Pipeline
Research platform

Nitric oxide (NO)-donors: the Nicox expertise

Nicox has developed a leading position in the therapeutic application of NO-donating compounds, based on a strong research platform which creates New Molecular Entities (NMEs). Our specialized Research Center in Italy has worked on many R&D studies covering various therapy areas such as cardiovascular, inflammation and ophthalmology creating one of the most significant patent portfolios in the area. Nicox’s compounds, known as NO-donors, are designed to donate nitric oxide with a sustained pharmacological effect at tissue level aiming at avoiding the drawbacks related to the rapid burst of nitric oxide associated with traditional nitrates.

Focus on ocular disorders

Consistent with Nicox’s strategic positioning in ophthalmology our research platform is focused on ocular conditions where nitric oxide (NO) has been shown to play an important role. A specialized team in Nicox’s Italian research center, Nicox Srl, is pursuing targeted projects in collaboration with external research centers. This will enable Nicox to enhance its knowledge of the role and potential of nitric oxide (NO) in ophthalmology and to leverage its long-standing expertise in the therapeutic application of NO-donating compounds. Several studies conducted in animal models, as well as in humans, have shown that the release of NO reduces IOP1,2. The positive Phase 2 and Phase 3 results obtained with latanoprostene bunod and the subsequent approval of VYZULTA by the U.S. FDA validate the  potential of our NO-donating proprietary research platform in ophthalmology.

Our Research team has developed additional NO-donating prostaglandins, including NCX 470, in glaucoma and, in collaboration with Universities and other Research Institutions, is currently focused on our future-generation of stand alone NO-donors.

The role of NO in the ocular field

NO is an endogenous cell signaling molecule that plays a fundamental role in physiology. NO has been the object of strong scientific interest for many years, including with recognition through a Nobel Prize. There is growing recognition by the medical community of the connection between certain diseases (including glaucoma) and a deficiency in the production of NO3. This creates an opportunity to develop new pharmacological treatments that release NO when the human body is not able to generate it in physiologically relevant quantities to ensure proper functioning of biological processes. NO is present in ocular tissues, together with other components involved in the NO signaling cascade. Studies have shown that topical administration of traditional NO donors, such as nitroglycerine or isosorbide dinitrate, reduces IOP, reinforcing the role of NO in IOP regulation4,5,6. This is of particular interest in the potential treatment of glaucoma, which is often associated with an increased IOP and can lead eventually to blindness if not treated. Lower plasma levels of NO markers are found in open angle glaucoma patients compared to individuals without glaucoma7,8. Several studies conducted in animal models, as well as in humans, have shown that the release of NO reduces IOP.

References

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. Schuman J.S., Erickson K., Nathanson J.A. Nitrovasodilator Effects on Intraocular Pressure and Outflow Facility in Monkeys. Exp Eye Res.1994; 58:99-105Nathanson J.A. Nitrovasodilators as a New Class of Ocular Hypotensive Agents. J Pharmacol Exp Ther. 1992; 260:956-65. 2- 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. 3- Jain Biotech. Nitric Oxide Therapeutics, Markets and Companies. Feb 2017 4- 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. 5- Nathanson J.A. Nitrovasodilators as a New Class of Ocular Hypotensive Agents. J Pharmacol Exp Ther. 1992; 260:956-65. 6- Diestelhorst M., Hinzpeter B., Krieglstein G.K. The effect of isosorbid-mononitrate eye drops on the human intraocular pressure and aqueoes humour dynamics. International Ophthalmology 1991, 15:252-262 7- Winkler N.S., Fautsch M.P. Effects of prostaglandin analogues on aqueous humor outflow pathways. J Ocul Pharmacol Ther. 2014; 30:102–109. 8- Alm A., Nilsson SF. Uveoscleral outflow–a review. Exp Eye Res. 2009; 88:760-768.

Disease focus areas
Glaucoma
Glaucoma affects millions of patients worldwide and can lead to blindness if not treated.

What is glaucoma?

Glaucoma is a group of ocular diseases in which the optic nerve is injured, leading to peripheral and ultimately central visual field loss, if not treated. Glaucoma is frequently linked to abnormally high intraocular pressure in the eye (IOP), due to blockage or malfunction of the eye’s aqueous humor drainage system. Numerous eye drops are available to either decrease the amount of fluid produced in the eye or improve its flow out of the eye1. A significant portion of patients with open angle glaucoma require more than one medication to lower their IOP within target levels, highlighting the need for more effective treatments2,3,4. 3.5% of the worldwide population between 40 and 80 years of age are estimated to be affected by the most common forms of glaucoma5.

Glaucoma symptoms and causes

Abnormally high 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 can lead to optic nerve damage and vision loss if left untreated. In the healthy eye, a small amount of aqueous humor (the liquid present inside the eye ball) is continually produced, circulates and flows out of the eye to maintain a constant eye pressure. In glaucoma, the aqueous humor does not flow out of the eye properly, leading to a fluid pressure build up in the eye that will, over time, cause damage to the optic nerve fibers. The main risk factors for developing eye glaucoma are age, race and family history of glaucoma. 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 reduction 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 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 progression11,12.

Glaucoma treatment options

Current medications are targeted at reducing 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. Unfortunately, most of the glaucoma patients do not take their medication properly due to the lack of symptoms. Several large trials have demonstrated that reducing IOP can prevent the progression of glaucoma in both early and late stages of the disease. A significant portion of patients with open-angle glaucoma require more than one medication to lower their IOP within target levels, highlighting the need for more effective treatments2,3,4.

References

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): 7. 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

Conjunctivitis
Conjunctivitis is a very common eye disease with various causes.

What is conjunctivitis?

Conjunctivitis, also called red eye, is an inflammation of the conjunctiva (the thin layer of tissue that lines the outside of the white surface of the eye and the inner surface of the eyelids) and may affect one or both eyes. 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 anywhere between 15% and 40%1.

Conjunctivitis symptoms and causes

Symptoms may include eye redness, excessive watering, itchy burning eyes, discharge, blurred vision and increased sensitivity to light. Conjunctivitis can be caused by a viral or bacterial infection, or can be the result of an allergic reaction (45%, 45% and 10% of the cases, respectively).

 

Allergic conjunctivitis

For certain patients, the presence of allergens (substances that can trigger an allergic reaction) in the eye leads to allergic conjunctivitis. This may be seen seasonally, for example with certain types of pollens in the summer, or may be present year round, with allergens including smoke, animal fur and pollution. When pharmaceutical treatment is required, patients usually take oral antihistamines, or eye drops containing antihistamines, mast cell stabilisers or corticosteroids.

Reference

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

Blepharitis
Blepharitis is a condition where the edges of the eyelids become red and swollen.

Blepharitis 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 follicle) and scalp dandruff.
  • Posterior blepharitis affects the inner eyelids, the moist part which makes contact with the tear film of the eye, and is most commonly caused by problems with the oil glands, or Meibomian glands. Acne rosacea and scalp dandruff can also cause posterior blepharitis.

Because blepharitis often coexists with other related conditions, such as dry eye, it is difficult to study, and there is little consensus on the prevalence of the disease. Studies do 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, which limits Nicox’s ability to estimate prevalence and market size. Current standard of care includes lid scrubs, steroids, antibiotics, and antibiotic/steroid combinations. Surveys reveal that ophthalmologists 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.

References

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

Product Candidates
Glaucoma
Product
Product candidates
Anterior ocular inflammation, irritation and allergy
Product
Product candidates
Publications
VYZULTA
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.

http://www.aaojournal.org/article/S0161-6420(16)00064-6/pdf

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.

http://www.ajo.com/article/S0002-9394(16)30223-9/pdf

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.

http://bjo.bmj.com/content/bjophthalmol/99/6/738.full.pdf

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.

https://doi.org/10.1016/j.exer.2011.03.001

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

NCX 470

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.

http://iovs.arvojournals.org/article.aspx?articleid=2461805

NO donors

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.

http://iovs.arvojournals.org/article.aspx?articleid=2128944

Effects of diverse nitric oxide donation on ocular hemodynamic and intraocular pressure in normotensive rabbits.
Bastia E, Impagnatiello F, Miglietta D, Giambene B, Masini E, Almirante N.
Invest Ophthalmol Vis Sci. 2013;54(15):4450.
ARVO 2013, Seattle, Washington, USA

Download PDF

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

Download PDF

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

Download PDF

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

Download PDF