| Reference | 1. Am J Ophthalmol. 2017 Nov 30. pii: S0002-9394(17)30513-5. doi:
10.1016/j.ajo.2017.11.019. [Epub ahead of print] <br />
Two Phase 3 clinical trials comparing the safety and efficacy of netarsudil to
timolol in patients with elevated intraocular pressure. <br />
Serle JB(1), Katz LJ(2), McLaurin E(3), Heah T(4), Ramirez-Davis N(4), Usner
DW(5), Novack GD(6), Kopczynski CC(4); ROCKET-1 and ROCKET-2 Study Groups. <br />
Collaborators: Asrani S, Bacharach J, Belyea D, Berlin MS, Brubaker JW, Cacioppo
LR, Cohn EA, Cooke DL, DuBiner HB, El-Harazi SM, Evans R, Hartman CT, Jerkins GW,
Klugo KL, Korenfeld MS, Kwapizeski B, McLaurin EB, Myers JS, Okeke C, Peace JH,
Protzko EE, Reinstein NM, Ritch R, Rubin MS, Saltzmann RM, Schenker HI, Lee
Shettle P, Smetana S, Sturm RT, Sulkowski GM, Tsai J, Tubbs C, Tyson FC,
Vajaranant TS, Wirta DL, Wollan P, Woodruff TE, Alpern LM, Bacharach J, Barnebey
H, Benza R, Berenguer RA, Boyle JW 4th, Branch JD, Brown DC, Budenz DL, Lawrence
S, Christie WC, James C, Daines BS, Day DG, Depenbusch MJ, Dixon ED, DuBiner HB,
Duzman E, Eippert GA, El-Harazi SM, Evans RM, Gonzalez VH, Goyal RK, Graul T,
Haynes WL, Hirshfield GS, Kamae KK, Kim J, Kwapiszeski B, Lari HB, LePosa AG,
Levy N, Lin C, Linn J, Logan AG, Lozier JR, McCormack DL, McLaurin EB, Meier E,
Miller-Ellis E, Mundorf TK, Breckenridge Murphy RR, Pai VC, Peace JH, Realini A,
Sall K, Sharpe ED, Silverstein SM, Simmons BG, Simmons ST, Smith S, Smith S,
Smyth-Medina RJ, Stamper R, Sturm RT, Swanic MJ, Tepedino ME, Tsai J, Armin V,
Walters TR, Weiss MJ, Wirta DL, WuDunn D. <br />
Author information: <br />
(1)Icahn School of Medicine at Mount Sinai, New York, NY.
(2)Wills Eye Hospital, Philadelphia, PA.
(3)Total Eye Care, Memphis, TN.
(4)Aerie Pharmaceuticals, Inc., Bedminster, NJ, and Durham, NC.
(5)SDC, Tempe, AZ.
(6)PharmaLogic Development, Inc., San Rafael, CA; Departments of Pharmacology and
Ophthalmology, University of California, Davis, School of Medicine. Electronic
address: [email protected]. <br />
PURPOSE: To evaluate the efficacy and ocular and systemic safety of netarsudil
0.02% ophthalmic solution, a rho-kinase inhibitor and norepinephrine transporter
inhibitor, in patients with open-angle glaucoma and ocular hypertension.
DESIGN: Double-masked, randomized non-inferiority clinical trials.<br />
METHODS: After a washout of all pre-study ocular hypotensive medications,
eligible patients were randomized to receive netarsudil 0.02%, q.d., timolol 0.5%
b.i.d., and (ROCKET-2 only), netarsudil 0.02%, b.i.d. Data through 3 months from
both studies are provided in this report.<br />
RESULTS: Enrolled into the two studies were 1,167 patients. Treatment with
netarsudil q.d. produced clinically and statistically significant reductions from
baseline intraocular pressure (p < 0.001), and was non-inferior to timolol in the
per-protocol population with maximum baseline IOP < 25 mmHg in both studies
(ROCKET-2, primary outcome measure and population, ROCKET-1, post hoc outcome
measure). Netarsudil b.i.d. was also non-inferior to timolol (ROCKET-2). The most
frequent adverse event was conjunctival hyperemia, the incidence of which ranged
from 50% (126/251, ROCKET-2) to 53% (108/203, ROCKET-1) for netarsudil q.d., 59%
(149/253, ROCKET-2) for netarsudil b.i.d., and 8% (17/208, ROCKET-1) to 11%
(27/251, ROCKET-2) for timolol (p < 0.0001for netarsudil vs. timolol).<br />
CONCLUSIONS: In two large, randomized, double-masked trials reported here,
once-daily dosing of netarsudil 0.02% was found to be effective and
well-tolerated for the treatment of patients with ocular hypertension and
open-angle glaucoma. The novel pharmacology and aqueous humor dynamic effects of
this molecule suggest it may be a useful addition to the armamentarium of ocular
hypotensive medications. <br />
2. J Ocul Pharmacol Ther. 2017 Jun 13. doi: 10.1089/jop.2017.0023. [Epub ahead of
print] <br />
Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive
Agent for the Treatment of Glaucoma. <br />
Lin CW(1), Sherman B(1), Moore LA(1), Laethem CL(1), Lu DW(2), Pattabiraman
PP(3), Rao PV(3), deLong MA(1), Kopczynski CC(1). <br />
Author information: <br />
(1)1 Aerie Pharmaceuticals, Inc. , Durham, North Carolina.
(2)2 National Defense Medical Center , Taipei City, Taiwan .
(3)3 Department of Ophthalmology, Duke University School of Medicine , Durham,
North Carolina. <br />
PURPOSE: Rho-associated protein kinase (ROCK) inhibitors lower intraocular
pressure (IOP) by increasing aqueous outflow through the trabecular meshwork
(TM). The preclinical characterization of netarsudil, a new ROCK/norepinephrine
transporter (NET) inhibitor currently in clinical development, is presented
herein.<br />
METHODS: The kinase inhibitory activity of netarsudil was compared to its
esterase metabolite, netarsudil-M1, and 3 other ROCK inhibitors using a
commercially available kinase assay kit. Disruption of actin stress fibers was
measured in primary porcine TM cells and disruption of focal adhesions in
transformed human TM (HTM) cells. Induction of fibrosis markers after exposure to
transforming growth factor-β2 (TGF-β2) was conducted in primary HTM cells. Ocular
hypotensive activity and tolerability of topical formulations were evaluated in
normotensive Dutch Belted rabbits and Formosan Rock monkeys. In vitro corneal
metabolism assays were conducted using dog, pig, rabbit, monkey, and human
corneas. In vivo ocular pharmacokinetics was studied in Dutch Belted rabbits.
RESULTS: Netarsudil inhibited kinases ROCK1 and ROCK2 with a Ki of 1 nM each,
disrupted actin stress fibers and focal adhesions in TM cells with IC50s of 79
and 16 nM, respectively, and blocked the profibrotic effects of TGF-β2 in HTM
cells. Netarsudil produced large reductions in IOP in rabbits and monkeys that
were sustained for at least 24 h after once daily dosing, with transient, mild
hyperemia observed as the only adverse effect.<br />
CONCLUSION: Netarsudil is a novel ROCK/NET inhibitor with high potency in
biochemical and cell-based assays, an ability to produce large and durable IOP
reductions in animal models, and favorable pharmacokinetic and ocular
tolerability profiles. <br />
3. Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):6197-6209. doi:
10.1167/iovs.16-20189. <br />
Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms. <br />
Ren R(1), Li G(2), Le TD(3), Kopczynski C(4), Stamer WD(2), Gong H(1). <br />
Author information: <br />
(1)Department of Ophthalmology, Boston University School of Medicine, Boston,
Massachusetts, United States 2Department of Anatomoy and Neurobiology, Boston
University School of Medicine, Boston, Massachusetts, United States.
(2)Department of Ophthalmology, Duke University, Durham, North Carolina, United
States.
(3)Department of Ophthalmology, Boston University School of Medicine, Boston,
Massachusetts, United States.
(4)Aerie Pharmaceuticals, Inc., Durham, North Carolina, United States. <br />
Purpose: Netarsudil is a Rho kinase/norepinephrine transporter inhibitor
currently in phase 3 clinical development for glaucoma treatment. We investigated
the effects of its active metabolite, netarsudil-M1, on outflow facility (C),
outflow hydrodynamics, and morphology of the conventional outflow pathway in
enucleated human eyes.<br />
Methods: Paired human eyes (n = 5) were perfused with either 0.3 μM netarsudil-M1
or vehicle solution at constant pressure (15 mm Hg). After 3 hours, fluorescent
microspheres were added to perfusion media to trace the outflow patterns before
perfusion-fixation. The percentage effective filtration length (PEFL) was
calculated from the measured lengths of tracer distribution in the trabecular
meshwork (TM), episcleral veins (ESVs), and along the inner wall (IW) of
Schlemm/’s canal after global and confocal imaging. Morphologic changes along the
trabecular outflow pathway were investigated by confocal, light, and electron
microscopy.<br />
Results: Perfusion with netarsudil-M1 significantly increased C when compared to
baseline (51%, P < 0.01) and to paired controls (102%, P < 0.01), as well as
significantly increased PEFL in both IW (P < 0.05) and ESVs (P < 0.01). In
treated eyes, PEFL was significantly higher in ESVs than in the IW (P < 0.01) and
was associated with increased cross-sectional area of ESVs (P < 0.01). Percentage
effective filtration length in ESVs positively correlated with the percentage
change in C (R2 = 0.58, P = 0.01). A significant increase in juxtacanalicular
connective tissue (JCT) thickness (P < 0.05) was found in treated eyes compared
to controls.<br />
Conclusions: Netarsudil acutely increased C by expansion of the JCT and dilating
the ESVs, which led to redistribution of aqueous outflow through a larger area of
the IW and ESVs. <br />
4. Eur J Pharmacol. 2016 Sep 15;787:20-31. doi: 10.1016/j.ejphar.2016.04.002. Epub
2016 Apr 13. <br />
Visualization of conventional outflow tissue responses to netarsudil in living
mouse eyes. <br />
Li G(1), Mukherjee D(2), Navarro I(1), Ashpole NE(1), Sherwood JM(3), Chang J(2),
Overby DR(3), Yuan F(2), Gonzalez P(1), Kopczynski CC(4), Farsiu S(5), Stamer
WD(6). <br />
Author information: <br />
(1)Department of Ophthalmology, Duke University, Durham, NC 27710, USA.
(2)Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
(3)Department of Bioengineering, Imperial College London, London SW7 2AZ, United
Kingdom.
(4)Aerie Pharmaceuticals, Inc., Durham, NC 27713, USA.
(5)Department of Ophthalmology, Duke University, Durham, NC 27710, USA;
Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
(6)Department of Ophthalmology, Duke University, Durham, NC 27710, USA;
Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
Electronic address: [email protected]. <br />
Visual impairment due to glaucoma currently impacts 70 million people worldwide.
While disease progression can be slowed or stopped with effective lowering of
intraocular pressure, current medical treatments are often inadequate.
Fortunately, three new classes of therapeutics that target the diseased
conventional outflow tissue responsible for ocular hypertension are in the final
stages of human testing. The rho kinase inhibitors have proven particularly
efficacious and additive to current therapies. Unfortunately, non-contact
technology that monitors the health of outflow tissue and its response to
conventional outflow therapy is not available clinically. Using optical coherence
tomographic (OCT) imaging and novel segmentation software, we present the first
demonstration of drug effects on conventional outflow tissues in living eyes.
Topical netarsudil (formerly AR-13324), a rho kinase/ norepinephrine transporter
inhibitor, affected both proximal (trabecular meshwork and Schlemm/’s Canal) and
distal portions (intrascleral vessels) of the mouse conventional outflow tract.
Hence, increased perfusion of outflow tissues was reliably resolved by OCT as
widening of the trabecular meshwork and significant increases in cross-sectional
area of Schlemm/’s canal following netarsudil treatment. These changes occurred in
conjunction with increased outflow facility, increased speckle variance intensity
of outflow vessels, increased tracer deposition in conventional outflow tissues
and decreased intraocular pressure. This is the first report using live imaging
to show real-time drug effects on conventional outflow tissues and specifically
the mechanism of action of netarsudil in mouse eyes. Advancements here pave the
way for development of a clinic-friendly OCT platform for monitoring glaucoma
therapy. <br />
5. Bioorg Med Chem Lett. 2016 May 15;26(10):2475-80. doi:
10.1016/j.bmcl.2016.03.104. Epub 2016 Apr 1. <br />
Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle
glaucoma. <br />
Sturdivant JM(1), Royalty SM(2), Lin CW(2), Moore LA(2), Yingling JD(2), Laethem
CL(2), Sherman B(2), Heintzelman GR(2), Kopczynski CC(2), deLong MA(2). <br />
Author information: <br />
(1)Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC
27703, United States. Electronic address: [email protected].
(2)Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC
27703, United States. <br />
Inhibition of Rho kinase (ROCK) to improve fluid outflow through the trabecular
meshwork and lower intraocular pressure is a strategy for the development of new
anti-glaucoma agents. Alpha-aryl-beta-amino isoquinoline analogs were identified
as potent ROCK inhibitors. Compounds that provided a longer duration of
intraocular pressure reduction in Dutch Belted rabbits also inhibited
norepinephrine transporter. Ester 60 improved bioavailability of its parent ROCK
inhibitor, 29 (Ki=0.2nM) and demonstrated an effective and sustained IOP
reduction for 24h after dosing. From these studies, netarsudil (a.k.a. AR-13324)
was discovered and is currently in clinical trials for the treatment of glaucoma
and ocular hypertension. <br />
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