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Drugs offer activation combination of Tie2 pathway in DR, DME


May provide better anatomic improvement, decreased DR severity scores

Tie2 activators combined with anti-vascular endothelial growth factor therapy translate to improved anatomic function and decreased diabetic retinopathy severity scores.

Reviewed by Peter K. Kaiser, MD

Tie2, a tyrosine kinase receptor, has become an important focus of research, and when combined with vascular endothelial growth factor (VEGF) therapy the two may provide better outcomes for patients with diabetic retinopathy (DR) and diabetic macular edema (DME) than with VEGF drugs alone.

How it works

During gestation, the Tie pathway is key to the development of the ocular and vascular structures and its absence is lethal to normal development, according to Peter K. Kaiser, MD. Dr. Kaiser is the Chaney Family Endowed Chair in Ophthalmology Research, and professor of ophthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland.

In adults, the Tie pathway is the “gatekeeper” of vascular quiescence, he noted. It regulates blood and vascular homeostasis, inflammation, and pathologic angiogenesis and has a key role in cancer and diabetes. When things are working normally, the key Tie2 ligand, angiopoietin 1 (Ang1), binds and activates Tie2, which promotes the integrity of blood vessels.

Dr. Kaiser said this is done by forming into high order oligomers that produces clustering of the Tie2 receptor required for activation. In contrast to Ang1, Ang2 is a weak agonist that is released in the presence of hypoxia, inflammation, and VEGF.

Ang2 is mainly found in dimer form and does not cause Tie2 receptor clustering and thus no receptor activation. This leads to vascular leakage, inflammation, and vascular instability. The Tie receptors are found largely on endothelial cells that provide the microenvironment in which activation can occur.

“The Tie1 receptor is an orphan receptor that regulates Tie2 receptor trafficking and is necessary for full Tie2 activation,” Dr. Kaiser said.

RELATED: Anti-VEGF expansion treats all DR stagesActivation (phosphorylation) of Tie2 is instrumental in a number of essential functions, including enhanced endothelial cell survival, decreased leakage, and anti-inflammatory effects. On the flip side of the coin, deactivation (dephosphorylation) of Tie2, results from the activity of Ang2 that prevents clustering of the Tie2 receptors, causes pericyte detachment from vessels, increased vascular leakage, and inflammation.

Another player in this cascade is vascular endothelial-protein tyrosine phosphatase (VE-PTP), rheostat that modulates the effect of Ang2 on Tie2, Dr. Kaiser explained. VE-PTP dephosphorylates the Tie2 receptor and mediates cross-talk with the VEGF receptor 2, which shows how the tyrosine kinase pathways are interrelated. It works independent of Ang1 and Ang2.

Effects of ang and tie in retinal disease

Ang1 is protective against vascular dysfunction in diabetes, but this effect is counteracted by the presence of dyslipidemia and hyperglycemia. Hyperglycemia also elevates the levels of Ang2, which is associated with the increased severity of DR. In the vitreous, Ang2 levels are elevated in patients with proliferative DR and Ang1 levels decrease. As a result, activating Tie2 in patients with diabetes is a goal.

Pharmaceutical intervention

The first drug tried to achieve this goal was nesvacumab (REGN910, Regeneron Pharmaceuticals/Bayer), an experimental antibody to Ang2 that leads to activation of Tie2. The phase II RUBY clinical study showed that the Ang 2 antibody combined with intravitreal injection of aflibercept (Eylea, Regeneron Pharmaceuticals) resulted in an increase in fluid resolution when compared with aflibercept alone (90.4% versus 74.0%, p=0044) in patients with DME. This outcome was also true for the combination therapy in patients with DR.

“The combination of Ang2 inhibitor and aflibercept led to decreased severity of DR, and the reduction was greater in association with higher Ang2 levels in patients with severe and proliferative disease,” Dr. Kaiser said.

A second drug, faricimab (Genentech Inc./Roche), was found in the phase 2 Boulevard Study to activate Tie2 and block VEGF in DME. Again, combining Ang2 inhibition and anti-VEGF therapy resulted in better fluid control and better visual outcomes than ranibizumab alone. It is particularly true in patients who had received previous anti-VEGF treatment.

The study also showed improved DR severity scores compared with anti-VEGF therapy alone, Dr. Kaiser emphasized. A third drug, AKB-9778 (Aerpio Pharmaceuticals), is a small-molecule inhibitor of VE-PTP. This formulation activates Tie2 regardless of the levels of Ang1 or Ang2, Dr. Kaiser explained. This activity is in contrast to the activity of nesvacumab that, when administered alone, did not significantly activate Tie2 in human endothelial cells.

The TIME2 phase IIa study of AKB-9778 also showed that the combination of the Tie2 activator and ranibizumab (Lucentis, Genentech Inc.) showed significant (p=.008) decreases in the central retinal thickness and the diabetic retinopathy severity compared with either of the drugs alone.

Interestingly, AKB-9778 is administered by subcutaneous injection. The results of elevated Ang2 levels are substantial: improved proteinuria, peripheral neuropathy, erectile dysfunction, myocardial function, and wound healing.


“Diabetic studies with three different Tie2 activators reported significantly improved anatomic measures and diabetic retinopathy severity scores compared with anti-VEGF alone,” Dr. Kaiser concluded.

“As a result of the unique mode of action and interplay between VEGF and Tie2 pathways, combining these modalities may achieve even better treatment outcomes in our diabetic patients.”

RELATED: Laser treatment for DME: Still a place at the table


Peter K. Kaiser, MD
E: pkkaiser@aol.com
Dr. Kaiser is a consultant to Aerpio Pharmaceuticals, Allegro Ophthalmics, Bayer, Regeneron, and SciFluor.

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