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ALG-1001 (Luminate, Allegro Ophthalmics) has a number of different mechanisms of action that benefit patients chronically treated with anti-vascular endothelial growth factor drugs and those who are treatment naïve.
Reviewed by David Boyer, MD
Take-home: ALG-1001 (Luminate, Allegro Ophthalmics) has a number of different mechanisms of action that benefit patients chronically treated with anti-vascular endothelial growth factor drugs and those who are treatment naïve.
ALG-1001 (Luminate, Allegro Ophthalmics), a first-in-class integrin peptide therapy, met the primary endpoint of vision non-inferiority to bevacizumab (Avastin, Genentech Inc.), an anti-vascular endothelial growth factor therapy (anti-VEGF), with 12-week durability in a population of patients with mostly chronic diabetic macular edema (DME).
ALG-1001 seems to be a strong player with different mechanisms of action that benefit patients who have been receiving chronic anti-VEGF therapy and those who are treatment naïve.
In the DEL MAR Phase IIb stage 2 clinical trial, ALG-1001 was evaluated as a sequential therapy or used in combination with bevacizumab in 80 patients with DME. ALG-1001 works by affecting multiple angiogenic pathways, according to David Boyer, MD.
In previous studies of the drug, ALG-1001 exhibited a strong track record with a few mechanisms of activity. A study sponsored by the manufacturer showed that ALG-1001 binds to the retinal pigment epithelium for several months.
In another sponsored study from Johns Hopkins University, ALG-1001 appeared to have 4 times more anti-angiogenic activity compared with aflibercept (Eylea, Regeneron Pharmaceuticals) in a murine model of retinopathy of prematurity. Another study from Johns Hopkins University also showed that ALG-1001 reduced vascular leakage. Other investigations have shown that the formulation affects only stressed retinal cells and has an anti-inflammatory effect, Dr. Boyer pointed out.
“These multiple mechanisms of action appear to reset the retina back to its normal balance by turning off the machinery of angiogenesis,” he added. “This is different from anti-VEGF therapy.”
Dr. Boyer is clinical professor ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles.
The previous phase II, stage 1 DME study results indicated that ALG-1001 monotherapy was not inferior to bevacizumab and showed 12-week durability compared with monthly bevacizumab treatment.
The multicenter phase IIb stage 2 clinical trial evaluated the safety and efficacy of ALG-1001 compared with bevacizumab pre-treatment or combined with bevacizumab in 80 patients, 60% of whom had been treated chronically with anti-VEGF therapy.
The study had 3 arms: administration of 0.5 mg or 1.0 mg of ALG-1001 with bevacizumab pretreatment, administration of 0.5 mg or 1.0 mg of ALG-1001 and bevacizumab combination therapy, and a bevacizumab control arm of 5 monthly injections. The primary endpoint was the mean best-corrected visual acuity (BCVA) at week 20 with 12 weeks off of ALG-1001 treatment versus every-4-week bevacizumab injections, Dr. Boyer recounted.
At the 5-month follow-up evaluation, Dr. Boyer reported that the primary endpoint of BCVA non-inferiority was met. Regarding the 0.5-mg or 1.0-mg doses of ALG-1001 with the 1.25-mg dose of bevacizumab pretreatment, compared to the bevacizumab control, the mean BCVA showed non-inferiority through week 20.
“The (ALG-1001) results were achieved after 1 treatment of 1.25 mg bevacizumab (week 0) followed by 3, 1.0-mg (ALG-1001) injections at weeks 1, 4, and 8 followed by 12 weeks off of the treatment, compared to 5 injections of bevacizumab administered every 4 weeks. The data showed the mean letter gain in BCVA was 7.1 for patients in the group treated with ALG-1001 and bevacizumab pre-treatment (sequential) group compared to 6.7 letters for patients in the monthly bevacizumab-treated control group.
Importantly, no adverse effects related to ALG-1001 occurred.
“Bevacizumab pretreatment helps clear the initial VEGF burden,” Dr. Boyer explained. “ALG-1001 turns off VEGF production, angiogenesis, and reduces inflammation. Adding 1 bevacizumab pre-treatment in the stage 2 study improved the BCVA achieved with 1.0 mg of ALG-1001 by about 40%, compared to the 1.0-mg dose of ALG-1001 without bevacizumab pre-treatment in the stage 1 study. In the two combination arms, no increased efficacy over monthly bevacizumab was seen.”
Dr. Boyer believes that these results are promising. “An important consideration is that ALG-1001 might be efficacious for the 50% of the patients with DME who have not had an adequate respond to repeated anti-VEGF treatments alone,” he added.
David Boyer, MD
This article is based on a presentation Dr. Boyer delivered at the 2017 American Society of Retina Specialists meeting. Dr. Boyer is a consultant to Allegro Ophthalmics and a member of the company’s Scientific Advisory Board. ALG-1001 currently is investigational and not approved by the FDA for use in the United States.