Latanoprostene bunod shows promise in patients with open-angle glaucoma, ocular hypertension

Take-home

Findings from the CONSTELLATION study show that once-daily latanoprostene bunod lowered IOP more than twice-daily timolol in patients with open-angle glaucoma or ocular hypertension.

By Michelle Dalton, ELS; Reviewed by John H. Liu, PhD

La Jolla, CA-Once-daily latanoprostene bunod lowered IOP more than twice-daily timolol in an 8-week randomized crossover study of patients with open-angle glaucoma or ocular hypertension, according to results from the CONSTELLATION study.

Lead author for the study, John H. Liu, PhD, of the Department of Ophthalmology and Hamilton Glaucoma Center, University of California–San Diego, La Jolla, CA, said the randomized, single-center, open-label, 2-period, 8-week study included a crossover at 4 weeks between latanoprostene bunod 0.024% once-daily with timolol maleate 0.5% twice-daily.

“A comparison against timolol is an industry standard,” he said. “I hope that this new compound will be compared against other prostaglandin analogues in the future.”

The CONSTELLATION STUDY

In the CONSTELLATION study (registered at clinicaltrials.gov under NCT01707381), 20 subjects between 43 and 82 years old, who had baseline IOPs of at least 22 mm Hg in one eye and less than 36 mmHg in both eyes and a diagnosis of open-angle glaucoma or ocular hypertension were enrolled.

Both treatment-naïve and pre-treated patients were included (as long as they met the IOP requirements after washout). Among the exclusion criteria were people with irregular daily sleep schedules; people with previous or active corneal disease, severe dry eye, active optic disc hemorrhage, a history or central or branch retinal vein occlusion, a history of macular edema, or who had very narrow angles.

Additionally, patients with angle closure, congenital, and secondary glaucoma were also excluded, as were patients who had undergone ocular laser surgery within 3 months prior to the screening visit.

Study details

Patients were housed in a sleep laboratory for 24 hours and a baseline IOP profile was created. IOP of both eyes was measured with a pneumatonometer every two hours in the sitting and supine positions from 8 a.m. to 10 p.m., and in the supine position only from 12 to 6 a.m.

During the first period of the study subjects were randomly assigned 1:1 to either of 2 treatment sequences: latanoprostene bunod 0.024% instilled in both eyes at 8 p.m. or timolol maleate 0.5% instilled twice a day at 8 a.m. and 8 p.m.

After four weeks of treatment, subjects were housed in the sleep laboratory for a second 24-hour period IOP measurement. At the end of the 24 hours, subjects were crossed over to receive the comparator treatment, which initiated period 2.

“If needed, a washout of glaucoma medication was done before the baseline 24-hour IOP measurement,” Dr. Liu said. “After the crossover, the second test agent was treated for 4 weeks. At the same time, the first test agent was in the washout for 4 weeks.”

After the period 2 treatment time frame ended, patients returned to the sleep laboratory for a third 24-hour IOP measurement.

How the compounds differ

Latanoprostene bunod differs from latanoprost in that the former compound is metabolized in situ to latanoprost acid plus butanediol mononitrate. Butanediol mononitrate is a nitric-oxide (NO)-donate moiety, Dr. Liu said.

“Nitric oxide can dilate blood vessels,” he said. “Previous animal studies indicated that nitric oxide can also lower IOP.”

In this study, latanoprostene bunod lowered IOP for 24 hours (day and night), whereas timolol was able to reduce only the daytime IOP. The mean change from baseline in IOP was 3.9±0.28 mm Hg for latanoprostene bunod treated eyes and 2.4 ± 0.29 mm Hg for timolol treated eyes during the diurnal/wake period; 2.75 ± 0.45 mm Hg for latanoprostene bunod and 0.2 ± 0.46 mm Hg for timolol during the nocturnal/sleep period; and 3.5 ± 0.24 mmHg for latanoprostene bunod and 1.7±0.25 mm Hg for timolol during the entire 24 hour period.

Dr. Liu added the sample size was too small to determine if any differences existed by age, gender, or length of time since diagnosis.

Clinically, Dr. Liu said the promising aspect of the study is that latanoprostene bunod “seems to have IOP-lowering efficacy during the daytime and at night.”

Latanoprostene bunod program

Latanoprostene bunod will be co-promoted in the United States by Nicox and Bausch + Lomb. In January 2013, Bausch + Lomb initiated a phase III clinical program for latanoprostene bunod with two pivotal studies, APOLLO and LUNAR. These studies are designed to compare the efficacy and safety of latanoprostene bunod administered once daily with timolol maleate 0.5% administered twice daily in lowering IOP in patients with open-angle glaucoma or ocular hypertension.

The primary endpoint of both studies, which will include a combined total of about 800 patients, is the reduction in mean IOP measured at specified time points during three months of treatment.

In July 2013, Bausch + Lomb also initiated two studies in Japan.

JUPITER is a phase III study enrolling about 130 subjects. Its purpose is to demonstrate the clinical safety of latanoprostene bunod 0.024% administrated once daily over a 1-year treatment period.

KRONUS is a phase I study. Its primary objective is to evaluate the effect of latanoprostene bunod 0.024% administered once daily in reducing IOP measured over a 24-hour period in approximately 24 healthy male Japanese subjects.

A confirmatory efficacy study is expected to be required for the Japanese registration of latanoprostene bunod.

John H. Liu, PhD

E: joliu@ucsd.edu

This article was adapted from Dr. Liu’s presentation at the 2014 meeting of the Association for Research in Vision and Ophthalmology. Dr. Liu has received financial support from Aerie Pharmaceuticals, Alcon Laboratories, Allergan, Bausch + Lomb, NASA, and Sensimed.