Nicox products and product candidates

	Pre-clinical	Phase 1	Phase 2	Phase 3	NDA	Marketed

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


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

		Licenced to Ocumension Therapeutics: 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, currently 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, is ongoing in the U.S. and China with our local Chinese partner Ocumension Therapeutics

Expected milestones

Topline results of the Denali trial expected in 2025
Initiation of two new Phase 3b clinical trials investigating the dual mechanism of action (nitric oxide and prostaglandin analog) in IOP lowering and potential retinal benefits of NCX 470 planned in H1 2023

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, is being conducted at clinical sites in the U.S. and China with topline results expected in 2025. The Denali trial also includes a long term safety extension through 12 months.

Two new Phase 3b clinical trials evaluating the dual mechanism of action (NO and prostaglandin analog) in IOP lowering and the potential retinal benefits of NCX 470 are planned to start in H1 2023. These new clinical trials will evaluate (i) the effect of NCX 470 on Episcleral Venous Pressure (EVP) and outflow through the trabecular meshwork and (ii) ocular perfusion via Optical Coherence Tomography (OCT) angiography on retinal vessels. Together, these studies are designed to validate NCX 470’s dual mechanism of action in humans and potentially demonstrate some of the beneficial effects 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 covered worldwide under a composition of matter patent until 2029 with a potential extension of up to 5 years in the U.S. and EU and a formulation patent until 2039 in the U.S., EU, Japan and China.

NCX 1728

Lead compound in a new class of NO-donating molecules

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

NCX 1728

Nonclinical developement

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

NCX 1728, an NO-donating PDE5 inhibitor, is the lead compound of a new class of NO-donating molecules. The mechanism of action for this novel class of molecules is based entirely on NO-mediated activity. PDE5 inhibition has been shown to enhance the efficacy and the duration of NO-mediated effects. NCX 1728 is under evaluation for development in certain retinal conditions. In addition to intraocular pressure lowering, NO has a role in ocular perfusion which may be beneficial in a number of orphan retinal conditions for which there is no standard treatment.

Nonclinical 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 in the development stage for dry eye disease

NCX 4251

Partnered in China

Available for out-licensing outside China

Expected milestones:

NCX 4251 is a novel patented ophthalmic suspension of fluticasone propionate nanocrystals, in development 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 application 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.

Once-daily NCX 4251, fluticasone propionate ophthalmic suspension 0.1% was evaluated in the Mississippi Phase 2b clinical trial, versus placebo in patients with acute exacerbations of blepharitis. The primary outcome measure in the Mississippi trial 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 trial did not meet the primary or secondary efficacy endpoints. Following positive post hoc results from the Mississippi trial and a subsequent meeting with the U.S. Food and Drug Administration (FDA), the future development of NCX 4251 is focused on dry eye disease. Post hoc results 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, 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 covered worldwide by patents until 2033 and to 2040 by additional patents granted in the EU and Japan).

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 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 multiple countries including the United States, with other approvals and launches ongoing.

VYZULTA^®

Commercialized in 8 territories – Approved in 18 territories

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 the U.S., Canada, Argentina, Hong Kong, Mexico, Taiwan, Thailand and Ukraine by exclusive licensee Bausch + Lomb and approved in Bahrain, Brazil, Colombia, Jordan, Lebanon, Qatar, Singapore, South Korea, Turkey and United Arab Emirates. 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 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, has been exclusively licensed in the U.S. to U.S. partner Eyevance Pharmaceuticals and is commercialized there since March 2020. 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 Eyevance Pharmaceuticals.

Positive Phase 3 results in China with Chinese partner Ocumension Therapeutics.

Licensed to partners across Southeast Asia and China, Middle East and Mexico

Expected milestones:

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.

Commercialized in the U.S. by exclusive U.S. partner Eyevance Pharmaceuticals since March 2020. Positive results in February 2022 from a Phase 3 clinical trial in China, run by local partner Ocumension Therapeutics, required for a submission of a New Drug Application (NDA) for approval to commercialize ZERVIATE in China.

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 and with Laboratorios Grin in Mexico.

The ZERVIATE formulation is protected by granted patents in the U.S. to 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 scientific and strategic position in the therapeutic application of nitric oxide (NO)-donating compounds based on our internally-developed NO-donating research platform, specifically in ophthalmology, supported by an extensive patent portfolio.

This platform underpins our product candidates that target glaucoma, including VYZULTA^®, our first approved product in the U.S., commercialized by our exclusive global licensee, Bausch + Lomb.

Nitric oxide donation

The Nicox expertise

NO is a well-known small naturally-occurring signaling molecule whose target is an intracellular enzyme, soluble guanylate cyclase (sGC), which converts guanosine triphosphate to the second messenger, cyclic guanosine monophosphate (cGMP). The NO stimulated increase in the concentration of cGMP in the trabecular meshwork leads to the sequestration of intracellular calcium, the 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 intraocular pressure (IOP).

NO lowers IOP via distinct cellular and molecular pathways compared to other pharmaceutical agents currently used to treat ocular diseases including glaucoma and ocular hypertension. By designing our proprietary molecules with a dual mechanism of action, we may be able to achieve increased IOP lowering efficacy compared to the molecules acting by a single mode of action. Based on this approach, our partnered approved product VYZULTA^®, the only NO donating molecule approved for an ophthalmic indication in the U.S., and our product candidate NCX 470 currently in clinical development, are comprised of a parent prostaglandin analog (PGA) and a NO-donating moiety.

We have also explored NO-donating compounds of different chemical and pharmacological classes in order to combine the NO donation effects with other existing MOA and thus to potentially increase the overall IOP lowering potentials of the resulting new molecular entities. Our lead research program is NO-donating PDE5 inhibitors (PDE5), fully owned by Nicox: PDE5 is a key enzyme that accelerates the degradation of the second messenger, cGMP produced by sGC following its stimulation by NO. By inhibiting PDE5 we may enhance and prolong the effect of NO on IOP reduction.

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

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

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, 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 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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