Intravitreal Injection With Anti-vascular Endothelial Growth Factor Drugs For Age-related Macular Degeneration

BackgroundAge-related macular degeneration (AMD) is the leading cause of vision loss in thepeople aged over65in European countries and the United States. AMD is clinicallyclassified to atrophic type (dry AMD) and exudative type (wet AMD) which showedchoroidal neovascularization (CNV) in the macular area. The occurrence anddevelopment of CNV will result in vision loss, even blindness in AMD patients. ForAMD treatment, the traditional methods such as laser photocoagulation, radiotherapy,vitrectomy and intravitreal injection with glucocorticoid have defects and are unable toguarantee treatment effect. In recent years, photodynamic therapy (PDT) andintravitreal injection with anti-vascular endothelial growth factor (VEGF) bring thetreatment of CNV to a new era. By PDT, laser irradiation causes photochemical effectin the photosensitizer, which prompts occlusion of the formed CNV and reduces therisk of severe vision loss in AMD patients. But the long-term vision will still declineprobably. Continuous intravitreal injection with anti-VEGF drugs can improve thevisual acuity of AMD patients, but monthly injection will increase the risk of surgeryand the patient’s burden. Studies have confirmed that PDT with anti-VEGF therapy can obviously decrease numbers of therapy and reduce the psychological and economicburden of patients as well as related complications. However, combined treatment stillhas not reached a consensus, and the criterion of retreatment regimenare different.Optical coherence tomography (OCT) is a kind of new technology which canintuitively and accurately display the retinal interlayer structure changes. OCT cancompare macular morphologic changes before and after treatment, so it is of greatimportance in evaluating the effect of anti-VEGF drugs in AMD. In the first part of thisstudy, patients with clinical AMD were included, and treatment effect after PDTcombined with anti-VEGF therapy were analyzed retrospectively to investigate visual,In recent years, anti-VEGF agents such as pegaptanib, ranibizumab, bevacizumaband aflibercept were applied to treat patients with CNV related diseases like AMD inpractice, which achieved encouraging outcome. Self-researched and developed by ourcountry, conbercept (KH902) is recombinant fusion protein designed as a receptordecoy with higher affinity of all VEGF isoforms than ranicizumab in vitro. In fact,KH902could inhibit effectively growth, migration, sprouting and angiogenesisinduced by VEGF in vitro. In addition, its special design of structure prolongs itsacting time in the eyes and makes it possible of reducing injecting number andlowering surgery risk. Meanwhile, phase I clinical trial verified that vision improved20letters without vision loss at6weeks after single injection. Recently, KH902targeting atAMD has been finished phase II clinical trial. In the second part of this study, wereported the result of our center for this multi-center, randomized controlled trial.1. Effect of photodynamic therapy combined with intravitrealbevacizumab on wet age-related macular degeneraionObjective：To investigate the effect of photodynamic therapy (PDT) combined with intravitrealbevacizumab on wet age-related macular degeneration (AMD). Methods：In this retrospective study,34eyes (28cases) diagnosed with wet AMD receivedPDT combined intravitreal injection of bevacizumab, including25eyes with classicCNV and9eyes with minimally classic CNV by fluorescein angiography; On opticalcoherence tomography (OCT),23eyes showed intraretinal fluid (IRF) and11eyespresented subretinal fluid (SRF). After signing informed consent, all patientsunderwent initial standard PDT followed by intravitreal bevacizumab (1.25mg) withinsucceeding3to7days. Best corrected visual acuity (BCVA) and OCT with routine eyeexaminations were evaluated monthly. Additional bevacizumab (1.25mg) was injectedintravitreally if new or increasing fluid appreciated on OCT, or BCVA lowered morethan5letters even with stabilized fluid. Injection was discontinued if no fluid wasshowed on OCT ("dry macular"), or BCVA was stabilized even with fluid after twoconsecutive injections. BCVA and central retinal thickness (CRT) were analyzed andcompared between baseline and6month follow-up. The correlation betweenparameters such as baseline BCVA, greatest linear dimension (GLD), type of CNV,SRF or IRF and posttreatment BCVA will be analyzed. The injection number ofbevacizumab and complications were recorded.Results：Compared to baseline, BCVA improved (9.4±10.2) letters and reach44.9±21.3letters (t=5.438，P＜0.01) and CRT decreased (184.6±214.6) μm (t=4.810，P＜0.01) at6month visit. The average of injection number was1.9±0.9(including initial injectionof combination therapy). With multiple lineal regression analysis, only baseline BCVAcorrelated to post treatment BCVA at6month visit (r=0.802，P＜0.01). The type ofCNV, GLD, SRF or IRF on OCT and CRT at baseline were not associated topost-treatment BCVA (r=0.053,-0.183,0.139and0.053, respectively. P＞0.05). BCVAof eyes with SRF (14.7letters) increased more than eyes with IRF (6.9letters) on OCT(t=-2.207，P=0.035). The change of BCVA after treatment (t=-0.076), change of CRT(t=-1.028) and number of injections (Z=-1.505) were not different between classic CNV and minimally classic CNV (P＞0.05). The change of CRT (t=-0.020) andnumber of injections (Z=-0.237) did not present difference between SRF and IRF (P＞0.05). The change of BCVA (t=1.159) and number of injections (Z=-1.194) were notcorrelated to whether residual fluid or not at6month visit (P＞0.05). No severecomplications were noticed during follow-up.Conclusions:For wet AMD patients, PDT combined intravitreal bevacizumab on OCT guidedretreatment regimen could improve visual acuity, reduce intraretinal and subretinalfluid, and control CNV progress in the short-term.2. PhaseⅡclinical trials of intravitreal injection of KH902on wetmacular degenerationObjective：To observe the safety and efficacy of KH902injected intravitreally with differentdoses, different frequencies and multiple injections for the treatment of CNVsecondary to AMD.Methods：The whole trial was a double-blind, randomized, multicenter and parallel-groupstudy. In our center,14cases (14eyes) with wet AMD were included according to thecriteria of this clinical trial. All participants were randomly assigned to groupsreceiving different dosages (0.5mg,2.0mg) and different frequencies of drugdelivery (monthly vs as needed) of injection with recombinant VEGFreceptor-antibody fusion proteins (KH902) for12consecutive months. BCVA, CRTand fundus fluorescence angiographic (FFA) changes of CNV leakage before andafter the treatment were analyzed and compared. Results：Of all14participants, BCVA improved11.7±14.9letters (P=0.012) aftertreatment, CRT reduced204.4±125.4μm (P<0.001), leakage areas were stable (9.0±7.2mm2vs7.5±7.3mm2, P=0.113). One month post-injection, BCVA increased to58.0±14.0from51.14letters and stabilized during the12–month follow-up(P=0.214).In addition, CRT decreased to291.3±79.5μm from445.1μm at one monthpost-injection and stabilized during the12–month follow-up (P=0.331). In monthlytreatment group, BCVA and leakage area were stabilized (68.0±16.6letters/4.5±6.3mm2at12months vs59.7±9.5letters/5.4±5.5mm2at baseline, P=0.160and0.396),CRT decreased to245.2±51.7μm from412.0±103.7μm at baseline (P=0.013). In PRNgroup, BCVA improved after treatment (57.7±16.3letters at12month vs42.6±13.6letters at baseline, P=0.045), while CRT reduced (248.1±67.1μm at12month vs466.9±113.7μm at baseline, P=0.003). However, leakage area didn’t change (10.5±7.4mm2at12month vs12.6±7.1mm2at baseline, P=0.215). No differences were shownbetween monthly treatment and PRN group in BCVA change, CRT and leakage area atthe end of follow-up(P=0.411，0.264and0.123, respectively). In0.5mg group, BCVAimproved after treatment (65.5±18.1letters at12month vs46.5±12.3letters at baseline,P=0.045), while CRT reduced (261.8±48.0μm at12month vs433.0±134.4μm atbaseline, P=0.045). However, leakage area didn’t change (6.2±8.6mm2at12month vs9.0±9.4mm2at baseline, P=0.127). In2.0mg group, BCVA and leakage area werestabilized (60.9±16.5letters/8.4±6.6mm2at12months vs54.2±15.5/9.0±5.8mm2atbaseline, P=0.141and0.588). No differences were shown between0.5mg group and2.0mg group in BCVA change, CRT and leakage area at the end of follow-up(P=0.116,0.307and0.438, respectively).The mean injection number was7.3±2.3during1year follow-up; no differencewas displayed between0.5mg and2.0mg groups. One endophthalmitis was noticed anddocumented after last injection in2.0mg and monthly treatment group. Conclusion:Multiple injections with intravitreal KH902presented good safety andeffectiveness. After monthly injections during initial3months, further as-neededtherapy or monthly treatment may maintain the improved eyesight in patients, and caneffectively control and stabilize the progress of CNV in subject eyes. Two dosesinjection can significantly improve vision in patients with wet AMD, monthlyinjection and as-needed injection has similar curative effect. Thus, in order to reducethe potential risks of adverse events caused by anti-VEGF drug and in considerationof economics,0.5mg dose is more reasonable than2.0mg, but further studies wereneeded to find optimal doses and treatment frequency and guide clinical practice.