Low-dose atropine after the FDA CRL: A setback or a catalyst for precision myopia pharmacotherapy?

The global rise in myopia prevalence has established myopia as a major public health concern, with projections suggesting that nearly half of the world’s population may be affected by 2050.¹ Although optical and behavioral interventions have demonstrated efficacy in slowing progression, a scalable pharmacologic solution remains an unmet need. Low-dose atropine has long been considered a promising candidate. However, the recent FDA complete response letter (CRL)2 for atropine 0.01% highlights important limitations in the current evidence, including modest treatment effects and uncertain clinical relevance. This decision presents an opportunity to reassess not only the role of atropine but also the broader framework for evaluating pharmacologic myopia control.

Regulatory perspective: Clinical meaningfulness and limitations of current evidence

In the FDA’s CRL, several key concerns were identified. The overall treatment effect observed in the phase 3 SYD-101-001 trial (NCT03918915) was modest throughout the study duration (0.079 D/y for 0.01% and 0.067 D/y for 0.03%). Although the trial met its primary end point, the magnitude of effect was small, diminished over time, and was not considered clinically meaningful, as it would not meaningfully alter refractive outcomes or reduce the need for corrective lenses. Additionally, no significant benefit was observed in axial length, suggesting limited impact on long-term risks such as retinal complications.

The FDA further noted that chronic daily use in a pediatric population is difficult to justify given the minimal benefit. Supporting evidence from additional studies was also deemed insufficient, as many were of short duration, conducted in nonrepresentative populations (primarily Asian cohorts), or failed to demonstrate consistent efficacy in non-Asian populations. These limitations raise important concerns regarding the generalizability of the findings to the intended US population.

Biological and pharmacologic considerations underlying the modest observed effect

Variability in intraocular drug absorption

Topical ocular drug delivery is inherently variable, particularly when the proposed site of action is the posterior segment. Factors influencing intraocular drug availability include tear film turnover, corneal permeability, conjunctival and scleral absorption, protein binding within the tear film, and nasolacrimal drainage.

Common clinical conditions such as ocular allergy—associated with increased tear turnover, conjunctival hyperemia, and higher tear component of inflammatory mediators, which are protein in nature—may further alter drug absorption. Unlike systemic pharmacotherapy, intraocular drug concentrations are rarely quantified in clinical trials, leading to substantial variability in effective dosing.

Additionally, iris pigmentation may act as a drug reservoir, influencing the pharmacokinetics of atropine under once-daily dosing. Studies that do not account for iris color may therefore be confounded by differences in drug depot effects related to pigmentation.

Genetic and environmental heterogeneity in myopia pathogenesis

Differences in treatment response across populations—particularly between Asian and non-Asian cohorts—have been consistently reported.3-5 These variations likely reflect differences in genetic predisposition to axial elongation, environmental exposures (eg, near work, outdoor activity), and baseline progression rates.

Such findings suggest that atropine efficacy may be population-dependent rather than universally consistent, underscoring the importance of subgroup analyses in future studies.

Differential responsiveness to retinal signaling pathways

Atropine is believed to modulate retinal and scleral signaling pathways involved in ocular growth.⁶ However, variability in these biological pathways may result in heterogeneous treatment responses, with distinct subgroups of pharmacologic “responders” and “nonresponders.”

Potential surrogate markers of treatment response—such as choroidal thickening or vascular changes—could be incorporated into future trials to identify nonresponders early. This approach may improve study power and facilitate timely transition to alternative therapies when needed.

Limitations in posterior segment drug delivery

The sclera and choroid are widely considered key target tissues in myopia control and axial inhibition by atropine.⁶ However, drug delivery to these structures is influenced by axial length (ie, diffusion distance) and vitreous volume. It is plausible that eyes with longer axial lengths receive lower effective drug concentrations at the target site, potentially reducing therapeutic efficacy in patients with more advanced myopia.

Future directions: Toward precision myopia pharmacotherapy

Biomarker-guided treatment

Dynamic pupillometry may serve as a functional surrogate for atropine absorption in the anterior segment, whereas choroidal imaging provides a quantifiable measure of drug bioavailability at the proposed site of action. Together, these measures may help characterize individual variability in treatment response and guide personalized dosing strategies.

Advanced drug delivery and posterior segment targeting

Emerging technologies offer potential solutions to current limitations in ocular drug delivery. These include nanoparticle-based formulations to enhance ocular surface retention, mucoadhesive systems to reduce tear washout, and sustained-release platforms to improve dosing consistency.⁷ Techniques such as scleral iontophoresis may further enhance drug penetration into posterior segment tissues, potentially improving therapeutic outcomes.⁸

Stratified clinical trial design

Future clinical trials should consider stratification by axial length, ethnicity, and environmental exposure, along with the integration of pharmacodynamic biomarkers. Such approaches may uncover clinically meaningful benefits within specific subgroups that are obscured in aggregate analyses.

In conclusion, the FDA’s decision underscores the importance of demonstrating clinically meaningful outcomes in myopia control. However, the modest effects observed with low-dose atropine likely reflect limitations in drug delivery, study design, and patient heterogeneity rather than an absence of biological activity.

References:

1. Holden BA, Fricke TR, Wilson DA, et al. Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050. Ophthalmology. 2016;123(5):1036-1042. doi:10.1016/j.ophtha.2016.01.006

2. FDA. Complete response letter for atropine sulfate ophthalmic solution 0.01%. October 22, 2025. Accessed March 27, 2026. https://download.open.fda.gov/crl/CRL_NDA219694_20251022.pdf

3. Yam JC, Jiang Y, Tang SM, et al. Low-concentration Atropine for Myopia Progression (LAMP study): a randomized, double-blinded, placebo-controlled trial of 0.05%, 0.025%, and 0.01% atropine eye drops in myopia control. Ophthalmology. 2019;126(1):113-124. doi:10.1016/j.ophtha.2018.05.029

4. Yam JC, Li FF, Zhang X, et al. Two-year clinical trial of the Low-concentration Atropine for Myopia Progression (LAMP) study: phase 2 report. Ophthalmology. 2020;127(7):910-919. doi:10.1016/j.ophtha.2019.12.011

5. Repka MX, Weise KK, Chandler DL, et al. Low-dose 0.01% atropine eye drops vs placebo for myopia control: a randomized clinical trial. JAMA Ophthalmol. 2023;141(8):756-765. doi:10.1001/jamaophthalmol.2023.2855

6. McBrien NA, Stell WK, Carr B. How does atropine exert its anti-myopia effects? Ophthalmic Physiol Opt. 2013;3(3):373-378. doi:10.1111/opo.12052

7. Diebold Y, Calonge M. Applications of nanoparticles in ophthalmology. Prog Retin Eye Res. 2010;29(6):596-609. doi:10.1016/j.preteyeres.2010.08.002

8. Eljarrat-Binstock E, Domb AJ. Iontophoresis: a non-invasive ocular drug delivery. J Control Release. 2006;110(3):479-489. doi:10.1016/j.jconrel.2005.09.049