthly IVC for 3 months followed by IVC PRN (3 + PRN) in the FALCON study, the trend of improvement in visual acuity with conbercept is similar to that obtained with ranibizumab in the Ranibizumab for the Treatment of Macular Edema following BRAVO (BRAnch Retinal Vein Occlusion: Evaluation of Efficacy and Safety) study17 and Ranibizumab for the Treatment of Macular Edema after CRUISE (Central Retinal Vein OcclUsIon Study: Evaluation of Efficacy and Safety) trial18 as well as aflibercept in the VIBRANT study2 and the GALILEO study,19 all of which used a regimen of monthly intravitreal injection over 6 months followed by intravitreal injection as needed (6 + PRN). All the studies suggest that the effect of anti-VEGF agents on macular edema secondary to RVO occurs very soon after the initiation of treatment. In addition, 11 patients with BCVA ≤35 ETDRS letters (20/200 Snellen equivalent) were included in the FALCON study whose BCVA and CRT improved after treatment, demonstrating the benefit of conbercept on patients with vision worse than that typically enrolled in such trials.
Despite the shorter loading phase, visual acuity improvement in patients with BRVO at Month 3 in the FALCON study was comparable with that of patients in the BRAVO17 study and VIBRANT2 study, and the visual acuity benefits at Month 9 in the FALCON study was also similar to that in the BRAVO study. Moreover, in the 9-month whole study period, 27.6% of patients need ≤6 injections. It suggested that, for these patients, intravitreal conbercept injection monthly for 6 months would result in unnecessary treatment, and a shorter loading phase of three injections plus PRN treatment may provide similar outcomes as those seen in Phase 3 trials with other anti-VEGF agents. For patients with CRVO, the visual acuity benefits gained at Months 3, 6, and 9 were very close to that gained in the CRUISE18 study treated in which patients received 0.5 mg ranibizumab, but less than that in the GALILEO19 and COPERNICUS20 studies, both of which used aflibercept (also a VEGF receptor fusion protein like conbercept). A longer loading phase might result in more visual acuity improvement in patients with CRVO.
In the FALCON study, there was a trend for patients with BRVO gaining more visual acuity benefits than those with CRVO at Months 3 and 9 (14.6 vs. 11.5 and 17.8 vs. 14.2, respectively), but these differences were not statistically significant (P = 0.24 and P = 0.216, respectively), suggesting that intravitreal conbercept injection was effective in treating both BRVO and CRVO. In the Month 3 to Month 9 period, the change of BCVA from baseline of patients with CRVO showed a higher fluctuation than that of patients with BRVO. The pathological changes of CRVO, like superficial hemorrhages, cotton wool spots, retinal edema, and capillary nonperfusion, occurring in all four quadrants of the retina,1 is associated with more severe vision loss3 than that seen in patients with BRVO. The mean BCVA at baseline of CRVO was worse than that of BRVO in the current study (48.8 letters vs. 57.8 letters, 20/100 vs. 20/63 Snellen equivalent, P = 0.02), and so the CRT (768.4 μm vs. 563.8 μm, P = 0.0000) and MV (14.8 mm3 vs. 12.7 mm3, P = 0.015). Furthermore, the recurrence and severity of ME in CRVO was higher than that in BRVO. In this study, in parallel with the increases in BCVA, patients with BRVO or CRVO experienced a substantial reduction in CRT and MV, and subsequent decreases in BCVA were accompanied by increases in CRT and MV. After consecutive injections for 3 months, 100% of patients with BRVO and 90% of patients with BRVO gained ≥0 letters; more than half gained ≥15 letters. Accordingly, the proportion of CRT decreasing to 320 μm was 90% in patients with BRVO and 60% in patients with CRVO, and that decreasing to 250 μm was 47% and 27%, respectively. Almost half of the patients did not require an injection at Month 3. The CRT and MV increased immediately at Month 4, with a concomitant decrease in BCVA. After reinjection at Months 4 and 5, the visual and anatomical outcomes improved in patients with CRVO. Re-treatment was not indicated in almost half of the patients at Month 6, with resultant increases in CRT and MV at Month 7 and simultaneous decrease in BCVA. Unlike CRVO, patients with BRVO received conbercept injection at Month 4 to achieve stability and basically maintained the same benefits. The ME was identified as the main reason for the vision loss once again in the FALCON study, and anti-VEGF therapy was effective in ME resolution and concomitant improvement in visual acuity.
It was worth noting that no patient with BRVO experienced a loss of ≥15 letters at any point during the study, and no patient with CRVO had a loss of ≥15 letters at the end of the study. Several studies have investigated the efficacy of other anti-VEGF agents. The BRAVO study reported that 3 patients (2.3%) receiving monthly injections of 0.5 mg ranibizumab (n = 131) experienced a visual acuity loss from baseline BCVA of ≥15 letters at Month 12, whereas 1 patient (0.7%) in the 0.3 mg ranibizumab (n = 134) group experienced the same loss.17 The number of the patients who had a visual acuity loss of ≥15 letters was 3 (2.3%) and 5 (3.8%) in the 0.5 mg group (n = 130) and 0.3 mg group (n = 132) in the CRUISE study,18 1 (1.0%) and 6 (5.3%) in the group receiving aflibercept monthly from baseline to week 24 plus PRN treatment from weeks 24 to 52 (n = 103 and 114 respectively) in the GALILEO study19 and COPERNICUS study,20 respectively. These findings compare favorably with the results of the current study, and support previous studies with respect to anti-VEGF agents ability to maintain vision. The subjects were not excluded by poor vision or excessive retinal thickening as noted by BCVA and CRT in FALCON study. Allowing patients with worse vision and anatomical baseline characteristics more closely resembles the variety of patients who may require treatment in the real world.
No unexpected safety findings were reported. The safety outcomes were consistent with those reported in the Phase I and II studies of conbercept in wet AMD.15,16 The key AEs were either because of the injection procedure or the result of the underlying disease. An increase in the rates of macular edema and reduced visual acuity seen in patients receiving IVC after changing the treatment regimen from fixed dosing to PRN dosing suggests that some patients would have benefited from regular or additional monthly dosing rather than being treated in response to the recurrence of disease.
In conclusion, the FALCON study demonstrated efficacy of IVC in the treatment of macular edema due to RVO and was generally well tolerated. Intravitreal injection of conbercept offers the potential to manage patients with this sight-threatening condition. The results do suggest that while three monthly injections may be appropriate for the initial management of BRVO, a longer loading phase might be necessary for patients with CRVO. A longer loading phase in patients with BRVO may lead to unnecessary IVC injections. The results of the FALCON study are promising and certainly merit further study and progression to Phase III programs.
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The FALCON study group investigators were Yingzi Li, Ying Huang, Weiwei Zheng, Tingye Zhou, Qianqian Zhu, Jirong Li, PengQu, Xiaoqiu Shen (Retina Department, The Affiliated Eye Hospital of Wenzhou Medical University). Liqin Gao, Yongpeng Zhang, Haixia Ji, Ying Xiong, Wei Yan, Shiqiang Zhao, Wei Zhang, Rong Shen (Department of Ophthalmology, Beijing Tongren hospital affiliated to Capital Medical University). Xiaojing Li, Fenglei Kuang, Zhili Niu, Biwei Zeng, Kun Luo (Chengdu Kanghong Biotechnology, Inc, Chengdu, China).
Keywords:© 2017 by Ophthalmic Communications Society, Inc.
retinal vein occlusion; macular edema; conbercept; vascular endothelial growth factor; best-corrected visual acuity