Drugs, Devices and Target Pathway Research

Drugs, Devices and Target Pathway Research

Diabetes-related retinopathy

Current treatment options for diabetes-related retinopathy include: intravitreal injections of pharmacological agents, usually corticosteroids (main effect is to suppress inflammation) or anti-VEGF agents (VEGF=Vascular Endothelial Growth Factor, anti-VEGF agents inhibit the growth of new blood vessels), which may be either used alone or in combination with laser treatment to treat progressive diabetes-related retinopathy and diabetes-related macular edema. 

Although the current therapies are effective at preventing vision loss and frequently result in visual gain for patients with both Proliferative diabetes-related retinopathy and diabetes-related macular edema, unmet treatment needs still exist. 

A significant proportion (40%–50%) of eyes with diabetes-related macular edema do not respond fully to anti-VEGF treatment or become refractory to it, indicating that molecular mechanisms responsible retinal vascular abnormalities can vary between individual eyes. 

There is an urgent need for new treatment options for patients with Proliferative diabetes-related retinopathy and diabetes-related macular edema. Details of some of the new drug targets and drugs currently being evaluated in clinical trials are provided below: 

New research directions in Diabetes-related Retinopathy 

Diabetes-related retinopathy is a very complex disease and many different cellular and molecular mechanisms and pathways contribute to its progression (Figure 1). Many of the existing drugs for diabetes-related retinopathy target these pathways to halt or slow the progression of the disease. For example, inhibition of VEGF pathway activity with VEGF inhibitor prevents the process of angiogenesis (formation of new blood vessels) and their leakage into the retina, while corticosteroids display anti-inflammatory and anti-angiogenic effects. Several newer drugs being investigated work by targeting other pathways associated with the diseases, summarised below:

Neuroprotective agents

One area of current research is the evaluation of so-called ‘neuroprotective’ agents – studies have shown the damage and loss of retinal nerve cells (neurodegeneration) is one of the first stages in the development of diabetes-related retinopathy . A recent clinical study investigated whether treatment with eye drops of two neuroprotective agents (somatostatin and brimonidine) for 2 years could slow or stop the progression of diabetes-related retinopathy in  patients with early stages of the disease. [7, 8] The study results showed that although these agents did not prevent or stop neurodegeneration in the overall patient population, there was evidence that they were effective in stopping progression in the subgroup of patients who had pre-existing neurodegeneration. The authors concluded screening for the signs of neuron degeneration among people with type 2 diabetes is likely to help identify the subgroup of individuals that neuroprotective treatments may benefit. 

Angiopoietin inhibitors 

Angiopoietins are a family of growth factor molecules that play an important role in angiogenesis (development of new blood vessels), working together with VEGF.[9] Two types of angiopoietins, angiopoetin-1 and angiopoetin-2 (Ang-1 and Ang-2) play a major part in the angiogenesis of the retina in diabetes-related retinopathy , through their differing interactions with a receptor molecules known as Tie2, which is mainly found on endothelial cells which line the inside of blood vessels. The binding of angiopoetin-1 to Tie2 maintains blood vessel stability, whereas binding of Ang2 to Tie2 results in blood vessel instability, leading to angiogenesis, vascular permeability (leaky blood vessels), and inflammation. Angiopoetin-2 is found in very large amounts in eyes with retinal diseases such as diabetes-related retinopathy[9], where it is thought to overcome the stabilising effects of Ang1. 

Several drugs that specifically target the angiopoietin-Tie2 pathway, with the aim of restoring its normal function, are being evaluated for the treatment of diabetes-related retinopathy/diabetes-related macular edema. in clinical trials. These include angiopoetin-2 inhibitor drugs, including faricimab , a so-called bispecific antibody that blocks the actions of both angiopoetin-2 and VEGF. Results from a Phase 2 clinical trial (BOULEVARD) conducted in patients with diabetes-related macular edema demonstrated promising efficacy with faricimab, and larger Phase 3 clinical trials to evaluate its efficacy and safety are currently underway (NCT03622593 and NCT03622580).

A novel investigational Tie2 receptor activator, AKB-9778 , has also been shown to provide benefit for the reduction of  diabetes-related macular edema when used in combination with anti-VEGF therapy (ranibizumab) in a Phase 2 clinical trial, [10] and is also currently being evaluated as single treatment in a Phase 2 clinical trial of patients with non-proliferative diabetes-related retinopathy  (NCT02050828).

Plasma kallikrein inhibitors

The plasma kallikrein-kinin system (KKS) is another complex molecular pathway that has been implicated in the development of proliferative diabetes-related retinopathy and diabetes-related macular edema through increasing vascular permeability, edema and  inflammation.[11] 

Several agents that specifically target molecules involved in the KKS pathway are under evaluation in early stage clinical studies, including a Plasma Kallikrein Inhibitor, KVD001 ,  which is currently being evaluated in a sham-controlled Phase 2 clinical trial in people with center-involving  diabetes-related macular edema,  who have already received prior anti-VEGF treatment (NCT03466099).

Integrin peptide therapy

ALG-1001  is a novel integrin peptide therapy that target specific integrin receptors, which are involved in the development of new blood vessels in diabetes-related retinopathy. A 12-week Phase 2 clinical trial demonstrated that ALG-1001 was non-inferior to monthly treatment with an anti-VEGF therapy (bevacizumab) for the treatment of diabetes-related macular edema. In this study, ALG-1001 was administered after, or in combination with bevacizumab in 80 patients with  diabetes-related macular edema.[12] 

Figure 1 Schematic of key cellular and molecular events in the progression of diabetes-related retinopathy.[13] 

Diabetic retinopathy

Current treatment options for diabetic retinopathy include: intravitreal injections of pharmacological agents, usually corticosteroids (main effect is to suppress inflammation) or anti-VEGF agents (VEGF=Vascular Endothelial Growth Factor, anti-VEGF agents inhibit the growth of new blood vessels), which may be either used alone or in combination with laser treatment to treat progressive DR and DME. 

Although the current therapies are effective at preventing vision loss and frequently result in visual gain for patients with both Proliferative DR and DME, unmet treatment needs still exist. 

A significant proportion (40%–50%) of eyes with DME do not respond fully to anti-VEGF treatment or become refractory to it, indicating that molecular mechanisms responsible retinal vascular abnormalities can vary between individual eyes. 

There is an urgent need for new treatment options for patients with Proliferative DR and DME. Details of some of the new drug targets and drugs currently being evaluated in clinical trials are provided below: 

New research directions in DR

Diabetic retinopathy is a very complex disease and many different cellular and molecular mechanisms and pathways contribute to its progression (Figure 1). Many of the existing drugs for DR target these pathways to halt or slow the progression of the disease. For example, inhibition of VEGF pathway activity with VEGF inhibitor prevents the process of angiogenesis (formation of new blood vessels) and their leakage into the retina, while corticosteroids display anti-inflammatory and anti-angiogenic effects. Several newer drugs being investigated work by targeting other pathways associated with the diseases, summarised below:

Neuroprotective agents

One area of current research is the evaluation of so-called ‘neuroprotective’ agents – studies have shown the damage and loss of retinal nerve cells (neurodegeneration) is one of the first stages in the development of DR. A recent clinical study investigated whether treatment with eye drops of two neuroprotective agents (somatostatin and brimonidine) for 2 years could slow or stop the progression of DR in diabetic patients with early stages of the disease. [7, 8] The study results showed that although these agents did not prevent or stop neurodegeneration in the overall patient population, there was evidence that they were effective in stopping progression in the subgroup of patients who had pre-existing neurodegeneration. The authors concluded screening for the signs of neuron degeneration among people with type 2 diabetes is likely to help identify the subgroup of individuals that neuroprotective treatments may benefit. 

Angiopoietin inhibitors 

Angiopoietins are a family of growth factor molecules that play an important role in angiogenesis (development of new blood vessels), working together with VEGF.[9] Two types of angiopoietins, angiopoetin-1 and angiopoetin-2 (Ang-1 and Ang-2) play a major part in the angiogenesis of the retina in DR, through their differing interactions with a receptor molecules known as Tie2, which is mainly found on endothelial cells which line the inside of blood vessels. The binding of angiopoetin-1 to Tie2 maintains blood vessel stability, whereas binding of Ang2 to Tie2 results in blood vessel instability, leading to angiogenesis, vascular permeability (leaky blood vessels), and inflammation. Angiopoetin-2 is found in very large amounts in eyes with retinal diseases such as DR[9], where it is thought to overcome the stabilising effects of Ang1. 

Several drugs that specifically target the angiopoietin-Tie2 pathway, with the aim of restoring its normal function, are being evaluated for the treatment of DR/DME in clinical trials. These include angiopoetin-2 inhibitor drugs, including faricimab , a so-called bispecific antibody that blocks the actions of both angiopoetin-2 and VEGF. Results from a Phase 2 clinical trial (BOULEVARD) conducted in patients with DME demonstrated promising efficacy with faricimab, and larger Phase 3 clinical trials to evaluate its efficacy and safety are currently underway (NCT03622593 and NCT03622580).

A novel investigational Tie2 receptor activator, AKB-9778 , has also been shown to provide benefit for the reduction of DME when used in combination with anti-VEGF therapy (ranibizumab) in a Phase 2 clinical trial, [10] and is also currently being evaluated as single treatment in a Phase 2 clinical trial of patients with non-proliferative DR (NCT02050828).

Plasma kallikrein inhibitors

The plasma kallikrein-kinin system (KKS) is another complex molecular pathway that has been implicated in the development of proliferative DR and DME through increasing vascular permeability, edema and  inflammation.[11] 

Several agents that specifically target molecules involved in the KKS pathway are under evaluation in early stage clinical studies, including a Plasma Kallikrein Inhibitor, KVD001 ,  which is currently being evaluated in a sham-controlled Phase 2 clinical trial in people with center-involving DME,  who have already received prior anti-VEGF treatment (NCT03466099).

Integrin peptide therapy

ALG-1001  is a novel integrin peptide therapy that target specific integrin receptors, which are involved in the development of new blood vessels in DR. A 12-week Phase 2 clinical trial demonstrated that ALG-1001 was non-inferior to monthly treatment with an anti-VEGF therapy (bevacizumab) for the treatment of DME. In this study, ALG-1001 was administered after, or in combination with bevacizumab in 80 patients with DME.[12] 

Figure 1 Schematic of key cellular and molecular events in the progression of diabetic retinopathy.[13]