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Article ; Online: Pharmacogenomic Analysis of Response to Topical Tumor Necrosis Factor α Antagonist Licaminlimab (OCS-02) in Dry Eye Disease.

Donnenfeld, Eric / Baudouin, Christophe / Galor, Anat / Weissgerber, Georges / He, Yunsheng / Perez, Victor L

2024

Abstract: Purpose: The purpose of this study was to evaluate the pharmacogenomics of response to topical ocular tumor necrosis factor α (TNFα) inhibitor licaminlimab in patients with DED.: Methods: Three single-nucleotide polymorphisms (SNPs) associated with ... ...

Abstract	Purpose: The purpose of this study was to evaluate the pharmacogenomics of response to topical ocular tumor necrosis factor α (TNFα) inhibitor licaminlimab in patients with DED. Methods: Three single-nucleotide polymorphisms (SNPs) associated with Sjögren syndrome, 3 in the TNFα gene and 1 in the TNF receptor 1 (TNFR1) gene, were assessed for association with response to licaminlimab in participants from a randomized, vehicle-controlled, Phase 2 study in which adults with DED and severe ocular discomfort persisting despite treatment with artificial tears received licaminlimab or vehicle for 6 weeks. Response was assessed for change from baseline in Global Ocular Discomfort score at Day 29 of treatment. The pharmacogenomic analysis was a prospectively specified exploratory objective of the study. mRNA expression for TNFα, interleukin (IL) 1β, and IL8 in conjunctival epithelium cells was determined. The relationship between SNPs and response to licaminlimab was assessed using a mixed model repeated measures analysis. Results: SNP rs1800693 in the TNFR1 gene showed a significant effect on response to licaminlimab (P < 0.0001, initial association test); no effect was seen for any of the other SNPs tested. The CC genotype of rs1800693 was associated with much greater response to licaminlimab than the CT or TT genotypes: LS mean changes from baseline to Day 29 in Global Ocular Discomfort score were -29.5, -0.09, and -3.90, in patients with the CC, CT, and TT genotypes, respectively (P < 0.0001). No significant effect was observed in vehicle-treated patients. Improvements from baseline were seen in 3/4 licaminlimab-treated participants with the CC genotype. Conjunctival epithelium cell levels of mRNA for TNFα, IL1β, and IL8 decreased from baseline in participants with the CC genotype, but not with the CT or TT genotypes. Between-genotype differences in mRNA levels were not observed in participants receiving vehicle. Conclusions: The CC genotype of rs1800693, relatively common in patients with DED, was strongly associated with response to licaminlimab and decreased inflammatory cytokine gene expression in ocular surface cells during treatment. This study is one of the first to our knowledge to investigate pharmacogenomics in the treatment of DED.
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	604826-2
ISSN	1536-4798 ; 0277-3740
ISSN (online)	1536-4798
ISSN	0277-3740
DOI	10.1097/ICO.0000000000003510
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Article: Topical Anti-TNFα Agent Licaminlimab (OCS-02) Relieves Persistent Ocular Discomfort in Severe Dry Eye Disease: A Randomized Phase II Study.

Shettle, Lee / McLaurin, Eugene / Martel, Joseph / Seaman, John W / Weissgerber, Georges

Clinical ophthalmology (Auckland, N.Z.)

2022 Volume 16, Page(s) 2167–2177

Abstract: Purpose: To assess the efficacy, safety, and pharmacokinetics of new topical ocular anti-TNFα antibody fragment licaminlimab in the relief of persistent ocular discomfort in severe dry eye disease (DED).: Patients and methods: Patients with ≥6-month ... ...

Abstract	Purpose: To assess the efficacy, safety, and pharmacokinetics of new topical ocular anti-TNFα antibody fragment licaminlimab in the relief of persistent ocular discomfort in severe dry eye disease (DED). Patients and methods: Patients with ≥6-month history of DED, regular use of artificial tears, and best-corrected visual acuity (BCVA) of ≥55 letters in each eye (Early Treatment Diabetic Retinopathy Score) at baseline were included in this multicenter, randomized, vehicle-controlled, double masked study. A total of 514 patients were screened. After a 2-week run-in with Vehicle, all qualifying patients received Vehicle eye drops for 4 weeks. Patients with global ocular discomfort score ≥50 at the end of this 4-week period were randomized to receive licaminlimab (60 mg/mL ophthalmic solution) (69 patients) or Vehicle (65 patients) for 6 weeks. The primary efficacy endpoint was change from baseline in global ocular discomfort score at Day 29. Safety assessments included adverse events and ophthalmology examination including intraocular pressure (IOP). Serum licaminlimab levels were also determined. Results: Change from baseline to Day 29 in global ocular discomfort score was statistically significantly greater for licaminlimab than for Vehicle (p = 0.041). No safety issues were identified. Serum licaminlimab was undetectable in most patients; the maximum concentration observed was 8.47 ng/mL. Conclusion: Topical ocular licaminlimab demonstrated statistically significant improvement in global ocular discomfort score compared to Vehicle in patients with severe DED, with good tolerability, no increase in IOP, and minimal systemic drug exposure.
Language	English
Publishing date	2022-07-06
Publishing country	New Zealand
Document type	Case Reports ; Clinical Trial
ISSN	1177-5467
ISSN	1177-5467
DOI	10.2147/OPTH.S366836
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Article ; Online: Topical Ocular Anti-TNFα Agent Licaminlimab in the Treatment of Acute Anterior Uveitis: A Randomized Phase II Pilot Study.

Pasquali, Theodore A / Toyos, Melissa M / Abrams, David B / Scales, David K / Seaman, John W / Weissgerber, Georges

Translational vision science & technology

2022 Volume 11, Issue 6, Page(s) 14

Abstract: Purpose: Licaminlimab is a new anti-TNFα antibody fragment for topical ocular application. This phase II study assessed the tolerability, treatment effect, and pharmacokinetics of licaminlimab in acute anterior uveitis (AAU).: Methods: In this ... ...

Abstract	Purpose: Licaminlimab is a new anti-TNFα antibody fragment for topical ocular application. This phase II study assessed the tolerability, treatment effect, and pharmacokinetics of licaminlimab in acute anterior uveitis (AAU). Methods: In this multicenter, randomized, parallel-group, double-masked study, 43 adult patients with non-infectious AAU and Standardization of Uveitis Nomenclature (SUN) anterior chamber (AC) cell score of 2+ or 3+ were randomized (3:1 ratio) to licaminlimab (60 mg/mL, 8 drops/day for 15 days, 4 drops/day for 7 days, then matching vehicle for 7 days) or dexamethasone eye drops (8 drops/day for 15 days, tapering to 1 drop/day over 14 days). The primary efficacy end point was clinical response (≥2-step decrease in AC cell grade at day 15). A treatment effect was considered as established if the lower limit of the 95% posterior interval of the responder rate was >30%. Serum levels of licaminlimab were determined. Results: The day 15 response rate for licaminlimab was 56%; the lower bound of the 95% credible interval was 40% (i.e. >30%), demonstrating a treatment effect according to prespecified criteria. By day 4, 36% of licaminlimab-treated patients were responders; 76% had an AC cell grade of 0 on ≥1 post-treatment visit. The day 15 dexamethasone response rate was 90% (no inferential between-arm comparison was planned). Both treatments were well-tolerated. Intraocular pressure increased from baseline with dexamethasone but not licaminlimab. Licaminlimab was undetectable in serum in most patients. Conclusions: Licaminlimab is the first biologic demonstrated to have a treatment effect on an intraocular condition with topical ocular application. The trial met its primary objective and the observed responder rate for licaminlimab was 56.0%. Ocular administration of licaminlimab was well-tolerated in adult subjects with AAU for up to 35 days.
MeSH term(s)	Acute Disease ; Adult ; Dexamethasone/therapeutic use ; Glucocorticoids/therapeutic use ; Humans ; Pilot Projects ; Prospective Studies ; Treatment Outcome ; Uveitis, Anterior/drug therapy
Chemical Substances	Glucocorticoids ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2022-06-01
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2674602-5
ISSN	2164-2591 ; 2164-2591
ISSN (online)	2164-2591
ISSN	2164-2591
DOI	10.1167/tvst.11.6.14
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Article ; Online: Therapeutic response in the HAWK and HARRIER trials using deep learning in retinal fluid volume and compartment analysis.

Schmidt-Erfurth, Ursula / Mulyukov, Zufar / Gerendas, Bianca S / Reiter, Gregor S / Lorand, Daniel / Weissgerber, Georges / Bogunović, Hrvoje

Eye (London, England)

2022 Volume 37, Issue 6, Page(s) 1160–1169

Abstract: Objectives: To assess the therapeutic response to brolucizumab and aflibercept by deep learning/OCT-based analysis of macular fluid volumes in neovascular age-related macular degeneration.: Methods: In this post-hoc analysis of two phase III, ... ...

Abstract	Objectives: To assess the therapeutic response to brolucizumab and aflibercept by deep learning/OCT-based analysis of macular fluid volumes in neovascular age-related macular degeneration. Methods: In this post-hoc analysis of two phase III, randomised, multi-centre studies (HAWK/HARRIER), 1078 and 739 treatment-naive eyes receiving brolucizumab or aflibercept according to protocol-specified criteria in HAWK and HARRIER, respectively, were included. Macular fluid on 41,840 OCT scans was localised and quantified using a validated deep learning-based algorithm. Volumes of intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED) for all central macular areas (1, 3 and 6 mm) in nanolitres (nL) and best corrected visual acuity (BCVA) change in ETDRS letters were associated using mixed models for repeated measures. Results: Baseline IRF volumes decreased by >92% following the first intravitreal injection and consistently remained low during follow-up. Baseline SRF volumes decreased by >74% following the first injection, while PED volume resolved by 68-79% of its baseline volume. Resolution of SRF and PED was dependent on the substance and regimen used. Larger residual post-loading IRF, SRF and PED volumes were all independently associated with progressive vision loss during maintenance, where the differences in mean BCVA change between high and low fluid volume subgroups for IRF, SRF and PED were 3.4 letters (p < 0.0001), 1.7 letters (p < 0.001) and 2.5 letters (p < 0.0001), respectively. Conclusions: Deep-learning methods allow an accurate assessment of substance and regimen efficacy. Irrespectively, all fluid compartments were found to be important markers of disease activity and were relevant for visual outcomes.
MeSH term(s)	Humans ; Angiogenesis Inhibitors/therapeutic use ; Deep Learning ; Intravitreal Injections ; Ranibizumab/therapeutic use ; Retinal Detachment ; Subretinal Fluid ; Tomography, Optical Coherence ; Vascular Endothelial Growth Factor A ; Wet Macular Degeneration/drug therapy
Chemical Substances	Angiogenesis Inhibitors ; Ranibizumab (ZL1R02VT79) ; Vascular Endothelial Growth Factor A
Language	English
Publishing date	2022-05-06
Publishing country	England
Document type	Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial
ZDB-ID	91001-6
ISSN	1476-5454 ; 0950-222X
ISSN (online)	1476-5454
ISSN	0950-222X
DOI	10.1038/s41433-022-02077-4
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Zs.B 3010: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Brolucizumab: A Newly Developed Anti-VEGF Molecule for the Treatment of Neovascular Age-Related Macular Degeneration.

Tadayoni, Ramin / Sararols, Laura / Weissgerber, Georges / Verma, Rohini / Clemens, Andreas / Holz, Frank G

Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde

2020 Volume 244, Issue 2, Page(s) 93–101

Abstract: Background: Despite the success of anti-vascular endothelial growth factors (anti-VEGFs), currently, there is a need for highly effective compounds that can alleviate the burden of managing neovascular age-related macular degeneration (nAMD).: Purpose! ...

Abstract	Background: Despite the success of anti-vascular endothelial growth factors (anti-VEGFs), currently, there is a need for highly effective compounds that can alleviate the burden of managing neovascular age-related macular degeneration (nAMD). Purpose: To review the milestones in the molecular and clinical development of brolucizumab, the first single-chain antibody fragment (scFv) designed specifically for intraocular use in humans. Methods: In this article, we summarize the preclinical and current clinical evidence of brolucizumab administration with an overview of the other treatment regimens and additional indications under investigation. Results: The unique molecular design of brolucizumab led to a low molecular weight of only 26 kDa, allowing for a concentrated molar dose of 1 intravitreal injection compared with other anti-VEGF agents. Phase I and II clinical trial outcomes validated the efficacy of brolucizumab in the treatment of nAMD with signals of a more durable treatment effect. The pivotal phase III trials, HAWK and HARRIER, which included a total of 1,817 patients, established that brolucizumab can be administered every 3 months while maintaining disease control. Conclusions: The preclinical and clinical data on brolucizumab provide evidence of sustained disease control with longer injection intervals, thus potentially reducing the treatment burden in patients with nAMD.
MeSH term(s)	Angiogenesis Inhibitors/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Humans ; Intravitreal Injections ; Macular Degeneration/drug therapy
Chemical Substances	Angiogenesis Inhibitors ; Antibodies, Monoclonal, Humanized ; brolucizumab (XSZ53G39H5)
Language	English
Publishing date	2020-11-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	209735-7
ISSN	1423-0267 ; 0030-3755
ISSN (online)	1423-0267
ISSN	0030-3755
DOI	10.1159/000513048
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Article ; Online: EFFECT OF RETINAL THICKNESS VARIABILITY ON VISUAL OUTCOMES AND FLUID PERSISTENCE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Post Hoc Analysis of the HAWK and HARRIER Studies.

Dugel, Pravin U / Jhaveri, Chirag D / Chakravarthy, Usha / Wykoff, Charles C / Singh, Rishi P / Hamilton, Robin / Weissgerber, Georges / Mulyukov, Zufar / Holz, Frank G

Retina (Philadelphia, Pa.)

2021 Volume 42, Issue 3, Page(s) 511–518

Abstract: Purpose: To determine the association between central subfield thickness (CST) variability and visual outcomes in eyes with neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor therapies.: Methods: In this ...

Abstract	Purpose: To determine the association between central subfield thickness (CST) variability and visual outcomes in eyes with neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor therapies. Methods: In this post hoc, treatment-agnostic analysis, patients (N = 1,752) were grouped into quartiles of increasing CST variation. The association between CST variability and best-corrected visual acuity was measured from baseline, or from the end of the loading phase, until the end of the study using a multilevel modeling for repeated-measures model. The association between CST variability and the presence of retinal fluid was also assessed. Results: Increased CST variability was associated with worse best-corrected visual acuity outcomes at the end of study, with a least-square mean difference in best-corrected visual acuity of 8.9 Early Treatment Diabetic Retinopathy Study letters between the quartiles with the lowest and highest CST variability at the final visit. Increased variability was also associated with a higher mean fraction of visits with the presence of fluid. Conclusion: More stable CST was associated with better visual outcomes at the end of treatment suggesting that CST variability may provide a more reliable prognostic marker of visual outcomes than the presence of fluid alone, with the potential to enhance the clinical care of neovascular age-related macular degeneration patients.
MeSH term(s)	Aged ; Angiogenesis Inhibitors/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Choroidal Neovascularization/diagnostic imaging ; Choroidal Neovascularization/drug therapy ; Choroidal Neovascularization/physiopathology ; Double-Blind Method ; Female ; Humans ; Intravitreal Injections ; Male ; Middle Aged ; Organ Size ; Prospective Studies ; Receptors, Vascular Endothelial Growth Factor/therapeutic use ; Recombinant Fusion Proteins/therapeutic use ; Retina/diagnostic imaging ; Retina/pathology ; Subretinal Fluid/physiology ; Tomography, Optical Coherence ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Visual Acuity/physiology ; Wet Macular Degeneration/diagnostic imaging ; Wet Macular Degeneration/drug therapy ; Wet Macular Degeneration/physiopathology
Chemical Substances	Angiogenesis Inhibitors ; Antibodies, Monoclonal, Humanized ; Recombinant Fusion Proteins ; VEGFA protein, human ; Vascular Endothelial Growth Factor A ; aflibercept (15C2VL427D) ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1) ; brolucizumab (XSZ53G39H5)
Language	English
Publishing date	2021-12-16
Publishing country	United States
Document type	Clinical Trial, Phase III ; Comparative Study ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
ZDB-ID	603192-4
ISSN	1539-2864 ; 0275-004X
ISSN (online)	1539-2864
ISSN	0275-004X
DOI	10.1097/IAE.0000000000003349
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Article ; Online: Efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy in Japanese participants of HAWK.

Ogura, Yuichiro / Jaffe, Glenn J / Cheung, Chui Ming Gemmy / Kokame, Gregg T / Iida, Tomohiro / Takahashi, Kanji / Lee, Won Ki / Chang, Andrew A / Monés, Jordi / D'Souza, Divya / Weissgerber, Georges / Gedif, Kinfemichael / Koh, Adrian

The British journal of ophthalmology

2021 Volume 106, Issue 7, Page(s) 994–999

Abstract: Purpose: To compare the efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy (PCV) over 96 weeks in the HAWK study.: Design: HAWK was a global, 2-year, randomised, double-masked, multicentre phase III ... ...

Abstract	Purpose: To compare the efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy (PCV) over 96 weeks in the HAWK study. Design: HAWK was a global, 2-year, randomised, double-masked, multicentre phase III trial in participants with neovascular age-related macular degeneration. Methods: Of the Japanese participants with PCV, 39 received brolucizumab 6 mg and 30 received aflibercept 2 mg. After 3 monthly loading doses, brolucizumab-treated eyes received an injection every 12 weeks (q12w) but were adjusted to q8w if disease activity was detected. Aflibercept-treated eyes received fixed q8w dosing. Mean change in best-corrected visual acuity (BCVA), the proportion of participants on q12w, retinal thickness, retinal fluid changes and safety were assessed to Week 96. Results: Mean change in BCVA (early treatment diabetic retinopathy study (ETDRS) letters) from baseline to week 48/week 96 was+10.4/+11.4 for brolucizumab and +11.6/+11.1 for aflibercept. For brolucizumab-treated eyes, the probability of only q12w dosing after loading through week 48 was 76%, and 68% through week 96. Fluid resolution was greater with brolucizumab than aflibercept: respective proportions of eyes with intraretinal fluid and/or subretinal fluid were 7.7% and 30% at week 48% and 12.8% and 16.7% at week 96. Brolucizumab exhibited an overall well-tolerated safety profile despite a higher rate of intraocular inflammation compared with aflibercept. Conclusion: In Japanese eyes with PCV, brolucizumab q12w/q8w monotherapy resulted in robust and consistent BCVA gains that were comparable to q8w aflibercept dosing. Anatomical outcomes favoured brolucizumab over aflibercept, with 76% of brolucizumab participants maintained on q12w dosing after loading to week 48.
MeSH term(s)	Angiogenesis Inhibitors/therapeutic use ; Animals ; Antibodies, Monoclonal, Humanized ; Eye Diseases/drug therapy ; Hawks ; Humans ; Intravitreal Injections ; Japan ; Receptors, Vascular Endothelial Growth Factor ; Recombinant Fusion Proteins ; Tomography, Optical Coherence ; Treatment Outcome ; Visual Acuity
Chemical Substances	Angiogenesis Inhibitors ; Antibodies, Monoclonal, Humanized ; Recombinant Fusion Proteins ; aflibercept (15C2VL427D) ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1) ; brolucizumab (XSZ53G39H5)
Language	English
Publishing date	2021-07-22
Publishing country	England
Document type	Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	80078-8
ISSN	1468-2079 ; 0007-1161
ISSN (online)	1468-2079
ISSN	0007-1161
DOI	10.1136/bjophthalmol-2021-319090
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Article ; Online: A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration.

Poor, Stephen H / Weissgerber, Georges / Adams, Christopher M / Bhatt, Harit / Browning, David J / Chastain, James / Ciulla, Thomas A / Ferriere, Michael / Gedif, Kinfemichael / Glazer, Louis C / Joondeph, Brian C / Normand, Guillaume / Sheth, Veeral / Watters, Christie / Grosskreutz, Cynthia L

American journal of ophthalmology

2022 Volume 239, Page(s) 180–189

Abstract: Purpose: To evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for anti-vascular endothelial growth factor therapy over a 12-week period in patients with ... ...

Abstract	Purpose: To evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for anti-vascular endothelial growth factor therapy over a 12-week period in patients with neovascular age-related macular degeneration. Design: A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study. Methods: Trial includes n = 90 patients with active choroidal neovascularization due to neovascular age-related macular degeneration and under anti-vascular endothelial growth factor treatment. All patients received an intravitreal injection of ranibizumab at baseline and were retreated when there was evidence of disease recurrence (rescue). Patients were randomized 1:1 to receive topical LHA510 or vehicle for 12 weeks. Drops were administered twice a day for 8 weeks and then 3 times a day for the last 4 weeks. Main outcome measure: The primary outcome was the number of patients requiring rescue over 84 days of topical dosing. Key secondary outcome measures were time to first rescue, total number of ranibizumab injections, changes in central subfield thickness, and changes of visual acuity from baseline to day 84. Results: The extended per protocol set included 70 patients of whom 25 of 33 patients in the LHA510 group (75.8%) and 25 of 37 patients in the placebo group (67.6%) required rescue by day 84 (P = .8466). Secondary and subgroup analysis did not support evidence of efficacy. Twenty-one of 46 patients administered LHA510 developed a reversible corneal haze that resolved with cessation of treatment and did not recur in patients restarted at once daily frequency. Conclusion: In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.
MeSH term(s)	Angiogenesis Inhibitors ; Humans ; Indoles ; Intravitreal Injections ; Macular Degeneration/drug therapy ; Neoplasm Recurrence, Local ; Pyrazoles ; Pyrimidines ; Ranibizumab/therapeutic use ; Receptors, Vascular Endothelial Growth Factor/therapeutic use ; Treatment Outcome ; Vascular Endothelial Growth Factor A ; Wet Macular Degeneration/chemically induced ; Wet Macular Degeneration/diagnosis ; Wet Macular Degeneration/drug therapy
Chemical Substances	Angiogenesis Inhibitors ; Indoles ; Pyrazoles ; Pyrimidines ; Vascular Endothelial Growth Factor A ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1) ; acrizanib (F2CB8801I3) ; Ranibizumab (ZL1R02VT79)
Language	English
Publishing date	2022-03-02
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
ZDB-ID	80030-2
ISSN	1879-1891 ; 0002-9394
ISSN (online)	1879-1891
ISSN	0002-9394
DOI	10.1016/j.ajo.2022.02.019
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Article ; Online: HAWK and HARRIER: Ninety-Six-Week Outcomes from the Phase 3 Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration.

Dugel, Pravin U / Singh, Rishi P / Koh, Adrian / Ogura, Yuichiro / Weissgerber, Georges / Gedif, Kinfemichael / Jaffe, Glenn J / Tadayoni, Ramin / Schmidt-Erfurth, Ursula / Holz, Frank G

Ophthalmology

2020 Volume 128, Issue 1, Page(s) 89–99

Abstract: Purpose: To report the 96-week outcomes from HAWK and HARRIER.: Design: Phase 3, prospective, randomized, double-masked, multicenter studies comparing efficacy and safety of brolucizumab 3 mg (HAWK only) and 6 mg with aflibercept 2 mg in eyes with ... ...

Abstract	Purpose: To report the 96-week outcomes from HAWK and HARRIER. Design: Phase 3, prospective, randomized, double-masked, multicenter studies comparing efficacy and safety of brolucizumab 3 mg (HAWK only) and 6 mg with aflibercept 2 mg in eyes with neovascular age-related macular degeneration (nAMD). Participants: Treatment-naïve eyes with nAMD were randomized 1:1:1 to brolucizumab 3 mg (n = 358), brolucizumab 6 mg (n = 360), aflibercept 2 mg (n = 360; HAWK) or 1:1 to brolucizumab 6 mg (n = 370), aflibercept 2 mg (n = 369; HARRIER). Methods: After 3 monthly loading doses, brolucizumab patients received every (q)-12-week (w) dosing, possibly adjusting to q8w dosing if disease activity was present at predefined disease activity assessment (DAA) visits. Aflibercept was dosed in a fixed q8w regimen. Visual and anatomic parameters were assessed throughout. Primary end point was at week 48 (48w), confirmed at 96w. Main outcome measures: Mean best-corrected visual acuity (BCVA) change from baseline, proportion of patients on an q12w regimen, retinal thickness, retinal fluid changes, and safety, all to 96w. Results: Mean change (least squares [LS] mean ± standard error) in BCVA from baseline to 96w in HAWK was 5.6±0.79 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for brolucizumab 3 mg, 5.90±0.78 letters for brolucizumab 6 mg, and 5.3±0.78 letters for aflibercept and in HARRIER was 6.1±0.73 letters for brolucizumab 6 mg and 6.6 ± 0.73 letters for aflibercept. Greater central subfield thickness reductions were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean, -174.8 μm vs. -148.7 μm; 95% confidence interval for treatment difference, -46.2 to -5.9 μm; P = 0.0115) and HARRIER (LS mean, -197.7 μm vs. -155.1 μm; 95% confidence interval for treatment difference, -62.0 to -23.3 μm; P < 0.0001). The proportions of eyes with intraretinal fluid and/or subretinal fluid (IRF/SRF) at 96w in HAWK were 31% (P = 0.0688) and 24% (P = 0.0002) for brolucizumab 3 mg and 6 mg and 37% for aflibercept, whereas in HARRIER, they were 24% for brolucizumab 6 mg (P < 0.0001) and 39% for aflibercept. At 92w (last DAA), a 45.4% and 38.6% probability was observed for brolucizumab 6 mg patients of maintaining an q12w treatment regimen in HAWK and HARRIER, respectively. Brolucizumab exhibited an overall well-tolerated safety profile. Conclusions: Visual outcomes from 48w to 96w confirm the efficacy achieved at 48w. Brolucizumab demonstrated greater fluid resolution compared with aflibercept. The q12w potential for brolucizumab observed at 48w was maintained to 96w.
MeSH term(s)	Angiogenesis Inhibitors/administration & dosage ; Antibodies, Monoclonal, Humanized/administration & dosage ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Therapy, Combination ; Follow-Up Studies ; Macula Lutea/pathology ; Prospective Studies ; Receptors, Vascular Endothelial Growth Factor/administration & dosage ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors ; Recombinant Fusion Proteins/administration & dosage ; Time Factors ; Tomography, Optical Coherence/methods ; Treatment Outcome ; Visual Acuity/drug effects ; Wet Macular Degeneration/diagnosis ; Wet Macular Degeneration/drug therapy ; Humans
Chemical Substances	aflibercept (15C2VL427D) ; Angiogenesis Inhibitors ; Antibodies, Monoclonal, Humanized ; brolucizumab (XSZ53G39H5) ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1) ; Recombinant Fusion Proteins
Language	English
Publishing date	2020-06-20
Publishing country	United States
Document type	Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	392083-5
ISSN	1549-4713 ; 0161-6420
ISSN (online)	1549-4713
ISSN	0161-6420
DOI	10.1016/j.ophtha.2020.06.028
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Article ; Online: Use of Composite End Points in Early and Intermediate Age-Related Macular Degeneration Clinical Trials: State-of-the-Art and Future Directions.

Terheyden, Jan Henrik / Schmitz-Valckenberg, Steffen / Crabb, David P / Dunbar, Hannah / Luhmann, Ulrich F O / Behning, Charlotte / Schmid, Matthias / Silva, Rufino / Cunha-Vaz, José / Tufail, Adnan / Weissgerber, Georges / Leal, Sergio / Holz, Frank G / Finger, Robert P

Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde

2020 Volume 244, Issue 5, Page(s) 387–395

Abstract: The slow progression of early age-related macular degeneration (AMD) stages to advanced AMD requires the use of surrogate end points in clinical trials. The use of combined end points may allow for shorter and smaller trials due to increased precision. ... ...

Abstract	The slow progression of early age-related macular degeneration (AMD) stages to advanced AMD requires the use of surrogate end points in clinical trials. The use of combined end points may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite end points as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite end points used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite end point categories were: combined structural and functional end points, combined structural end points, combined functional end points and combined multicategorical end points. The majority of the studies included binary composite end points. There was a lack of sensitivity analyses of different end points against accepted outcomes (i.e., progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined end points in clinical studies of early stages of AMD exists, and no surrogate end points have been accepted for AMD progression.
MeSH term(s)	Disease Progression ; Humans ; Macular Degeneration/diagnosis
Language	English
Publishing date	2020-12-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	209735-7
ISSN	1423-0267 ; 0030-3755
ISSN (online)	1423-0267
ISSN	0030-3755
DOI	10.1159/000513591
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