Oral Minocycline Fails to Slow Enlargement of Geographic Atrophy

Tiarnan D. L. Keenan, BM, BCh, PhD

Credit: National Eye Institute

Oral minocycline, a microglial inhibitor, was not associated with a slowing in the rate of enlargement of geographic atrophy (GA) in age-related macular degeneration (AMD), according to new research.¹

In the phase 2 nonrandomized trial, the mean GA enlargement rate did not decrease over the 24-month study period, compared with the preceding 9-month run-in phase. Investigators observed no consistent signals of a clinically meaningful treatment effect for minocycline for structural or visual acuity end points.

“The most likely explanation for the absence of a difference in the primary outcome measure is that minocycline has no substantial association with slowing GA enlargement,” wrote the investigative team, led by Tiarnan D. L. Keenan, BM, BCh, PhD, National Eye Institute, National Institutes of Health.

Enlargement in GA area is a recognized primary outcome measure in numerous clinical trials, being the basis of two recent US Food and Drug Administration (FDA) approvals, pegcetacoplan (SYFOVRE) and avacincaptad pegol (IZERVAY), for the treatment of GA. Despite these landmark approvals, the therapies are relatively modest in anatomic efficacy, require frequent intravitreal injections, and elevate the risk of neovascular AMD.

Minocycline is approved by the FDA for the treatment of infectious disorders, acting as an anti-inflammatory agent and inhibitor of microglial activation. This multicenter, prospective, single-arm, phase 2 nonrandomized study sought to evaluate the safety and anatomic efficacy of oral minocycline in inhibiting GA progression in AMD.

The trial was conducted between December 2016 and April 2023, with patients recruited from the NIH Clinical Center in the United States and Bristol Eye Hospital in the United Kingdom. Eligible patients were ≥55 years of age and had GA from AMD in 1 or both eyes. Each participant underwent a 9-month run-in phase and then began taking oral minocycline 100 mg, twice daily, for 24 months.

Analysis of the study data took place from September 2022 to May 2023. For the primary outcome, investigators aimed to assess the difference in the rate of change in study eyes, by fundus autofluorescence (FAF), between the 24-month treatment phase and the 9-month run-in phase.

A total of 37 participants were enrolled in the trial; the cohort had a mean age of 74.3 years and 21 [57%] patients were female. After a single study discontinuation, 36 participants initiated the treatment phase, 21 (58%) completed at least 22 months, and 15 discontinued treatments. Discontinuations included 8 by request, 6 for adverse events or illness, and 1 for death.

In the enrolled population, the estimated mean square-root transformed GA enlargement rate in study eyes was 0.31 mm per year during the run-in phase and 0.28 mm per year during the treatment phase. The primary outcome measure, the mean difference in enlargement rates between the two phases, was evaluated at –0.03 mm per year (P = .39).

Secondary outcome measures of the GA enlargement also revealed no difference between the two study phases. The measure of mean difference in the rate of change between the 2 phases was 0.2 letter score per month (95% CI, –0.4 to 0.9; P = .44) for visual acuity and 0.7 µm per month (95% CI, –0.4 to 1.8; P = .20) for subfoveal retinal thickness.

In the safety analysis, investigators recorded 129 treatment-emergent adverse events among 32 study participants. Of these events, 49 (38%) were deemed related to minocycline, with the majority (71%) being mild. The most common adverse events reported were an increase in serum thyrotropin level (15 participants) and skin hyperpigmentation or discoloration (8 participants).

Keenan and colleagues noted the potential disadvantages of existing therapeutic approaches may continue to make alternative strategies for GA treatment desirable, despite the lack of a consistent, clinically meaningful treatment effect with minocycline.

“It may be necessary to elucidate more clearly the pathogenetic mechanisms underlying GA incidence and progression to develop therapies that target the underlying disease processes,” investigators wrote.

References

1. _{Keenan TDL, Bailey C, Abraham M, et al. Phase 2 Trial Evaluating Minocycline for Geographic Atrophy in Age-Related Macular Degeneration: A Nonrandomized Controlled Trial. JAMA Ophthalmol. Published online March 14, 2024. doi:10.1001/jamaophthalmol.2024.0118}