In 2019, Oxurion announced positive topline data for the compound THR-149, a highly potent plasma kallikrein inhibitor to treat diabetic macular edema (DME). Not only was THR-149 safe and well-tolerated, the phase 1 clinical trial also showed fast onset of action in BCVA from day 1, following a single injection. “I am very encouraged to see signs of efficacy so early post-treatment, and to observe a clear durable benefit to the patient’s vision as measured by BCVA”, explains Dr. Pravin Dugel, M.D.
Anti-VEGF is the standard of care for DME patients at the moment, but 40% has little or no benefit of these treatments. By targeting a VEGF independent pathway, an alternative treatment can be developed for poor or nonresponders to anti-VEGF treatment.
THR-149 is a plasma kallikrein (PKal) inhibitor, a preclinically well validated compound to prevent the induction of retinal vascular permeability (leading to edema), inflammation and the prevention of microhemorrhages. Literature data show that patients with DME have elevated levels of plasma kallikrein and that the vitreous level of plasma kallikrein varies less compared to VEGF, making it a potentially more effective target for the treatment of DME.
The phase 1 clinical trial for THR-149 evaluated the safety of a single intravitreal injection of THR-149 in 12 patients with visual impairment due to center-involved DME. Three doses were tested: 3 patients were injected with 0.005 mg (‘low dose’), 3 with the middle dose (0.021 mg), and 6 with a high dose (0.125 mg). All 12 completed the study and attended all study visits from day 0 to day 90.
Safety THR-149 confirmed
In the phase 1 clinical trial for THR-149 no dose-limiting toxicities and no serious adverse events were reported, indicating THR-149 is safe to use and well-tolerated. This means THR-149 is safe to use and well-tolerated.
One adverse event was deemed related to study treatment (likely injection procedure). All ocular adverse events were likely due to the injection procedure, underlying disease progression or concomitant diseases.
Signs of efficacy THR-149
Signs of efficacy were also observed in this clinical trial. Efficacy of treatments for diabetic macular edema (DME) is determined by measuring best corrected visual acuity (BCVA), mean central subfield of thickness (CST), and macular volume (MV). BCVA relates directly to vision, while CST and MV measure the edema level.
Impressively, a single injection with THR-149 improved BCVA from day 1 with 3.9 letters. The mean improvement in BCVA was highest at day 14 (7.5), and improvement was maintained at 6.4 letters after 90 days.
Impact on swelling
Changes in CST were marginal on day 1, followed by increase until study end. Mean CST change was minimal and within the variability of measurement. This means that changes in BCVA seem to be unrelated to changes in CST.
This clinical trial also linked macular volume with BCVA improvement: lower macular volume is apparently indicative of better BCVA response. Macular volume was maintained over time in patients defined as BCVA responders among patients with 10 or more letters improvement in at least two consecutive visits. “Macular volume could potentially become a new anatomical predictor for BCVA improvement”, Dr. Pravin Dugel notes.
“Diabetic macular edema evolves from being driven by permeability to being driven by inflammation. Anti-VEGF treatment seems to be very good at stopping permeability but doesn’t work on inflammation. Preclinical models of diabetes show that PKal mediates vascular hyperpermeability, leukocytosis, inflammation, and microhemorrhages. As a Pkal inhibitor, THR-149 is very promising because it allows us to possibly find a different mechanism of action”, Dr. Dugel explains.
The results of the phase 1 study take THR-149 to a phase 2 clinical study with multiple injections. “These positive findings give us the information and confidence needed to plan the next stage of THR-149’s clinical development. They also demonstrate that THR-149 has the clinical profile to potentially become the best-in-class PKal inhibitor and VEGF-independent therapy for treatment of DME”, says Patrik De Haes, M.D., CEO of Oxurion.
THR-149 could become a stand-alone therapy for suboptimal responders to the current standard of care (anti-VEGF injections). Or it could potentially be a therapy for all DME patients in combination with anti-VEGF treatment. As such, it could improve the vision (and lives) of millions of DME patients.
Preparing a phase 2 study
Oxurion is currently preparing a phase 2 trial for THR149 evaluating whether multiple doses of the compound can increase and prolong the visual improvement observed in the phase 1 study. THR-149 will be evaluated in patients who do not or do not optimally react to anti-VEGF treatment (non-responders/poor responders). Oxurion believes that if the phase 2 trial replicates and maintains the observed benefit from the phase 1 study, the compound can become a compelling drug candidate with clear value to the market.