Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study.

BACKGROUND: Frequent anti-vascular endothelial growth factor A (VEGF-A) injections reduce the risk of rapid and severe vision loss in patients with neovascular age-related macular degeneration (nAMD); however, due to undertreatment, many patients lose vision over time. New treatments that provide sustained suppression of VEGF-A are needed. RGX-314 (currently known as ABBV-RGX-314) is an adeno-associated virus serotype 8 vector that expresses an anti-VEGF-A antigen-binding fragment, which provides potential for continuous VEGF-A suppression after a single subretinal injection. We report results on the safety and efficacy of subretinal injection of RGX-314 in patients with nAMD. METHODS: For this open-label, multiple-cohort, multicentre, phase 1/2a, dose-escalation study conducted at eight sites in the USA, we enrolled participants with nAMD aged 50-89 years who had previously been treated with anti-VEGF injections into five cohorts (with five different doses of RGX-314). To be eligible, participants had to have macular neovascularisation secondary to nAMD with subretinal or intraretinal fluid in the centre subfield, be pseudophakic (after cataract removal), and have a best-corrected visual acuity (BCVA) in the study eye between 20/63 and 20/400 for the first participant in each cohort and between 20/40 and 20/400 for others. Subretinal injection of RGX-314 was done without a pre-bleb by a wet-laboratory-trained vitreoretinal surgeon. Cohort 1 received 3 × 109 genome copies per eye, cohort 2 received 1 × 1010, and cohort 3 received 6 × 1010. Two additional dose cohorts (cohort 4: 1·6 × 1011; cohort 5: 2·5 × 1011) were added. Participants were seen 1 day and 1 week after administration of RGX-314, and then monthly for 2 years (up to week 106). The primary outcome was safety of RGX-314 delivered by subretinal injection up to week 26. This analysis includes all 42 patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT03066258. FINDINGS: Between May 12, 2017, and May 21, 2019, we screened 110 patients for eligibility and enrolled 68. 42 participants demonstrated the required anatomic response to intravitreal ranibizumab and then received a single RGX-314 injection (dose range 3 × 109 to 2·5 × 1011 genome copies per eye) and were followed up for 2 years. There were 20 serious adverse events in 13 participants, of which one was possibly related to RGX-314: pigmentary changes in the macula with severe vision reduction 12 months after injection of RGX-314 at a dose of 2·5 × 1011 genome copies per eye. Asymptomatic pigmentary changes were seen in the inferior retinal periphery several months after subretinal injection of RGX-314 most commonly at doses of 6 × 1010 genome copies per eye or higher. There were no clinically determined immune responses or inflammation beyond that expected following routine vitrectomy. Doses of 6 × 1010 genome copies or higher resulted in sustained concentrations of RGX-314 protein in aqueous humour and stable or improved BCVA and central retinal thickness with few or no supplemental anti-VEGF-A injections in most participants. INTERPRETATION: Subretinal delivery of RGX-314 was generally well tolerated with no clinically recognised immune responses. RGX-314 gene therapy provides a novel approach for sustained VEGF-A suppression in patients with nAMD that has potential to control exudation, maintain vision, and reduce treatment burden after a single administration. Results from this study informed the pivotal programme to evaluate RGX-314 in patients with nAMD. FUNDING: RegenxBio.

Association between anatomical resolution and functional outcomes in the mivi-trust studies using ocriplasmin to treat symptomatic vitreomacular adhesion/vitreomacular traction, including when associated with macular hole.

PURPOSE: To evaluate visual function in patients with symptomatic vitreomacular adhesion (VMA)/vitreomacular traction including when associated with macular hole after ocriplasmin treatment, and the association between resolution of the underlying condition and improvement in visual function. METHODS: Six hundred and fifty-two patients from 2 Phase 3 trials received a single intravitreal injection of ocriplasmin 125 µg (n = 464) or placebo (n = 188). Mean and categorical changes from baseline in best-corrected visual acuity and 25-item Visual Function Questionnaire scores were used to evaluate visual function. Subgroups with VMA resolution and full-thickness macular hole closure were compared. RESULTS: Overall, 42% of patients who achieved VMA resolution at Day 28 had a ≥2-line improvement in best-corrected visual acuity at Month 6, and 20% had a ≥3-line improvement. Likewise, 69% of patients with nonsurgical full-thickness macular hole closure at Day 28 had a ≥2-line improvement at Month 6, and 48% had a ≥3-line best-corrected visual acuity improvement. Mean improvements in 25-item Visual Function Questionnaire scores were associated with achieving VMA resolution and nonsurgical full-thickness macular hole closure. CONCLUSION: In patients with symptomatic VMA/vitreomacular traction, VMA resolution and nonsurgical full-thickness macular hole closure were each associated with improvements in visual function. Resolving the underlying anatomical condition in symptomatic VMA/vitreomacular traction will increase the probability of achieving a clinically meaningful improvement in visual function.

Efficacy of intravitreal ocriplasmin for treatment of vitreomacular adhesion: subgroup analyses from two randomized trials.

PURPOSE: To evaluate the efficacy of a single intravitreal injection of ocriplasmin 125 µg across relevant subpopulations of patients with symptomatic vitreomacular adhesion (VMA)/vitreomacular traction (VMT), including when associated with macular hole. DESIGN: Two multicenter, randomized, placebo-controlled, double-masked, 6-month studies. PARTICIPANTS: A total of 652 randomized patients (464 receiving ocriplasmin; 188 receiving placebo). METHODS: A single intravitreal injection of ocriplasmin 125 µg or placebo in the study eye. MAIN OUTCOME MEASURES: Prespecified subgroup analyses were conducted to evaluate the effects on the proportion of patients with nonsurgical resolution of focal VMA at day 28, nonsurgical full-thickness macular hole (FTMH) closure at month 6, and categoric improvement in best-corrected visual acuity (BCVA) at month 6. RESULTS: Resolution of VMA at day 28 was achieved more often in younger patients (<65 years), eyes without epiretinal membrane, eyes with FTMH, phakic eyes, and eyes with a focal VMA ≤ 1500 µm. Eyes with FTMH width ≤ 250 µm were more likely to achieve nonsurgical FTMH closure. Categoric ≥ 2-line and ≥ 3-line improvement in BCVA occurred more often in younger patients (<65 years) and in patients with a lower baseline BCVA (<65 letters). Treatment differences in favor of ocriplasmin were generally observed across each subgroup of subpopulations studied. CONCLUSIONS: Subgroup analyses confirmed the positive effect of ocriplasmin across relevant subpopulations.

Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes.

BACKGROUND: Vitreomacular adhesion can lead to pathologic traction and macular hole. The standard treatment for severe, symptomatic vitreomacular adhesion is vitrectomy. Ocriplasmin is a recombinant protease with activity against fibronectin and laminin, components of the vitreoretinal interface. METHODS: We conducted two multicenter, randomized, double-blind, phase 3 clinical trials to compare a single intravitreal injection of ocriplasmin (125 µg) with a placebo injection in patients with symptomatic vitreomacular adhesion. The primary end point was resolution of vitreomacular adhesion at day 28. Secondary end points were total posterior vitreous detachment and nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy, and change in best-corrected visual acuity. RESULTS: Overall, 652 eyes were treated: 464 with ocriplasmin and 188 with placebo. Vitreomacular adhesion resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (P<0.001). Total posterior vitreous detachment was more prevalent among the eyes treated with ocriplasmin than among those injected with placebo (13.4% vs. 3.7%, P<0.001). Nonsurgical closure of macular holes was achieved in 40.6% of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P<0.001). The best-corrected visual acuity was more likely to improve by a gain of at least three lines on the eye chart with ocriplasmin than with placebo. Ocular adverse events (e.g., vitreous floaters, photopsia, or injection-related eye pain--all self-reported--or conjunctival hemorrhage) occurred in 68.4% of ocriplasmin-injected eyes and in 53.5% of placebo-injected eyes (P<0.001), and the incidence of serious ocular adverse events was similar in the two groups (P=0.26). CONCLUSIONS: Intravitreal injection of the vitreolytic agent ocriplasmin resolved vitreomacular traction and closed macular holes in significantly more patients than did injection of placebo and was associated with a higher incidence of ocular adverse events, which were mainly transient. (Funded by ThromboGenics; ClinicalTrials.gov numbers, NCT00781859 and NCT00798317.).

Characterization of vitreoretinal interface disorders using OCT in the interventional phase 3 trials of ocriplasmin.

PURPOSE: We determined the reproducibility of a novel optical coherence tomography (OCT) protocol designed to evaluate formally vitreoretinal interface abnormalities on scans obtained during two phase 3 studies of intravitreal ocriplasmin to treat symptomatic vitreomacular adhesion with or without macular hole. METHODS: Certified technicians obtained time-domain OCT scans that included a macular thickness map (MTM), Fast MTM, and three high resolution linear scans: one 10 mm horizontal and one 10 mm vertical through the optic nerve head (ONH), and one 10 mm 5-degree-offset through the ONH and fovea. Reading Center teams graded all 3695 scans from 652 study eyes for pre-established quantitative and morphologic features. Grading reproducibility at baseline and follow-up visits was tested for presence of vitreomacular adhesion (VMA), width of vitreous adhesion (focal <1500 µm versus broad >1500 µm), presence and minimum width of full thickness macular hole (FTMH), and presence of epiretinal membrane (ERM). RESULTS: Team grading reproducibility for VMA (kappa 0.91, 95% confidence interval [CI] 0.81-1.00), broad versus focal width of vitreous adhesion (kappa 0.87, 95% CI 0.78-0.95), FTMH (kappa 0.87, 95% CI 0.78-0.95), and ERM (kappa 0.87, 95% CI 0.78-0.95) was high. Percent agreement was 97%, 92%, 95%, and 82% for VMA, vitreous adhesion width, FTMH, and ERM, respectively. For repeated measurements of FTMH width, the intraclass correlation was 0.89 (95% CI 0.85-0.93), and the mean paired difference between grading team measurements was 34.4 µm (95% limits of agreement -149.5-218.2 µm). CONCLUSIONS: Quantitative and morphologic vitreoretinal interface features were assessed reproducibly using a newly developed OCT scan acquisition and grading protocol. This protocol will be useful to evaluate OCT endpoints in future clinical trials, and can facilitate identification of vitreoretinal interface pathology during care of individual patients. (ClinicalTrials.gov number, NCT00781859 and NCT00798317.).

A placebo-controlled trial of microplasmin intravitreous injection to facilitate posterior vitreous detachment before vitrectomy.

PURPOSE: To evaluate the safety and efficacy of a preoperative intravitreous injection of microplasmin in patients scheduled for vitreous surgery. DESIGN: Phase 2, multicenter, placebo-controlled, double-masked, parallel-group, dose-ranging clinical trial. PARTICIPANTS: One hundred twenty-five patients scheduled for pars plana vitrectomy (PPV), primarily for treatment of either vitreomacular traction or macular hole. INTERVENTION: A single intravitreous injection of either microplasmin at 1 of 3 doses (25 microg, 75 microg, or 125 microg in 100 microl) or placebo injection administered 7 days before PPV. MAIN OUTCOME MEASURES: Presence or absence of posterior vitreous detachment (PVD) at the time of PPV, progression of PVD, and resolution of vitreomacular interface abnormality precluding the need for PPV. RESULTS: Rates of total PVD at the time of surgery were 10%, 14%, 18%, and 31% in the placebo group (n = 30), 25-microg (n = 29), 75-microg (n = 33), and 125-microg microplasmin groups (n = 32), respectively. The secondary end point resolution of vitreomacular interface abnormality precluding the need for vitrectomy at the 35-day time point was observed at rates of 3%, 10%, 15%, and 31% in the placebo, and the 25-microg, the 75-microg, and the 125-microg microplasmin groups, respectively. At the 180-day time point, the equivalent rates were 3%, 7%, 15%, and 28%, respectively. CONCLUSIONS: Microplasmin injection at a dose of 125 microg led to a greater likelihood of induction and progression of PVD than placebo injection. Patients receiving microplasmin were significantly more likely not to require vitrectomy surgery. More definitive evaluation in phase 3 clinical trials therefore is warranted. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.