Safety and Efficacy of Intravitreal Risuteganib for Non-Exudative AMD: A Multicenter, Phase 2a, Randomized, Clinical Trial

Abstract

BACKGROUND AND OBJECTIVE:To evaluate the safety and efficacy of 1.0 mg risuteganib in subjects with nonexudative age-related macular degeneration (AMD). PATIENTS AND METHODS:This was a phase 2a, prospective, double-masked, sham-controlled study. Eyes with nonexudative (dry) AMD and Early Treatment Diabetic Retinopathy Study (ETDRS) bestcorrected visual acuity (BCVA) between 20/40 and 20/200 were included. Subjects were randomized to intravitreal 1.0 mg risuteganib or sham injection. At Week 16, subjects in the risuteganib group received a second 1.0-mg dose and the sham group crossed over to receive a dose of 1.0 mg risuteganib and were evaluated at Week 28. The primary endpoint was proportion of subjects with 8 letters ETDRS or more BCVA gain from baseline to Week 28 in the risuteganib group versus baseline to Week 12 for the sham group. BCVA was tested and subjects were observed for adverse events (AEs) every 4 weeks until completion of the study at 32 weeks. RESULTS:Forty-five subjects (risuteganib, n = 29; sham, n = 16) were enrolled in the study, of whom 39 (risuteganib, n = 25; sham, n = 14) completed the study and were included in the per protocol efficacy analysis. At baseline, mean age was 78.8 and 75.9 years and mean BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met by 48% of the risuteganib group at Week 28 and 7% of the sham group at Week 12 (P = .013). Of the risuteganib subjects, 20% gained 15 letters or more at Week 28, whereas no patients in the sham group at Week 12 achieved this visual acuity gain. The only ocular treatmentrelated treatment-emergent AE was vitreous floaters, which spontaneously recovered without sequelae. No drug-related serious AE was reported. CONCLUSIONS:Risuteganib demonstrated significant BCVA improvement in patients with non-exudative AMD. No drug-related AEs were seen during a 32week observation period.

Adhesion Molecule Targeted Therapy for Non-Infectious Uveitis

“…In phase II AMD studies adopting the intravitreal administration, 48% of patients gained ≥8 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. BCVA from baseline to week 28 in the risuteganib arm had no severe adverse drug reaction (ClinicalTrials.gov Identifier: NCT03626636) [ 64 ]. THR-687 (Oxurion, Leuven, Belgium) is another pan integrin receptor antagonist targeting αVβ3, αVβ5, and α5β1 [ 65 ].…”

The Transcriptome Profile of Retinal Pigment Epithelium and Müller Cell Lines Protected by Risuteganib Against Hydrogen Peroxide Stress

“… 52 This also connects to the clinical setting where RSG improved vision in dry AMD patients with early disease stage, before significant and irreversible retinal damage has occurred. 22 In the advanced stage of dry AMD (geographic atrophy), where retinal damage is extensive, 2 late-stage investigational drugs (Zimura and APL-2) can only slow down but not stop lesion growth. 53 Thus, we combined drug pretreatment and RNA-seq to further investigate the regulatory dynamics involved in H 2 O 2 cytotoxicity and protection by RSG.…”

“…Four hundred micromolar of RSG was used because it is the cell culture equivalence of the clinical dose (1.0 mg injection into 4 mL of vitreous volume). 22 One hundred micromolar of H 2 O 2 was used as this concentration was found to induce moderate cytotoxicity in ARPE-19 30 and MIO-M1 31 cells, which simulates the elevated oxidative stress that leads to progressive cell death in the relevant retinal diseases where RSG is currently being investigated. After exposure, cells were incubated for 48 h in fresh media before cell harvest, and cell viability measurement by trypan blue assay with an automated ViCell analyzer (Beckman Coulter, Inc., Fullerton, CA).…”

“…Several clinical trials showed that RSG has a good safety profile and improved visual acuity in dry AMD and DME patients. 22 , 23 In a preclinical model of human RPE cells stressed with cigarette smoke toxin, RSG treatment reduced cell death and ROS level, upregulated cytoprotective genes, and improved mitochondrial bioenergetics and metabolic activity. 24 In RPE cells constructed to contain AMD donor mitochondria, RSG exposure reduced the expression of apoptosis and angiogenesis genes.…”

Neuroprotection for Age-Related Macular Degeneration

“…The small peptide integrin regulator risuteganib (Allegro Ophthalmics, San Juan Capistrano, CA), which reduces ROS and enhance mitochondrial function in preclinical studies, has also shown J o u r n a l P r e -p r o o f promise. In a recent Phase 2a study, patients randomized to risuteganib had significant improvement in VA compared with control patients 15 . Of course, we should be cautious in interpreting these successes given the inherent limitations of early-phase studies.…”