Nicox Products and Product Candidates

	Pre-clinical	Phase 1	Phase 2	Phase 3	NDA	Marketed

In-house Development Product Candidates
NCX 470 \| novel NO-donating bimatoprost eyedrop
NCX 470 \| novel NO-donating bimatoprost eyedrop Glaucoma & Ocular Hypertension Partnered with Ocumension Therapeutics for the Chinese & SE Asian markets		Mont Blanc Phase 3 trial completed – Denali Phase 3 trial ongoing
NCX 1728 \| NO-donating PDE5 inhibitor
NCX 1728 \| NO-donating PDE5 inhibitor Retinal Conditions


Out-licensed Products & Product Candidates
NCX 4251 \| fluticasone propionate nanocrystal suspension
NCX 4251 \| fluticasone propionate nanocrystal suspension Dry Eye Disease		Partnered with Ocumension Therapeutics for the Chinese market
VYZULTA^®
VYZULTA^® Glaucoma		Licenced to Bausch + Lomb: worldwide
ZERVIATE^®
ZERVIATE^® Allergic Conjunctivitis		Licenced to Harrow: United States

		Licenced to Ocumension Therapeutics for the Chinese & Southeast Asian markets

Ophthalmology market

Glaucoma, Allergic Conjunctivitis and Dry Eye Disease

$5.9bn

Worldwide sales

Worldwide sales of treatments targeting glaucoma were over $5.9 billion, out of a $24.9 billion worldwide market for ophthalmic drugs in 2021 (data from IQVIA Analytics Link 2021).

$2.9bn

Glaucoma treatments

In the U.S., sales of treatments targeting glaucoma totaled $2.9 billion in 2021 or 30% of the $9.8 billion U.S. market for ophthalmic drugs (data from IQVIA Analytics Link 2021).

$257m

Allergic conjunctivitis market

The annual U.S. market for prescription treatment of allergic conjunctivitis totals approximately $257 million in 2021 (data from IQVIA Forecast Link 2021).

$3.4bn

Dry eye disease market

The U.S prescription market for dry eye products in 2021 was estimated to be 6.1 million prescriptions for a value of $3.4 billion worldwide market for dry eye disease treatment (data from IQVIA Forecast Link 2021).

Our portfolio at a glance

Product candidates

NCX 470

Nicox’s lead clinical product candidate

NCX 470, is a novel nitric oxide (NO)-donating bimatoprost eye drop, in Phase 3 clinical development for the lowering of intraocular pressure (IOP) in patients with open angle glaucoma or ocular hypertension.

NCX 470

Mont Blanc Phase 3 trial completed – Second Phase 3 trial, Denali, ongoing in the U.S. and China with Nicox’s local partner Ocumension Therapeutics

Looking for commercial partnerships both for the U.S. and Japan

Expected milestones

Topline results of the Denali Phase 3 trial expected in 2025
Initiation of Whistler Phase 3b clinical trial investigating NCX 470’s dual mechanism of action (nitric oxide and prostaglandin analog) in IOP lowering planned in Q4 2023
Initiation of the Phase 3b clinical trial investigating NCX 470’s potential benefits on the retina expected in 2024

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 United States. 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 intraocular pressure lowering from baseline. NCX 470 0.1% was statistically superior to latanoprost 0.005% in intraocular pressure 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 and topline results are expected in 2025. The Denali trial also includes a long-term safety extension through 12 months.

Mont Blanc and Denali have been designed to fulfil 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 IOP lowering. 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, the Whistler trial, investigating NCX 470’s dual mechanism of action (NO and prostaglandin analog) in IOP lowering is planned to start in Q4 2023. Another Phase 3b clinical trial exploring the potential benefits of NCX 470 on the retina is expected to start in 2024. The Whistler trial will evaluate the effect of NCX 470 on Episcleral Venous Pressure (EVP) and outflow through the trabecular meshwork. The other Phase 3b trial will evaluate ocular perfusion via Optical Coherence Tomography (OCT) angiography on retinal vessels. Together, these trials are designed to validate NCX 470 dual mechanism of action in humans and potentially demonstrate some of the beneficial effects of NCX 470 on the retina that have been observed in nonclinical models.

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

Lead compound in a new class of NO-donating molecules

NCX 1728 is an NO-donating PDE5 inhibitor under preclinical evaluation for development in retinal conditions

NCX 1728

Preclinical evaluation

Expected milestones

Research data on mechanism of action (MoA) in retinal conditions

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.

Preclinical development in relevant models is underway to evaluate the mechanism of action.

Out-licensed products

NCX 4251

A novel, patented, ophthalmic suspension of fluticasone propionate nanocrystals

NCX 4251, a novel, patented, ophthalmic suspension of fluticasone propionate nanocrystals, is at clinical development stage for dry eye disease

NCX 4251

Exclusively partnered for the Chinese market

Available for out-licensing outside China

Expected milestones:

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^®

A prostaglandin analog with one of its metabolites being nitric oxide (NO)

VYZULTA^® (latanoprostene bunod ophthalmic solution), 0.024%, indicated for the reduction of intraocular pressure (IOP) in patients with open angle glaucoma or ocular hypertension. It is exclusively licensed worldwide to Bausch + Lomb, a leading global eye health company. VYZULTA is commercialized in more than 15 countries, including the U.S. and is also approved in a number of other countries.

VYZULTA^®

Commercialized in more than 15 countries, including the U.S. – Approved in a number of other countries.

Expected milestones:

Ongoing global approvals and launches in newly approved geographies

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. and is also approved in a number of other countries.

VYZULTA is covered by a composition of matter patent in the U.S. to 2025, with eligibility for up to 5-year extension confirmed by the U.S. Patent and Trademark Office, USPTO.

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

ZERVIATE^®

Indicated for the treatment of ocular itching associated with allergic conjunctivitis

ZERVIATE® (cetirizine ophthalmic solution), 0.24%, indicated for the treatment of ocular itching associated with allergic conjunctivitis, is commercialized in the U.S. by U.S. partner Harrow. ZERVIATE has been also exclusively licensed to Ocumension Therapeutics for development and commercialization in the Chinese and the majority of the South East Asian markets.

ZERVIATE^®

Commercialized in U.S. by U.S. partner Harrow

New Drug Application in China submitted by Chinese licensing partner Ocumension Therapeutics

Licensed to partners across Southeast Asia and China, Middle East

Expected milestones:

Approval of the New Drug Application and launch expected in China in 2024
Ongoing global roll-out through partnerships

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://myzerviate.com/.

Watch how our science works

Nitric oxide donation

The Nicox expertise

We have developed a leading position in the therapeutic application of nitric oxide (NO)-donating compounds in ophthalmology using our proprietary expertise in generating novel, patentable molecules that release NO, creating a significant patent portfolio.

Our NO-donating research platform produced NO-donating compounds targeting glaucoma, including VYZULTA^®, our first FDA-approved product, commercialized in the United States and other countries by our exclusive global licensee, Bausch + Lomb, and NCX 470, currently in Phase 3 clinical development.

Nitric oxide donation

The Nicox expertise

We have focused our research efforts on ocular disorders in which NO is believed to play a role, including lowering intraocular pressure (IOP) in glaucoma or in retinal health.

NO is a well-known, small, naturally occurring signaling molecule known to stimulate an intracellular enzyme, soluble guanylate cyclase (sGC), which converts guanosine triphosphate to the second messenger, cyclic guanosine monophosphate (cGMP). NO/sGC signaling pathway plays a key role in the regulation of IOP homeostasis and ocular blood flow. The NO stimulated increase in cGMP in the trabecular meshwork leads to the reduction of intracellular calcium, relaxation of the trabecular meshwork and, consequently, an increase in the outflow of the aqueous humor from the anterior segment of the eye through the primary or conventional outflow pathway. All of the foregoing events are thought to lead to lowering of IOP and enhance ocular perfusion. The effect of NO on IOP may be further increased and/or prolonged by phosphodiasterase type-5 (PDE5) inhibitors, which inhibit the degradation of cGMP.

We are applying key learnings from our research activities to NO-donating moieties attached to other non-PGA therapeutic classes of compounds with the goal of enhancing the NO-mediated effects. This novel class of molecules has the potential for development in retinal conditions and a candidate in this series is under preclinical development for retinopathies and other back-of-eye diseases.

Pipeline, Markets and Science

Nicox Products and Product Candidates

Ophthalmology market

Worldwide sales

Glaucoma treatments

Allergic conjunctivitis market

Dry eye disease market

Our portfolio at a glance

Product candidates

NCX 470

Nicox’s lead clinical product candidate

Expected milestones

NCX 1728

Lead compound in a new class of NO-donating molecules

Expected milestones

Out-licensed products

NCX 4251

A novel, patented, ophthalmic suspension of fluticasone propionate nanocrystals

Expected milestones:

VYZULTA®

A prostaglandin analog with one of its metabolites being nitric oxide (NO)

Expected milestones:

ZERVIATE®

Indicated for the treatment of ocular itching associated with allergic conjunctivitis

Expected milestones:

Nitric oxide donation

The Nicox expertise

Publications

NCX 470 Exerts Retinal Cell Protection and Enhances Ophthalmic Artery Blood Flow After Ischemia/Reperfusion Injury of Optic Nerve Head and Retina

NCX 470, a Nitric Oxide Donating Bimatoprost versus Latanoprost Has Greater Proportion of Subjects Achieving ≥10 mmHg IOP Decrease in Phase 3 Trial

NCX 470, a Nitric Oxide Donating Bimatoprost Compared with Latanoprost – Adaptive Design Period Results from the Phase 3 Mont Blanc Clinical Trial

Effects of NCX 470, a nitric oxide (NO)-donating bimatoprost, in an in vitro 3D-human trabecular meshwork (TM)/Schlemm’s canal (SC) tissue model

NCX 470, a nitric oxide (NO)-donating bimatoprost, preserves rabbit eyes from biochemical and functional changes associated with endothelin-1 (ET-1)-induced ischemia/reperfusion injury of optic nerve head and retina

NCX 470, a Nitric Oxide Donating Bimatoprost, Demonstrates Non-inferiority to Latanoprost in Phase 3 Mont Blanc Clinical Trial

NCX 470 Restores Ocular Hemodynamics and Retinal Cell Physiology After ET-1-Induced Ischemia/Reperfusion Injury of Optic Nerve and Retina in Rabbits

NCX 470, a nitric oxide (NO)-donating prostaglandin analog, restores ocular hemodynamics and photoreceptor function after endothelin-1-induced ischemia/reperfusion injury in rabbits

NCX 470, a nitric oxide (NO)-donating prostaglanding analog, elicits sustained IOP-lowering and modifies aqueous humor dynamic in non-human primates

A Randomized, Controlled Comparison of NCX 470 (0.021%, 0.042% and 0.065%) and Latanoprost 0.005% in Patients with Open-Angle Glaucoma or Ocular Hypertension: The Dolomites Study

Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma Francesco Impagnatiello; Elena Bastia; Nicoletta Almirante; Stefania Brambilla; Brigitte Duquesroix; Angela C Kothe; Michael V W Bergamini

NCX 470, a nitric oxide (NO)-donating bimatoprost lowers intraocular pressure in rabbits, dogs and non-human primate models of glaucoma Francesco Impagnatiello; Elena Bastia; Carol B Toris; Achim H Krauss; Ganesh Prasanna; Ennio Ongini Invest. Ophthalmol. Vis. Sci.. 2015; 56(7 ):5809. doi

Eyelid Application of NCX 4251 for Treatment of Signs and Symptoms of Dry Eye Disease

Latanoprostene Bunod 0.024% in Subjects With Open-angle Glaucoma or Ocular Hypertension: Pooled Phase 3 Study Findings Robert N. Weinreb, Jeffrey M. Liebmann, Keith R. Martin, Paul L. Kaufman,Jason L. Vittitow

Latanoprostene bunod 0.024% versus timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension The APOLLO Study. Weinreb RN, Scassellati Sforzolini B, Vittitow J, Liebmann J. Ophthalmol. 2016;123:965-73.

Comparison of latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular hypertension: The LUNAR Study. Medeiros FA, Martin KR, Peace J, Scassellati Sforzolini B, Vittitow JL, Weinreb RN. Am J Ophthalmol. 2016;168:250–9.

Long-term Safety and Efficacy of Latanoprostene Bunod 0.024% in Japanese Subjects with Open-Angle Glaucoma or Ocular Hypertension: The JUPITER Study Kazuhide Kawase, Jason L. Vittitow, Robert N. Weinreb, Makoto Araie For the JUPITER Study Group

Efficacy of Latanoprostene Bunod 0.024% Compared With Timolol 0.5% in Lowering Intraocular Pressure Over 24 Hours JOHN H.K. LIU, JOHN R. SLIGHT, JASON L. VITTITOW, BALDO SCASSELLATI SFORZOLINI, ROBERT N. WEINREB

Evaluation of the Effect of Latanoprostene Bunod Ophthalmic Solution, 0.024% in Lowering Intraocular Pressure over 24h in Healthy Japanese Subjects Makoto Araie, Baldo Scassellati Sforzolini, Jason Vittitow, Robert N. Weinreb

Regulation of endothelin-1-induced trabecular meshwork cell contractility by latanoprostene bunod. Cavet ME, Vollmer TR, Harrington KL, VanDerMeid K, Richardson ME. Invest Ophthalmol Vis Sci. 2015;56(6):4108-16. http://iovs.arvojournals.org/article.aspx?articleid=2363039

Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models. Krauss AH, Impagnatiello F, Toris CB, Gale DC, Prasanna G, Borghi V, Chiroli V, Chong WK, Carreiro ST, Ongini E. Exp Eye Res. 2011;93(3):250-5.

NCX 1728, a nitric oxide (NO)-donating PDE-5 inhibitor, but not its des-nitro derivative (NCX 1880), enhances ocular perfusion and improves photoreceptor function in rabbits with endothelin-1 (ET-1)-induced ischemia/reperfusion injury of optic nerve head and retina

NCX 1741, a novel NO-donating derivative of the phosphodiesterase-5 inhibitor avanafil, reduces IOP in models of ocular hypertension and glaucoma Impagnatiello F., Bastia E., Toris C., Fan S., Brambilla S., Galli C., Almirante N., Bergamini M.V.W.

Intraocular pressure (IOP) reduction elicited with NCX 1741, a dual acting nitric oxide (NO) and phosphodiesterase type-5 (PDE5) inhibitor or travoprost in a non-human primate model of ocular hypertension and glaucoma Impagnatiello F., Navratil T., Toris C.B., Bergamini M.V.W., et al.

NCX 667, a novel nitric oxide (NO) donor lowers intraocular pressure (IOP) via stimulation of trabecular meshwork/Schlemm’s canal outflow facility Impagnatiello F, Bastia E, Torrejon KY, Unser AM, Ahmed F. ARVO 2018, Honolulu, Hawaii, USA

Repeated dosing of NCX 667, a new nitric oxide (NO) donor, retains IOP-lowering activity in animal models of glaucoma. Bastia E, Impagnatiello F, Ongini E, Serle JB, Bergamini MVW. Invest Ophthalmol Vis Sci. 2017;58(8):2106. ARVO 2017, Baltimore, Maryland, USA

IOP-lowering effects of NCX 667 in combination with travoprost in ocular normotensive and transient hypertensive rabbits. Bastia E, Masini E, Durante M, Bergamini MVW., Ongini E, Impagnatiello F. Invest Ophthalmol Vis Sci. 2016;57(12):3031. ARVO 2016, Seattle, Washington, USA

Nitric oxide (NO): an emerging target for glaucoma. Cavet ME, Vittitow JL, Impagnatiello F, Ongini E, Bastia E. Invest Ophthalmol Vis Sci. 2014;55(8):5005-15.

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VYZULTA^®

ZERVIATE^®