Topical Nitric Oxide Donating Prostaglandin Analogues

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Article initiated by:

Abdelrahman M. Elhusseiny, MD, MSc, Ahmed Sallam, MD PhD FRCOphth, Noah Brown

All contributors:

Ahmad A. Aref, MD, MBA, Ahmad A. Aref, MD, MBA, Abdelrahman M. Elhusseiny, MD, MSc

Assigned editor:

Review:

Assigned status Update Pending

 by Ahmad A. Aref, MD, MBA on December 23, 2023.

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Introduction

Glaucoma is the most frequent cause of irreversible blindness worldwide. It was estimated to affect 76 million people aged 40-80 years in 2020, with a projection of 111.8 million by 2040. Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma. Numerous IOP-lowering medications have been developed, including topical prostaglandin analogues (PGAs), which are currently the first-line medical therapy for most types of glaucoma.

Recently, two nitric oxide (NO)-donating PGAs, latanoprostene bunod (LBN) 0.024% (Vyzulta®) and NCX 470 (Nicox SA), have been introduced. These drugs have dual mechanisms that have been proposed to improve the IOP-lowering capabilities of currently prescribed glaucoma medications.

Once exposed to esterases within the eye, LBN and NCX 470 are cleaved into their respective metabolites; a prostaglandin F2-alpha (PGF2α) agonist and a NO-donating moiety. PGF2α agonists increase uveoscleral outflow via matrix-metalloproteinase-mediated remodeling of the ciliary muscle, while NO induces vasodilation and smooth muscle relaxation, increasing trabecular outflow and decreasing IOP.

Latanoprostene Bunod

LBN is a novel NO-donating PGA metabolized in the eye into latanoprost acid, a PGF2α agonist, and butanediol mononitrate, a NO-donating moiety. Once LBN is metabolized, latanoprost acid binds to its receptor and increases uveoscleral outflow. This is accomplished by metalloproteinases that remodel the ciliary muscle's extracellular matrix. In addition, butanediol mononitrate can donate NO within the eye resulting in increased aqueous humor outflow via relaxation of the trabecular meshwork and Schlemm's canal.

To assess safety and efficacy, a series of clinical studies compared varying concentrations of LBN to two currently prescribed glaucoma medications, latanoprost 0.005% and timolol 0.5%.

The JUPITER study suggested that LBN 0.024% once daily was safe, well-tolerated, and resulted in no serious adverse effects for up to one year. The JUPITER study also demonstrated that LBN 0.024% resulted in a mean IOP reduction of 4.2 mm Hg (22%) at 4 weeks and 5.3 mm Hg (25%) at 52 weeks compared to baseline levels (p<0.001). The VOYAGER study compared LBN at varying concentrations to latanoprost 0.005%. LBN 0.024% and 0.040% provided a significantly greater mean diurnal IOP reduction compared to latanoprost 0.005%, with reductions of 9.00 (p=0.005), 8.93 (p=0.009), and 7.77 mm Hg, respectively. The CONSTELLATION study indicated that treatment with LBN 0.024% once daily significantly reduced the mean nocturnal IOP by 2.5 ± 3.1 mm Hg (p=0.002) compared to timolol 0.5%, which had a reduction of 2.3 ± 3.0 mm Hg (p=0.004).

Two further studies, the APOLLO and LUNAR studies, were pooled and analyzed. Results showed that LBN 0.024% once daily resulted in more significant IOP-lowering effects than timolol 0.5% twice daily over 12 months. Over 12 months, LBN 0.024% of treated eyes had a least-squares (LS) mean of mean IOP range of 17.8 to 18.7 mm Hg (p<0.001). In contrast, timolol 0.5% had an LS mean IOP range of 19.0 to 19.7 mm Hg. The APOLLO and LUNAR pooled analysis also showed that LBN safety was comparable to PGA treatment alone.

A recent retrospective study conducted by Radell and colleagues demonstrated the safety and efficacy of LBN 0.024% over two years. Results of this study indicated that LBN 0.024% was generally well-tolerated and decreased IOP by 2.1 ± 3.5 mm Hg (p<0.0001) at the first follow-up (38.7 ± 36.5 days) and 2.5 ± 3.3 mm Hg (p<0.0001) at the last follow-up (235.9 ± 160.8 days).

Table 1 summarizes the major clinical studies evaluating the efficacy and safety of LBN.

Table 1: Summary of major clinical studies on LBN for treatment of primary open angle glaucoma (POAG) and ocular hypertension (OHT)
Study	Study Design	Number of Study Eyes (Patients)	Percentage of Patients on IOP-lowering Medication Within 30 Days of Enrollment	Mean Age of Study Population	Follow-up Period	Results
JUPITER Kawase and colleagues.	Single-arm, open-label	130 (130)	90.0%	62.5 ± 18.9 years	12 months	Mean reduction of IOP: At 4 weeks: 4.3 mm Hg (22%) At 52 weeks: 5.3 mm Hg (25%) Most common adverse effects: Conjunctival hyperemia: 17.7% Growth of eyelashes: 16.2% Eye irritation: 11.5% Eye pain: 10.0% Increased iris pigmentation: 10.0%
VOYAGER Weinreb and colleagues.	Phase II, randomized, investigator-masked, parallel-group, dose-ranging	413 (413)	56.4%	61.0 ± 11.44 years	28 days	Mean reduction of diurnal IOP (p-Value): LBN 0.006%: 7.81 mm Hg (0.913) LBN 0.012%: 8.26 mm Hg (0.258) LBN 0.024%: 9.00 mm Hg (0.005) LBN 0.040%: 8.93 mm Hg (0.009) Latanoprost 0.005%: 7.77 mm Hg
CONSTELLATION Liu and colleagues.	Randomized crossover	25 (25)	24%	60.3 ± 10.6 years	28 days	Mean reduction of nocturnal IOP (p-Value): LBN 0.024%: 2.5 ± 3.1 mm Hg (0.002) Timolol 0.5%: 2.3 ± 3.0 mm Hg (0.004)
APOLLO Weinreb and colleagues.	Phase III, randomized, multicenter, double-masked, parallel-group	420 (420)	71.9%	64.2 ± 10.6 years	3 months	LS mean of mean IOP (p-Value): LBN 0.024% range: 17.8 - 18.7 mm Hg (≤0.002 at all timepoints) Timolol 0.5% range: 19.1 - 19.8 mm Hg
LUNAR Medeiros and colleagues.	Phase III, randomized, multicenter, double-masked, parallel-group	387 (387)	72%	64.7 ± 9.75 years	3 months	LS mean of the mean IOP (p-Value): LBN 0.024% range: 17.7 – 19.2 mm Hg (≤0.25 at all time points except for the 8 AM measurement at week 2 – 0.216) Timolol 0.5% range: 18.8 – 19.6 mm Hg
APOLLO and LUNAR Pooled Analysis Weinreb and colleagues.	Phase III, randomized, multicenter, double-masked, parallel-group, noninferiority	840 (840)	72%	64.5 ± 10.2 years	12 months	LS mean of mean IOP (P-Value): LBN 0.024% range: 17.8 - 18.9 mm Hg (<0.001 at all timepoints) Timolol 0.5% range: 19.0 - 19.7 mm Hg
Two Year Experience with Latanoprostene Bunod in Clinical Practice Radell and colleagues.	Retrospective review	102 (56)	100%	68.8 ± 12.4 years	24 months	Mean IOP change (p-Value): Visit 1 vs. visit 2 (before LBN prescription): +1.3 ± 4.0 mm Hg (0.002) Visit 2 vs. visit 3 (prescription until first follow-up on LBN): -2.1 ± 3.5 mm Hg (<0.0001) Visit 3 vs. visit 4 (prescription until last follow-up on LBN): -2.5 ± 3.3 mm Hg (<0.0001) Visit 3 vs. visit 4 (first follow-up on LBN until last follow-up on LBN): -0.3 ± 3.1 mm Hg (0.28)

NCX 470

NCX 470, like LBN, is a NO-donating PGA with the chemical name hexanoic acid. NCX 470 is metabolized into prostamide bimatoprost, which is then further metabolized into bimatoprost acid and 6-(nitrooxy)-hexanoic acid. Bimatoprost acid is a PGF2α agonist, while 6-(nitrooxy)-hexanoic acid is a NO-donating moiety.

The Dolomites trial is the only clinical trial that investigated NCX 470. This study compared NCX 470 at varying concentrations (0.021%, 0.042%, and 0.065%) to latanoprost 0.005% at 8:00 AM, 10:00 AM, and 4:00 PM each week for 4 weeks. NCX 470 treatment decreased the mean diurnal IOP at week 4 for all three concentrations that were non-inferior to latanoprost 0.005%. After 4 weeks, NCX 470 0.021%, 0.042%, and 0.065% decreased diurnal IOP by 7.83, 8.24, and 8.67 mmHg, respectively (p<0.0001). Comparatively, latanoprost 0.005% resulted in a diurnal IOP reduction of 7.43 mm Hg after four weeks. NCX 470 0.042% and NCX 470 0.065% displayed a statistically significantly greater reduction in mean diurnal IOP compared to latanoprost 0.005% (p=0.0281 and 0.0009, respectively).

In terms of safety, a greater percentage of patients in the NCX 470 0.021% (30.6%), 0.042% (48.1%), and 0.065% (46.7%) treatment groups experienced at least 1 ocular treatment-emergent adverse event (TEAE) compared to the latanoprost 0.005% treatment group (19.6%). The most common TEAE was conjunctival hyperemia, experienced by 10.8%, 22.2%, and 16.8% of patients in the NCX 470 0.021%, 0.042%, and 0.065% treatment groups, respectively. The second most common TEAE was instillation site pain at 7.2%, 9.3%, and 11.2% for the NCX 470 0.021%, 0.042%, and 0.065% treatment groups, respectively. Four total ocular TEAEs in three patients resulted in study withdrawal due to conjunctival hyperemia and instillation eye pain or conjunctival hyperemia and dry eye. Despite these reported adverse events, NCX 470 was well-tolerated at all three dosages.

NCX 470 treatment decreased the mean diurnal IOP at week 4 for all three concentrations that were non-inferior to latanoprost 0.005%. After 4 weeks, NCX 470 0.021%, 0.042%, and 0.065% decreased diurnal IOP by 7.83, 8.24, and 8.67 mmHg, respectively (p<0.0001). Comparatively, latanoprost 0.005% resulted in a diurnal IOP reduction of 7.43 mm Hg after four weeks. NCX 470 0.042% and NCX 470 0.065% displayed a statistically significantly greater reduction in mean diurnal IOP compared to latanoprost 0.005% (p=0.0281 and 0.0009, respectively).

A phase III clinical trial named Mont Blanc is currently underway and has recently closed screening for additional patients. Nicox SA is expected to release results from this study as early as November 2022 and will include the safety and efficacy of a higher dosage, NCX 470 0.1%.

Conclusion

Current PGAs such as latanoprost and bimatoprost are effective at lowering IOP and treating glaucoma. However, novel drugs like LBN and NCX 470 may have superior IOP reduction capability due to their ability to donate NO.