What’s next in the neovascular AMD pipeline?

New York-The therapeutic pipeline for neovascular age-related macular degeneration (AMD) contains a host of promising investigational agents. Only time will tell how any one will shape the future of AMD management.

Vascular endothelial growth factor (VEGF) continues to be a major target for the investigational agents, although there are compounds that act against VEGF and/or other factors involved in the complex cascade of events leading to angiogenesis. Recently, Jason Slakter, MD, highlighted several of the compounds.

“These particular agents are notable in terms of the number of inquiries I am receiving about them from scientists and clinicians, but it may turn out that others in the pipeline are equally or more important,” said Dr. Slakter, a macular disease specialist in private practice, New York.

• MP0112 is a VEGF antagonist belonging to a novel class of molecules known as DARPins that were specifically designed to provide enhanced receptor affinity and durability. Results of pharmacokinetics studies support an intravitreal dosing regimen of once every 4 months for MP0112, and findings from a rabbit model demonstrated that it had more persistent activity than ranibizumab. The compound is in clinical trials.
• The VEGF receptor Flt-1 along with placental growth factor (PlGF) are targets for adeno-associated virus serotype 2 (AAV2)-mediated intravitreal gene delivery of sFLT01 (Genzyme). Results from preclinical studies provide proof of principle that this gene therapy approach successfully establishes “an intraocular factory” for production of the therapeutic agent and showed efficacy for suppressing laser-induced CNV when administered 1 year prior to the laser challenge. Early clinical trials are evaluating the safety and biological activity of this agent.
• Squalamine is a small-molecule aminosterol that inhibits VEGF, platelet derived growth factor, and basic fibroblast growth factor signaling through chaperoning of the modulatory protein calmodulin. It was initially developed for administration by IV infusion and reached phase III clinical development, but that research was abandoned as intravitreal antiVEGF agents became available. Based on evidence of potent anti-exudative activity, squalamine was reformulated into a topical preparation (OHR Pharmaceutical) that was shown to achieve significant levels in posterior pole tissues in preclinical animal studies. It is now under investigation as a noninvasive approach to treatment of exudative AMD in a phase II study.
• Sonepcizumab (Lpath) is a monoclonal antibody targeting sphingosine 1-phosphate (S1P), a bioactive lipid that promotes angiogenesis, vascular permeability, inflammation, and fibrosis. Results from a phase I study in patients with very advanced AMD revealed no safety concerns and showed evidence that sonepcizumab had biological activity. An analysis in patients with primarily occult neovascular disease showed the treatment was associated with a marked reduction in active lesion area, and a phase II study is comparing sonepcizumab as monotherapy or combined with ranibizumab (Lucentis, Genentech) or bevacizumab (Avastin, Genentech) versus anti-VEGF treatment alone.

Dr. Slakter receives grant research support from Allergan, Genentech, Genzyme, Lpath, OHR, and Regeneron, and is a consultant to Lpath, OHR, and Regeneron.

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