Phase II data on a novel peptide candidate – plasma kallikrein (PKal) (THR-149) – for treatment of diabetic macular edema (DME)

An interim analysis from a Phase II study for a novel peptide (THR-149) is aimed to prevent the induction of retinal vascular permeability, neurodegeneration and inflammation of DME. The analysis confirmed that their IDMC (Independent Data Monitoring Committee) recommended continuation of the study based upon the outcome of the futility analysis, including a two-part, randomized, prospective, multi-centre study assessing multiple (3) injections of THR-149 in DME patients. According to a news release from their sponsor (Oxurion, a small biotech, headquartered in Leuven, Belgium), Dr. Andy De Deene, chief development officer of Oxurion, stated that,. “this trial is evaluating THR-149 for the treatment of DME against the current standard of care anti-VEGF therapy. THR-149 could provide an important alternative for the up to 50% of patients with DME who respond sub-optimally to anti-VEGF”.


According to the sponsor, the novel peptide, summarised in the database (NCT04527107), is a mediator of vascular leakage, inflammation, micro-haemorrhages and neurodegeneration. The THR-149 is a potent bicyclic peptide inhibitor developed using phage display-based peptide libraries with rationally designed synthetic modifications.  The kallikrein-kinin system itself (KKS) is a metabolic cascade that, when activated, triggers the release of vasoactive kinins, particularly the serine protease, PKal.  Upon activation, PKal cleaves its substrate, high-molecular-weight kininogen, to release bradykinin (BK), an agonist at the B2 receptor (B2R). BR can be further converted to Des-Arg9-BK, which activates the B1 receptor (B1R). B2R is constitutively expressed and mediates most normal physiological effects of kinins.  In contrast, B1R is usually expressed at very low levels however, it is highly inducible and overexpressed following tissue injury and is involved in chronic inflammation. In the eye, KKS activation increases vascular permeability, retinal thickening, inflammation and neurodegeneration, responses which are exacerbated in diabetes and this is a VEGF-independent mediator of the disease.


Following the initial analysis for the Phase II data, the researchers stated that multiple IVT injections (up to three) of THR-149 were safe and well-tolerated.  A mean BCVA gain of 6.1 letters was seen at 3-month, with gains observed up to 6-month. as well as central subfield thickness (CST) stabilization over the 6-month study period.  In addition, researchers reported that “post-hoc analysis, excluding 2 subjects with abnormalities on OCT, showed a mean gain in BCVA of 9.3 letters at month 3, which was maintained up to month 6”. If positive data are completed at the relevant endpoints at the end of September 2023, a subsequent Phase III clinical trial could position THR-149 as an important second line therapy for DME patients.”