Study zeroes in on the sustained mechanism of action of the therapeutic.
Reviewed by Douglas J. Rhee, MD
Bimatoprost SR (Lumigan; Allergan) lives up to its name. It provides a lengthy sustained IOP reduction well past the point of implant degradation, as the results of the APOLLO study indicated.1
Douglas Rhee, MD, professor and chairman of the Department of Ophthalmology and Visual Sciences at the University Hospital Eye Institute at Case Western Reserve University School of Medicine in Cleveland, Ohio, hypothesized about the reason(s) for this extended mechanism of action.
This tiny commercially available implant that is injected into the anterior chamber of the eye is associated with the finding that 28% to 40% of patients have sustained lowering of the IOP 1 to 2 years after degradation. This finding was unexpected because the implant is designed to last 3 to 4 months. This type of response has been documented previously, but its mechanism is not understood, Rhee commented, pointing out that a prolonged IOP reduction from topical prostaglandin analogues (PGA) manifested as failure of the drugs to wash out of potential candidates for investigational trials. After medications were stopped, the IOPs did not return up as high as the baseline levels before treatment in some patients.2
The known mechanism of PGAs instilled in the acute phase enhances the uveoscleral outflow but also that of the trabecular meshwork (TM).
“The medications induce a change in the matrix metalloproteinase (MMP) enzymes that break down the extracellular matrix and enhance aqueous outflow,” Rhee said.
This activity results in a shift in the activity of the MMPs and tissue inhibitors of the MMPs (TIMPs) that results in more aqueous outflow if more enzymes are present rather than more TIMPs. When this happens, more outflow occurs through the uveoscleral pathway. Rhee and his colleagues reported evidence of how the PGAs work in a previous study.3
What is known is that the drug achieves high-target tissue concentrations with doses that are continuous and not pulsatile and that PGAs have a dose-dependent effect on MMPs and TIMPs in the ciliary body smooth muscle, TM endothelial, and scleral fibroblast cells. However, Rhee said he believes other effects also are at work.
In a molecular genetic study4 in which investigators from Case Western Reserve University and Duke University collaborated, the results showed that the effect on MMP1 increased and was highly variable, possibly explaining the sustained effect in some but not all patients. However, another mechanism is possible. A histologic study5 reported that, in monkeys treated for over 1 year, large empty spaces were visible that were incompletely covered by endothelial-like cells. This lining may have allowed the spaces to persist.
“We believe bimatoprost, free acid induces lymphangiogenesis in the human ciliary body, creating the endothelial-lined passages observed in the study of Lütjen-Drecoll and colleagues. The endothelial-lined passages are likely why these pathways might persist, thus explaining the extended IOP lowering,” Rhee explained.
Rhee and his colleagues believe PGAs induce new lymphatic vessel formation and don’t just increase outflow through preexisting lymphatics. The investigators are currently testing different concentrations of bimatoprost, free acid and analyzing lymphangiogenic proteins that indicate that new lymphatic vessels are growing.
“The preliminary results validate earlier work that lymphatics are present in the ciliary body, and for some of the lymphangiogenic factors, there appears to be a dose-related response, meaning our hypothesis may be correct,” he said, adding that a prolonged IOP reduction even after washout of topical medications has been seen.
“PGAs will induce a dose-dependent change in both the TM, ciliary body, and scleral fibroblasts, which are the target tissues for aqueous drainage, and there is a dose-dependent effect on these enzymes,” he said. “MMP1 might be involved, but we believe the sustained effect might result from lymphangiogenesis, which is not yet proven. There is an unmet need to identify patients who will have this sustained response.”