Diabetes is a prevalent global disease that is estimated to increase by 54% among Americans between 2015 and 2030.¹ With the rising population of diabetic patients comes an increase in related pathologies associated with the disease, including ocular manifestations of diabetes, diabetic retinopathy, and diabetic macular edema (DME). Although the consequences of these diseases can be mitigated by controlling blood glucose levels, some patients continue to face the ocular repercussions of the disease for years despite their efforts. The growing population of diabetics has also prompted a growing need for new pathways to address diabetic eye disease treatments, especially in patients who do not respond well to the current standard of care. This article focuses on 2 new agents from Oxurion — THR-687 and THR-149 — that aim to establish a new avenue of treatment for patients with DME.

BACKGROUND

Diabetic macular edema is characterized by leakage of fluid in the macula due to abnormal angiogenesis and blood vessel damage from uncontrolled blood sugar, resulting in central vision loss in the retina.² Roughly 20% of patients currently suffering from both types of diabetes are estimated to also have DME.³ The current standard-of-care treatments focus on a key protein upregulated during angiogenesis, vascular endothelial growth factor (VEGF). VEGF is a vascular permeability factor that signals for the growth of new blood vessels and is present in mammals as 4 types (VEGF-A, B, C, and D), which interact in an isoform-selective fashion with 3 transmembrane receptor tyrosine kinase receptors, VEGFR-1, VEGFR-2, and VEGFR-3.

The 3 anti-VEGF treatments used to treat DME today are the off-label bevacizumab (Avastin; Genentech), and the 2 FDA-approved drugs, ranibizumab (Lucentis; Genentech) and aflibercept (Eylea; Regeneron). Bevacizumab and ranibizumab bind to VEGF-A, whereas aflibercept binds to VEGF-A and VEGF-B, as well as placental growth factor. These agents function well for patients with DME and vastly improve their outcome potential, but the benefits come at the cost of a high treatment burden due to frequent clinic visits and injections. In addition, up to 40% of patients with DME do not adequately respond to anti-VEGF treatment in terms of best-corrected visual acuity (BCVA) improvements and/or central subfield thickness (CST) reductions on optical coherence tomography.^4,5 As a result, researchers have identified new pathways and agents to broaden the treatment options and improve BCVA and CST outcomes in patients with DME.

THR-687

Integrins are heterodimeric transmembrane receptors that mediate cell-to-cell or cell-to-extracellular communication, with cell-to-extracellular communication present in the retinal matrix. Integrins are factors in many ocular diseases, including corneal neovascularization, glaucoma, age-related macular degeneration (AMD), and DME.⁶ There are 4 classes of integrin receptors, including the functional arginine-glycine-aspartic acid (RGD) class identified to function in angiogenesis permeability, inflammation, and fibrosis. Because of these factors, the RGD class has been revealed as a potential target for retinal diseases.⁷

THR-687 is a potent, small-molecule pan-RGD integrin receptor antagonist that inhibits integrins both upstream and downstream of VEGF, resulting in the potential for broader efficacy for both diabetic retinopathies and neovascular AMD (Figure 1).^8,9 Preclinical studies show inhibition of vascular leakage after intravitreal injections in a monkey with choroidal neovascularization, along with decreases in vascular leakage in a diabetic mouse model.⁹ In a phase 1 open-label, dose-escalation study, THR-687 was tested at 3 dose levels (0.4 mg, 1.0 mg, and 2.5 mg) in a total of 12 subjects with a previous response to either anti-VEGFs or corticosteroids for DME. The primary outcome evaluated safety by recording the incidence of any dose-limiting toxicities (DLT) up to day 14 following a single intravitreal injection. Secondary outcomes evaluated adverse events (AE) throughout the 3-month duration of the study.

No DLTs were observed, but 1 treatment-related AE was seen at each dose level. Mean BCVA gains for all treated patients were rapid and peaked at 1 month postinjection at +9.2 letters, with an average gain at 3 months of +8.3 letters. The 2.5 mg high-dose group had the most letters gained, +11 letters at day 14 and +12.5 letters at 3 months with a decrease in CST of -106 mm on Day 14, with -36.5 mm at month 3. All dose levels of THR-687 were safe and well tolerated and had a rapid onset of action in measurable clinical assessments, with the high dose displaying the strongest impact on BCVA improvements and CST reductions.

THR-149

The plasma kallikrein-kinin system (plasma KKS) is activated during vascular injury and functions by mediating factors in innate inflammation, blood flow, and coagulation.¹⁰ Human and animal vitreous samples indicate the plasma KKS in diabetic retinopathy as plasma KKS components, such as plasma kallikrein (pKal), coagulation factor XII, and a high-molecular-weight kininogen are increased in the samples. Diabetic rodents have also shown upregulated retinal bradykinin B1 receptor (B1R1) levels, while both B1R and B2R are known to be expressed in human retinas. The plasma KKS present in the eye leads to increased retinal vascular permeability, vasodilation, and thickening, all of which promote the plasma KKS as a target for treating DME. In addition, in diabetic animal models, PK inhibitors and B1R antagonists decreased retinal vascular hyperpermeability and inflammation, supporting the potential for this emerging pathway in treating DME.

THR-149 is a potent reversible peptide inhibitor of plasma kallikrein (pKal) that functions by inhibiting the release of bradykinin in the plasma and vitreous (Figure 2).^11-17 The molecule is a VEGF-independent target, a new prospect for treatment in anti-VEGF nonresponding patients. In the phase 1 open-label dose-escalation study, 12 patients previously treated with anti-VEGF and/or corticosteroid agents received a single intravitreal injection of 3 dose levels of THR-149 (0.005 mg, 0.022 mg, and 0.13 mg). The primary outcomes evaluated safety and DLTs up to day 14, with secondary outcomes evaluating AEs throughout the study. No DLTs were experienced by any patients. Three nonocular, non-treatment-related serious AEs and 1 treatment-related ocular AE were also experienced. All ocular AEs were attributed to the injection procedure, underlying disease progression, or concomitant diseases. Patients experienced a rapid onset of BCVA gains, with a mean gain of +6.4 letters at month 3 for all treated subjects. The mean CST changes were minimal, as the initial reaction showed a small decrease followed by a minimal but not clinically significant increase to the end of the study. All dose levels of THR-149 were safe and well tolerated.¹¹

CONCLUSION

Both RGD-integrins and the plasma KKS play a role in DME pathogenesis, potentially revealing factors in patients not responding to the current standard-of-care anti-VEGF agents. With new agents that can inhibit these pathways, physicians will have a broader spectrum of treatment options for patients with DME. Both THR-687 and THR-149 are currently preparing to enter phase 2 trials in patients with DME. These trials will evaluate the efficacy and safety of these novel agents in improving outcomes for patients with DME. RP

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