First-in-class glaucoma therapy shows promise in phase II study


Topical AR-13324 0.02% (Rhopressa, Aerie Pharmaceuticals) significantly lowered IOP in eyes with ocular hypertension or open-angle glaucoma in a 28-day phase II study.



Topical AR-13324 0.02% (Rhopressa, Aerie Pharmaceuticals) significantly lowered IOP in eyes with ocular hypertension or open-angle glaucoma in a 28-day phase II study.


By Cheryl Guttman Krader; Reviewed by Jason Bacharach, MD

Sonoma County, CA-Results from a phase II study showed that topical AR-13324 0.02% (Rhopressa, Aerie Pharmaceuticals)-an investigational rho kinase/norepinephrine transporter (ROCK/NET) inhibitor-significantly reduced IOP in eyes with ocular hypertension or open-angle glaucoma.

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Based on the findings from that trial, a phase III registration trial was designed and is now under way comparing once-daily AR-13324 0.02% with twice-daily timolol 0.5%.

“The phase II data suggest that AR-13324 0.02% may be an excellent option for initial treatment in eyes with lower IOP, and the phase III study investigating its use is enrolling eyes with unmedicated IOPs ranging from >20 to <27 mm Hg,” said Jason Bacharach, MD, a glaucoma specialist in Sonoma County, CA.

“We are hopeful in seeing positive results in this large cohort,” he added.

About the phase II study

The phase II study randomly assigned 224 patients with an unmedicated IOP between 22 and 36 mm Hg to treatment with AR-13324 0.01%, AR-13324 0.02%, or latanoprost 0.005%. Patients used their assigned study medication once daily in the evening for 28 days.


Mean unmedicated baseline diurnal IOP was similar in the three study groups and ranged from 25.5 to 25.8 mm Hg. At the end of the study, mean diurnal IOP in the AR-13324 0.01%, AR-13324 0.02%, and latanoprost groups was reduced by 5.5, 5.7, and 6.8 mm Hg, respectively. In all groups, the decrease from baseline was statistically significant.

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With its approximately 1 mm Hg lesser efficacy compared with latanoprost, AR-13324 did not meet the protocol criterion for non-inferiority to the prostaglandin analogue. However, findings from a pre-specified subset analysis of patients stratified by unmedicated baseline IOP showed that AR-13324 0.02% was non-inferior to latanoprost in eyes with baseline IOP ≤26 mm Hg. In the latter subgroup, the mean decrease in diurnal IOP was 5.7 mm Hg for eyes treated with AR-13324 0.02% and 6.0 mm Hg in the latanoprost-treated eyes.

The study was recently published online in Ophthalmology, and the paper will appear in the February 2015 issue of the journal. Dr. Bacharach is lead author of the paper.

Reason for IOP-lowering efficacy

The explanation for the similar IOP-lowering efficacy of AR-13324 0.02% and latanoprost in eyes with IOP ≤26 mm Hg is not that the ROCK /NET inhibitor is more effective when treating these lower IOPs. Rather, the findings reflect the fact that latanoprost and all prostaglandin analogues work less well for decreasing IOP the lower the starting level, Dr. Bacharach noted.

“This is a well-known phenomenon observed in the original registration studies for latanoprost where for every 1 mm Hg lower baseline IOP, the IOP-reducing effect of latanoprost was about 0.5 mm Hg less,” he said.

The IOP inclusion criterion for the AR-13324 0.02% pivotal trial is not expected to have any impact on its indication, assuming efficacy and safety are demonstrated and the drug is approved, Dr. Bacharach added.


“The phase II study showed that AR-13324 was also very effective in eyes with higher IOPs,” he said.

AR-13324 was generally safe and well tolerated in the phase II study. Ocular/conjunctival hyperemia was the most common side effect and was recorded in 57% of eyes treated with AR-13324 0.02% and 16% of latanoprost-treated eyes.

However, the hyperemia associated with AR-13324 was mild in most cases and seemed to be most prominent in the evening post-dosing and diminish overnight while patients were asleep.

In addition, the incidence of hyperemia associated with AR-13324 decreased throughout the study, whereas the incidence of conjunctival hyperemia in the latanoprost group increased with time.

Multimodal actions

AR-13324 reduces IOP via several mechanisms. First, ROCK inhibition reduces resistance to outflow through the trabecular meshwork.

In addition, AR-13324 reduces aqueous humor production, which is thought to be secondary to its NET inhibition, and there is also evidence AR-13324 reduces episcleral venous pressure.

However, the ability of AR-13324 and related drugs to increase trabecular meshwork outflow may provide a benefit in glaucoma that is unrelated to reduction in IOP, Dr. Bacharach said.

“The aqueous humor contains nutrients and antioxidants, and findings from preclinical studies suggest that restoration of aqueous flow through the diseased trabecular meshwork may have a positive impact on the disease pathology,” he explained.


AR-13324 0.02% is also being developed as a fixed-combination product with latanoprost 0.005% (PG324 0.02%; Roclatan, Aerie Pharmaceuticals). Results of a randomized phase IIb study showed that all post-treatment timepoints, mean IOP was 1.6 to 3.2 mm Hg lower in eyes treated with PG324 compared with using latanoprost 0.005% and 1.7 to 3.4 mm Hg lower compared with a AR-13324 0.02% monotherapy group.

“The results of the phase IIb study are very encouraging and suggest that AR-13324 may be an excellent addition to a prostaglandin analogue for patients who do not respond sufficiently to the prostaglandin alone,” Dr. Bacharach said.


Jason Bacharach, MD


Dr. Bacharach is an investigator in the AR-13324 and PG-324 studies and is a consultant to Aerie Pharmaceuticals. He was also a clinical trial investigator for a ROCK inhibitor that was being developed by Amakem.





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