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.

Changes in vascular density in the macula after pars plana vitrectomy for idiopathic macular hole with macular peeling and one type of flap.

BACKGROUND AND AIMS: The aim of this study was to evaluate changes in vascular density in the macula after pars plana vitrectomy for idiopathic macular hole (IMD) with macular peeling and flap. METHODS: A prospective study of 35 eyes in 34 patients who had undergone standard surgery. Evaluated parameters were best-corrected visual acuity (BCVA), intraocular pressure (IOP), central macular thickness (CRT), macular volume (TMV) and vascular density of the superficial and deep capillary plexus. The follow-up period was one year. RESULTS: We divided the total group into two: temporal and circular flap and total group. We compared the values after surgery with the preoperative values. In the total group, BCVA increased from 48.38 to 71.44 letters (P≤0.05). IOP changed from 15.24 to 14.76 mmHg (P>0.05). CRT decreased from 432.27 to 323.64 µm (P≤0.05). TMV changed from 0.26 to 0.25 mm3 (P>0.05). The vascular density of the superficial plexus decreased from 32 to 28% (P≤0.05). The intercapillary space of the superficial plexus increased from 68 to 72% (P≤0.05). The vascular density of the deep plexus increased from 17 to 23%. The intercapillary space of the deep vascular plexus decreased from 83 to 77%. Changes in vascular density and intercapillary space of the deep plexus were statistically significant for certain months after operations (P≤0.05). There were no significant differences between subgroups. CONCLUSION: The superficial plexus vascular density is almost the same in the temporal flap and in the foveal-sparing flap is decreased, and the deep plexus vascular density increased statistically significantly during the follow-up period after surgery.

Biosimilar SB11 versus reference ranibizumab in neovascular age-related macular degeneration: 1-year phase III randomised clinical trial outcomes.

BACKGROUND/AIMS: To provide longer-term data on efficacy, safety, immunogenicity and pharmacokinetics (PK) of ranibizumab biosimilar SB11 compared with the reference ranibizumab (RBZ) in patients with neovascular age-related macular degeneration (nAMD). METHODS: Setting: Multicentre. Design: Randomised, double-masked, parallel-group, phase III equivalence study. Patient population: ≥50 years old participants with nAMD (n=705), one 'study eye'. INTERVENTION: 1:1 randomisation to monthly intravitreal injection of 0.5 mg SB11 or RBZ. Main outcome measures: Visual efficacy endpoints, safety, immunogenicity and PK up to 52 weeks. RESULTS: Baseline and disease characteristics were comparable between treatment groups. Of 705 randomised participants (SB11: n=351; RBZ: n=354), 634 participants (89.9%; SB11: n=307; RBZ: n=327) completed the study until week 52. Previously reported equivalence in primary efficacy remained stable up to week 52 and were comparable between SB11 and RBZ. The adjusted treatment difference between SB11 and RBZ in full analysis set at week 52 of change from baseline in best-corrected visual acuity was -0.6 letters (90% CI -2.1 to 0.9) and of change from baseline in central subfield thickness was -14.9 µm (95% CI -25.3 to -4.5). The incidence of ocular treatment-emergent adverse events (TEAEs) (SB11: 32.0% vs RBZ: 29.7%) and serious ocular TEAE (SB11: 2.9% vs RBZ: 2.3%) appeared comparable between treatment groups, and no new safety concerns were observed. The PK and immunogenicity profiles were comparable, with a 4.2% and 5.5% cumulative incidence of antidrug antibodies up to week 52 for SB11 and RBZ, respectively. CONCLUSIONS: Longer-term results of this study further support the biosimilarity established between SB11 and RBZ.

Efficacy and Safety of a Proposed Ranibizumab Biosimilar Product vs a Reference Ranibizumab Product for Patients With Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial.

Importance: Neovascular age-related macular degeneration is the leading cause of blindness in individuals 50 years or older. The availability of a ranibizumab biosimilar product (SB11) may facilitate access to an effective alternative to this treatment. Objective: To demonstrate equivalence of efficacy, similar safety, and similar immunogenicity of SB11 compared with the reference ranibizumab. Design, Setting, and Participants: This randomized, double-masked, parallel-group phase 3 equivalence study was conducted in 75 centers in 9 countries from March 14, 2018, to December 9, 2019, among 705 participants 50 years or older with neovascular age-related macular degeneration with active subfoveal choroidal neovascularization lesions. Analysis was performed on an intent-to-treat basis. Interventions: Intravitreous injection of SB11 or ranibizumab, 0.5 mg, every 4 weeks through week 48. Main Outcomes and Measures: Preplanned interim analysis after all participants completed the week 24 assessment of primary efficacy end points at week 8 for change from baseline in best-corrected visual acuity (BCVA) and week 4 for central subfield thickness (CST), with predefined equivalence margins for adjusted treatment differences of -3 letters to 3 letters for BCVA and -36 µm to 36 µm for CST. Results: Baseline and disease characteristics among 705 randomized participants (403 women [57.2%]; mean [SD] age, 74.1 [8.5] years) were comparable between treatment groups (SB11, 351; ranibizumab, 354). Least-squares mean (SE) changes in BCVA from baseline at week 8 were 6.2 (0.5) letters in the SB11 group vs 7.0 (0.5) letters in the ranibizumab group, with an adjusted treatment difference of -0.8 letter (90% CI, -1.8 to 0.2 letters). Least-squares mean (SE) changes in CST from baseline at week 4 were -108 (5) µm in the SB11 group vs -100 (5) µm in the ranibizumab group, with an adjusted treatment difference of -8 µm (95% CI, -19 to 3 µm). Incidences of treatment-emergent adverse events (231 of 350 [66.0%] vs 237 of 354 [66.9%]), including serious treatment-emergent adverse events (44 of 350 [12.6%] vs 44 of 354 [12.4%]) and treatment-emergent adverse events leading to study drug discontinuation (8 of 350 [2.3%] vs 5 of 354 [1.4%]), were similar in the SB11 and ranibizumab groups. Immunogenicity was low, with a cumulative incidence of antidrug antibodies up to week 24 of 3.0% (10 of 330) in the SB11 group and 3.1% (10 of 327) in the ranibizumab group. Conclusions and Relevance: These findings of equivalent efficacy and similar safety and immunogenicity profiles compared with ranibizumab support the use of SB11 for patients with neovascular age-related macular degeneration. Trial Registration: ClinicalTrials.gov Identifier: NCT03150589.

Two-year results of a combined regimen of aflibercept treatment in three types of choroidal neovascular membrane in the wet form of age-related macular degeneration: Real-life evidence in the Czech Republic.

AIM: To present the results of a 2-year therapy with aflibercept in real-life practice in a mixed regimen in patients with a neovascular form of age-related macular degeneration (nAMD) and to evaluate the treatment response of various types of choroidal neovascular membranes (CNV) - occult (Type 1), classic (Type 2) and minimally classic (Type 4). METHODS: This was a multicentric, prospective, observational study of a series of cases. Patients diagnosed with the wet form of AMD were treated in a fixed regimen (3 injections at intervals of 1 month and then injections at 8-week intervals) in the first year, and in a pro re nata regimen (PRN) in the second year. The period of investigation was 24 months. The development of the best corrected visual acuity (BCVA) was evaluated by means of ETDRS optotypes (Early Treatment Diabetic Retinopathy Study) and the central retinal thickness (CRT). Measurements were performed prior to the commencement of therapy and then after 4, 8, 12, 16, 20 and 24 months. RESULTS: The therapeutically naïve group consisted of 135 eyes of 135 patients. Sixty-one eyes suffered from CNV of the 1st type, 50 eyes from CNV of the 2nd type and 24 eyes from CNV of the 4th type. The average baseline of BCVA ± SD in Type 1 CNV was 56.1 ± 10.8 letters of ETDRS, and then, respectively, 62.2 ± 12.9 letters, 62.8 ± 15.1 letters and 59.4 ± 13.2 letters after 4, 12 and 24 months. The average baseline value of CRT ± SD for Type 1 CNV was 442.4 ± 194.9 µm, and then 302.5 ± 144.4 µm, 277.7 ± 106.5 µm and 327.6 ± 138.6 µm at months 4, 12 and 24. The average baseline value of BCVA ± SD in Type 2 CNV was 55.6 ± 9.9 letters of ETDRS, and then 62.5 ± 11.1 letters, 62.5 ± 14.2 letters and 60.6 ± 15.1 letters after 4, 12 and 24 months. The average baseline value of CRT ± SD in Type 2 CNV was 446.8 ± 159.1 µm, and then 327.4 ± 127.0 µm, 316.7 ± 139.1 µm and 352.5 ± 132.4 µm at 4, 12 and 24 months. In Type 4 CNV, the average baseline value of BCVA ± SD was 56.7 ± 9.0 letters of ETDRS, and then 59.1 ± 10.6 letters, 59.2 ± 12.6 letters and 58 ± 8.8 letters after 4, 12 and 24 months. The average baseline value of CRT ± SD in Type 4 CNV was 492.1 ± 187.0 µm, and then 333.3 ± 137.5 µm, 326.7 ± 122.4 µm and 328.4 ± 132 µm at months 4, 12 and 24. All these changes were statistically significant (p < 0.05). CONCLUSION: Therapy with aflibercept in a mixed regimen in patients with the wet form of AMD during the investigation resulted in a statistically significant improvement in BCVA and decrease in CRT in both the occult and classic type of CNV. Both the functional and anatomical response to therapy was worse in the minimally classic type (Type 4) of CNV. SUMMARY DECLARATION: Patients suffering from the neovascular form of age-related macular degeneration were treated with aflibercept in a mixed regimen (fixed in the first year and PRN in the second year). After 24 months of examination, a significant improvement of both morphological and functional results was observed in three types of choroidal neovascular membrane.

The Interface Between Psychiatry and Ophthalmology.

OBJECTIVE: The aim of this article is to review the interface between psychiatry and ophthalmology at several levels, such as the influence of psychopharmacology on eye disorders, the occurrence of psychiatric symptoms in eye diseases, and the neuroophthalmological examination methods supporting the validity of psychiatric diagnoses. MATERIALS AND METHODS: We searched the PubMed computer database for the key words "Psychiatry" and "Ophthalmology" on the 28th of August, 2018 to obtain relevant articles which were consequently summarized. RESULTS: The results showed that most patients with ocular disease simultaneously have one or more psychiatric symptoms. We also found a prevalence of eye-related side effects in patients who use psychiatric drugs. At the same time, we observed that some ophthalmology methods of diagnostics can be used as diagnostic tools in psychiatry. CONCLUSIONS: Most studies showed a significant relation between psychiatry and ophthalmology, such as eye symptoms and diseases following long-term use of psychotropics as well as psychiatric symptoms and syndromes in patients with eye disorders. Our review may be beneficial to psychiatrists, ophthalmologists, and, last but not least, the patients themselves.

Ranibizumab 0.5†mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study.

AIMS: To demonstrate non-inferiority of ranibizumab treat-and-extend (T&E) with/without laser to ranibizumab pro re nata (PRN) for best-corrected visual acuity (BCVA) in patients with diabetic macular oedema (DMO). METHODS: A 24-month single-masked study with patients randomised 1:1:1 to T&E+laser (n=121), T&E (n=128) or PRN (control; n=123). All patients received monthly injections until BCVA stabilisation. The investigator decided on re-treatment in the PRN and treatment-interval adaptations in the T&E groups based on loss of BCVA stability due to DMO activity. Likewise, laser treatment was at investigator's discretion. Collectively, these features reflect a real-life scenario. Endpoints included mean average change in BCVA from baseline to months 1-12 (primary), mean BCVA change from baseline to months 12 and 24, treatment exposure and safety profile. RESULTS: Both T&E regimens were non-inferior to PRN based on mean average BCVA change from baseline to months 1-12 (T&E+laser: +5.9 and T&E: +6.1 vs PRN: +6.2 letters; both p<0.0001). Mean BCVA change at month 24 was similar across groups (+8.3, +6.5 and +8.1 letters, respectively). The mean number of injections was 12.4 and 12.8 in the T&E+laser and T&E groups and 10.7 in the PRN group. The T&E regimens showed 46% reduction in the number of clinic visits. Over 70% of patients maintained their BCVA, with treatment intervals of ≥2 months over 24 months. Safety profile was consistent with that described in the product information. CONCLUSIONS: T&E is a feasible treatment option for patients with DMO, with a potential to reduce treatment burden. Slightly more injections were required versus PRN, likely due to the specifics of the T&E regimen applied here. TRIAL REGISTRATION NUMBER: NCT01171976.

The efficacy of ranibizumab treatment in clinical practice in patients with the wet form of age-related macular degeneration. The results of the Czech National Registry.

AIMS: The aim of this communication was to evaluate ranibizumab in the treatment of wet age-related macular degeneration. METHODS: Anonymised data on treatment efficacy and safety were consecutively entered into the Czech national database. From 01/09/2008 to 25/10/2011, 671 patients/685 eyes treated with ranibizumab monotherapy were entered in the registry. 454 ranibizumab treated eyes and 444 patients were monitored for 12-months. The dependent variable used to monitor disease progression and treatment results was change in visual acuity in the ETDRS (Early Treatment Diabetic Retinopathy Study) chart over time. RESULTS: After 12 months of treatment, a loss of < 15 letters in the ETDRS chart was found in 81.5% of eyes treated with ranibizumab. A gain of ≥ 15 letters was found in 9.7% of eyes on ranibizumab. The results for our patients treated in clinical practice with ranibizumab were poorer than those in the SUSTAIN (Ranibizumab in Patients With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration) study. A rationale for this was sought in a sub-analysis. CONCLUSIONS: Sub-analysis demonstrated that treatment naive CNV (choroidal neovascularization), occult CNV and lower height of the macular oedema at the outset of the disease may be positive prognostic factors for final visual acuity in anti-VEGF (vascular endothelial growth factor) treated patients.

Cost and effectiveness of therapy for wet age-related macular degeneration in routine clinical practice.

PURPOSE: Evaluation of the cost and effectiveness of therapy for patients with the wet form of age-related macular degeneration (AMD) in routine clinical practice. METHODS: A retrospective multicentre evaluation of changes in the best-corrected visual acuity in applied kinds of therapy and a comparison with the cost of individual therapeutic procedures. RESULTS: An overall total of 788 eyes of 763 patients with an average age of 73.2 ± 8.6 years was evaluated for a 1-year minimum period. In the ranibizumab and pegaptanib therapy groups, a reduction of 1.3 letters (p = 0.303) and 1.4 letters (p = 0.197) was found, respectively. In the group of photodynamic therapy (PDT) with verteporfin, a reduction of 5.2 letters was achieved (p < 0.001). Under the conditions of routine practice in the Czech Republic, the annual cost is highest (EUR 5,467.63/patient) in patients with pegaptanib therapy. The annual cost in patients with ranibizumab therapy is lower by EUR 1,220.16. The cost is nearly half (EUR 2,783.65) in the group treated with PDT with verteporfin. CONCLUSION: An initiation of AMD therapy by ranibizumab is cost-effective as compared to pegaptanib. Both ranibizumab and pegaptanib are significantly more efficient as compared to PDT with verteporfin. Therapy with ranibizumab and pegaptanib, as compared to PDT with verteporfin, prevents the loss of 1 line of vision on the ETDRS chart for EUR 1,225.98 and 2,286.18, respectively.