Treatment of geographic atrophy with subconjunctival sirolimus: results of a phase I/II clinical trial

Abstract

Purpose: To investigate the safety and effects of subconjunctival sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of geographic atrophy (GA).

Methods: The study was a single-center, open-label phase II trial, enrolling 11 participants with bilateral GA; eight participants completed 24 months of follow-up. Sirolimus (440 μg) was administered every 3 months as a subconjunctival injection in only one randomly assigned eye in each participant for 24 months. Fellow eyes served as untreated controls. The primary efficacy outcome measure was the change in the total GA area at 24 months. Secondary outcomes included changes in visual acuity, macular sensitivity, central retinal thickness, and total drusen area.

Results: The study drug was well tolerated with few symptoms and related adverse events. Study treatment in study eyes was not associated with structural or functional benefits relative to the control fellow eyes. At month 24, mean GA area increased by 54.5% and 39.7% in study and fellow eyes, respectively (P = 0.41), whereas mean visual acuity decreased by 21.0 letters and 3.0 letters in study and fellow eyes, respectively (P = 0.03). Substantial differences in mean changes in drusen area, central retinal thickness, and macular sensitivity were not detected for all analysis time points up to 24 months.

Conclusions: Repeated subconjunctival sirolimus was well-tolerated in patients with GA, although no positive anatomic or functional effects were identified. Subconjunctival sirolimus may not be beneficial in the prevention of GA progression, and may potentially be associated with effects detrimental to visual acuity. (ClinicalTrials.gov number, NCT00766649.).

Figures

Figure 1

Change in GA area measurement on color fundus photography (CFP) in the study and fellow eyes from baseline for all participants completing 24 months of study follow up (n = 8). (A) Change in GA area from baseline to month 24 for each participant (as indicated by P1, P4, P5, and so forth) in study and fellow eyes. (B) Mean absolute increase in GA area from baseline at 6, 12, 18, and 24 months. (C) Mean percentage increase in GA area from baseline at 6, 12, 18, and 24 months. P values indicate results of a two-tailed paired t-test.

Figure 2

Visual acuity changes in the study and fellow eyes in participants completing 24 months of follow-up (n = 8). (A) Change in visual acuity (in ETDRS letters) from baseline to 24 months for each participant (indicated by number) for study eye and fellow eye. (B) Mean change in visual acuity in study and fellow eyes from baseline at 6, 12, 18, and 24 months. P values indicate the results of two-tailed paired t-tests between pairs of study and fellow eyes. (C) Proportions of the study and fellow eyes experiencing a >5-letter loss in visual acuity from baseline at 6, 12, 18, and 24 months. (D) Proportions of the study and fellow eyes experiencing a >10-letter loss in visual acuity from baseline at 6, 12, 18, and 24 months.

Figure 3

Change in central retinal subfield thickness as measured by SD-OCT in the study and fellow eyes from baseline for all participants completing 24 months of study follow-up (n = 8). (A) Change in central retinal subfield thickness from baseline to month 24 for each participant in study and follow eyes. (B) Mean change in central retinal subfield thickness from baseline at 6, 12, 18, and 24 months. (C) Mean change in macular volume from baseline at 6, 12, 18, and 24 months. P values indicate results of a two-tailed paired t-test.

Figure 4

Change in microperimetry test parameters in the study and fellow eyes from baseline in all participants completing study follow-up (n = 8). (A) Mean change in the number of scotomatous points from baseline at 6, 12, 18, and 24 months. (B) Mean change in retinal sensitivity of nonscotomatous points from baseline at 6, 12, 18, and 24 months. All comparisons between study and fellow eyes at each time point were nonsignificant (P > 0.05, as computed by a two-tailed paired t-test).