Latanoprostene Bunod, a Dual-acting Nitric Oxide Donating Prostaglandin Analog for Lowering of Intraocular Pressure

Abstract

Current topical treatments for glaucoma have limited efficacy in lowering intraocular pressure (IOP) and/or can produce side effects and tolerability problems. At present, IOP remains the only known modifiable risk factor to delay the progression of glaucoma. The novel IOP-lowering treatment latanoprostene bunod (LBN) is a nitric oxide (NO)-donating prostaglandin F2αanalog that is rapidly metabolized in situ to latanoprost acid and butanediol mononitrate, an NO-donating moiety. LBN has a dual action in that it enhances aqueous humor outflow via both the uveoscleral and trabecular meshwork pathways. It is undergoing regulatory review by the Food and Drug Administration (FDA) for the reduction of IOP in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). In the dose-ranging VOYAGER study, LBN 0.024%, the lower of the most effective concentrations evaluated, demonstrated significantly greater IOP lowering and comparable side effects compared with latanoprost 0.005%. The recent APOLLO phase III clinical study (n=420) found LBN 0.024% demonstrated significantly greater reductions in IOP than timolol 0.5% in patients with OAG or OHT at various time points over 3 months. The same study found the proportion of patients with IOP ≤18 mmHg was significantly greater with LBN 0.024% than with timolol 0.5%. In the LUNAR study (n=420), LBN 0.024% was non-inferior to timolol 0.5% over 3 months’ treatment. LBN treatment also resulted in significantly greater IOP lowering than timolol at all time-points with the exception of the first post-baseline assessment. In JUPITER, a study of 130 subjects with OAG or OHT, LBN 0.024% was safe and well tolerated when used for up to a year, and provided significant and sustained IOP reduction. Further, in CONSTELLATION, a study of 25 patients with OHT or OAG, IOP lowering with LBN 0.024% was consistently lower than baseline during both the diurnal/wake and nocturnal/sleep periods whereas timolol 0.5% reduced IOP only during the diurnal period. In addition, LBN 0.024% treatment resulted in a significantly increased diurnal ocular perfusion pressure versus baseline and nocturnal ocular perfusion pressure versus timolol 0.05%. Similarly, in KRONUS, a single-arm, single-center, openlabel study of 24 healthy Japanese subjects, LBN 0.024% significantly lowered mean IOP over a 24-hour period. Across these studies, LBN has demonstrated a favorable safely profile and good ocular tolerability. It is hypothesized that LBN’s dual action on the outflow pathways accounts for the improved efficacy when compared with latanoprost and timolol.