Use of Clinical Pharmacology in Slowing the Myopia Epidemic

Abstract

Myopia (nearsightedness) is in epidemic proportions in the world today. The eyecare community has long been desirous of pharmacological treatments to slow myopic progression. Most recently, two proprietary formulations of low‐dose atropine were approved. In this article, the author summarizes the challenge to develop therapies for a chronic, preventative, and pediatric treatment, and how clinical pharmacologists' knowledge of pharmaceutics, pharmacokinetics, and therapeutics can optimize the development of therapies to slow myopic progression.

Myopia (nearsightedness) is a refractive error due to axial elongation of the eye. The worldwide prevalence of myopia is in epidemic proportions. ¹ While there are refractive devices and procedures to correct some of the optical properties of the elongated myopic globe, these do not affect the vision‐threatening morbidities of an elongated eye such as retinal detachment and glaucoma, or fully treat many of the quality of life issues for these pediatric patients and their parents. I propose that clinical pharmacologists can provide unique value in developing chronic prophylactic pharmacotherapies to slow myopic progression in the areas of dose–response and rebound characterization, handling variability across populations and formulations, informing long‐term pediatric benefit–risk, pharmacokinetics, and adherence.

LESSONS LEARNED

In the past 50 years, eye care specialists have evaluated topical ocular anti‐muscarinic agents (initially in high, mydriatic concentrations, ² and then in lower concentrations ³ ) to slow myopia progression. By evidence‐based medicine criteria, the early studies were open‐label and uncontrolled, and thus of lower quality. At the turn of the century, double‐masking and concurrent controls were used, improving the validity of the results. This work resulted in regulatory approvals in Japan, the United Kingdom, and the European Union, ⁴ but as of March 2026, not in the United States. This lack of success may be related to inadequate benefit/risk (slowing of myopic progression/mydriasis and loss of accommodation), as well as corporate financial reasons. ⁵ , ⁶ , ⁷

CHALLENGES

The vision science community does not know either the exact mechanism of myopic progression or the mechanism of the approved pharmacotherapies. Myopia has both a polygenic “nature” component (myopic parents tend to have myopic children) and a “nurture” component (myopia tends to start when children start reading, and its occurrence is negatively related outdoor light exposure). The relatively recent increase in the prevalence of myopia suggests that the “nurture” component may be more powerful than the “nature.” The nurture component generated an initial “accommodation” hypothesis, which led to the prophylactic use of anti‐muscarinic agents, which block accommodation. However, as M₁‐selective anti‐muscarinic agents (e.g., pirenzepine) are effective in avian models of myopia, ⁸ and the cholinergic receptors in the intraocular muscles of birds are nicotinic, not muscarinic, the anti‐myopic effect cannot be simply attenuation of accommodation. Anti‐muscarinic agents may also possess serotonergic antagonistic effects. Thus, other hypotheses such as retinal/brain feedback loops have been proposed. These feedback loops may be the reason for the rebound seen after cessation of therapy. This was seen in controlled trials by Chua et al., ³ wherein the concentration of atropine with the greatest efficacy during treatment led to the greatest rebound when therapy was stopped.

Myopia is typically a slow and variable progressive disease. The natural history of the disease in children is 0.1–0.7 diopters (D)/year in the United States with variability of similar magnitude to the mean. ⁹ Myopia progresses more rapidly in children in East Asia, although with high variability, so from a clinical trial perspective, the signal‐to‐noise ratio is similar to children in North America. ⁶ , ⁷ Thus, even pilot studies must be relatively large—50 to 100 subjects per group—and long—2 years or longer in order to detect a potential treatment effect. Adherence, as measured by electronic monitors, was over 80% of doses taken in one study, ⁷ presumably due to motivated parents (who themselves may be myopic).

There are pharmaceutics challenges as well. Simply diluting commercially available 1% atropine to 0.01% to 0.025% for therapeutic use is not possible, as lower concentrations of atropine are not stable in standard formulations. In the short‐term, eye care specialists in the United States have used compounding pharmacies to provide low‐dose atropine for their pediatric patients. However, the formulation and quality of such products is below that of marketed product made using Good Manufacturing Practices. Such prescriptions also must be paid for out of pocket by the patients' families.

Unfortunately, one of the tools of the clinical pharmacologist—clinical pharmacokinetics—has not been useful to date. While single aqueous humor samples of ~50 to 100 μL can be obtained via paracentesis, most ophthalmologists would be reticent to perform this procedure in an otherwise healthy child. Thus, the clinical pharmacologist is limited to using preclinical models as both pharmacokinetic and pharmacodynamic surrogates, which are not always generalizable to the human condition. Even with these models, the exact ocular structure involved in mediating axial elongation is not known—it may be iris/ciliary body or it may be the retina. So without knowing the exact site of action for a drug, it is challenging to interpret nonclinical pharmacokinetic data as to ocular tissue distribution. Pharmacokinetics are important to deal with variability in patients, as the iris and retina contain melanin; this can affect the amount of free drug for some compounds and varies with the patient's eye color.

INNOVATION

To my knowledge, no new chemical entities have been evaluated in pivotal, controlled efficacy trials to slow myopic progression. Rather, vision scientists used atropine—a drug used since antiquity, and well known in the eye for its diagnostic mydriatic and accommodative blocking effects. Another “borrowed” molecule was pirenzepine, used orally to treat dyspepsia in Europe. Atropine is equipotent at both the M₁‐(axial elongation – efficacy) and M₃‐ (mydriasis/accommodation – undesirable activity) muscarinic receptors. Pirenzepine is more M₁‐selective by a factor of ~10—good, but not at the level of selectivity that one might desire. Much of the innovation has come from firms developing novel, potentially proprietary formulations of atropine. There are competing factors here—for chronic topical ocular products, the commonly used preservative benzalkonium chloride may inflame the cornea and conjunctiva, and thus, non‐preserved products are preferred. However, such products require special container/closure systems, typically at greater cost. Also, benzalkonium chloride enhances intraocular bioavailability, and thus, non‐preserved formulations may require higher concentrations of the active to achieve similar intraocular tissue concentrations.

EVIDENCE GAPS AND REGULATORY NEEDS

Two decades ago, the US FDA recommended trials of 4‐year duration, with a washout of 6 or more months for evaluation of drugs to slow myopic progression. ¹⁰ Recent approvals in Asia and Europe were based upon 2‐year data, and the US FDA is probably expecting 3 year data for pivotal studies. In some cases, 6 months of post‐treatment washout is also required to evaluate myopic rebound. Such long‐term, large trials require large resources—which is an investment decision for pharmaceutical firms. There are a number of devices such as specially designed contact lenses and glasses that are approved to slow myopic progression. The availability of these devices, as well as the approval of low concentration atropine in countries in Europe and Asia, suggests ethical concerns in long‐term trials with a negative (i.e., placebo or vehicle) control.

Gaps in evidence were noted above—the mechanism of the myopic disease, the mechanism of approved pharmacotherapies, the reason for rebound, lack of clinical pharmacokinetics, and the dose–response for efficacy, safety, and the benefit/risk. Clinical pharmacologists have skills and the “toolbox” to help bridge these gaps. This may start with a key province of our profession—dose–response, as well as innovative design of controlled clinical trials (including appropriate sample size and handling of dropouts). It may also include modeling of nonclinical and clinical pharmacodynamic and pharmacokinetic data to interpolate the unavailable data—pharmacogenomics. It may also extend to education of regulators as to how modern tools can aid in the judgment of substantial evidence of safety and efficacy of novel treatments. Given the escalating global burden of myopia, I hope that firms continue to invest in slowing this disease. I recall the teachings of clinical pharmacologist W. Leigh Thompson, MD, Ph.D., DSc.—“the patient is waiting.”

FUNDING

No funding was received for this work.

DISCLOSURE

The author consults for numerous ophthalmic, pharmaceutical, and medical device firms. A detailed list is available in the supplemental material.

Supporting information

Data S1.