Multiple challenges remain for diabetic macular edema with unmet needs to improve treatment outcomes, speed of treatment benefit, and the duration of response.
An integrin antagonist (THR-687, Oxurion) shows promising efficacy as a treatment for diabetic macular edema (DME) in a multicenter phase 1 clinical trial, said Raj K. Maturi, MD.
The open-label, non-randomized, dose-escalating study enrolled 12 patients who were followed for 3 months after receiving one intravitreal injection of THR-687. The study met its primary endpoint as there were no dose-limiting toxicity events by day 14 post-injection. Exploratory efficacy analyses showed that THR-687 had the potential for rapid onset of action and reasonable durability for improving visual acuity, explained Maturi at the 2020 virtual meeting of the American Academy of Ophthalmology.
“Multiple challenges remain in the management of DME with unmet needs to improve treatment outcomes, speed of treatment benefit, and the duration of response. Unlike anti-VEGF agents, integrin antagonists have a broader biologic effect because integrins contribute to the activation of multiple growth factor receptors and are involved in multiple processes resulting in pathological angiogenesis and vascular leakage,” said Maturi, clinical associate professor of ophthalmology, Indiana University School of Medicine, and private practice, Midwest Eye Institute, Indianapolis, Indiana.
“Based on the encouraging findings of this phase 1 study, a multiple dose, two-part phase 2 study is planned to select the dose level of THR-687 and to compare it to aflibercept (Eylea, Regeneron) for treatment-naïve patients with DME,” Maturi added.
Patients were eligible for the phase 1 trial if they had center-involved DME with a central subfield thickness (CST) ≥320 µm on spectral-domain optical coherence tomography, BCVA between 23 and 62 ETDRS letters, and a history of and current response to treatment with anti-VEGF or corticosteroid therapy.
The study included three sequential dose groups—three patients received THR-687 0.4 mg, three patients were treated with THR-687 1.0 mg, and six patients were treated with THR-687 2.5 mg. Baseline mean BCVA was 56.3 letters for the overall cohort and well-balanced between the three dose groups. Baseline mean CST was 541.8 µm and lower in the highest dose group (499 µm) than in the two lower dose groups (557 and 612 µm).
The safety analyses showed a total of nine adverse events among five subjects, but there were no dose-limiting toxicities or serious adverse events.
“All treatment-related adverse events were in the study eye, most were likely related to the injection procedure, and the others were likely due to underlying disease progression or concomitant diseases,” Maturi said.
Three patients, including one treated with the 1.0 mg dose of THR-687 and two patients in the highest dose group, required rescue treatment that per protocol-defined criteria was given for ≥10-letter BCVA worsening or ≥50 µm increase in CST as assessed by the study investigator. The BCVA and CST data for these patients were censored at the time of rescue injection and carried forward for the efficacy endpoint analyses.
Results from BCVA testing showed a rapid onset of improvement action with a mean gain of 3.1 letters seen in the overall cohort on the day after injection, and a gain of 7.2 letters by day seven. A mean improvement of 9.2 letters was seen at month 1, which represented the peak gain, and BCVA remained improved from baseline by a mean of 8.3 letters at month 3.
The change in BCVA appeared to be dose-related.
“The most pronounced improvement in BCVA was observed in the highest dose group that had a mean improvement of 9.8 letters by day 7, 11.2 letters by day 14, and a mean gain of 12.5 letters at month 3,” Maturi noted.
In the overall cohort, the treatment was associated with a marginal beneficial effect on CST at 7 days and at 1 month with an increase thereafter. However, the highest dose treatment group had a mean CST decrease of 106 µm at day 14 and maintained a decrease of 36.5 µm at month 3.