Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial

Abstract

Purpose: To investigate the safety and effects of intravitreal sirolimus for the potential treatment of geographic atrophy (GA).

Methods: The study was a single-center, open-label, phase I/II trial enrolling six participants with bilateral GA treated with intravitreal sirolimus in only one randomly assigned eye, with the fellow eye as control. The primary efficacy outcome measure was the change in total GA area from baseline on color fundus photography (CFP); secondary outcomes included changes in GA area on fundus autofluorescence (FAF), visual acuity, central retinal thickness (CRT), and macular sensitivity from baseline.

Results: Although no systemic adverse events were attributed to treatment, two of six participants had ocular adverse events that were possibly associated. The treated eye of one participant developed abnormal paralesional changes on FAF that were associated with accelerated retinal thinning. This accelerated retinal thinning was also seen in the treated eye of a second participant. Because of concern that these events were associated with treatment, treatment was suspended. Comparisons of treated and fellow eyes for change in visual acuity, change in GA area, and change in CRT showed no evidence of treatment benefit and generally favored the untreated fellow eye.

Conclusions: While paralesional FAF changes and rapid retinal thinning observed are potentially part of the natural course of GA, they may possibly be related to treatment. No general evidence of anatomical or functional benefit was detected in treated eyes. Further data on intravitreal sirolimus for GA treatment will be available from a larger phase II trial. (ClinicalTrials.gov number, NCT01445548.).

Keywords: age-related macular degeneration; clinical trial; geographic atrophy; sirolimus.

Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

Figures

Figure 1

Fundus changes in participant 6 during study treatment and follow-up. (A) Fundus autofluorescence images were obtained using a modified fundus camera (mFC). The right eye was randomized to receive investigational product (Study) while the left (Fellow) eye was observed without treatment. At month 4, after receiving two intravitreal injections of investigational product, the central GA lesion in the study eye demonstrated an expansion in the area of hypoautofluorescence at the superior and inferior margins (arrowheads). Investigational product administration was suspended at this month 4 visit and withheld thereafter. At month 8, the size and appearance of the GA lesion in the study eye appeared relatively stable. The fellow eye demonstrated no marked changes. (B) Changes in absolute (left) and square root transform (right) of GA area in the study and fellow eye at month 6 from baseline were measured from mFC FAF images. (C) Horizontal B-scans aligned through the center of the macula for the study and fellow eyes from baseline to month 8 were obtained. Marked central retinal thinning was observed at month 1 (indicated by arrows) in the study eye but not in the fellow eye. (D) Change in central retinal thickness (left) and central macular volume (right) from baseline to month 8 documented a rapid decline in the first 2 months in the study eye, which stabilized following drug suspension at month 4 (dashed line).

Figure 2

Fundus changes in participant 5 during study treatment and follow-up. (A) mFC FAF images demonstrated bilateral central GA lesions at baseline that gradually expanded in both study and fellow eye in a manner not inconsistent with the natural history of GA. (B) Absolute (left) and square root transform (right) increase in GA area in the study and fellow eye at month 6 and month 12 were plotted, demonstrating a greater increase in GA area in the study eye at month 12 compared with that in the fellow eye. (C) Horizontal aligned B-scans through the center of the macula from baseline to month 12 were obtained. Longitudinal analysis demonstrated noticeable thinning of the central macula beginning at month 4 in the study eye (loci indicated by arrows). Investigational product administration was suspended for the month 6 visit and withheld thereafter. (D) Change in central retinal thickness (left) and central macular volume (right) from baseline to month 12 in the study and fellow eyes documented a rapid decline over the first 4 months in the study eye, which stabilized following drug suspension at month 6 (dashed line), while measures in the fellow eye remained comparatively stable over time.

Figure 3

Change in GA area measurement on color fundus photography (CFP) in the study and fellow eyes from baseline. (A) Changes in the square root transform of GA area from baseline to the month of last available follow-up (visits are plotted for each participant as indicated by P1, P2, and so on) for study (black bars) and fellow (white bars) eyes. The latest month for image grading was 12 months for participants P1 through P5 and 6 months for P6. (B) Mean increase in absolute GA area from baseline at month 6 (n = 5 participants, data for P1 unavailable) and month 12 (n = 5, data for P6 unavailable). (C) Mean increase in square root transform of GA area from baseline at month 6 and month 12 (n = 5).

Figure 4

Change in central retinal subfield thickness as measured by SD-OCT in the study and fellow eyes from baseline. (A) Change in central retinal subfield thickness from baseline to the latest month in study (black bars) and fellow (white bars) eyes. The latest month for image grading was 12 months for participants P1 through P5 and 8 months for P6. In four of six participants, the decrease in central subfield thickness was greater in the study compared with the fellow eye. (B) Mean change in central retinal subfield thickness from baseline at 2, 4, 6, 8, 10, and 12 months. Number of participants (n) available for analysis is indicated at each time point. (C) Mean change in central macular volume from baseline at 2, 4, 6, 8, 10, and 12 months.

Figure 5

Change in visual acuity from baseline in the study and fellow eyes. (A) Change in visual acuity (in ETDRS letters) from baseline to the latest month for each participant (indicated by number) for the study eye (black bars) and fellow (white bars) eye. The latest month for which data were available was 12 months for participants P1 through P5 and 8 months for P6. In five of six participants, a greater loss in visual acuity occurred in study eye as compared with fellow eye. (B) Mean change in visual acuity in study and fellow eyes from baseline at 1, 2, 4, 6, 8, 10, and 12 months. Number of participants (n) is indicated at each time point. (C) Proportions of the study and fellow eyes experiencing a ≥10 ETDRS letter loss in visual acuity from baseline at 1, 2, 4, 6, 8, 10, and 12 months. (D) Proportions of the study and fellow eyes experiencing a ≥15 ETDRS letter loss in visual acuity from baseline at 1, 2, 4, 6, 8, 10, and 12 months. P1 was absent between month 6 and month 10, while P6 completed 8 months of follow-up.

Figure 6

Change in microperimetry test parameters in the study and fellow eyes from baseline. (A) Mean change in the number of scotomatous points from baseline at 6 and 12 months for the study eye (black bars) and fellow eye (white bars). Number of participants (n) for which data were available is indicated at each time point. (B) Mean change in the average retinal sensitivity of nonscotomatous points from baseline at 6 and 12 months. All comparisons between study and fellow eyes at each time point were not found to be significant.