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

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. A phase 2 multicent...

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Vydané v:	American journal of ophthalmology Ročník 239; s. 180 - 189
Hlavní autori:	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.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Elsevier Inc 01.07.2022 Elsevier Limited
Predmet:	Antibodies Clinical trials Diabetic retinopathy Drug dosages Immunoglobulins Kinases Laboratories Macular degeneration Monoclonal antibodies Patients Vascular endothelial growth factor United States > US
ISSN:	0002-9394, 1879-1891, 1879-1891
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Abstract	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. A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study. 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. 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. 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. In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.
AbstractList	PurposeTo 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.DesignA phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study.MethodsTrial 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 measureThe 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.ResultsThe 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.ConclusionIn spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy. 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.PURPOSETo 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.A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study.DESIGNA phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study.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.METHODSTrial 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.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.MAIN OUTCOME MEASUREThe 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.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.RESULTSThe 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.In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.CONCLUSIONIn spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy. 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. A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study. 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. 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. 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. In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.
Author	Ciulla, Thomas A. Poor, Stephen H. Grosskreutz, Cynthia L. Glazer, Louis C. Normand, Guillaume Weissgerber, Georges Chastain, James Gedif, Kinfemichael Bhatt, Harit Joondeph, Brian C. Sheth, Veeral Adams, Christopher M. Ferriere, Michael Watters, Christie Browning, David J.
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publication-title: J Med Chem doi: 10.1021/acs.jmedchem.7b01731
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Snippet	To evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for... PurposeTo evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for...
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SubjectTerms	Antibodies Clinical trials Diabetic retinopathy Drug dosages Immunoglobulins Kinases Laboratories Macular degeneration Monoclonal antibodies Patients Vascular endothelial growth factor
Title	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
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