Portfolio and Disease Areas

NCX 470 is a novel nitric oxide (NO)-donating bimatoprost eye drop that leverages the potent intraocular pressure (IOP)-lowering effects of NO and prostaglandin analogs (PGAs). NCX 470 incorporates Nicox’s proprietary NO-donating research platform and bimatoprost in a single molecule. NCX 470 is designed to release bimatoprost and NO into the eye to lower IOP by two different pathways in patients with open-angle glaucoma or ocular hypertension. NO is a well-known small, naturally occurring signaling molecule that plays a key role in the regulation of IOP through activation of soluble guanylate cyclase (sGC). NO brings additional IOP-lowering efficacy by enhancing aqueous humor drainage from the eye via a different mechanism of action to that of PGAs. Bimatoprost, marketed under the brand name LUMIGAN® by AbbVie, Inc., is the leading branded PGA. PGAs are the most widely used class of drugs for IOP-lowering in patients with open-angle glaucoma or ocular hypertension. We believe that the proven dual mechanism of action can achieve superior IOP-lowering compared to the parent compound alone. Beneficial effects of NCX 470 have additionally been demonstrated in an in vivo model of retinal cell damage (see Press Release of September 29, 2021).

Topline results from the first Mont Blanc Phase 3 clinical trial evaluating the IOP lowering efficacy of once-daily dosed NCX 470 ophthalmic solution 0.1% compared to latanoprost ophthalmic solution 0.005% in patients with open-angle glaucoma or ocular hypertension were announced on October 31, 2022. The first of two Phase 3 trials for NCX 470, Mont Blanc, met the efficacy requirements for approval in the U.S. Daily dosing of NCX 470 0.1% met the primary efficacy objective of demonstrating non-inferiority to latanoprost 0.005%, with NCX 470 showing 8.0 to 9.7 mmHg IOP lowering from baseline. NCX 470 0.1% was statistically superior to latanoprost 0.005% in IOP reduction from baseline at 4 of the 6 timepoints, and numerically greater at all 6 timepoints. However, the secondary efficacy objective, statistical superiority to latanoprost, was not achieved. NCX 470 0.1% was well tolerated. Latanoprost, marketed as Xalatan and available as a generic, is the most prescribed PGA in the U.S.

The similarly designed and ongoing second Phase 3 trial, Denali, conducted at clinical sites in the U.S. and China is ongoing.  The completion of recruitment of U.S. patients of Denali Phase 3 trial expected in Q4 2024. Topline results are expected in H2 2025. The Denali trial also includes a long-term safety extension through 12 months.

Mont Blanc and Denali trials have been designed to fulfill the regulatory requirements for safety and efficacy Phase 3 trials to support NDA submissions in the U.S. and China.

Exploratory nonclinical studies in a well-defined model with optic nerve head and retina damage (ET-1-induced ischemia/reperfusion) investigated the NCX 470 effects beyond its IOP lowering properties. The results suggest that NCX 470 improves ocular perfusion and retinal function in damaged eyes compared to vehicle and to Lumigan^® and may therefore have protective properties for the retina.

A Phase 3b clinical trial, Whistler, investigating NCX 470’s dual mechanism of action (NO and PGA) in IOP lowering has been initiated in December 2023. The Whistler trial will enroll approximately 20 healthy volunteers with ocular hypertension in a double-masked, placebo-controlled study which will investigate the action of NCX 470 on aqueous humor parameters including trabecular meshwork outflow and episcleral venous pressure. Each subject will participate in the trial for ~8 days. The results of Whistler trial are expected in Q1 2025.

Results from the Dolomites Phase 2 trial for NCX 470 in glaucoma were reported in 2019: (see Press Release of October 2, 2019).

NCX 470 is protected worldwide by composition of matter patents until 2029, with a potential extension of up to 5 years in the U.S. and EU and by formulation patents to 2039 in the U.S., EU, Japan and China as well other territories.

NCX 1728, an NO-donating Phosphodiesterase-5 (PDE5) inhibitor, is the lead compound of a new class of NO-donating molecules in which the NO-mediated effects are enhanced and prolonged by concomitant PDE5 inhibition in the same molecule. PDE5 inhibition has been shown to enhance the efficacy and the duration of NO-mediated effects. This class of molecules has the potential to be developed for retinal conditions and. NCX 1728 is under preclinical evaluation in this area.

NCX 4251 is a novel patented ophthalmic suspension of fluticasone propionate nanocrystals, at clinical stage in dry eye disease. NCX 4251 will be the first topical ophthalmic fluticasone product, a two-week, once-daily treatment leveraging Nicox’s proprietary formulation technology. Fluticasone propionate has an affinity for the glucocorticoid receptor approximately ten times greater than dexamethasone, a corticosteroid commonly used in ophthalmology. NCX 4251 is being developed as a topical treatment with unique mode of administration to the eyelid margins via an applicator, minimizing the potential steroid exposure through the cornea which can lead to damaging side effects such as intraocular pressure (IOP) increase found with current topical steroids.

NCX 4251 has been evaluated in a Phase 2 trial, Danube, and a larger Phase 2b trial, Mississippi, both of which studied patients with blepharitis. In the Mississippi trial, once-daily NCX 4251, fluticasone propionate ophthalmic suspension 0.1% was evaluated, versus placebo in patients with acute exacerbations of blepharitis. The primary outcome measure was the proportion of patients achieving complete cure in all three hallmark signs and symptoms of blepharitis, eyelid redness, eyelid debris and eyelid discomfort, at Day 15, with two secondary outcome measures on signs and symptoms of dry eye. The Mississippi trial did not meet the primary or secondary efficacy endpoints. Following a post hoc analysis of the results and a meeting with the U.S. FDA, the development of NCX 4251 is focused on dry eye disease.

Post hoc results of Mississippi trial showed a statistically and clinically significant reduction in dry eye symptoms versus placebo in patients who scored more highly for a key sign of dry eye disease (fluorescein staining). Statistically significant improvements in a number of dry eye symptoms and improvements in one sign (p=0.0524) were seen. NCX 4251 was found to be safe and well-tolerated over 14 days’ treatment, with no serious adverse events, and all of the adverse events for the NCX 4251 treatment arm were mild. There were no discontinuations in the trial due to an adverse event.

The future development of NCX 4251 in the U.S. will require initial manufacturing scale-up followed by two additional efficacy clinical trials, both evaluating one sign and one symptom of dry eye disease, providing long term safety data, and certain additional clinical and non-clinical data to support an NDA submission in the U.S.

Similar to ZERVIATE, we intend to seek regulatory approval for NCX 4251 using the FDA’s 505(b)(2) regulatory pathway. This enables us to rely, in part, on the FDA’s prior findings of safety and efficacy for fluticasone propionate, or published literature, in support of our NDA.

NCX 4251 is protected worldwide by patents until 2033 and to 2040 by additional patents granted in the EU,Japan and China).

VYZULTA, exclusively licensed worldwide to Bausch + Lomb, is a prostaglandin analog with one of its metabolites being nitric oxide (NO). VYZULTA is indicated for the reduction of IOP in patients with open-angle glaucoma or ocular hypertension in the U.S. At approval, VYZULTA was the first eye drop approved in the past 20 years with a novel approach to reduce IOP.

VYZULTA is commercialized in more than 15 countries, including the U.S. where it is covered by a composition of matter patent to 2029.

For further details on VYZULTA, please visit our partner’s dedicated website www.vyzulta.com.

ZERVIATE is a novel, patented eye drop formulation of cetirizine approved in the U.S. for ocular itching associated with allergic conjunctivitis.

ZERVIATE in now commercialized in the U.S. by exclusive U.S. partner Harrow, Inc., following the acquisition in July 2023 of the commercial rights to certain U.S. ophthalmology products from Santen by Harrow. A New Drug Application (NDA) for approval to commercialize ZERVIATE in China for ocular itching associated with allergic conjunctivitis has been submitted by local partner Ocumension Therapeutics in April 2023.  The approval and launch of ZERVIATE in China are expected in 2024.

Nicox has also signed exclusive license agreements with Samil Pharmaceutical for the development and commercialization of ZERVIATE in South Korea, with ITROM Pharmaceutical Group in certain Gulf and Arab markets.

The ZERVIATE formulation is protected by granted patents in the U.S. to 2030 and 2032, and in Europe, Japan and Canada to 2030.

For further details on ZERVIATE in the U.S., please visit our partner’s dedicated website https://www.zerviate.com