Two Phase 3 Clinical Trials Comparing the Safety and Efficacy of Netarsudil to Timolol in Patients With Elevated Intraocular Pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2)

Serle, Janet B.; Katz, L. Jay; McLaurin, Eugene; Heah, Theresa; Ramirez-Davis, Nancy; Usner, Dale W; Novack, Gary D.; Kopczynski, Casey; Groups, Rocket Study

doi:10.1016/j.ajo.2017.11.019

Cited by 204 publications

(258 citation statements)

References 27 publications

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“…No treatment-related serious AEs were reported in any treatment arm ( Cornea verticillata was reported in 15.4% (74/482) of patients receiving netarsudil/latanoprost FDC, 11.6% (58/498) of those receiving netarsudil, and no patients (0/488) receiving latanoprost. This frequency was as observed in previous studies with netarsudil [15]. Most cases of cornea verticillata were mild: 98.6% (73/74) of affected patients treated with netarsudil/latanoprost FDC and 96.6% (56/58) of affected patients treated with netarsudil.…”

Section: Safetysupporting

confidence: 88%

“…Netarsudil, a Rho kinase (ROCK) inhibitor, was approved by the US Food and Drug Administration in December 2017 for reducing IOP in patients with OAG or OHT [10]. Netarsudil targets the underlying pathophysiology of elevated IOP, increased trabecular outflow resistance, and thereby increases trabecular outflow and reduces IOP [11][12][13][14][15][16]. Latanoprost, the most commonly prescribed prostaglandin analogue, has a complementary mechanism of action, lowering IOP by increasing uveoscleral outflow [9,17].…”

Section: Introductionmentioning

confidence: 99%

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Fixed-Dose Combination of Netarsudil and Latanoprost in Ocular Hypertension and Open-Angle Glaucoma: Pooled Efficacy/Safety Analysis of Phase 3 MERCURY-1 and -2

et al. 2020

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Introduction: New open-angle glaucoma (OAG) and ocular hypertension (OHT) therapies that reduce treatment burden and improve outcomes relative to currently available agents are needed. Netarsudil, a novel Rho kinase inhibitor approved by the US Food and Drug Administration, reduces intraocular pressure (IOP) by increasing trabecular outflow. Two phase 3 superiority studies compared a fixeddose combination (FDC) of netarsudil and the prostaglandin latanoprost with each active component for IOP-lowering efficacy. Methods: Pooled efficacy and safety data were analyzed from MERCURY-1 and -2 studies in patients with OAG or OHT. Patients instilled one drop of netarsudil (0.02%)/latanoprost (0.005%) FDC (n = 483), netarsudil (0.02%, n = 499), or latanoprost (0.005%, n = 486) into each eye

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Section: Safetysupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Fixed-Dose Combination of Netarsudil and Latanoprost in Ocular Hypertension and Open-Angle Glaucoma: Pooled Efficacy/Safety Analysis of Phase 3 MERCURY-1 and -2

et al. 2020

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“…Even though dysfunction of the trabecular outflow pathway is responsible for elevated IOP, clinically, most of IOP-lowering medications target the unconventional outflow pathway or secretion. New medications targeting the predominant drainage pathway (the TM pathway) are in high demand, including two recently approved medications (8, 12, 13). Thus, rho kinase inhibitors and nitric oxide drugs are the results of research over the last 25 years that identified important regulatory processes in the trabecular outflow pathway (8).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

Drewry

Cai

Helwa

et al. 2018

Preprint

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Purpose Regulation of intraocular pressure is dependent upon homeostatic responses of trabecular meshwork (TM) cells to mechanical stretch. Despite the important roles of miRNAs in regulating TM function and aqueous outflow, it remains unclear how miRNA and their target genes interact in response to physiological cyclic mechanical stretch. We aimed to identify differentially expressed miRNAs and their potential targets in human TM cells in response to cyclic mechanical stress.Methods Monolayers of TM cells from non-glaucomatous donors (n=3-6) were cultured in the presence or absence of 15% mechanical stretch, 1 cycle/s, for 6 or 24-hours using computer-controlled Flexcell Unit. We profiled the expression of 800 miRNAs using NanoString Human miRNA assays and identified differentially expressed miRNAs using the Bioconductor Limma package. We identified differentially expressed genes using Operon Human Oligo Arrays with GeneSpring software. Pathway analysis with WebGestalt identified stretch-related pathways. We used Integrative miRNA Target Finder from Ingenuity Pathway Analysis to identify potential miRNA-mRNA regulations. ResultsWe identified 540 unique genes and 74 miRNAs with differential expression in TM cells upon cyclic mechanical stretch. Pathway analysis indicated the significant enrichment of genes involved in Wnt-signaling, receptor protein serine/threonine kinase signaling, TGF-β pathway, and response to unfolded protein. We also identified several miRNA master regulators, including miR-19b-3p and miR-93-5p, which may act as switches to control several mechano-responsive genes. ConclusionsThis study suggests that cyclic mechanical stress of TM cells triggers alterations in the expression of both mRNAs and miRNAs implicated in glaucoma-associated pathways.

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“…Aqueous humor production is reduced primarily through its action on the norepinephrine transporter, while the inhibition of Rho-kinase reduces stiffness [26] and stress fibers in the TM as seen with other Rho-kinase inhibitors [30] . The impact on vessel diameters is variable, but in clinical use, conjunctival hyperemia is a common observation [31] and probably caused by rendering vascular smooth muscle cells less sensitive to intracellular Ca 2+ [32] .…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent effects of netarsudil, a Rho-kinase inhibitor, on the distal outflow tract

Chen

Waxman

Wang

et al. 2020

Preprint

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AbstractPurposeTo characterize the effects of netarsudil on the aqueous humor outflow tract distal to the trabecular meshwork (TM). We hypothesized that netarsudil increases outflow facility in eyes with and without circumferential ab interno trabeculectomy (AIT) that removes the TM.Methods64 porcine anterior segment cultures were randomly assigned to groups with (n=32) and without circumferential AIT (n=32). Cultures were exposed to 0.1, 1, and 10 μM netarsudil (N= 8 eyes per concentration). For each concentration, IOP and vessel diameters were compared to their respective pretreatment baselines. Outflow tract vessel diameters were assessed by spectral-domain optical coherence tomography (SDOCT) and rendered in 4D (XYZ time-series).ResultsNetarsudil at 1 μM reduced IOP in both eyes with TM (−0.60±0.24 mmHg, p = 0.01) and in eyes without TM (−1.79±0.42 mmHg, p<0.01). At this concentration, vessels of the distal outflow tract dilated by 72%. However, at 0.1 μM netarsudil elevated IOP in eyes with TM (1.59±0.36 mmHg, p<0.001) as well as in eyes without TM (0.23±0.32 mmHg, p<0.001). Vessels of the distal outflow tract constricted by 31%. Similarly, netarsudil at a concentration of 10 μM elevated IOP both in eyes with TM (1.91±0.193, p<0.001) and in eyes without TM (3.65±0.86 mmHg, p<0.001). At this concentration, outflow tract vessels constricted by 27%.ConclusionIn the porcine anterior segment culture, the dose-dependent IOP changes caused by netarsudil matched the diameter changes of distal outflow tract vessels. Hyper- and hypotensive properties of netarsudil persisted after TM removal.

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Two Phase 3 Clinical Trials Comparing the Safety and Efficacy of Netarsudil to Timolol in Patients With Elevated Intraocular Pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2)

Cited by 204 publications

References 27 publications

Fixed-Dose Combination of Netarsudil and Latanoprost in Ocular Hypertension and Open-Angle Glaucoma: Pooled Efficacy/Safety Analysis of Phase 3 MERCURY-1 and -2

Fixed-Dose Combination of Netarsudil and Latanoprost in Ocular Hypertension and Open-Angle Glaucoma: Pooled Efficacy/Safety Analysis of Phase 3 MERCURY-1 and -2

Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

Dose-dependent effects of netarsudil, a Rho-kinase inhibitor, on the distal outflow tract

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