Nitric Oxide Donating Prostaglandin-Related Drugs

Key points of this article

Nitric oxide (NO)-donating prostaglandin analogs are novel drugs that lower intraocular pressure through a dual mechanism of PGF2α receptor agonism and NO donation. Latanoprostene bunod (LBN) 0.024% acts on both the uveoscleral outflow pathway and the trabecular outflow pathway, achieving 25–35% intraocular pressure reduction¹⁾²⁾. Phase III trials (APOLLO, LUNAR) demonstrated superiority over timolol 0.5%¹⁾. NCX 470 is a bimatoprost-derived NO-donating PGA, and phase II trials reported superiority over latanoprost.

1. What are nitric oxide-donating prostaglandin analogs?

Prostaglandin analogs (PGAs) are widely used as first-line therapy for glaucoma¹⁾²⁾. PGAs lower intraocular pressure primarily by enhancing aqueous humor outflow through the uveoscleral pathway.

Nitric oxide (NO)-donating PGAs are novel drugs that add an NO-donating function to conventional PGAs. They have a dual action: after being metabolized by intraocular esterases into a PGF2α receptor agonist and an NO-donating moiety, the PGF2α action enhances uveoscleral outflow, while NO relaxes the smooth muscle of the trabecular meshwork and Schlemm’s canal, increasing outflow through the trabecular pathway.

Currently, two NO-donating PGAs are under development:

Drug	Parent PGA	Concentration	Development status
LBN (Vyzulta®)	Latanoprost	0.024%	FDA approved
NCX 470	Bimatoprost	0.042–0.1%	Phase III trials ongoing

Q How is latanoprostene bunod (LBN) different from latanoprost?

A

Latanoprost is a PGF2α receptor agonist that primarily acts on the uveoscleral outflow pathway. LBN contains a nitric oxide (NO)-donating moiety (butanediol mononitrate) in addition to latanoprost acid. NO relaxes the trabecular meshwork and Schlemm’s canal, thereby also increasing outflow through the trabecular outflow pathway, resulting in dual-pathway enhancement of aqueous humor outflow ¹⁾²⁾. In the VOYAGER trial, LBN 0.024% demonstrated significantly greater intraocular pressure (IOP) reduction than latanoprost 0.005% (9.00 vs 7.77 mmHg, p = 0.005) ¹⁾.

3. Clinical Trials and Evidence of Efficacy

Latanoprostene Bunod (LBN)

The efficacy and safety of LBN have been evaluated in multiple clinical trials ¹⁾.

VOYAGER Trial (Phase II)

Design: Randomized, investigator-masked, dose-ranging study. 413 eyes, 28 days

Results: Mean diurnal IOP reduction with LBN 0.024% was 9.00 mmHg, significantly superior to 7.77 mmHg with latanoprost 0.005% (p = 0.005) ¹⁾

APOLLO and LUNAR Trials (Phase III)

Design: Randomized, double-masked, non-inferiority trials. 840 eyes (pooled analysis), 12 months

Results: Mean IOP with LBN 0.024% once daily ranged from 17.8 to 18.9 mmHg, significantly lower than 19.0 to 19.7 mmHg with timolol 0.5% twice daily at all time points (p < 0.001) ¹⁾

JUPITER trial (single-arm, open-label, 130 eyes, 12 months) showed that LBN 0.024% achieved a mean IOP reduction of 4.3 mmHg (22%) at week 4 and 5.3 mmHg (25%) at week 52¹⁾.

CONSTELLATION trial (crossover, 25 eyes) showed that LBN 0.024% significantly lowered nighttime IOP compared to timolol 0.5% (2.5 vs 2.3 mmHg, p = 0.002).

NCX 470

NCX 470 is a NO-donating PGA derived from bimatoprost. The Dolomites trial (Phase II) compared three concentrations (0.021%, 0.042%, 0.065%) of NCX 470 with latanoprost 0.005% for 4 weeks. NCX 470 0.042% (8.24 mmHg, p = 0.028) and 0.065% (8.67 mmHg, p = 0.0009) showed significantly greater IOP reduction than latanoprost (7.43 mmHg).

5. Side Effects and Safety

Side Effects of LBN

The side effect profile of LBN is similar to that of conventional PGAs¹⁾²⁾. Pooled analysis of APOLLO and LUNAR confirmed that safety is comparable to PGA monotherapy¹⁾.

Ocular local side effects: Conjunctival hyperemia (most common), eyelash growth/increase, eye irritation, eye pain, increased iris pigmentation²⁾

Common PGA side effects: Periorbital skin pigmentation, periorbital fat atrophy (periorbitopathy), cystoid macular edema (in aphakic/pseudophakic eyes with posterior capsule rupture), reactivation of herpes keratitis, uveitis¹⁾²⁾

Side Effects of NCX 470

In the Dolomites trial, higher concentrations were associated with higher rates of adverse events. Conjunctival hyperemia was the most common (22.2% in the 0.042% group), followed by instillation site pain. Three patients discontinued, but overall tolerability was good.

Precautions

Since LBN has PGA side effects (iris pigmentation, eyelid pigmentation, eyelash changes, etc.), cosmetic side effects should be considered when treating one eye. Use with caution in patients with a history of herpes keratitis or active uveitis¹⁾³⁾.

Q Is LBN available in Japan?

A

LBN (Vyzulta®) was approved by the FDA in 2017 and is used in the United States, but it is not approved in Japan (as of March 2026). The Japanese Glaucoma Treatment Guidelines (5th edition) do not mention LBN. In Japan, conventional PGAs (latanoprost, travoprost, tafluprost, bimatoprost) are used as first-line agents.

6. Detailed Mechanism of Action

Action of PGF2α Receptor Agonist

LBN is metabolized by intraocular esterases to latanoprost acid. Latanoprost acid binds to the PGF2α receptor and remodels the extracellular matrix of the ciliary muscle via matrix metalloproteinases (MMPs), widening the ciliary muscle spaces ¹⁾²⁾. This facilitates aqueous humor outflow through the uveoscleral outflow pathway.

Action of Nitric Oxide

Butanediol mononitrate, a metabolite of LBN, releases NO in the eye. NO activates soluble guanylate cyclase, increasing cGMP. Increased cGMP induces relaxation of trabecular meshwork cells and Schlemm’s canal endothelial cells, increasing aqueous humor outflow through the trabecular outflow pathway.

Through this dual-pathway action, LBN may exert a more potent intraocular pressure-lowering effect compared to conventional PGAs (which only affect uveoscleral outflow) ²⁾.

Metabolism of NCX 470

NCX 470 is metabolized in the eye to bimatoprost, which is further broken down into bimatoprost acid and 6-(nitrooxy)hexanoic acid. Bimatoprost acid stimulates the PGF2α receptor, while the NO-donating moiety relaxes the trabecular meshwork. It has a similar dual mechanism of action to LBN, but differs in that its basic skeleton is bimatoprost.

7. Latest Research and Future Perspectives

NO-donating PGAs represent a new approach in glaucoma pharmacotherapy ²⁾. By adding an NO-donating function to conventional PGAs, a single agent can promote aqueous humor outflow via two pathways.

Long-term safety data for LBN are accumulating, and retrospective studies in real clinical practice have confirmed its efficacy and tolerability over two years.

For NCX 470, a Phase III trial (Mont Blanc study) is ongoing, and data on the safety and efficacy of the 0.1% high dose are anticipated.

Future challenges:

• Verification of long-term prognosis (including neuroprotective effects) of LBN and NCX 470
• Elucidation of the detailed mechanism of NO’s direct effect on the trabecular meshwork
• Evaluation of combined effects with other NO-donating drugs
• Approval and clinical introduction in various countries including Japan

Disclaimer

This article provides educational information for ophthalmology healthcare professionals and is not intended as a guide for individual diagnosis or treatment. Actual clinical decisions should be made under the responsibility of the attending physician.

Q How far has the development of NCX 470 progressed?

A

NCX 470 is a NO-donating PGA derived from bimatoprost developed by Nicox SA. The Phase II Dolomites study demonstrated superiority over latanoprost. The Phase III Mont Blanc study is underway, and results of safety and efficacy data for the 0.1% high dose are awaited. If approved, it could become the second NO-donating PGA after LBN.

8. References

1. American Academy of Ophthalmology. Primary Open-Angle Glaucoma Preferred Practice Pattern®. 2020.

2. European Glaucoma Society. Terminology and Guidelines for Glaucoma, 6th Edition. Br J Ophthalmol. 2025.

3. American Academy of Ophthalmology. Primary Open-Angle Glaucoma Suspect Preferred Practice Pattern®. 2020.