It’s well-established that the incidence and prevalence of glaucoma is affected by gender, but the reasons for this remain unclear. Noting that some previous studies have found a correlation between having given birth and glaucoma, researchers in South Korea set out to pursue this further.
A study published in the January 2019 issue of The Journal of Glaucoma used a population-based, cross-sectional analysis of data from the Korean National Health and Nutrition Examination Survey, conducted in 2010 and 2011, to investigate any association between pregnancy, delivery and the prevalence of open-angle glaucoma in 1,798 postmenopausal South Korean women. Demographic information, comorbidities and health-related behaviors were included in the analysis. Excluded from the database were subjects with evidence of retinal detachment or age-related macular degeneration; pseudophakic and aphakic subjects; anyone who did not undergo an ophthalmic evaluation; and anyone with a history of intraocular surgery. (The authors note that one limitation of their study was the small number of women in the survey who had no pregnancies, making it impossible to draw any conclusions regarding subjects in that situation.)
Several correlations between number of pregnancies and glaucoma were found:
• There was a significant difference between the open-angle glaucoma group and the no-glaucoma group in both the number of deliveries the women had undergone and the subject’s age at the time of the first delivery.
• When the analysis was adjusted to account for age, hypertension and intraocular pressure, the lowest increased risk for open-angle glaucoma was associated with two deliveries; women with one delivery had a greater risk of open-angle glaucoma than those with two deliveries (p=0.023). Those with three or more deliveries also had a greater risk of open-angle glaucoma than those with two deliveries (p=0.027).
• Giving birth for the first time between the age of 16 to 20 years or 21 to 23 years was associated with a two-fold increased risk of open-angle glaucoma, compared to a reference group of subjects aged 24 to 26 (p<0.05).
The authors conclude that these findings suggest that changes taking place in the body during pregnancy may affect the development of glaucoma.
Without further data, any explanation for these effects is theoretical, but the authors hypothesize a number of possible explanations for their findings. These include: high estrogen levels during pregnancy; transient events during labor, including systemic hypotension and decreased ocular perfusion because of massive bleeding, inducing glaucoma-like changes in the optic nerve; increased oxytocin levels during labor inducing capillary constriction and decreasing aqueous outflow; stress during labor causing the release of epinephrine and norepinephrine, increasing IOP; and valsalva maneuvers during labor producing intermittent increases in IOP.
While all of these changes are short-lived, raising the question of whether they could have such a significant impact, the authors note that the risk of glaucoma increases with more pregnancies/births. The primary exception to that is that the risk didn’t increase between the first and second births; the authors hypothesize that this might reflect the optic nerve’s ability to recover from small insults below a certain threshold. Only when the challenging conditions recur three or more times would the physiologic insult cause the likelihood of later glaucoma to increase further.
Farewell ... and Welcome
This issue marks a changing of the guard in our Retinal Insider department. After 20 years of expertly co-editing the column alongside Carl Regillo, MD, Emmett Cunningham, MD, PhD, is stepping down. Review and its readers thank Dr. Cunningham for his fine work. In his place comes Yoshihiro Yonekawa, MD, an expert clinician and surgeon currently at Massachusetts Eye and Ear Infirmary, but soon to be at Wills Eye Hospital. We’d like to take this opportunity to welcome Dr. Yonekawa to the magazine.
“This population-based study showed an association between pregnancy and risk of open-angle glaucoma,” notes Peter A. Netland, MD, PhD, Vernah Scott Moyston Professor and Chair at the University of Virginia in Charlottesville. “The physiologic changes that take place during pregnancy are complex and numerous. The possibility of a hormone effect on the risk of glaucoma is interesting and merits further investigation.”
New Drugs Approved by FDA
Two companies, Aerie Pharmaceuticals and Bausch + Lomb, received Food and Drug Adminstration approvals in recent months.
Aerie’s glaucoma drug Rocklatan (netarsudil and latanoprost ophthalmic solution) 0.02%/0.005% has been approved by the U.S. Food and Drug Administration for the treatment of open-angle glaucoma and ocular hypertension. It’s the first q.d. fixed-dose combination of a prostaglandin analog and a Rho kinase inhibitor.
The approval was supported by two Phase III trials, MERCURY 1 (NCT 02558400) and MERCURY 2 (NCT 02674854). The company reports that Rocklatan achieved the primary 90-day efficacy endpoint, as well as positive 12-month safety and efficacy results, showing statistically significant intraocular pressure reduction vs. either latanoprost or netarsudil alone at each time point.
For its part, Bausch + Lomb announced the FDA approval of a treatment for postoperative inflammation and pain following ocular surgery: corticosteroid Lotemax SM. B+L says that Lotemax SM uses submicron technology to deliver fast drug dissolution in tears and improve drug exposure into the aqueous, and that it provides two times greater penetration to the aqueous humor compared to Lotemax Gel (loteprednol etabonate ophthalmic gel) 0.5%.
The drug has the lowest preservative percentage in a loteprednol etabonate formulation, and has a pH close to that of human tears, B+L adds.
In one randomized study, at postop day eight, the new drug cleared anterior chamber cells in 29 percent of patients vs. 9 percent of patients who were administered only vehicle, and 73 percent of the Lotemax SM patients reported being clear of pain vs. 48 percent of vehicle patients.
Court Moves Against Drug Compounder
The federal court in the Northern District of Texas has ordered JMA Partners, doing business as Guardian Pharmacy Services in Dallas, to stop producing compounded drug products that are intended to be sterile until the company shows it has complied with the Federal Food, Drug, and Cosmetic Act and other requirements.
According to an announcement of the decision by the FDA, the agency inspected Guardian in 2016 and, as a result, issued the pharmacy a warning letter for unsanitary conditions, among other FD&C Act violations. Then, in 2017, the FDA received adverse event reports regarding at least 43 patients who received ocular injections of a drug compounded by Guardian containing triamcinolone and moxifloxacin during cataract surgery. The patients reportedly suffered symptoms that included decreased vision, poor night vision, loss of color vision and reductions in best-corrected vision. Upon investigation, the FDA says it found a high percentage of an excipient, poloxamer 407, and the presence of potential process-degradation products in the compounded drug.
The current consent decree requires Guardian to stop sterile operations until it takes corrective action such as hiring a qualified independent expert to inspect its operation, establishes a comprehensive quality control program and receives authorization from the FDA to resume operating.
Companies Hope Success is in the Genes
In a mini feeding frenzy of sorts, spurred by the potential of gene therapy, Roche agreed to purchase Luxturna-maker Spark Therapeutics in February for approximately $4.3 billion, and in March Biogen announced that it’s buying gene-therapy maker Nightstar for about $877 million.
According to an official statement by Roche, in addition to the already approved Luxturna, a one-time gene therapy for biallelic RPE65 mutation-associated retinal dystrophy, Spark Therapeutics’ lead clinical asset is SPK-8011, a novel gene therapy for the treatment of haemophilia A, which is expected to start a Phase III clinical trial in 2019.
Nightstar’s lead candidate is the adeno-associated viral vector-based therapy NSR-REP1, a gene therapy for the treatment of choroideremia, a rare, X-linked genetic retinal disorder that currently has no treatment. NSR-REP1 is currently in a Phase III trial. The company has other potential treatments in the works as well, including gene therapies targeting X-linked retinitis pigmentosa and Stargardt’s disease. REVIEW