Topical mecamylamine for diabetic macular edema

Abstract

Purpose: Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models. The safety and bioactivity of topical mecamylamine, an antagonist of nACh receptors, was tested in patients with diabetic macular edema.

Design: A multicenter phase I/II clinical trial.

Methods: Twenty-three patients with chronic diabetic macular edema received 1% mecamylamine topically twice daily for 12 weeks, the primary end point. Patients underwent safety assessments, measurement of best-corrected visual acuity (BCVA), and measurement of foveal thickness using optical coherence tomography at baseline, 1, 4, 8, 12, and 16 weeks.

Results: Mecamylamine drops were well tolerated and there were no drug-related safety problems. Mean improvement in BCVA at 1, 4, 8, 12, and 16 weeks was 2.8, 1.9, 2.4, 0.8, and 3.1 letters, respectively. There was little change in mean excess foveal thickness. There was substantial heterogeneity in response, because 8 patients showed convincing improvement in BCVA, foveal thickness, or both, 9 patients showed equivocal or no substantial changes, and 4 patients showed worsening. Five patients showed a substantial improvement in BCVA, foveal thickness, or both between their last visit while receiving mecamylamine and 1 month after stopping mecamylamine.

Conclusions: This study suggested that administration of topical mecamylamine, a nonspecific nACh receptor blocker, may have heterogeneous effects in patients with diabetic macular edema. Variable expression of nACh receptor subtypes on endothelial cells that have different effects on permeability would provide an explanation for these results and should be investigated, because more specific nACh receptor blockers may dissociate antipermeability and propermeability effects.

Trial registration: ClinicalTrials.gov NCT00536692.

Conflict of interest statement

Potential Conflicts of Interest

QDN, DVD, and PAC receive research support and have an institutional consulting agreement through which JHU receives compensation with Genentech, Inc. PAC has an institutional consulting agreement with GlaxoSmithKline. QDN is a consultant for Bausch and Lomb and has research support from Genentech, Inc. and Regeneron, Inc. PAC serves on the data and safety monitoring committee for a phase III trial sponsored by Regeneron, Inc. and has research support from Alimera and CoMentis for diabetic macular edema trials. These activites are being managed by the Conflict of Interest Committee of the Johns Hopkins University School of Medicine. JPC is a scientific advisor and holds equity in Comentis, and receives royalties as an inventor on Stanford patents licensed to Comentis. JSH is a consultant for Genentech, Alcon, Allergan, Bausch and Lomb, Eyemaginations, Fovea, Genzyme, Heidelburg, IScience, ISTA, Jerini, LPath, NeoVista, Nodal Vision, Novagali, Novartis, Optherion, Oxigene, Paloma, Pfizer, Regeneron, Resolvyx, Schering Plough, Scyfix, VisionCare and has received honoraria from Genentech, Heidelberg, Jerini, NeoVista, Optimedica, and Regeneron.

Copyright 2010 Elsevier Inc. All rights reserved.

Figures

Figure 1. Eight patients who showed evidence of improvement on topical mecamylamine

Each column containing nine rows is shown for 8 patients who demonstrated some evidence of improvement. The top row shows the patient identifier with the first two digits indicating the site and the next 3 digits indicating the enrollment number. Rows 2–7 show a horizontal cross-section time domain optical coherence tomography scan through the fovea at each time point of the study, baseline (BL), day 7 (D7), month 1 (M1), month 2 (M2), month 3 (M3), and month 4 (M4). The seventh row in each column shows a bar chart depicting excess center subfield thickening at each time point and the eighth row show a line graph depicting the change from BL in best-corrected visual acuity (BCVA) shown as number of letters read at 4 meters on an Early Treatment Diabetic Retinopathy (ETDRS) chart. Mecamylamine drops were stopped at M3, the primary endpoint of the study, and thus the data for M4 was obtained 1 month after stopping mecamylamine. Patients 01–008, 03–007, and 02–003 showed improvements in BCVA of 9, 6, and 14 letters at the primary endpoint along with substantial reduction in excess center subfield thickening. Patient 01–003 showed improvement in BCVA of 15 letters along with a modest reduction in excess center subfield thickening. Patient 03–005 showed improvement in BCVA of 22 letters despite a modest change in EFT and Patient 01–011 showed an improvement in BCVA of 9 letters with little change in EFT. Patients 01–002 and 03–009 had mild macular edema at BL that was essentially completely eliminated by M3 with normal appearing scans, but this was not accompanied by substantial improvement in BCVA.

Figure 2. Red free fundus photographs and fluorescein angiogram patient 01–009 at baseline (BL) and month 3 (M3) after starting mecamylamine

The red free photograph at M3 shows a substantial reduction in exudates compared to the photograph at BL. The fluorescein angiogram at BL shows substantial leakage during the early and mid phases resulting in pooling of dye in a petaloid pattern during the late phase of the angiogram. At M3 there is less leakage and less pooling of dye in the macula during the late phase of the angiogram.

Figure 3. Three patients who showed some evidence of improvement during their course, but had a sudden drop in best-corrected visual acuity (BCVA) at the primary endpoint and rebound improvement after stopping mecamylamine

The top row shows the patient identifier with the first two digits indicating the site and the next 3 digits indicating the enrollment number. Rows 2–7 show a horizontal cross-section time domain optical coherence tomography scan through the fovea at each time point of the study, baseline (BL), day 7 (D7), month 1 (M1), month 2 (M2), month 3 (M3), and month 4 (M4). The seventh row in each column shows a bar chart depicting excess center subfield thickening at each time point and the eighth row show a line graph depicting the change from BL in BCVA shown as number of letters read at 4 meters on an Early Treatment Diabetic Retinopathy (ETDRS) chart. Mecamylamine drops were stopped at M3, the primary endpoint of the study, and thus the data for M4 was obtained 1 month after stopping mecamylamine. Patients 01–010, 02–005, and 03–013 all had a similar pattern in that they showed some evidence of improvement through week 8, but during the last 4 weeks of mecamylamine treatment there was a substantial drop in BCVA that recovered one month after mecamylamine was stopped.

Figure 4. Six patients who showed equivocal change or no substantial change on topical mecamylamine

The top row shows the patient identifier with the first two digits indicating the site and the next 3 digits indicating the enrollment number. Rows 2–7 show a horizontal cross-section time domain optical coherence tomography scan through the fovea at each time point of the study, baseline (BL), day 7 (D7), month 1 (M1), month 2 (M2), month 3 (M3), and month 4 (M4). The seventh row in each column shows a bar chart depicting excess center subfield thickening at each time point and the eighth row show a line graph depicting the change from BL in best-corrected visual acuity (BCVA) shown as number of letters read at 4 meters on an Early Treatment Diabetic Retinopathy (ETDRS) chart. Mecamylamine drops were stopped at M3, the primary endpoint of the study, and thus the data for M4 was obtained 1 month after stopping mecamylamine. Patients 01–009 and 03–012 showed improvements in BCVA of 8 and 7 letters, respectively, but this was not accompanied by a substantial change in excess center subfield thickness. Patients 01–007 and 01–006 showed minimal change in BCVA and no change (01–006) or modest worsening (01–007) in excess center subfield thickening. Patients 03–004 and 02–004 showed essentially no change in BCVA (+3 and +1) and a modest improvement (03–004) or worsening (02–004) in excess center subfield thickness.

Figure 5. Four patients who showed evidence of worsening on mecamylamine

The top row shows the patient identifier with the first two digits indicating the site and the next 3 digits indicating the enrollment number. Rows 2–7 show a horizontal cross-section time domain optical coherence tomography scan through the fovea at each time point of the study, baseline (BL), day 7 (D7), month 1 (M1), month 2 (M2), month 3 (M3), and month 4 (M4). The seventh row in each column shows a bar chart depicting excess center subfield thickening at each time point and the eighth row show a line graph depicting the change from BL in best-corrected visual acuity (BCVA) shown as number of letters read at 4 meters on an Early Treatment Diabetic Retinopathy (ETDRS) chart. Mecamylamine drops were stopped at M3, the primary endpoint of the study, and thus the data for M4 was obtained 1 month after stopping mecamylamine. Patient 03–002 had a 15 letter reduction in BCVA and a 248 μm increase in excess central subfield thickening over the 3 months on mecamylamine and 1 month after stopping mecamylamine, there was resolution of the macular edema by a reduction of 516 μm in excess center subfield thickness accompanied by a gain of 14 letters in BCVA. Patient 01–005 had a 20 letter reduction in BCVA and a 238 μm increase in excess central subfield thickening over the 3 months on mecamylamine and 1 month after stopping mecamylamine the BCVA had improved by 10 letters and the excess center subfield thickening had a small reduction of 20 μm. Patient 03–010 had severe edema with excess center subfield thickness at BL of 492 μm that was reduced by 128 μm at M2, but increased by 78 μm at M3 when BCVA was reduced by 9 letter compared to baseline. After stopping mecamylamine the edema continued to worsen and the BCVA remained the same. Patient 03–011 was withdrawn from the study for alternative treatment at M2 because of a reduction in BCVA of 14 letters and an increase in excess center subfield thickness of 288 μm.

Figure 6. Change from baseline in best-corrected visual acuity (BCVA) and excess foveal thickness (FTH) during 12 weeks of treatment with topical mecamylamine and 4 weeks after discontinuation

The mean (upper panel) and median (lower panel) change from baseline in BCVA (Y axis on left) in letters read at 4 meters on an ETDRS visual acuity chart is shown by the black lines. The mean (upper panel) and median (lower panel) change from baseline in excess FTH (Y axis on right) is shown at each study visit by the bars.

Figure 7. Aqueous VEGF levels at baseline and after 7 or 84 days of treatment with topical mecamylamine

All of the nine patients entered at one site had aqueous taps at baseline, day 7, and day 84 and VEGF levels were measured by ELISA. Each value represents a mean of 3 separate assays. There were small reductions in mean and median VEGF levels between baseline and day 84 that were not statistically significant (upper panel). The VEGF levels for each patient at the 3 time points are shown in the lower panel along with their outcome category. Category 1 consists of patient shown in Figure 1 who showed evidence of improvement. Category 2 consists of patients shown in Figure 3 who showed some evidence of improvement during their course, but had a sudden drop in best-corrected visual acuity at the primary endpoint and rebound improvement after stopping mecamylamine. Category 3 consists of patients shown in Figure 4 who showed equivocal change or no substantial change. Category 4 consists of patients shown in Figure 5 who showed evidence of worsening on mecamylamine. There was no consistent correlation between alteration of VEGF level and outcome category.