Intraocular Pressure–Lowering Activity of NCX 470, a Novel Nitric Oxide–Donating Bimatoprost in Preclinical Models

Abstract

PURPOSE. The prostaglandin F2alpha (PGF2a) analogue bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470, a dual-acting compound combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal.METHODS. New Zealand white rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were determined in aqueous humor (AH), cornea (CR), and iris/ciliary body (ICB) by liquid chromatography-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits.RESULTS. NCX 470 (0.14%, 30 lL) lowered IOP in tOHT-rabbits with an E max of À7.2 6 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 lL) was noneffective in this model. NCX 470 (0.042%, 30 lL) was more effective than equimolar (0.03%, 30 lL) bimatoprost in ONT-dogs (IOP change, À5.4 6 0.7 and À3.4 6 0.7 mm Hg, respectively, P < 0.05) and in OHT-monkeys (IOP change, À7.7 6 1.4 and À4.8 6 1.7 mm Hg, respectively, P < 0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 lL) or bimatoprost (0.03%, 30 lL) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 hours after NCX 470 dosing.CONCLUSIONS. NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2a and NO/cGMP signaling pathways.

Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma

“…Moreover, enhanced vasodilatation, anti‐inflammatory effects and antiplatelet activity have been attributed to NO making this class of molecules particularly interesting as impaired ocular blood flow and inflammation seem to also contribute to glaucoma progression (Resch et al ., ; Costa et al ., ). Various NO‐donating PGs have been described in recent years for their enhanced IOP‐lowering activity in animal models of ocular hypertension and glaucoma compared with standard of care treatments (Borghi et al ., ; Impagnatiello et al ., ; Krauss et al ., ; Impagnatiello et al ., ). Among others, LBN, a compound discovered at Nicox and later licensed by Bausch + Lomb, has been advanced through phase 3 and recently received FDA approval for the reduction of IOP in patients with open‐angle glaucoma and ocular hypertension (Vyzulta™, LBN ophthalmic solution, 0.024%,).…”

“…Nonclinical pharmacological studies have demonstrated that the IOP‐lowering efficacy of NCX 470 is greater than that of equimolar doses of bimatoprost in well‐established animal models of glaucoma and ocular hypertension. In particular, NCX 470 was shown to lower IOP in transient ocular hypertensive rabbits (previously shown to respond poorly to FP receptor agonists, Borghi et al ., ) probably by inducing the release of NO (Impagnatiello et al ., ). Additionally, NCX 470 0.042% lowered IOP more effectively than equimolar doses of bimatoprost (0.03%) in ocular normotensive dogs (Figure A, Impagnatiello et al ., ) and in laser‐induced ocular hypertensive non‐human primates (Figure B, Impagnatiello et al ., ).…”

“…In particular, NCX 470 was shown to lower IOP in transient ocular hypertensive rabbits (previously shown to respond poorly to FP receptor agonists, Borghi et al ., ) probably by inducing the release of NO (Impagnatiello et al ., ). Additionally, NCX 470 0.042% lowered IOP more effectively than equimolar doses of bimatoprost (0.03%) in ocular normotensive dogs (Figure A, Impagnatiello et al ., ) and in laser‐induced ocular hypertensive non‐human primates (Figure B, Impagnatiello et al ., ). This compound holds promise to become the best in class as it adds NO‐mediated efficacy to that of bimatoprost, whose Lumigan 0.03% formulation was considered to be the most efficacious PG analogue among those approved to date.…”

Targeting Schlemm’s Canal in the Medical Therapy of Glaucoma: Current and Future Considerations

“…The effectiveness of several IOP-lowering therapies that focus on the mechanisms underlying ECM turnover and cell stiffness has already been successfully demonstrated. These include adenosine A1 receptor agonists [39–45], nitric oxide donors [12, 46–48], Rho Kinase inhibitors [49] and actin depolymerizers (Tables 1, 2) [23, 25, 26, 50–53]. …”

“…In a more recent study, Impagnatiello et al [48] compared the IOP-lowering activity of NCX 470, a novel NO-donating bimatoprost, with equivalent dosage of bimatoprost in ocular hypertensive rabbits, ocular normotensive dogs, and hypertensive non-human primates. This novel compound was effective in lowering IOP in all 3 animal models, and a repeated daily dosing of NCX 470 in dogs resulted in sustained IOP-lowering activity over time.…”