Purpose
To evaluate the ocular and systemic safety and systemic absorption of AR-13324 in normotensive, healthy volunteers.
Design
Open-label, noncomparative, single-arm phase 1 clinical trial.
Methods
setting : Phase 1 clinical trials unit. patient or study population : Eighteen normal adult volunteers. intervention or observation procedures : Subjects received AR-13324 ophthalmic solution 0.02% once daily in the morning in each eye for 8 days. main outcome measures : Plasma concentrations of AR-13324 and its presumed human metabolite, AR-13503, and ocular safety measures.
Results
There were no observed plasma AR-13324 concentrations higher than the lower limit of quantitation at any time point in any subject. Only 1 plasma sample from 1 subject (day 8 at 8 hours after dose administration) had an AR-13503 concentration higher than the lower limit of quantitation (0.11 ng/mL). AR-13324 dosed once daily in the morning produced substantial reductions in baseline intraocular pressure of up to 6 mm Hg that were statistically significant ( P < .001) at all time points after dose administration. All but 1 subject exhibited transient conjunctival hyperemia to some degree in the 8-hour period after morning dosing.
Conclusions
AR-13324 ophthalmic solution 0.2%, administered once daily in the morning for 8 days, produced little or no quantifiable systemic exposure to the parent compound or a presumed metabolite. Clinically and statistically significant reductions in intraocular pressure were observed in these normotensive subjects that were more pronounced compared with what has been observed commonly with other ocular hypotensive therapies in this population.
Longitudinal studies of treatment of glaucoma and ocular hypertension demonstrate that lowering intraocular pressure (IOP) decreases the development of glaucomatous visual field loss. Current treatment guidelines for the management of glaucomatous disease center on the reduction of IOP, be it by pharmacologic, surgical, or laser methods.
There are a host of approved, effective ocular hypotensive medications. For up to half of patients, however, a single glaucoma medication is not sufficiently effective as monotherapy to achieve target IOP. The medical treatment regimen for these patients typically increases in complexity, requiring coadministration of 2 or more glaucoma medications, 1 or more of which requires dosing 2 to 3 times daily. As glaucoma treatment regimens increase in complexity, patients become less compliant with the therapy. Thus, there remains a need for novel pharmacotherapies that can produce effective IOP lowering while providing a convenient, once-daily dosing regimen.
A new class of topical agents being evaluated for the treatment of glaucoma is Rho kinase inhibitors. Rho kinase inhibitors seem to lower IOP through a different mechanism of action than current glaucoma medications, altering the actin cytoskeleton of cells within the trabecular outflow pathway of the eye to increase aqueous humor drainage (Wang RF. IOVS 2009;50:ARVO E-Abstract 1465).
AR-12286 is a potent and selective Rho kinase inhibitor that was evaluated previously for its effectiveness in lowering IOP in both normotensive volunteers and in patients with elevated IOPs. In patients with open-angle glaucoma or ocular hypertension, AR-12286 ophthalmic solution 0.25% produced reductions in IOP of 6 mm Hg at peak effect and 3.2 mm Hg at trough when dosed once daily in the morning for 7 days. In normotensive volunteers, AR-12286 ophthalmic solution 0.5%, dosed once daily in the morning for 8 days, produced reductions in IOP of 6.8 mm Hg at peak and 2.9 mm Hg at trough. Most IOP-lowering medications produce substantially smaller IOP reductions in subjects with lower baseline IOPs compared with those with higher baseline IOPs. The ability of an IOP-lowering compound to produce similar IOP reductions in hypertensive patients and normotensive volunteers is an uncommon finding.
AR-13324 is a new compound under development for the treatment of glaucoma that is a potent Rho kinase inhibitor and also an inhibitor of the norepinephrine transporter. A study of aqueous humor dynamics in normotensive nonhuman primates revealed that AR-13324 reduces IOP by increasing outflow facility, like other Rho kinase inhibitors, but it also decreases the production of aqueous.
The ability of AR-13324 to decrease aqueous production may result from its inhibition of the norepinephrine transporter, because Rho kinase inhibitors that lack this activity have no effect on aqueous production (Wang R-F. IOVS 2012;53:ARVO E-Abstract 1994). In a first-in-human study in ocular hypertensive patients diagnosed with open-angle glaucoma or ocular hypertension, once-daily administration of AR-13324 ophthalmic solution 0.01% to 0.04% in the morning for 7 days produced large reductions in IOP that were statistically and clinically significant. The 0.02% concentration of AR-13324 seemed to reach the top of the dose-response curve and produced IOP reductions of 6.9 mm Hg at peak and 5.8 mm Hg at trough. The only safety finding of note was dose-related ocular hyperemia that declined in incidence and severity with repeated dosing (Weiss MJ. IOVS 2013;ARVO E-abstract 754; clinicaltrial.gov identifier, NCT01528787 ). The objective of the present study was to evaluate the ocular and systemic safety and the systemic absorption of AR-13324 in normotensive, healthy volunteers.
Methods
Subjects
This was an open-label, noncomparative, single-arm phase 1 clinical trial conducted at the Celerion facility in Tempe, Arizona, in November 2013. The study was approved by Chesapeake IRB (Columbia, Maryland), and all subjects were provided with and signed a written informed consent to participate in this research study. Subjects included in this study were healthy adults within 25% of their ideal weights with no clinically significant screening results (laboratory profile, medical history, electrocardiography, physical examination). Tobacco use was prohibited. Subjects underwent a complete dilated eye examination and were required to have bilateral IOP measurements between 14 and 20 mm Hg as measured by Goldmann applanation tonometry and best-corrected visual acuity of 20/40 (0.3 logarithm of the minimal angle of resolution) or better in each eye. Excluded from the study were individuals with recent blood donations, clinically significant systemic disease, or use of any medication that could have a substantial effect on IOP within 30 days before screening or during the study. Also excluded from the study were individuals with chronic or acute ophthalmic disease; those with previous glaucoma diagnosis; previous refractive, intraocular, or laser surgery; those with central corneal thickness of more than 600 μm; and women of childbearing potential who were pregnant, nursing, planning a pregnancy, or not using a medically acceptable form of birth control.
Study Conduct
After confirmation of qualifications, subjects received AR-13324 ophthalmic solution 0.02% once daily in the morning in each eye for 8 days. Ocular safety was evaluated in the clinic throughout this period and blood samples were collected at multiple times after dosing for subsequent measurement of AR-13324 and its presumed metabolite, AR-13503.
Subjects who met the initial entry criteria were screened for general health including clinical laboratory tests (chemistry panel, complete blood count, and urinalysis), electrocardiography, and a complete dilated eye examination. IOP was measured in the morning and then 4 and 8 hours subsequently to generate a diurnal baseline.
Subjects returned on a subsequent day between 08:00 and 10:00 am to begin the dosing period (day 1). This morning visit included an eye examination and IOP measurement, after which study medication was instilled by site personnel. Additional examinations occurred over the next 8 hours. Vital signs and blood draws were obtained at 0.25, 0.5, 1, 2, 4, and 8 hours after instillation. Biomicroscopy was carried out at all time points except 0.25 hours after instillation, and IOP was measured at 4 and 8 hours after instillation. On days 2 to 7 of each period, subjects self-administered their masked investigational medication in the morning and so noted in a diary. Contact lens wear was not allowed within 30 minutes of instillation of study medication. Subjects returned for a final visit on day 8. The procedures conducted on day 8 were the same as those conducted on day 1. This study is registered with www.clinicaltrials.gov as study number NCT01997879 .
Pharmacokinetics
Plasma concentrations of AR-13324 and its presumed human metabolite, AR-13503, were determined using high-performance liquid chromatography-tandem mass spectrometry methods validated with respect to accuracy, precision, linearity, sensitivity, and specificity at Tandem Labs–RTP, Durham, North Carolina. The lower limit of quantitation for both molecules was 0.1 ng/mL. Subjects for whom there was insufficient data (fewer than 3 data points higher than the low limit of quantitation) to calculate the pharmacokinetic parameters were not to be included in pharmacokinetic statistical analyses.
Data Management and Statistics
The sample size of 18 subjects was based on the typical size of similar phase 1 studies. IOP results at screening, day 1, and day 8 were summarized by time point and treatment. Within each time point, 2 consecutive IOP measurements of each eye were obtained. If the 2 measurements differed by more than 2 mm Hg, a third measurement was obtained. IOP was analyzed as the mean of 2 measurements or as the median of 3 measurements. The value used for IOP analysis was the average from both eyes. Descriptive statistics were reported for actual and change from diurnally adjusted baseline values by treatment and time point. The screening IOP measurements at hours −0.5, 4, and 8 served as the baseline values for the corresponding IOP measurements at hours −0.5, 4, and 8 on subsequent days. A paired t test was conducted to compare the within-treatment postdose value against the corresponding baseline value at each postdose time point. The frequency of treatment-emergent adverse events was summarized using the Medical Dictionary for Regulatory Activities version 16.1 (MedDRA, McLean, Virginia) preferred terms and system organ classes.
Results
Patient Disposition and Demographics
All 18 enrolled subjects successfully completed the study. The subjects were all white; 61% (11/17) were of Hispanic or Latino ethnicity and 78% (14/18) were women. The mean age was 47.6 years (range, 24 to 74 years; Table 1 ).
| Measure | Overall (n = 18; 100%) |
|---|---|
| Gender | |
| Female | 14 (78) |
| Male | 4 (22) |
| White race | 18 (100) |
| Ethnicity | |
| Hispanic or Latino | 11 (61) |
| Not Hispanic or Latino | 7 (39) |
| Age (y) | 47.6 ± 16.5 |
| Weight (lbs) | 147.4 ± 24.5 |
| Height (in) | 63.8 ± 4.4 |
| Body mass index (kg/m 2 ) | 25.4 ± 3.1 |
| Mean central corneal thickness (μm) a | 550.7 ± 31.0 |
| Mean cup-to-disc ratio (μm) a | 0.35 ± 0.18 |
Pharmacokinetics
There were no observed plasma AR-13324 concentrations above the lower limit of quantitation at any time point in any subject. Only 1 plasma sample from 1 subject (day 8 at 8 hours after dose administration) had an AR-13503 concentration above the lower limit of quantitation (0.11 ng/mL). As a result, no pharmacokinetic analyses could be performed.
Intraocular Pressure
AR-13324 dosed once daily in the morning produced substantial reductions from baseline IOP that were statistically significant ( P < .001) at all time points after dosing ( Table 2 ; Figure 1 ). On day −1, baseline mean IOP at −0.5 hours, 4 hours, and 8 hours was 16.3 mm Hg, 16.6 mm Hg, and 15.9 mm Hg, respectively. Following the first morning dose on day 1, mean IOP at 4 and 8 hours was reduced to 14.5 mm Hg (−2.1 mm Hg) and 13.4 mm Hg (−2.5 mm Hg), respectively. Additional IOP reduction was observed on day 8 of treatment, with mean IOP at −0.5 hours (24 hours after day 7 dosing), 4 hours, and 8 hours reduced to 12.3 mm Hg (−3.9 mm Hg), 10.5 mm Hg (−6.0 mm Hg), and 11.2 mm Hg (−4.8 mm Hg), respectively. Mean diurnal IOP on day 8 was reduced from 16.2 mm Hg at baseline to 11.3 mm Hg, a 30% reduction. Reductions in mean diurnal IOP of 25% or more at day 8 were achieved by 13 (72%) of 18 subjects on day 8, and reductions of 35% or more were achieved by 5 (28%) of 18 subjects.
| Statistics by Time Point | Baseline (n = 18) a | Result (n = 18) | Change from Baseline (n = 18) |
|---|---|---|---|
| Screening | |||
| Mean | 16.17 | ||
| SD | 1.590 | ||
| Median | 16.00 | ||
| P value b | |||
| Day 1 | |||
| Hour −0.5 | |||
| Mean | 16.28 | 16.17 | −0.11 |
| SD | 2.074 | 2.203 | 1.614 |
| Median | 16.00 | 16.00 | −0.25 |
| P value b | .7737 | ||
| Hour 4 | |||
| Mean | 16.56 | 14.50 | −2.06 |
| SD | 2.093 | 1.963 | 1.381 |
| Median | 15.50 | 14.00 | −1.50 |
| P value b | <.0001 | ||
| Hour 4 | |||
| Mean | 15.94 | 13.42 | −2.53 |
| SD | 1.806 | 2.211 | 1.230 |
| Median | 15.50 | 13.25 | −2.50 |
| P value b | <.0001 | ||
| Day 8 | |||
| Hour 0.5 | |||
| Mean | 16.28 | 12.33 | −3.94 |
| SD | 2.074 | 2.550 | 1.617 |
| Median | 16.00 | 11.75 | −4.00 |
| P value b | <.0001 | ||
| Hour 4 | |||
| Mean | 16.56 | 10.53 | −6.03 |
| SD | 2.093 | 2.581 | 1.929 |
| Median | 15.50 | 10.25 | −6.00 |
| P value b | <.0001 | ||
| Hour 8 | |||
| Mean | 15.94 | 11.17 | −4.78 |
| SD | 1.806 | 2.345 | 1.776 |
| Median | 15.50 | 10.50 | −4.50 |
| P value b | <.0001 |
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