Biosimilar candidate CT-P42 in diabetic macular edema: 24-week results from a randomized, active-controlled, Phase III study.

OBJECTIVE: To demonstrate the therapeutic similarity of CT-P42 compared to reference aflibercept (Eylea®) in adult patients with diabetic macular edema (DME). DESIGN: Randomized, active-controlled, double-masked, Phase III clinical trial PARTICIPANTS: Patients with a diagnosis of either type 1 or 2 diabetes mellitus (DM) with DME involving the center of the macula. METHODS: Patients were randomized (1:1) to receive either CT-P42 or reference aflibercept (2 mg/0.05 mL) by intravitreal injection every 4 weeks (5 doses) then every 8 weeks (4 doses) in the main study period. Results up to Week 24 are reported herein. MAIN OUTCOME MEASURES: The primary endpoint was mean change from baseline at Week 8 in best corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Equivalence between CT-P42 and reference aflibercept was to be concluded if the two-sided 95% confidence interval (CI) (global assumptions) and two-sided 90% CI (US Food and Drug Administration [FDA] assumptions) for the treatment difference fell entirely within the equivalence margin of ±3 letters, as assessed in the full analysis set. RESULTS: Overall, 348 patients were randomized (CT-P42: 173; reference aflibercept: 175). BCVA improved from baseline to Week 8 in both groups, with a least squares mean (standard error) improvement of 9.43 (0.798) and 8.85 (0.775) letters in the CT-P42 and reference aflibercept groups, respectively. The estimated between-group treatment difference was 0.58 letters, with the CIs within the pre-defined equivalence margin of ±3 letters (95% CI -0.73, 1.88 [global]; 90% CI -0.52, 1.67 [FDA]). Through Week 24, other efficacy results for the two groups, in terms of change in BCVA and retinal central subfield thickness, as well as ETDRS Diabetic Retinopathy Severity Scale score, supported therapeutic similarity. Pharmacokinetics, usability, safety (including the proportions of patients experiencing at least one treatment-emergent adverse event [CT-P42: 50.3%; reference aflibercept: 53.7%]), and immunogenicity were also comparable between groups. CONCLUSIONS: This study in patients with DME demonstrated equivalence between CT-P42 and reference aflibercept (2 mg/0.05 mL) in terms of efficacy, with similar pharmacokinetic, usability, safety, and immunogenicity profiles.

Serum autoantibodies against hexokinase 1 manifest secondary to diabetic macular edema onset.

AIMS: Autoantibodies against hexokinase 1 (HK1) were recently proposed to be associated with diabetic macular edema (DME). We hypothesized that anti-HK1 autoantibodies can be used as DME markers and to predict DME onset. MATERIALS AND METHODS: Serum from patients with 1) DME, 2) diabetes mellitus (DM), 3) allergies or autoimmunities, and 4) control subjects was tested for anti-HK1 and anti-hexokinase 2 (HK2) autoantibodies by immunoblotting. Patients with DM were prospectively followed for up to nine years, and the association of anti-HK1 antibodies with new-onset DME was evaluated. The vitreous humor was also tested for autoantibodies. RESULTS: Among patients with DME, 32 % were positive for anti-HK1 autoantibodies (42 % of those with underlying type 1 DM and 31 % of those with underlying type 2 DM), and 12 % were positive for anti-HK2 autoantibodies, with only partial overlap of these two groups of patients. Anti-HK1 positive were also 7 % of patients with DM, 6 % of patients with allergies and autoimmunities, and 3 % of control subjects. The latter three groups were anti-HK2 negative. Only one of seven patients with DM who were initially anti-HK1 positive developed DME. CONCLUSIONS: Anti-HK1 autoantibodies can be used as DME markers but fail to predict DME onset.

Randomized Trial of Biosimilar XSB-001 versus Reference Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration.

OBJECTIVE: To evaluate the efficacy, safety, and immunogenicity of a ranibizumab biosimilar candidate (XSB-001) versus reference product (Lucentis) for neovascular age-related macular degeneration (nAMD). DESIGN: Phase III, multicenter, randomized, double-masked, parallel-group study. PARTICIPANTS: Patients with nAMD. METHODS: Eligible patients were randomized (1:1) to receive intravitreal injections of XSB-001 or reference ranibizumab (0.5 mg [0.05 ml]) in the study eye once every 4 weeks for 52 weeks. Efficacy and safety assessments continued through 52 weeks of treatment. MAIN OUTCOME MEASURES: Primary end point was change from baseline in best-corrected visual acuity (BCVA) by ETDRS letters at week 8. Biosimilarity was concluded if the 2-sided 90% confidence interval (CI) (United States) or 95% CI (rest of world) for the difference in least-squares (LS) mean change in BCVA at week 8 between treatment groups was within the predefined equivalence margin of ± 3.5 letters. RESULTS: In total, 582 patients (n = 292 XSB-001, n = 290 reference ranibizumab) were randomized. Mean age was 74.1 years, most patients (85.2%) were White, and 55.8% were women. Mean BCVA score at baseline was 61.7 and 61.5 ETDRS letters in the XSB-001 and reference ranibizumab groups, respectively. At week 8, the LS mean (standard error [SE]) change in BCVA from baseline was 4.6 (0.5) ETDRS letters in the XSB-001 group and 6.4 (0.5) letters in the reference ranibizumab group (LS mean [SE] treatment difference: -1.8 [0.7] ETDRS letters; 90% CI, -2.9 to -0.7; 95% CI, -3.1 to -0.5). The 90% CI and 95% CI for LS mean difference in change from baseline were within the predefined equivalence margin. At week 52, LS mean (SE) change in BCVA was 6.4 (0.8) and 7.8 (0.8) letters, respectively (LS mean [SE] treatment difference, -1.5 [1.1] ETDRS letters; 90% CI, -3.3 to 0.4; 95% CI, -3.6 to 0.7). There were no clinically meaningful differences between treatments in anatomical, safety, or immunogenicity end points through week 52. CONCLUSIONS: XSB-001 demonstrated biosimilarity to reference ranibizumab in patients with nAMD. Treatment with XSB-001 for 52 weeks was generally safe and well tolerated, with a safety profile similar to the reference product. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

Microincision 25G pars plana vitrectomy with peeling of the inner limiting membrane and air tamponade in idiopathic macular hole.

PURPOSE: To evaluate the success of a mini-invasive technique for operation of idiopathic macular hole (IMH). METHODS: We retrospectively examined 29 patients (30 eyes) in whom 25-G pars plana vitrectomy (PPV), peeling of the inner limiting membrane (ILM), and application of air tamponade were performed. The group of the patients included 7 males and 22 females (76%), age range 57-79 years (median 70). The follow-up period was 3-47 months (median 17). RESULTS: Pars plana vitrectomy was indicated only in the stages of full-thickness macular hole. Prior to operation, 13 eyes (43%) were in stage 2, 15 eyes (50%) in stage 3, and 2 eyes (7%) in stage 4. The IMH healed in 28 eyes after operation. Persistence of IMH occurred in 2 eyes (7%). After subsequent reoperation with extension of the peeling zone of the ILM and gas tamponade (with 10% C3F8), these macular holes also healed (100%). Prior to carrying out PPV, best-corrected visual acuity (BCVA) ranged between 20/40 and 20/500 (median 20/125). At the end of the follow-up period, BCVA was improved to 20/40 (median). The change in the final BCVA compared to the initial visual acuity was statistically significant (p = 0.008; Wilcoxon). CONCLUSIONS: The 25-G PPV with peeling of the ILM and air tamponade is an effective technique and presents no increased risks in comparison with routine procedures. The main benefit of the intervention is its good tolerance by the patient, particularly with respect to painfulness and postoperative irritation.

Intraoperative Optical Coherence Tomography in Vitreoretinal Surgery.

INTRODUCTION: The objective of this article is to provide an overview of the current situation with the use of intraoperative optical coherence tomography (iOCT), and to present our own experience with this technology. METHODOLOGY: retrospective evaluation of case reports of typical pathologies of the retina which were resolved by means of standard pars plana vitrectomy (PPV) with the use of intraoperative optical coherence tomography (iOCT) integrated into the surgical microscope OPMI Lumera 700 / Rescan 700 (Zeiss). Auxiliary techniques: best corrected visual acuity (BCVA) was tested on ETDRS tables, biomicroscopy was performed with a 78D lens and optical coherence tomography (OCT) with a Zeiss Cirrus instrument. The operations were performed in retrobulbar anaesthesia, three-port 23G PPV and with the aid of the surgical unit Constellation (ALCON). RESULTS: we present three case reports of 2 women (pathology of type of disorder of the vitreoretinal interface) and 1 man (proliferative diabetic retinopathy), with an average age of 63 years. In the first 2 cases the observation period was 3 months, while the man with diabetic retinopathy was observed for 15 months. All surgical procedures with the use of iOCT were conducted without perioperative or postoperative complications. In all cases full anatomical success was achieved. In the first two cases BCVA improved substantially, and in the last case very good initial BCVA was stabilised over the long term. CONCLUSION: The use of iOCT provides the surgeon with simultaneous control both in surgical manipulations in close proximity to the retina and also in detailed virtualisation of the finding on the ocular fundus. The result is an excellent perioperative overview, up-to-date information for the surgeon, higher precision of the procedure and thus also improved postoperative results.Key words: intraoperative optical coherence tomography, vitreoretinal surgery.

Re-operation of idiopathic macular hole after failed initial surgery.

BACKGROUND: Persistent idiopathic macular hole (IMH) after initial pars plana vitrectomy (PPV) appears in approx. 12% of cases. It is, therefore, one of the most common complications. IMH re-operation results tend to be better in eyes where IMH had been closed, while IMH re-operations in cases when the initial surgery had failed tend to be less successful: IMH often becomes even larger and visual acuity decreases, anatomical success rate of closure is about 60% and the resulting postoperative visual acuity is about 20/100. AIMS: To establish anatomical and functional success rate of repeated operations of recurrent idiopathic macular hole. MATERIALS AND METHODS: We evaluated the retrospective results of re-operations of persisting IMH that is cases in which the initial surgery did not result in closure: 6 eyes in 6 patients out of the overall 55 operated on IMH (primary PPV failed in almost 11% of cases). The follow-up period was 18 months (since the first surgery). RESULTS AND CONCLUSION: After the second PPV, the IMH was closed in 100% of operated eyes. It was not necessary to perform a third PPV during the follow-up period. In all cases the visual acuity improved. Anatomical and functional results of IMH treatment can be considered satisfactory. We consider the following combination of factors significant for the anatomical success rate of PPV: IMH size and stage, technical precision of the ILM peeling and the suction of the IMH contents, strict adherence to the recommended head positioning in early postoperative period, and IMH duration.

Effects of treatment change in patients with neovascular age-related macular degeneration; results from the Czech National Registry.

AIMS: To determine the effectiveness of second line treatments in patients with neovascular AMD who did not respond adequately to primary treatment. METHODS: Retrospective, multicentre assessment. The frequency of primary treatment failure and outcomes of subsequent secondary treatment were assessed according to the type of primary treatment, type of CNV and change in BCVA over a 12 month period. RESULTS: At the time of assessment 750 entries (750 treated eyes, 725 treated patients) had follow-up longer than 12 months. A treatment change required 7.7% subjects treated with ranibizumab, 20.5% with pegaptanib and 22% with PDT and verteporfin. Average BCVA of all patients at the beginning of primary treatment was 50.7 ± 3 letters and 43 ± 3.5 letters in 12(th) month (P<0.001). The mean decrease in BCVA was 7.7 ± 0.6 letters during the first 6 months of observation. During the next 6 months, no significant change occurred. The change of primary therapy was required on average after 6.5 ± 2.1 months. CONCLUSION: BCVA loss was the most significantly decelerated in patients who received ranibizumab as a secondary therapy following unsuccessful treatment with pegaptanib sodium.

Haemorheopheresis could block the progression of the dry form of age-related macular degeneration with soft drusen to the neovascular form.

PURPOSE: To evaluate the influence of haemorheopheresis on anatomical and functional findings in patients with soft-drusen maculopathy. METHODS: We investigated 29 eyes (16 patients) and randomized 25 eyes (16 controls) with soft-drusen maculopathy [soft, confluent and reticular drusen, drusenoid retinal pigment epithelium detachment (RPED)]. Each patient received a series of eight haemorheophereses (cascade filtration of 1.5 plasma volume) within 10 weeks. The patients were followed up using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, optical coherence tomography, fluorescein angiography, electroretinography and measurements of pulsed ocular blood flow. RESULTS: After the procedures, there was a substantial reduction in rheologically active substances [lipoproteins, α2-macroglobulin, immunoglobulin M (IgM), fibrinogen], plasma and blood viscosity. At the 1.5-year follow-up, we noticed soft drusen absorption; reattachment of drusenoid RPED and stabilization or improvement of visual acuity occurred in 72% of patients in comparison to only 39% of patients in the control group. Full-field electroretinograms showed significantly higher scotopic activity of treated patients in comparison with the control group, and mainly insignificant differences in photopic activity between both groups. Despite the significant increase of activity in the paramacular retina in treated patients, the differences in amplitudes of multifocal electroretinography (mfERG) average responses were insignificant between groups. CONCLUSION: Haemorheopheresis seems to be capable of changing the activity of promoters of the natural course of soft-drusen maculopathy, its development and progression. Visual acuity and electrical activity of the retina can be stabilized or even improved. The therapy has been shown to be effective and safe.

[Macular hole--contemporary knowledge and possibilities of treatment]. / Makulární díra--soucasné poznatky a moznosti lécby.

Macular hole is a disease of the central area of the retina - site of the sharppest vision. Signs of this can be metamorphopsia and different degree of loss of the central vision. More than 100 years didn't exist succesfull treatment but knowledges of that disease have been started since 19 century. The authors evaluate case of macular hole, the differencial diagnosis, up date cognitions and possibilities of the treatment.

[Results of transpupillary thermotherapy by patients with age-related macular degeneration 6 months after treatment (pilot study)]. / Výsledky transpupilární termoterapie u pacientu s vekem podmínenou makulární degenerací 6 mesícu po lécbe (pilotní studie).

We demonstrated the effectiveness of transpupillary thermotherapy (TTT) for the treatment of choroidal neovascularization (CNV) by patients with age- related macular degeneration (ARMD). CNV secondary to ARMD is a leading case of vision loss in patients older than 50 years. TTT is new promising method for the treatment CNV by ARMD. It is able to close CNV while maintaining visual function and in small percentage visual function improving. We have performed TTT by 30 patients (30 eyes) with subfoveolar CNV. We have demonstrated the stabilization or improvement of visual acuity by 16 patients (52%), improvemend two or more lines was documented by 5 patients (17%).

[Age-related macular degeneration--contemporary possibilities of treatment]. / Vekem podmínená makulární degenerace sítnice--soucasné moznosti lécby.

Age-related macular degeneration (AMD) is a complex multifactorial disease, that affects the central region of the retina. AMD is a leading cause of blindness among people over 50 years of age in the industrialized world. Two types of macular degeneration exist, the "dry" form and the "wet-neovascular" form. Neovascular AMD is responsible for 80-90% of cases of severe, irreversible central vision loss in patients over 65 years of age with AMD. The authors present contemporary possibilities of treatment of the patients with this disease.