Investigational wet AMD therapies aim for innovative targets

Reviewed by Peter K. Kaiser, MD

Many investigational drugs under development for the treatment of neovascular age-related macular degeneration (nvAMD) have advanced into the clinical trial stage, including several that are being evaluated in pivotal trials, said Peter K. Kaiser, MD.

Discussing the pharmaceutical pipeline, Dr. Kaiser provided a broad overview based on mechanism of action.

Highlighting agents that target vascular endothelial growth factor (VEGF) in the extracellular space, he said there are modalities that block VEGF-A. This group includes abicipar pegol (Allergan), a pegylated-designated Ankyrin repeat protein (DARPin); and brolucizumab (Alcon Laboratories), a single-chain, antibody fragment inhibitor of VEGF-A.

Both abicipar pegol and brolucizumab are in phase III study. In addition, OPT-302 (Ophthea), a trap molecule that blocks VEGF-C and VEGF-D, is being study in a phase I trial.

“OPT-302 is being investigated in combination with a VEGF-A blocker with the hope of achieving better blockade of the extracellular VEGF levels,” explained Dr. Kaiser, professor of ophthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, OH.

He also noted that the patents for ranibizumab and bevacizumab (Avastin, Genentech), which also block VEGF-A, expire in the United States in 2019, and three companies are developing a ranibizumab biosimilar agent.

Novel targets

Other drugs in clinical development for nvAMD block platelet-derived growth factor (PDGF), with the aim of blocking pericyte recruitment to neovascular vessels. Investigational agents acting on PDGF include E10030 (Fovista, Ophthotech), MP0260/AGN-150998 (Allergan), and OHR-102 (squalamine, Ohr Pharmaceuticals).

E10030 blocks PDGF-BB. It failed in a phase III study in combination with bevacizumab or aflibercept (Eylea, Regeneron Pharmaceuticals). MP0260/AGN-150998 is a bispecific DARPin that blocks both PDGF-BB and VEGF.

OHR-102 is being developed as a topical drop. It is a calmodulin inhibitor that prevents growth factor receptor activation and interferes with the activity of PDGF, as well as VEGF and basic fibroblast growth factor. It is also being investigated in a phase III trial.

Drugs in development for nvAMD also include several that act as tyrosine kinase inhibitors-DE-120 (Santen), PAN-90806 (Panoptica), and OTX-IVT (Ocular Therapeutix). Results reported in October, 2016, from a phase I/II trial with topical PAN-90806 showed promising biological efficacy. The other agents are in phase II trials.

Angiopoietin-2

Angiopoietin-2

The angiopoietin pathway is another target of investigational treatments for nvAMD. Dr. Kaiser explained that angiopoietin-2 promotes vascular leakage through Tie-2 inhibition. Tie-2–which is expressed on endothelial cells–activation limits vascular permeability, blocks neovascularization, and is inhibited by VE-PTP.

Agents in this group include two drugs that block angiopoietin-2-RG7716 (Genentech) and nesvacumab (Regeneron Pharmaceuticals)-and another that activates the Tie-2 transmembrane receptor tyrosine kinase by inhibiting VE-PTP-AKB-9778 (Aerpio Therapeutics).

“Tie-2 activation is the target in treating nvAMD because it leads to vascular stability,” Dr. Kaiser said. “An interesting feature of the Aerpio agent is that they should work to reactivate the Tie-2 receptor even in the presence of angiopoietin-2.”

Two other investigational drugs for treatment of nvAMD act as integrin inhibitors. They are volociximab (Ophthotech), an alpha5beta1 integrin inhibitor that was shown to be safe in a phase I trial, and Luminate (Allegro Ophthalmics), a pan-integrin blocker demonstrating favorable safety in a phase I/II trial.

Integrin inhibition is of interest considering the importance of integrins in regulating cellular adhesion, kinase signaling pathways, endothelial cell migration and apoptosis, VEGF receptor-2 activation, and sprouting and network formation during vascular development.

Finally, DE-122 (Santen), a transforming growth factor-beta inhibitor, will be entering into clinical development for use in combination with an anti-VEGF agent.

“It is known that TGF-beta helps to mediate escape from VEGF inhibition in endothelial cells, especially in a hypoxic environment, and so the rationale for combining DE-122 with an anti-VEGF agent is to prevent this escape,” Dr. Kaiser said.

Peter K. Kaiser, MD

E: kaiserp@ccf.org

This article is based on a presentation given by Dr. Kaiser at the Retina Subspecialty Day, held before the 2016 American Academy of Ophthalmology meeting.  Dr. Kaiser consults and lectures for a number of companies that market or are developing treatments for nvAMD. He has equity ownership in Ohr Pharmaceutical and Ophthotech Corp.