Biosimilars of anti-vascular endothelial growth factor for ophthalmic diseases: A review.

The development of intravitreally injected biologic medicines (biologics) acting against vascular endothelial growth factor (VEGF) substantially improved the clinical outcomes of patients with common VEGF-driven retinal diseases. The relatively high cost of branded agents, however, represents a financial burden for most healthcare systems and patients, likely resulting in impaired access to treatment and poorer clinical outcomes for some patients. Biosimilar medicines (biosimilars) are clinically equivalent, potentially economic alternatives to reference products. Biosimilars approved by leading health authorities have been demonstrated to be similar to the reference product in a comprehensive comparability exercise, generating the totality of evidence necessary to support analytical, pre-clinical, and clinical biosimilarity. Anti-VEGF biosimilars have been entering the field of ophthalmology in the US since 2022. We review regulatory and scientific concepts of biosimilars, the biosimilar development landscape in ophthalmology, with a specific focus on anti-VEGF biosimilars, and discuss opportunities and challenges facing the uptake of biosimilars.

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.

THE ROLE OF FREQUENCY DOUBLING TECHNOLOGY PERIMETRY IN EARLY DETECTION OF DIABETIC RETINOPATHY.

The aim was to assess whether standard automated perimetry (SAP) and frequency doubling technology (FDT) perimetry are able to detect the effect of diabetes mellitus (DM) on retinal function in DM patients in the early stage of disease and to analyze which method is more specific and sensitive. A randomized cross-sectional study was conducted in three different groups of patients to compare the capability of these two methods to examine visual field and to detect the change in light sensitivity. Visual function was assessed in 60 adults with normal retinal finding, 60 adults with DM without clinically detectable retinopathy and 60 adults with DM and non-proliferative diabetic retinopathy but normal visual acuity. FDT perimetry and SAP were performed in all study patients. The presence and severity of diabetic retinopathy was determined by taking and evaluating two 50° field color photographs per eye, macula-centered and disc-centered. The following results were obtained by analyzing parameters in the groups of diabetic patients: sensitivity and specificity of SAP and FDT for medium sensitivity 86.7/33.3 (p<0.061) and 71.7/41.7 (p<0.228), respectively; for medium deficit 41.7/76.7 (p<0.063) and 65/50 (p<0.362), respectively; for loss of variance/pattern standard deviation (LV/PSD) 51.7/61.7 (p<0.536) and 61.7/51.7 (p<0.666), respectively; and for foveal sensitivity 81.7/36.7 (p<0.096) and 23.3/86.7 (p<0.839), respectively. Analysis of parameters between diabetics and control group yielded sensitivity and specificity for medium sensitivity 71.7/61.7 (p<0.001) and 70.8/55 (p<0.002), respectively; for medium deficit 56.7/60 (p<0.058) and 77.5/43.3 (p<0.037), respectively; for LV/PSD 58.3/58.3 (p<0.042) and 33.3/83.3 (p<0.437), respectively; and for foveal sensitivity 82.5/53.3 (p<0.001) and 28.3/85 (p<0.195), respectively. We concluded that neither of these methods was sensitive and specific enough to distinguish diabetics without retinopathy from diabetics with retinopathy. Both of these methods were highly specific and sensitive to distinguish diabetics from healthy subjects, but neither of these methods proved superior.

Prevalence of Open Angle Glaucoma in Risk Groups in Slavonia and Baranya Region.

The aim of this prospective study was to detect primary open angle glaucoma (POAG) in its early stage in patients at a higher risk of its development, and to identify the risk group with the highest prevalence of POAG. The study was conducted at Department of Ophthalmology, Osijek University Hospital Centre, and included 250 patients divided into five groups, as follows: group 1, patients with diabetes type 1 and type 2; group 2, patients with arterial hypertension (blood pressure >140/90 mm Hg); group 3, patients with positive family history of POAG; group 4, patients with myopia between -3.0 and -8.0 diopters; and group 5, control group including patients aged 40 with no risk factors for POAG development. Study results showed that distribution of glaucoma patients was not equal across the groups. The prevalence of POAG in all patients was 5.6%, whereas in patients with positive family history of POAG it was 14%, which was statistically significantly higher than in patients with diabetes and myopia (4% both), as well as in control group. The difference was greatest in comparison to control group. There was no statistically significant difference in glaucoma incidence between the group of patients with positive family history (14%) and patients with systemic hypertension (6%). The results obtained suggest that of all risk factors analyzed, positive family history of POAG is the most important risk factor for glaucoma development in all risk groups.

Sensitivity of Diagnostic Tests for Dry Eye in Patients with Blepharospasm.

The aim of the study was to evaluate diagnostic tests for keratoconjunctivitis sicca (Schirmer test, tear break-up time (TBUT) test, and corneal staining with fluorescein and lissamine green dye) in patients with blepharospasm. This prospective study included 60 female patients older than 40 with blepharospasm, divided into two groups according to clinical symptoms. For fluorescein test, the surface under the ROC curve was 1.0 with standard error (SE) 0 and 95% confidence interval (95% CI) 0.940-1.0; for Schirmer test, the surface under the ROC curve was 0.817 with SE 0.0555 and 95% CI 0.696-0.905; for lissamine green test, the surface under the ROC curve was 0.813 with SE 0.056 and 95% CI 0.691-0.902; and for TBUT test, the surface under the ROC curve was 0.772 with SE 0.061 and 95% CI 0.645-0.870. According to the results of ROC curve, which determines the sensitivity and specificity of normal values, comparison of diagnostic tests for keratoconjunctivitis sicca used in this study showed that fluorescein test had the best sensitivity and specificity. Schirmer test should be avoided in patients with blepharospasm because its results are influenced by frequent blinking and are not appropriate for study interpretation. Despite the pathologic values of TBUT test (numerically), this test is still acceptable for patients with blepharospasm because its interval takes more time than the interval between two blinks.

Transcranial sonography and the pocket smell test in the differential diagnosis between parkinson's disease and essential tremor.

The aim of this study was to determine the specificity and sensitivity of transcranial sonography (TCS) and the Pocket Smell Test (PST) in differing Parkinson's disease from essential tremor. The results were compared with the dopamin transporter scan (DaTSCAN) findings. Based on the DaTSCAN finding we formed a group of patients with essential tremor (51 patients) and a group with the Parkinson's disease (59 patients). The control group consisted of 26 healthy one. To evaluate the olfactory dysfunction the PST was used, whereas by TCS the substantia nigra hyperechogenicity was marked. The sensitivity and specificity of each diagnostic method was statistically calculated. In confirming Parkinson's disease the specificity of TCS was 88.2 % and the sensitivity 94.9 %. The specificity of PST was 80.4 % whereas the sensitivity was 74.6 %. TCS and PST should be performed to evaluate which patients need to be examined by DaTSCAN.

Visual dysfunction in patients with Parkinson's disease and essential tremor.

The aim of this study was to determine the specificity and sensitivity of the Pelli-Robson and Ishihara diagnostic methods in differing Parkinson's disease from essential tremor compared to DaTSCAN (dopamine transporter scan) findings. The intention was to investigate whether visual dysfunction appears in the early state of Parkinson's disease. Therefore, we included patients with the symptomatology of parkinsonism lasting between 6 and 12 months. The study included 164 patients of which 59 (36.0%) suffered from Parkinson's disease, 51 (31.1%) from essential tremor, and 54 (32.9%) healthy patients which presented the control group. The specificity of Pelli-Robson test in confirming Parkinson's disease was 53% and the sensitivity 81.4%. The specificity of Ishihara test in confirming Parkinson's disease was 88.2%, and sensitivity 55.9%. We found that the colour and contrast dysfunction are present as the earliest symptoms of Parkinson's disease. In this study the Pelli-Robson test is highly sensitive and the Ishihara tables are highly specific in the differential diagnosis between Parkinson's disease and essential tremor, but neither of these methods fulfils the criteria for the validity of a test. We suggest performing both of these methods to evaluate which patients are indicated for DaTSCAN.

Clinical manifestation and neuroimaging methods in diagnosing basal ganglia calcifications.

The aim of this case study was to evaluate the clinical symptoms in patients with basal ganglia calcifications and compare the neuroimaging methods used in confirming this state. The clinical status and performed transcranial sonography of basal ganglia structures in patients with brain calcifications found by computed brain tomography was examined. In one of these patients DaTSCAN was performed. A large spectrum of different symptoms was found. Transcranial sonography of basal ganglia showed the hyperechogenicity of nucleus lenticularis in eight out of 10 patients. DaTSCAN, which was performed to one patient with parkinsonian signs and the hyperechogenicity of substantia nigra found by transcranial sonography, was normal. Transcranial sonography is a newly neuroimaging method which can contribute to diagnosing basal ganglia calcifications in patients with different neurological signs. Computed tomography of brain remains the most adequate technique in visualising calcifications.

Leber's hereditary optic neuroretinopathy (LHON) associated with mitochondrial DNA point mutation G11778A in two Croatian families.

Leber's hereditary optic neuroretinopathy (LHON) is manifested as a bilateral acute or subacute loss of central vision due to optic atrophy. It is linked to point mutations of mitochondrial DNA, which is inherited maternally. The most common mitochondrial DNA point mutations associated with LHON are G3460A, G11778A and T14484C. These mutations are linked with the defects of subunits of the complex I (NADH-dehydrogenase-ubiquinone reductase) in mitochondria. The G11778A mitochondrial DNA point mutation is manifested by a severe visual impairment. In this paper two Croatian families with the LHON G11778A mutation are presented. Three LHON patients from two families were younger males which had the visual acuity of 0.1 or below, the ophthalmoscopy revealed telangiectatic microangiopathy and papilloedema, while Goldmann kinetic perimetry showed a central scotoma. The mothers and female relatives were LHON mutants without symptoms, whereas their sons suffered from a severe visual impairment. Molecular diagnosis helps to explain the cause of LHON disease.

Effect of intraocular silicone oil on ocular tissue.

The aim of this study was to find out to which extent the instilled silicone oil affects the changes of lens, cornea, and the ocular pressure with regard to its time kept in the operated eye with a lens. The study was carried out on the sample of 40 patients, divided in three groups. The first group of patients with the silicone oil kept in the eye during 3 months, the second one during 3-6 months, and the third one during 6-9 months. Statistically important changes were observed in the progression of the lens opacification with the patients, progressively with the time of keeping the silicone oil in the eye. The followed cornea opacifications and increased ocular pressure were not statistically significantly linked with the length of keeping the silicone oil in the eye, so that it can be concluded that the silicone oil is the best substitute for the vitreous body but it should be removed from the eye, most frequently, in the period of 3-6 months from the date of its instillation, and after 3 weeks at the earliest.