Dataset Information

Phase 1 Dose-Escalation Study of Plasma Kallikrein Inhibitor THR-149 for the Treatment of Diabetic Macular Edema.

ABSTRACT:

Purpose

The purpose of this study was to evaluate the safety and preliminary efficacy of a single intravitreal injection of 3 dose levels of THR-149 in adults with center-involved diabetic macular edema (DME).

Methods

A phase 1, open-label, multicenter 3 + 3 dose-esclation study with 3-month follow-up. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) up to and including the Day 14 visit. Additional key endpoints included the incidence of (serious) adverse events ([S]AEs), mean change from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST), and additional imaging parameters on widefield fluorescein angiography and optical coherence tomography (OCT) angiography.

Results

Twelve subjects were treated: 3 subjects received THR-149 0.005 mg, 3 received 0.022 mg and 6 received 0.13 mg. Baseline ocular characteristics were balanced between subjects at each dose level. There were no DLTs or ocular SAEs, and all subjects completed the study. Six subjects experienced a total of 10 AEs in the study eye; 1 case of mild anterior chamber inflammation was deemed related to THR-149 and/or the injection procedure. Mean change from Baseline in BCVA was +7.5 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters on Day 14, and +6.4 ETDRS letters by Month 3. CST was variable, and mean CST change from baseline was +30.0 µm at Month 3. There were no clinically meaningful changes in imaging parameters.

Conclusions

THR-149 was safe and well tolerated; preliminary efficacy in terms of BCVA improvement was observed.

Translational relevance

This work bridges the gap between basic research and clinical care by providing first in human safety and preliminary efficacy data, supporting the further investigation of THR-149 as a potential treatment for DME.

SUBMITTER: Dugel PU

PROVIDER: S-EPMC8711005 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeTo evaluate the safety and preliminary efficacy of THR-687 in patients with center-involved diabetic macular edema (DME).DesignPhase 1, open-label, multicenter, 3 + 3 dose-escalation study with 3-month follow-up.ParticipantsPatients 18 years of age or older with visual impairment resulting from DME.MethodsSingle intravitreal injection of THR-687 (0.4 mg, 1.0 mg, or 2.5 mg).Main outcome measuresThe primary outcome measure was the incidence of dose-limiting toxicities (DLTs). The secondary outcome measure was the incidence of adverse events (AEs), including the occurrence of laboratory abnormalities. Exploratory outcome measures included changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST), assessments of ischemia and leakage on fluorescein angiography, and THR-687 levels in plasma.ResultsTwelve patients were treated: 3 patients received 0.4 mg of THR-687, 3 patients received 1.0 mg of THR-687, and 6 patients received 2.5 mg of THR-687. Most patients were men (9/12 patients). Their mean age was 57.8 years. No DLTs or serious AEs were reported at any of the dose levels tested. Overall, 9 AEs in the study eye were reported for 5 of 12 patients. Of those, 4 AEs in 3 of 12 patients were deemed treatment related by the investigator, all of which were mild, started on the day of the injection, and had resolved within 28 days without treatment. Overall, mean gains from baseline in BCVA were observed at all study visits with a rapid onset (7.2 Early Treatment Diabetic Retinopathy Study [ETDRS] letters at day 7) and a durability up to the end of the study (8.3 ETDRS letters at month 3). A mean decrease in CST was observed up to month 1. Overall, the mean BCVA gains and CST decreases were highest at the highest THR-687 dose level tested. THR-687 was undetectable in plasma at 7 days after the injection.ConclusionsAt all dose levels tested, a single intravitreal injection of THR-687 was safe and well tolerated. Preliminary efficacy was observed by a rapid gain in BCVA with 3 months' durability and a decrease in CST up to 1 month after the injection.