Biosimilar SB15 versus reference aflibercept in neovascular age-related macular degeneration: 1-year and switching results of a phase 3 clinical trial.

BACKGROUND/AIMS: To evaluate efficacy, safety, pharmacokinetics (PK) and immunogenicity of SB15 versus reference aflibercept (AFL), and switching from AFL to SB15 in neovascular age-related macular degeneration (nAMD). DESIGN: Prospective, double-masked, randomised, phase 3 trial. METHODS: Participants with nAMD were randomised 1:1 to receive SB15 (N=224 participants) or AFL (N=225). At week 32, participants either continued on SB15 (SB15/SB15, N=219) or AFL (AFL/AFL, N=108), or switched from AFL to SB15 (AFL/SB15, N=111). This manuscript reports 1-year and switching results of secondary efficacy endpoints such as changes from baseline to week 56 in best-corrected visual acuity (BCVA), central subfield thickness (CST, from internal limiting membrane (ILM) to retinal pigment epithelium), and total retinal thickness (TRT, from ILM to Bruch's membrane). Additional endpoints included safety, PK and immunogenicity. RESULTS: Efficacy results were comparable between groups. The least squares mean (LSmean) change in BCVA from baseline to week 56 was 7.4 letters for SB15/SB15 and 7.0 letters for AFL/AFL (difference (95% CI)=0.4 (-2.5 to 3.2)). The LSmean changes from baseline to week 56 in CST and TRT were -119.2 µm and -132.4 µm for SB15/SB15 and -126.6 µm and -136.3 µm for AFL/AFL, respectively (CST: difference (95% CI)=7.4 µm (-6.11 to 20.96); TRT: difference (95% CI)=3.9 µm (-18.35 to 26.10)). Switched and non-switched participants showed similar LSmean changes in BCVA from baseline to week 56 (AFL/SB15, 7.9 letters vs AFL/AFL, 7.8 letters; difference (95% CI)=0.0 (-2.8 to 2.8)). Safety, PK and immunogenicity were comparable between groups. CONCLUSIONS: Efficacy, safety, PK and immunogenicity were comparable between SB15 and AFL and between switched and non-switched participants.

Efficacy and Safety of the Aflibercept Biosimilar SB15 in Neovascular Age-Related Macular Degeneration: A Phase 3 Randomized Clinical Trial.

Importance: Aflibercept biosimilars can expand available treatment options in retinal diseases and have the potential to improve patient access to safe and effective therapy. Objective: To establish equivalence in efficacy and similarity in safety, pharmacokinetics, and immunogenicity of SB15 and reference aflibercept (AFL) in neovascular age-related macular degeneration (nAMD). Design, Setting, and Participants: This was a randomized double-masked parallel group phase 3 trial conducted at 56 centers in 10 countries from June 2020 to March 2022, including follow-up through 56 weeks. Of 549 screened participants, 449 participants 50 years and older with treatment-naive nAMD were included and randomly assigned to SB15 (n = 224) or AFL (n = 225). Key exclusion criteria included considerable scarring, fibrosis, atrophy, and hemorrhage. This report includes results up to the end of the parallel group period at week 32. Of the 449 randomized participants, 438 (97.6%) completed week 32 follow-up. Intervention: Participants were randomized 1:1 to receive 2 mg of SB15 or AFL every 4 weeks for the first 12 weeks (3 injections), followed by dosing every 8 weeks up to week 48, with final assessments at week 56. Main Outcomes and Measures: The primary end point was the change in best-corrected visual acuity (BCVA) from baseline to week 8 with predefined equivalence margins of -3 letters to 3 letters. Other key end points were changes in BCVA and central subfield thickness up to week 32, safety, pharmacokinetics, and immunogenicity. Results: The mean (SD) age among the 449 included participants was 74.0 (8.1) years, and 250 participants (55.7%) were female. Baseline demographic characteristics and most disease characteristics were comparable between treatment groups. The least squares mean change in BCVA from baseline to week 8 in the SB15 group was equivalent to that in the AFL group (6.7 letters vs 6.6 letters, respectively; difference, 0.1 letters; 95% CI, -1.3 to 1.4). Comparable efficacy between treatment groups was maintained up to week 32 (least squares mean change from baseline in BCVA: SB15, 7.6 letters vs AFL, 6.5 letters; least squares mean change from baseline in central subfield thickness: SB15, -110.4 µm vs AFL, -115.7 µm). No clinically relevant differences were observed in the incidence of treatment-emergent adverse events (TEAEs) (SB15, 107/224 [47.8%] vs AFL, 98/224 [43.8%]) and ocular TEAEs in the study eye (SB15, 41/224 [18.3%] vs AFL, 28/224 [12.5%]). The serum concentration profiles and cumulative incidences of overall antidrug antibody positive participants were comparable. Conclusions and Relevance: In this phase 3 randomized clinical trial, SB15 and AFL showed equivalent efficacy and comparable safety, pharmacokinetics, and immunogenicity in participants with nAMD. Trial Registration: ClinicalTrials.gov Identifier: NCT04450329.

Melatonin mitigates disrupted circadian rhythms, lowers intraocular pressure, and improves retinal ganglion cells function in glaucoma.

Glaucoma is a progressive optic neuropathy associated with damage to retinal ganglion cells (RGCs) and disrupted circadian rhythms. Melatonin is a promising substance to ameliorate glaucoma-associated compromised circadian rhythms, sleep, mood, and retinal cells function. However, studies estimating melatonin effects in glaucoma are currently lacking. Therefore, In this study, we investigated the effect of long-term (daily at 10:30 pm for 90 days) oral melatonin administration on systemic (Tb) and local to the organ of vision (IOP) circadian rhythms, pattern electroretinogram (PERG), sleep, and mood, depending on glaucoma stage in patients diagnosed with stable or advanced primary open-angle glaucoma. In a laboratory study in 15 of them, 24-hour records of salivary melatonin were obtained and MTNR1B receptor gene polymorphism was assessed. Melatonin increased the stability of the Tb circadian rhythm by improving its phase alignment and alignment with IOP. Melatonin time-dependently decreased IOP and IOP standard deviation (SD). IOP 24-hour mean and IOP SD decreases were more pronounced in individuals with the higher initial 24-hour IOP mean. Melatonin improved RGCs function in advanced glaucoma; N95 amplitude increase correlated positively with RGCs loss. The beneficial effects of melatonin on sleep and mood were greater in advanced glaucoma. Finally, delayed salivary melatonin and Tb phases were observed in MTNR1B G-allele carriers with advanced glaucoma. Combined, these results provide evidence for melatonin efficiency in restoring disrupted circadian rhythms in glaucoma with different effects of melatonin on systemic vs. local circadian rhythms, indicating that a personalized strategy of melatonin administration may further refine its treatment benefits.

Disruption of 24-Hour Rhythm in Intraocular Pressure Correlates with Retinal Ganglion Cell Loss in Glaucoma.

Parameters of 24-h rhythm in intraocular pressure (IOP) were assessed in patients with stable or advanced primary open-angle glaucoma (S-POAG/A-POAG) and referenced to the phase of "marker" circadian temperature rhythm of each patient. Body temperature and IOP were measured over a 72-h span in 115 participants (65 S-POAG and 50 A-POAG). Retinal Ganglion Cell (RGC) damage was assessed by high-definition optical coherence tomography. The 24-h IOP rhythm in A-POAG patients peaked during the night, opposite to the daytime phase position in S-POAG patients (p < 0.0001). The 24-h IOP phase correlated with RGC loss (p < 0.0001). The internal phase shift between IOP and body temperature gradually increased with POAG progression (p < 0.001). Angiotensin converting enzyme Alu-repeat deletion/insertion (ACE I/D) emerged as a candidate gene polymorphism, which may play a role in the alteration of the circadian IOP variability in advanced glaucoma. To conclude, a reliable estimation of the 24-h rhythm in IOP requires the degree of RGC damage to be assessed. In advanced POAG, the 24-h phase of IOP tended to occur during the night and correlated with RGC loss, being progressively delayed relative to the phase of temperature.

Alternative ways to optimize treatment for retinal vein occlusion with peripheral capillary non-perfusion: a pilot study.

PURPOSE:: We compared the efficacy and safety of ranibizumab versus ranibizumab plus scatter laser photocoagulation (SLP) in patients with chronic post-central retinal vein occlusion (CRVO) macular edema (ME). METHODS:: This prospective non-randomized pilot study included 250 patients with peripheral retinal ischemia and CRVO-related ME. The mean follow-up period was 24.5 ± 6.5 months. The clinical assessments conducted included best corrected visual acuity, optical coherence tomography, and multi-field fluorescein angiography with measurement of the ischemic area. The study population comprised two comparable patient groups with peripheral retinal ischemia that received different treatments for post-CRVO ME: ranibizumab with peripheral SLP of capillary non-perfusion areas (Group 1); and Lucentis® monotherapy (Group 2). Data analyses were performed using Statistica 7 software suite and included the estimation of х ± δ values and their dispersion and covariation coefficients at different stages of the study. RESULTS:: Clinically significant retinal ischemia was detected in 175 (70%) patients, occupying an average of 435.12 ± 225.13 mm2, i.e., 167.15 ± 45.16 optic disc areas. Peripheral ischemia was found in 125 patients, representing 50% of all patients with CRVO and 71.4% of all patients with ischemic CRVO. The mean number of ranibizumab injections in patients who underwent SLP was 3.5 ± 1.6. Patients treated with ranibizumab monotherapy for 24 months received 10.6 ± 2.5 injections. Functional and anatomic results were comparable in the two groups. CONCLUSIONS:: The combination of ranibizumab injections and peripheral SLP in capillary non-perfusion areas can significantly decrease the number of injections and reduce neovascular complications.

Alternative ways to optimize treatment for retinal vein occlusion with peripheral capillary non-perfusion: a pilot study / Opções alternativas para otimizar o tratamento da oclusão da veia retiniana sem perfusão capilar periférica (um estudo piloto)

ABSTRACT Purpose: We compared the efficacy and safety of ranibizumab versus ranibizumab plus scatter laser photocoagulation (SLP) in patients with chronic post-central retinal vein occlusion (CRVO) macular edema (ME). Methods: This prospective non-randomized pilot study included 250 patients with peripheral retinal ischemia and CRVO-related ME. The mean follow-up period was 24.5 ± 6.5 months. The clinical assessments conducted included best corrected visual acuity, optical coherence tomography, and multi-field fluorescein angiography with measurement of the ischemic area. The study population comprised two comparable patient groups with peripheral retinal ischemia that received different treatments for post-CRVO ME: ranibizumab with peripheral SLP of capillary non-perfusion areas (Group 1); and Lucentis® monotherapy (Group 2). Data analyses were performed using Statistica 7 software suite and included the estimation of х ± δ values and their dispersion and covariation coefficients at different stages of the study. Results: Clinically significant retinal ischemia was detected in 175 (70%) patients, occupying an average of 435.12 ± 225.13 mm2, i.e., 167.15 ± 45.16 optic disc areas. Peripheral ischemia was found in 125 patients, representing 50% of all patients with CRVO and 71.4% of all patients with ischemic CRVO. The mean number of ranibizumab injections in patients who underwent SLP was 3.5 ± 1.6. Patients treated with ranibizumab monotherapy for 24 months received 10.6 ± 2.5 injections. Functional and anatomic results were comparable in the two groups. Conclusions: The combination of ranibizumab injections and peripheral SLP in capillary non-perfusion areas can significantly decrease the number of injections and reduce neovascular complications.

RESUMO Objetivo: A investigação centra-se na terapia de edema macular pós-oclusão da veia retiniana central (OVCR) em casos com isquemia retiniana periférica. O objetivo foi comparar a eficácia e a segurança do tratamento com ranibizumab vs ranibizumab + fotocoagulação com laser de dispersão (SLP) em pacientes com edema macular crônico secundário a oclusão da veia retiniana central isquêmica. Métodos: O estudo prospectivo não-randomizado incluiu 250 pacientes com isquemia retiniana periférica e edema macular relacionados a oclusão da veia retiniana central. O tempo médio de seguimento foi de 24,5 ± 6,5 meses. A avaliação clínica incluiu acuidade visual melhor corrigida, tomografia de coerência óptica (OCT) e angiografia por fluoresceína multi-campo com a medição da área de isquemia. A população estudada foi constituída por dois grupos de pacientes comparáveis com o oclusão da veia retiniana central isquêmica, que receberam tratamento diferente. Em nossa prática anterior, utilizamos ranibizumab (Lucentis®) em monoterapia (de acordo com a licença do medicamento) para edema macular pós-oclusão da veia retiniana central com isquemia retiniana periférica (Grupo 2). Mais recentemente, começamos a combinar ranibizumab com SLP periférica de áreas não perfusão capilar (Grupo 1). As análises de dados foram realizadas com o software Statistica 7 e incluíram a estimação dos valores de х ± δ e seus coeficientes de dispersão e covariân cia em diferentes estágios do estudo. Resultados: Identificou-se isquemia retiniana clinicamente significativa em 175 (70%) pacientes, atingindo uma média de 435,12 ± 225,13 mm2, ou seja, 167,15 ± 45,16 áreas de disco óptico. Isquemia periférica foi encontrada em 125 casos, representando 50% de todos os pacientes com oclusão da veia retiniana central e 71,4% de todos os pacientes com oclusão da veia retiniana central isquêmica. O número médio de injeções de rani bizumab em pacientes com SLP foi de 3,5 ± 1,6. Os pacientes tratados com ranibizu mab em monoterapia durante 24 meses receberam 10,6 ± 2,5 injeções. Os resultados funcionais e anatômicos foram comparáveis nos dois grupos. Conclusões: A combinação de injeções de ranibizumab com SLP periférica em áreas de não-perfusão capilar pode diminuir significativamente o número de injeções e reduzir as complicações neovasculares.

Assessment of dry eye signs and symptoms and ocular tolerance of a preservative-free lacrimal substitute (Hylabak®) versus a preserved lacrimal substitute (Systane®) used for 3 months in patients after LASIK.

Laser-assisted in situ keratomileusis (LASIK) is commonly used to correct refractive defects. The procedure frequently results in dry eye symptoms, usually of short but sometimes longer duration. This study was designed to assess dry eye and ocular tolerability after LASIK in patients treated with a preservative-free lacrimal substitute (Hylabak®) or preserved lacrimal substitute (Systane®). In a single-center, investigator-masked, prospective, noninferiority, clinical study, patients undergoing LASIK surgery were randomized to receive Hylabak or Systane eye drops (one drop in each eye four times daily for 3 months). Fluorescein test scores were the primary efficacy variable and were similar on day 1 (mean 0.26 and 0.28 for Hylabak and Systane, respectively). At the final visit (day 84 ± 3) the fluorescein scores had improved to 0.11 and 0.04, respectively. The difference was not significant and thus noninferiority was established. A trend of more rapid improvement in the Hylabak group was evident. Both treatments were well tolerated and there were no serious adverse events, discontinuations for adverse events or other safety-related reasons, and no systemic adverse events. The results suggest that Hylabak is not less effective than Systane in reducing the symptoms of dry eye after LASIK surgery.