Pipeline of ophthalmic therapeutics

Our ophthalmic pipeline includes three programs in development, research programs which could provide future product candidates and two products approved for commercialization by the U.S. Food and Drug Administration (FDA).

The below table summarizes key information on the pipeline.

Nitric oxide donating platform research platform

Nitric oxide (NO)-donors: The Nicox expertise

We have developed a leading scientific and strategic positions in the therapeutic application of nitric oxide NO-donating compounds based on our proprietary NO-donating research platform. Using this proprietary expertise in generating novel, patentable molecules, which we believe are new chemical entities (NCEs), that release NO, our research center has conducted lead generation and lead evaluation in preclinical studies in ophthalmology, creating a significant patent portfolio.

NO is a small 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 cellular machinery to synthesize endogenous NO is present in ocular tissues, together with other components involved in the NO-signaling cascade via the activation of sGC. 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). The effect of NO in the sGC signaling cascade may be further increased or prolonged by sGC stimulators, which interact synergistically with NO to increase the concentration of cGMP. Additionally, the effect of NO may be further increased or prolonged by phosphodiesterase-5 (PDE5) inhibitors, which inhibit phosphodiesterase type-5, a key enzyme that degrades the second messenger, cGMP produced by sGC following its stimulation by NO.

Studies have shown that topical administration of traditional NO donors, such as nitroglycerin or isosorbide mononitrate, reduces IOP, reinforcing the role of NO in IOP regulation1,2,3. Lower plasma levels of NO markers are found in open angle glaucoma patients compared to individuals without glaucoma4. Several studies conducted in animal models, as well as in glaucoma patients, have shown that the release of NO activates sGC and lowers IOP5,6.

To-date, it has been established that NO plays a key role in the regulation of IOP and can be linked with another pharmaceutical agent. Release of NO and the subsequent activation of sGC is one of the mechanisms that is believed to lead to IOP-lowering by these novel molecules. We believe that by designing our proprietary molecules with a dual mechanism of action (MOA), we may be able to achieve increased IOP lowering compared to the parent compound alone. Based on this approach, our partnered approved product VYZULTA® and our product candidate NCX 470 currently in clinical development, are comprised of a parent prostaglandin analog (PGA) and a NO donor. NCX 470 is a novel second generation NO-donating bimatoprost analog that has demonstrated statistical superiority to latanoprost, based on the study’s pre-specified statistical analysis plan, in a Phase 2 study and which we believe also has the potential to become the first non-combination product with statistical superiority to a prostaglandin analog. We also believe NCX 470 has the potential to lower IOP lowering more than bimatoprost, an FDA approved PGA that is the current U.S. market leader by sales marketed under the brand LUMIGAN. The results from the Dolomites trial on NCX 470 together with the positive clinical Phase 2 and 3 results obtained with latanoprostene bunod, and the subsequent approval of VYZULTA by the U.S. FDA, demonstrate the potential of such dual MOA approach with our proprietary NO-donating research platformin ophthalmology7. Apart from VYZULTA, there are currently no NO-donating molecules approved for ophthalmic indications in the U.S.

We are actively researching NO-donating compounds of different chemical and pharmacological classes in order to add NO donation to another existing MOA and thus to potentially increase the overall IOP lowering potentials of the resulting new molecular entities. Our new research programs include the NO-donating PDE5 inhibitors (fully owned by Nicox), as well as the NO-donating sGC stimulators (in partnership with Ironwood).


  1. Diestelhorst M., Hinzpeter B., Krieglstein G.K. The effect of isosorbid-mononitrate eye drops on the human intraocular pressure and aqueous humor dynamics. International Ophthalmology 1991, 15:252-262.
  2. Nathanson J.A. Nitrovasodilators as a New Class of Ocular Hypotensive Agents. J Pharmacol Exp Ther. 1992; 260:956-65.
  3. Schuman J.S., Erickson K., Nathanson J.A. Nitrovasodilator Effects on Intraocular Pressure and Outflow Facility in Monkeys. Exp Eye Res.1994; 58:99-105
  4. Galassi F., Renieri G., Sodi A., Ucci F., Vannozzi L., Masini E. Nitric oxide proxies and ocular perfusion pressure in primary open angle glaucoma. Br J Ophthalmol. 2004; 88(6):757-60.
  5. Cavet M.E., Vittitow J.L., Impagnatiello F., Ongini E., Bastia E. Nitric oxide (NO): an emerging target for the treatment of glaucoma Invest Ophthalmol Vis Sci. 2014; 55(8):5005-15.
  6. Impagnatiello F., Bastia E., Almirante N., Brambilla S., Duquesroix B., Kothe A.C., Bergamini M.V.W. Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma. Br J Pharmacol. 2018; doi: 10.1111/bph.14328.
  7. Garcia G.A., Ngai P, Mosaed S. et al. Critical evaluation of latanoprostene bunod in the treatment of glaucoma. Clin.Ophthal. 2016:10 2035–2050.
Disease focus areas

Glaucoma affects millions of patients worldwide and can lead to blindness if not treated. It is a group of ocular diseases in which the optic nerve is injured, leading to peripheral and ultimately central visual field loss. Glaucoma can eventually progress to blindness, if not treated, and is currently considered to be the second leading cause of irreversible blindness worldwide. Glaucoma is frequently linked to abnormally high intraocular pressure (IOP) in the eye, (generally approximately above 22 mmHg) due to blockage or malfunction of the eye’s aqueous humor drainage system in the front of the eye. About 3.5% of the worldwide population between 40 and 80 years of age are currently estimated to be affected by the most common forms of glaucoma5.

Glaucoma symptoms and causes

High intraocular pressure (IOP) does not usually cause any symptoms, except in cases of acute angle closure where the IOP may rise to three or four times that of normal IOP, but it can lead to optic nerve damage and vision loss if left untreated. Optic nerve damage and vision loss can also occur in patients with normal IOP who are also treated with IOP lowering medications. The Normal Tension Glaucoma Study6,7 completed in 1998 showed that lowering IOP slowed the progression of normal tension glaucoma, a form of glaucoma where the patient’s IOP is within normal ranges. IOP lowering is associated with a decreased risk in progression to open angle glaucoma in subjects with ocular hypertension, as well as progression of visual field loss in patients with open angle glaucoma, with every mmHg of IOP lowering, resulting in a risk reduction in open angle glaucoma progression of approximately 10% to 20%8,9,10. Patients with open angle glaucoma who attain target IOP lowering have a lower risk of disease progression and vision loss11,12.

Current medications are targeted at lowering high IOP to slow the progression of the disease. Numerous eye drops are available to either decrease the amount of fluid produced in the eye or improve its flow out of the eye1. Nearly half of the patients with open-angle glaucoma require more than one medication to lower their IOP to a target level at which visual field loss is likely to be minimized or halted. The requirement for multiple medications to lower an individual patient’s IOP to its target level highlights the need for more effective treatments2,3,4.


  1. American Academy of Ophthalmology® (AAO) Preferred Practice Pattern® (PPP), Prum BE, Rosenberg LF, Gedde SJ, et al. Primary open-angle glaucoma Preferred Practice Pattern® guidelines. Ophthalmology. 2016 cited 2016 Jul 18;123(1):P41–P111
  2. Kass M.A., Heuer, D.K., Higginbotham E.J. et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002; 120:701–713 ([discussion 829–30).
  3. Kass M.A., Gordon M.O., Gao F. et al. Delaying treatment of ocular hypertension: the ocular hypertension treatment study. Arch Ophthalmol. 2010; 128:276–287.
  4. Schmier J.K., Hulme-Lowe C.K., Covert D.W. Adjunctive therapy patterns in glaucoma patients using prostaglandin analogs. Clin.Ophthal. 2014:8 1097-1104.
  5. Tham Y.C., Hons B., Li X. et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmol. 2014 Nov;121(11):2081–2090
  6. COLLABORATIVE NORMAL-TENSION GLAUCOMA STUDY GROUP. The Effectiveness of Intraocular Pressure Reduction in the Treatment of Normal-Tension Glaucoma. Am J Ophthalmol. 1998;126:498–505.
  7. The Advanced Glaucoma Intervention Study (AGIS): The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 2000 Oct;130(4):429-440. Leske MC, Heijl A, Hussein M, et al., Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003 Jan;121(1):48-56. Heijl A. Glaucoma treatment: by the highest level of evidence. Lancet. 2015 Apr 4;385(9975):1264-1266. Garway-Heath D.F. Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. The Lancet 2015; 385: 1295-304.
  8. Heijl A., Leske M.C., Bengtsson B. et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002; 120: 1268-1279.
  9. Garway-Heath D.F., Crabb D.P., Bunce C. et al. Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. The Lancet. 2015; 385: 1295–304.
  10. Heijl A. Glaucoma treatment: by the highest level of evidence. The Lancet. 2015 Apr 4; 385(9975):1264–1266.
  11. EGS Glaucoma Guidelines 4th Edition, e.g. P 17 -2014
  12. Heijl A., Leske M.C., Bengtsson B. et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002; 120: 1268-1279
Allergic Conjunctivitis

Allergic conjunctivitis occurs when an allergic reaction causes conjunctivitis. Conjunctivitis is an inflammation of the thin layer of tissue that lines the outside of the white surface of the eye and the inner surface of the eyelids. It may affect one or both eyes. The signs and symptoms may include eye redness, excessive watering, itchy burning eyes, discharge, blurred vision and increased sensitivity to light. It is estimated that more than 75 million people suffer from allergic conjunctivitis in the United States and the estimated prevalence of allergic conjunctivitis may be between 15% and 40%1.


  1. Rosario N, Bielory L. Epidemiology of allergic conjunctivitis. Curr Opin Allergy Clin Immunol. 2011;11:471–476.

Blepharitis is a condition in which the margins of the eyelids become painful, red and swollen and may contain dandruff like matter, as shown in the picture below, and occurs in two forms. Anterior blepharitis affects the outside front of the eyelids, where the eyelashes are attached, and is most commonly caused by bacteria, demodex (a tiny mite that lives in or near hair follicles) and scalp dandruff. Posterior blepharitis affects the inner edge of the eyelids, the moist part of which makes contact with the tear film of the eye, and is most commonly caused by problems with eyelid oil glands, the meibomian glands. Both forms of blepharitis are associated with significant inflammation of the eyelid and benefit from an anti-inflammatory treatment.

Blepharitis often coexists with other related conditions, such as dry eye, with an incidence that is similar to or higher than dry eye in evaluations of symptomatic patients (24% incidence of blepharitis versus 21% incidence of dry eye). It is believed that in patients with both blepharitis and dry eye, an improvement in blepharitis may lead to an improvement of the dry eye disease. Blepharitis is difficult to study, and there is not a definitive consensus on the prevalence of the disease. Studies show, however, that blepharitis is one of the most common conditions encountered in clinical practice. Of patients seen by ophthalmologists and optometrists, 37% and 47%, respectively, present with signs of the disease1.

There is currently no FDA-approved prescription product solely indicated for the treatment of blepharitis, Surveys reveal that ophthalmologists and optometrists consider anti-inflammatory activity to be the most important product attribute when selecting a treatment for both forms of blepharitis, which supports the development of NCX 42512.


  1. Lemp MA, Nichols KK. Blepharitis in the United States 2009: a survey-based perspective on prevalence and treatment. Ocul Surf. 2009; (2 Suppl):S1-S14
  2. Lemp MA, Nichols KK. Blepharitis in the United States 2009: a survey-based perspective on prevalence and treatment. Ocul Surf. 2009; (2 Suppl):S1-S14
Products and Product Candidates
NO-donating product candidates targeting glaucoma and other indications
Novel formulation targeting blepharitis
Out-licensed commercial products and product candidate
NCX 470
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

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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:


Intraocular pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical models.
Impagnatiello F, Toris CB, Batugo M, Prasanna G, Borghi V, Bastia E, Ongini E, Krauss AH.
Invest Ophthalmol Vis Sci. 2015;56(11):6558-64.


NCX 4251
Nonclinical Evaluation of NCX 4251, a Novel Steroid Therapy for Blepharitis, Targeted Directly to the Eyelid Margin to Improve Efficacy and Reduce the Potential for IOP Elevations
Robert Fechtner, MD; Tomas Navratil, PhD; Jean-Michel Bukowski, PhD; Frederic Pilotaz, PharmD; Amanda Graves; Akshay Nadkarni; Brigitte Duquesroix, MD; Angela Kothe, PhD, OD; Michael Bergamini, PhD; Harvey DuBiner, MD; Thomas Walters, MD; Donald Budenz, MD

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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

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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

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Efficacy of Latanoprostene Bunod 0.024% Compared With Timolol 0.5% in Lowering Intraocular Pressure Over 24 Hours

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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

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A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study.
Weinreb RN, Ong T, Scassellati Sforzolini B, Vittitow JL, Singh K, Kaufman PL; VOYAGER study group.
Br J Ophthalmol. 2015;99(6):738-45.


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.


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.


NO-donating PDE5 inhibitors
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.

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NO donors

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

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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

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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

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NCX 667, a novel nitric oxide (NO) donor, lowers intraocular pressure (IOP) in ocular normotensive and hypertensive eyes of rabbits and non-human primates.
Bastia E, Impagnatiello F, Almirante N, Lanzi C, Masini E, Toris C, Ongini E.
Invest Ophthalmol Vis Sci. 2015;56(7):1999.
ARVO 2015, Denver, Colorado, USA

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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.