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Karl G Csaky, Dean Bok, Roxana A. Radu, Srinivas R. Sadda; Complement C5 Inhibition as a Potential Treatment for Autosomal Recessive Stargardt Disease (STGD1): Design of a Clinical Trial Assessing a Novel Treatment and Primary Outcome Measure. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1569.
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In both animal and cell culture models, bisretinoids appear to activate complement leading to the formation of membrane attack complex (MAC) that can lead to RPE cell death. Further, C5a can also activate inflammasomes and lead to RPE cell damage. The presence of MAC has been documented in post mortem eyes of patients with STGD1. In Abca4-/- mice, inhibition of complement activation leads to a 30% increase in photoreceptor rescue at one year. Therefore inhibition of complement activation may have the potential to slow the progression of retinal degeneration in STGD1 patients.
A Phase 2b, randomized, double masked, sham controlled clinical trial evaluating the safety and efficacy of Zimura® (avacincaptad pegol), a C5 complement inhibitor, for patients with autosomal recessive Stargardt disease is underway. Inclusion criteria include: at least two pathogenic mutations of ABCA4 gene; best corrected visual acuity in the study eye between 20/20 - 20/200 Snellen equivalent and presence of at least one identifiable location of at least 250 micrometers contiguous width of ellipsoid zone loss on SD-OCT within the total 9 ETDRS subfields.
Approximately 120 patients will be enrolled in this 18 month study. The primary efficacy endpoint will be the mean rate of change in the area of ellipsoid zone defect measured by en face SD-OCT. Secondary endpoints will include the mean rate of change in the horizontal width of undetectable ellipsoid zone measured by a horizontal scan through the foveal center with SD-OCT; the mean rate of change in the area of atrophic lesion (definite decrease in autofluorescence - DDAF) measured by fundus autofluorescence (FAF).
Complement C5 may be a viable target for inhibition to potentially prevent or slow the progression of the autosomal recessive Stargardt disease. The downstream location of C5 within the complement cascade may have the additional advantage of decreasing the potential safety impact of upstream complement inhibition in the eye. The use of the change in area of ellipsoid zone defect measured by en face SD-OCT represents a new endpoint for atrophic retinal diseases and may provide additional information compared with enlargement of the area as seen on FAF.Acknowledgement to the Foundation Fighting Blindness for their support
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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