The frontline treatments for diabetic macular edema (DME) in the United States include intravitreal injections of anti-VEGF agents (ranibizumab, aflibercept, and bevacizumab) and, to a lesser extent, corticosteroids. Over a 2-year period, more than 1 out of 3 patients are expected to experience a gain in best-corrected visual acuity (VA) of >15 letters on anti-VEGFs.¹ Despite such advances in treatment, the Protocol T extension study showed that visual gains at 2 years are not fully maintained at 5 years. More than 1 out of 4 patients continue to experience visual acuity of 20/50 or worse.² Thus, while progress in the treatment of DME over the past decade has been remarkable, there remains a need for novel therapeutic approaches. The plasma kallikrein–kinin system (KKS) has been identified as a novel molecular mechanism of retinal dysfunction and edema that may contribute to the development of DME independently of VEGF. The research has recently proceeded from bench to bedside with clinical trials of plasma kallikrein inhibitors showing encouraging results.

PLASMA KALLIKREIN IN DIABETIC EYE DISEASE

Elevated levels of plasma kallikrein in the vitreous from patients with diabetic retinopathy and its role in retinal edema were first reported in 2007.³ Further studies from vitreous samples of Japanese patients with DME confirmed these findings and revealed that plasma kallikrein is elevated in all samples, whereas VEGF concentrations differ markedly (Figure 1).⁴ These observations identified a subgroup of DME eyes where little or no increase in VEGF was observed, a subgroup that may be less responsive to anti-VEGF therapies. The role of plasma kallikrein was evaluated in multiple studies in animals using both plasma prekallikrein knockout mice and selective plasma kallikrein inhibitors. These studies have demonstrated that plasma kallikrein is a significant contributor to retinal dysfunction and edema caused by hyperglycemia, hypertension, hemorrhage, inflammation, and VEGF.⁵

THE PLASMA KALLIKREIN–KININ SYSTEM AND EDEMA

The KKS has been studied for more than 60 years, and its effects on vascular permeability and inflammation are well described. Plasma kallikrein is the protease responsible for the generation of bradykinin, a potent peptide hormone with effects on vascular, neuronal, and inflammatory cells.⁶ This system is activated by multiple factors, including tissue damage, which is a chronic condition in diabetic retinopathy (Figure 2).⁷ Plasma kallikrein is a clinically significant mediator of vasogenic edema in the rare genetic disease hereditary angioedema (HAE). This genetic disease is caused by a genetic deficiency in the primary physiological inhibitor of plasma kallikrein, namely C1 inhibitor, and it is characterized by intermittent episodes of edema, which can be severe and life threatening.

The vitreous fluid contains low concentrations of C1 inhibitor. Intravitreal injection of C1 inhibitor in diabetic rats has been shown to reduce retinal vascular leakage.⁸ Intriguing new data suggest that plasma kallikrein and bradykinin can also disrupt neuroretinal function measured by electroretinography,⁹ findings that are consistent with the previously described effects of the KKS on neuronal cells.

INITIAL THERAPEUTIC RESULTS

The first study of a plasma kallikrein inhibitor in patients with DME and suboptimal response to anti-VEGF showed that plasma kallikrein inhibition in the vitreous is generally safe and well tolerated.¹⁰ The study was an open-label phase 1b study of the intravitreally administered plasma kallikrein inhibitor KVD001 (Kalvista Pharmaceuticals) in 14 patients with center-involved DME. Although not designed as an efficacy study, a trend in improved VA could be observed for patients receiving KVD001. A larger, sham-controlled, phase 2 study of 4 monthly injections of KVD001 in 123 patients did not meet its primary endpoint but confirmed the trend for VA benefit in subgroups of patients receiving KVD001.¹¹

Inhibition of the plasma KKS is emerging as a promising new avenue for the treatment of DME.¹² These first trials of plasma kallikrein inhibitors have provided information that will help guide future trials with both intravitreally and systemically administered plasma kallikrein inhibitors. The latter approach will benefit from the clinical information obtained in the development of plasma kallikrein inhibitors for HAE. Systemically administered plasma kallikrein inhibitors are approved for the prevention and treatment of attacks of edema in HAE.¹³ Orally administered plasma kallikrein inhibitors are efficacious in reducing retinal edema and preserving retinal function in preclinical models.¹⁴ Oral plasma kallikrein inhibitors are currently being evaluated for HAE and may provide an exciting new therapeutic opportunity to treat DME and prevent its development.

CONCLUSION

Plasma kallikrein inhibition emerges as a new therapeutic concept for the treatment of DME. It is a new pathway, independent of VEGF. It may be targeted orally and enhance the therapeutic options for retinal physicians. Additional efficacy studies are needed to evaluate the potential for plasma kallikrein inhibitors to help more patients with DME preserve and recover their vision. RP

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