Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration

Abstract

There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled doseranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/ sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline. apoptosis | retina | photoreceptor degeneration

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

“…Furthermore, CNTF may affect the physiology and survival of RPE cells (9,10), which are critical in normal vision and retinal degenerative diseases. Based on its significant and broad neuroprotective effects in damaged retinas, a secreted form of human CNTF delivered from an encapsulated cell device has been tested in clinical trials and approved by the Food and Drug Administration (FDA) to treat retinitis pigmentosa (RP) and geographic atrophy (GA), a subset of age-related macular degeneration (AMD) (11)(12)(13)(14). However, despite its clinical significance, the mechanisms of CNTF-elicited neuroprotection in diverse retinal pathological conditions remain unclear.…”

Clinical Characteristics and Current Treatment of Age-Related Macular Degeneration

“…Research in neuroprotection aims to identify agents that will interfere with cell death pathways and inhibit the loss of neural retina that is the ultimate cause of vision loss in AMD as well as many other disorders. (Trichonas et al 2010;Wong et al 2010;Zhang et al 2011a;Miller 2013;Tsai 2013). Subretinal transplantation of stem cells is also being investigated as a means of regenerating RPE cells and eventually, perhaps photoreceptors as well (Schwartz et al 2012).…”

New approaches and potential treatments for dry age-related macular degeneration

“…ECT implants are distinct from other drug delivery implants in that they do not primarily store drug but rather produce the therapeutic drug to be delivered in situ. The implant is 6 mm long with 1 mm diameter, is inserted into the vitreous and releases CNTF in two different output rates for a year or longer: 5 and 20 ng/day (26,28,29) . NT-501 was evaluated in a phase 2 clinical trial that enrolled 51 patients with GA secondary to AMD (29) .…”

“…The implant is 6 mm long with 1 mm diameter, is inserted into the vitreous and releases CNTF in two different output rates for a year or longer: 5 and 20 ng/day (26,28,29) . NT-501 was evaluated in a phase 2 clinical trial that enrolled 51 patients with GA secondary to AMD (29) . Patients were randomized to 3 groups (low and high dose of CNTF, or sham injection) and were followed up for 1 year.…”