KALAHARI study finds THR-149 to be safe, well-tolerated with preliminary efficacy as treatment for DME patients who respond suboptimally to anti-VEGF.
Reviewed by Arshad M. Khanani, MD, MA.
The phase 2 part A results of the KALAHARI Study that assessed the effects of THR-149 (Oxurion), a plasma kallikrein (PKal) inhibitor, found that up to 3 intravitreal injections were safe and well-tolerated in patients with diabetic macular edema (DME), according to Arshad M. Khanani, MD, MA, who reported the results at the Angiogenesis, Exudation, and Degeneration 2022 conference. He is from Sierra Eye Associates, Reno, NV.
PKal is a principle driver of DME pathology apart from vascular endothelial growth factor (VEGF) and is a validated target for edema, inflammation, and prevention of microhemorrhages, Dr. Khanani explained.
The value of a PKal inhibitor lies in the fact that it can potentially treat 40% to 50% of patients who do not respond well to anti-VEGF therapies.
In this study, 20 patients were randomized to 1 of 3 doses of THR-149, 0.01, 0.04, or 0.13 mg, to evaluate the systemic/ocular adverse events, serious adverse events, and the mean changes in the best-corrected visual acuity (BCVA) and central subfield thickness (CST).
Patient inclusion was based on a suboptimal response to 5 or more anti-VEGF injections and a CST of 320 microns or more and a BCVA of 73 Early Treatment Diabetic Retinopathy Study letters or fewer and 39 letters or more. Patients who were included also had had a last injection of aflibercept (Eylea, Regeneron Pharmaceuticals) 3 to 8 weeks before study screening.
The mean age of the treated patients was 63.4 years, 95% were Caucasian, and 60% were male. The demographics of patients in the 0.01-, 0.04-, and 0.13-mg groups were similar at baseline. The groups included 6, 6, and 8 patients, respectively.
Most patients had mild-to-moderate diabetic retinopathy (DR). Two patients randomized to the 0.01-mg dose had more severe DME and DR for a longer time. During the year before screening for this study, 80% of patients had received more than 5 anti-VEGF injections.
The CST in the group treated with the 0.13-mg dose was slightly thinner (421 microns compared with 465 and 470 microns in the 2 lower doses).
No serious adverse events or intraocular inflammation developed. Any adverse events that did develop were mild to moderate; 1 adverse event (worsening of DME) was associated with the treatment and 1 (IOP increase) with the injection procedure in the lower dose groups. The number of adverse events did not increase in association with the increasing dose or number of injections.
Dr. Khanani reported, “In the high-dose group, at month 3, 1 month after the third injection, the BCVA increased by a mean of 6.1 letters. The gain in BCVA was maintained out to month 6 with no need for rescue treatment.”
In addition, in the same group, the CST was stable out to month 6.
A post-hoc analysis of the BCVA changes found that 2 patients had abnormalities on optical coherence tomography (OCT). Their exclusion from the analysis showed a mean letter gain in BCVA of 9 or more letters that remained out to month 6.
In the high-dose group, 50% of subjects had a 2-line or more improvement in BCVA up to month 6, 4 months after their last THR-149 injection, without needing rescue therapy.
The take-home messages from part A are that up to 3 intravitreal injections of THR-149 were safe and well-tolerated. A mean gain of 6.1 letters of BCVA was seen at month 3 that was sustained out to month 6 accompanied by a stable CST.
Following the review of the results in part A, the high dose was selected for evaluation during part B, when the dose will be compared to aflibercept. Based on the post-hoc analysis, the target population was refined and patients with imaging abnormalities were excluded.
Based on the results in part A, the high-dose was selected for evaluation during part B when the dose will be compared with aflibercept. Patients are currently being enrolled in part B.
Dr. Khanani stated, “The data from the part A of the KALAHARI trial is encouraging. It shows that THR-149 has the potential to improve vision in patients with DME who have a sub-optimal response to anti-VEGF therapies.”