Early pipeline developments within the diabetic macular oedema (DME) space have recently garnered the attention of special interest, following the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, which took place in the first week of May and online from 11-12 May. The spotlight was placed on many up-and-coming pharmacotherapies, one of which was Oxurion’s THR-687.
Oxurion’s THR-687 is of special interest as it employs a novel mechanism of action (MOA), as a selective pan-RGD (arginylglycylaspartic acid) integrin antagonist, to treat diabetic retinopathy and various other vision-threatening retinal pathologies such as DME. At the ARVO annual meeting, data was presented for THR-687’s preclinical study in a diabetic rat model, showcasing its broader biological effect in comparison to current vascular endothelial growth factor (VEGF) inhibitor therapies, through its multifaceted abilities in preventing retinal vascular permeability, reactive gliosis, and inflammation.
During the study, rats were given three different doses of THR-687: high (75µg/eye), medium (16.7µg/eye), and low (6.7µg/eye). Results showed that the highest dose of THR-687 given to rats entirely prevented vascular leakage, whereas this pathology was reduced significantly by 34 ± 21% in rats who were administered the middle dose. In addition, the number of inflammatory cells was significantly reduced regardless of the dose administered to the study subjects; however, only the highest dose was successful in reducing vimentin expression back to baseline within Muller cells.
Current treatment paradigms for DME habitually include the administration of a VEGF inhibitor therapy, namely Bayer’s Eylea (aflibercept), as a first-line treatment option, or a corticosteroid therapy, specifically Allergan’s Ozurdex (dexamethasone LA), as a second-line treatment option. While the pharmacotherapeutic options that are currently marketed do cater to the needs of many patients, there is a subset of patients who do not respond well to existing treatments, or who are unable to comply with treatment regimens, particularly due to DME patients being of working age and having comorbid conditions relating to diabetes that they must also tend to. As a result, it is of paramount importance that these unmet needs are addressed in due course. Given the new MOA associated with THR-687, there is an anticipation that this therapy can help address this gap in the DME market.
But despite such promising results and the high anticipation of a new pharmacotherapy with an MOA reaching the market, Oxurion revealed last week that clinical trials for THR-687 would not be proceeding, following the release of its top-line results for INTEGRAL (NCT05063734), its Phase IIa trial for THR-687, and has additionally retracted the pharmacotherapy from its website. While the trial did meet its safety endpoints, with no reported serious adverse events (SAEs) for either of the issued dose levels (1.2mg and 2.0mg), efficacy endpoints for central subfield thickness and best-corrected visual acuity (BVCA) were not met. As a result, Oxurion is discontinuing the development of THR-687 and instead proceeding with the development of THR-149, a plasma kallikrein inhibitor, another MOA that has not yet entered the market within the DME space, for which Phase IIb results are expected to be published by next year.
This does, however, beg the question as to why Oxurion was still in pursuit of conducting preclinical studies with THR-687 if INTEGRAL did not meet efficacy endpoints. Success with the Phase I trial for THR-687 and promising findings from the recent preclinical study may, however, provide hope for the potential application of this pharmacotherapy in the context of another ophthalmological disease.