Purpose: The phase 2 BOULEVARD trial compared safety and efficacy of faricimab, a novel bispecific antibody targeting angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A), with ranibizumab in patients with diabetic macular edema (DME). Design: The BOULEVARD trial (ClinicalTrials.gov identifier, NCT02699450) was a prospective, randomized, active comparator-controlled, double-masked, multicenter, phase 2 study conducted at 59 sites in the United States. Participants: The trial enrolled patients 18 years of age or older with center-involving DME, best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central subfield thickness (CST) of 325 mm or more. Methods: Anti-VEGF treatment-naïve patients were randomized 1:1:1 to intravitreal 6.0 mg faricimab, 1.5 mg faricimab, or 0.3 mg ranibizumab, and patients previously treated with anti-VEGF were randomized 1:1 to 6.0 mg faricimab or 0.3 mg ranibizumab. Patients were dosed monthly for 20 weeks, followed by an observation period up to week 36 to assess durability. Main Outcome Measures: The prespecified primary outcome measure was mean change in BCVA from baseline at week 24 for faricimab versus ranibizumab in treatment-naïve patients. Key secondary and exploratory outcome measures included CST, Diabetic Retinopathy Severity Scale (DRSS) score, and durability as assessed by time to re-treatment. Results: The trial enrolled 229 patients (168 treatment-naïve and 61 previously treated with anti-VEGF). In treatment-naïve patients, 6.0 mg faricimab, 1.5 mg faricimab, and 0.3 mg ranibizumab resulted in mean improvements of 13.9, 11.7, and 10.3 ETDRS letters from baseline, respectively. The 6.0-mg faricimab dose demonstrated a statistically significant gain of 3.6 letters over ranibizumab (P ¼ 0.03). In both patient populations, faricimab resulted in dose-dependent reductions in CST, improvements in DRSS score, and longer time to retreatment during the observation period compared with ranibizumab. Faricimab showed no new or unexpected safety signals. Conclusions: The BOULEVARD trial met its primary end point; faricimab demonstrated statistically superior visual acuity gains versus ranibizumab at week 24 in treatment-naïve patients. Central subfield thickness reduction, DRSS score improvement, and extended durability outcomes support the primary outcome. These findings suggest the benefit of simultaneous inhibition of angiopoietin-2 and VEGF-A with faricimab for patients with DME.

IMPORTANCE Faricimab neutralizes angiopoietin-2 and vascular endothelial growth factor A via both simultaneous and independent binding. OBJECTIVE To evaluate extended dosing with faricimab, the first bispecific antibody designed for intraocular use, in patients with neovascular age-related macular degeneration. DESIGN, SETTING, AND PARTICIPANTSThis phase 2 randomized clinical trial was a 52-week multicenter, active comparator-controlled, parallel-group study. Study participants were enrolled in 25 sites in the US from January and March 2017 with treatment-naive choroidal neovascularization secondary to neovascular age-related macular degeneration and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score of 73 (approximate Snellen equivalent, 20/40) to 24 (approximate Snellen equivalent, 20/320). Analysis began January 2017 and ended March 2018.INTERVENTIONS Participants were randomized 1:2:2 to receive intravitreal ranibizumab, 0.5 mg, every 4 weeks or faricimab, 6.0 mg, every 12 or 16 weeks. Participants in the faricimab arms initially received 4 monthly injections of faricimab. No rescue injections were allowed. Participants randomized to dosing every 16 weeks were assessed for disease activity at week 24 using prespecified criteria. Those with no active disease continued dosing every 16 weeks through trial end; participants with disease activity continued received dosing every 12 weeks. MAIN OUTCOMES AND MEASURESMean change in BCVA from baseline at week 40. RESULTSOf 76 participants enrolled (mean [SD] age, 78.5 [8.5] years; age range, 56-94 years; 41 women [58%]; 69 white [97%]), 16 (21.0%) were randomized to ranibizumab every 4 weeks, 29 (38.2%) to faricimab every 12 weeks, and 31 (40.8%) to faricimab every 16 weeks. At week 24, 12 weeks after their last initiation injection, 65% (36 of 55) of all faricimab-treated participants had no disease activity. At week 40, adjusted mean BCVA gains from baseline (Early Treatment Diabetic Retinopathy Study letters) were +11.4 (80% CI, 7.8-15.0), +9.3 (80% CI, 6.4-12.3), and +12.5 (80% CI, 9.9-15.1) for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively. Participants received a mean (SD) total of 12.9 (0.25), 6.7 (0.91), and 6.2 (0.93) injections, for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively, through week 52. The secondary BCVA and anatomical imaging end points supported the primary end point and were comparable with ranibizumab every 4 weeks. No new or unexpected safety signals were identified.CONCLUSIONS AND RELEVANCE At week 52, faricimab dosing every 16 weeks and every 12 weeks resulted in maintenance of initial vision and anatomic improvements comparable with monthly ranibizumab. These results suggest a role for simultaneous neutralization of angiopoietin-2 and vascular endothelial growth factor A in providing sustained efficacy through extended durability, warranting further investigation.TRIAL REGISTRATION Cli...

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are principal investigators of trials sponsored by Novartis, the manufacturers of ranibizumab. Usha Chakravarthy has attended and been remunerated for attendance at advisory boards for Novartis, Bayer, Neovista, Oraya, Allergan, and Bausch and Lomb, and her employing institution has received payments from Novartis, Bayer, Neovista, Oraya, Alcon and Pfizer. Chris A Rogers has received an honorarium from Novartis for a lecture. The employing institutions of Susan Downes and Andrew J Lotery have received payments from Novartis. Susan Downes and Andrew J Lotery have received honoraria from Novartis for lectures. Andrew J Lotery has attended and been remunerated for attendance at advisory boards for Novartis and Bayer. Barnaby C Reeves has received a fee for teaching from Janssen-Cilag and is a member of the National Institute of Health Research (NIHR) Health Technology Assessment commissioning board and the NIHR Systematic Reviews Programme Advisory Group. James Raftery is a member of the NIHR Editorial Board and the NIHR Journals Library Editorial Group. He was previously Director of the Wessex Institute and Head of the NIHR Evaluation, Trials and Studies Coordinating Centre.Published October 2015 DOI: 10.3310/hta19780 This report should be referenced as follows: This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (www.publicationethics.org/).Editorial contact: nihredit@southampton.ac.ukThe full HTA archive is freely available to view online at www.journalslibrary.nihr.ac.uk/hta. Print-on-demand copies can be purchased from the report pages of the NIHR Journals Library website: www.journalslibrary.nihr.ac.uk Criteria for inclusion in the Health Technology Assessment journalReports are published in Health Technology Assessment (HTA) if (1) they have resulted from work for the HTA programme, and (2) they are of a sufficiently high scientific quality as assessed by the reviewers and editors.Reviews in Health Technology Assessment are termed 'systematic' when the account of the search appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others. HTA programmeThe HTA programme, part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. 'Health technologies' are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care.The journal is indexed in NHS Evidence via its abstracts included in MEDLINE and its Technology Assessment Reports inform National Institute for Health and Care Excellence (NICE) guidance. HTA research is also an important source of evidence for National Screening Committee (NSC) policy decisions.For more information about the HTA programme please visit the website: http://www.nets.nihr.ac.uk/programmes/hta This r...

the first bispecific antibody designed for intraocular use, simultaneously and independently binds and neutralizes angiopoietin 2 (Ang-2) and vascular endothelial growth factor A (VEGF-A). OBJECTIVE To assess the efficacy and safety of different doses and regimens of faricimab vs ranibizumab in patients with neovascular age-related macular degeneration (nAMD). DESIGN, SETTING, AND PARTICIPANTS AVENUE was a 36-week, multiple-dose-regimen, active comparator-controlled, double-masked, phase 2 randomized clinical study performed at 58 sites in the United States. Eligible participants were anti-VEGF treatment naive with choroidal neovascularization secondary to nAMD and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 73 (Snellen equivalent, 20/40) to 24 (Snellen equivalent, 20/320).

Aim: To compare the visual acuity (VA), spherical equivalent refractive error, motility, and anatomical outcomes in children with treated regressed threshold stage 3 retinopathy of prematurity (ROP) and those with spontaneously regressed subthreshold stage 3 ROP. Method: 6 month and 3 year data collected from infants examined between 1989 and 1999 with regressed stage 3 ROP, with or without treatment were retrospectively reviewed. Results: 85 infants were included in this study. 40 eyes received cryotherapy, 81 eyes laser photocoagulation, and 34 eyes had spontaneously regressed subthreshold stage 3 ROP. Grating acuity score >2 cycles/degree (c/d) at 6 months was predictive of optotype acuity >6/9 in 69% of eyes and a score ,2 c/d at 6 months was predictive of acuity ,6/9 in 88% of eyes. Eyes with subthreshold stage 3 ROP were twice as likely to have VA of 6/9 or better at 36 months than the treated eyes. The mean spherical equivalent refractive error at 36 months was 26.5 dioptres (D) (221.5D to +1.38D) in cryotherapy treated eyes, 22.4D (213D to +4D) in the laser group, and 20.22D (29D to +2.25D) in the subthreshold group. Eyes within the treated groups were more myopic than the eyes within the spontaneously regressed group (p = 0.005). At 36 months, 42 out of the 85 infants (that is, 49%) had strabismus (44% in the cryotherapy group, 26% in the laser group, and 25% in the subthreshold group). There was a statistically significant association between the presence of strabismus and anisometropia (p = 0.016) and strabismus and intraventricular haemorrhage (IVH) (p = 0.005). There was a statistically significant difference in the incidence of strabismus between mild and moderate and severe grade IVH (p = 0.01). Eight out of 40 eyes in the cryotherapy group and six out of the 81 eyes in the laser group developed macular ectopia. None of the eyes in the spontaneously regressed group had macular dragging. Conclusions: In this study, the grating acuity at 6 months was a good predictor of the 3 year optotype acuity in all groups. Eyes with spontaneously regressed subthreshold stage 3 ROP were associated with better vision at 3 years of age and a lesser degree of myopia compared to the treated groups. Strabismus developed predominantly in the treated groups and was frequently associated with neurological damage and/or anisometropia. The spontaneously regressed subthreshold stage 3 group had a better anatomical outcome compared to the groups in which the retinopathy regressed following treatment.

Syndromic retinitis pigmentosa (RP) is the result of several mutations expressed in rod photoreceptors, over 40 of which have so far been identified. Enormous efforts are being made to relate the advances in unraveling the patho-physiological mechanisms to therapeutic approaches in animal models, and eventually in clinical trials on humans. This review summarizes briefly the current clinical management of RP and focuses on the new exciting treatment possibilities. To date, there is no approved therapy able to stop the evolution of RP or restore vision. The current management includes an attempt at slowing down the degenerative process by vitamin supplementation, trying to treat ocular complications and to provide psychological support to blind patients. Novel therapeutic may be tailored dependant on the stage of the disease and can be divided in three groups. In the early stages, when there are surviving photoreceptors, the first approach would be to try to halt the degeneration by correction of the underlying biochemical abnormality in the visual cycle using gene therapy or pharmacological treatment. A second approach aims to cope with photoreceptor cell death using neurotrophic growth factors or anti-apoptotic factors, reducing the production of retino-toxic molecules, and limiting oxidative damage. In advanced stages, when there are few or no functional photoreceptors, strategies that may benefit include retinal transplantation, electronic retinal implants or a newly described optogenetic technique using a light-activated channel to genetically resensitize remnant cone-photoreceptor cells.

Aims: To introduce new terminology and validate its reliability for the analysis of optical coherence tomography (OCT) scans, compare clinical detection of cystoid macular oedema (CMO) and subretinal fluid (SRF) with OCT findings, and to study the effect of photodynamic therapy (PDT) on the foveal morphology. Methods: Patients with subfoveal, predominantly classic choroidal neovascularisation (CNV) secondary to age related macular degeneration (AMD) undergoing PDT were evaluated with refraction protocol best corrected logMAR visual acuity (VA), slit lamp biomicroscopy, stereoscopic fluorescein angiography (FFA), and OCT. New terminologies introduced to interpret the OCT scans were: neuroretinal foveal thickness (NFT), bilaminar foveal thickness (BFT), outer high reflectivity band thickness (OHRBT), intraretinal fluid (IRF), subretinal fluid (oSRF), and vitreomacular hyaloid attachment (VMHA). Results: Fifty six eyes of 53 patients were studied. VA was better in eyes with a thinner outer high reflectivity band (OHRBT) (p = 0.02) and BFT (p = 0.05). BFT was less in eyes that had undergone a greater number of PDT treatments (p = 0.04). There was poor agreement between OCT and clinical examination in the detection of CMO and subretinal fluid (k = 0.289 and k = 0.165 respectively). To validate the interpretation and measurements on OCT, two groups of 20 scans were analysed by two independent observers. There was good agreement between the observers in the detection of IRF, oSRF, and VMHA (p,0.001). Measurements of NFT and BFT had a high reproducibility, and of OHRBT reproducibility was low. Conclusions: New terminology has been introduced and tested. OCT appears to be superior to clinical examination and FFA in the detection of CMO. In this study, better vision was associated with a thinner OHRBT and/or the absence of SRF giving insight into the biological effect of PDT.A ge related macular degeneration (AMD) is a leading cause of registerable blindness in the developed world in people over the age of 65 and subfoveal choroidal neovascularisation (CNV) is the major cause of severe visual loss.