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The most common ocular adverse events include conjunctival hyperemia, eye irritation, eye pain and instillation site pain. Increased pigmentation of the iris and periorbital tissue and growth of eyelashes can occur.
In glaucoma patients, damage to the trabecular meshwork, through which the majority of the aqueous humor passes, can lead to reduced drainage and as a result elevated IOP. Lowering IOP, even in patients with normal baseline levels, can delay, or even prevent damage to optic nerves, helping to reduce the risk of glaucomatous visual field loss.
Preclinical studies have shown that NO plays a role in controlling IOP in normal eyes by increasing aqueous humor outflow through the trabecular meshwork and Schlemm's canal. Studies have also demonstrated that patients with glaucoma have reduced levels of NO signaling in their eyes, providing a rationale for the therapeutic value of NO-releasing molecules for patients with open-angle glaucoma or ocular hypertension.
Some of the clinical trials that evaluated Vyzulta include:
1. Vysulta vs. Timolol Study: The efficacy and safety of Vyzulta were evaluated in two randomized, multi-center, double-masked, parallel-group Phase 3 studies, APOLLO and LUNAR, comparing Vyzulta with timolol maleate ophthalmic solution 0.5% in subjects (N=831) with open-angle glaucoma or ocular hypertension.
The primary objective of these studies was to demonstrate that the mean IOP reduction over 3 months of treatment with Vyzulta once daily (QD) in the evening was non-inferior to timolol 0.5% twice daily (BID). A secondary objective was to demonstrate the superiority of Vyzulta QD to timolol 0.5% BID.
In both studies, Vyzulta met the primary efficacy endpoint. Vyzulta also demonstrated significantly greater IOP lowering than timolol 0.5% throughout the day at 3 months of treatment resulting in a reduction in mean diurnal IOP of 32% from baseline.2,3,4 The most common ocular adverse events included conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site pain (2%).1 No unexpected safety concerns were raised as a result of any of the ocular sign assessments or vital sign measurements.
2. Vyzulta vs. Latanoprost Study: In the Phase 2 VOYAGER study, 413 patients across 23 sites in the United States and Europe were randomized to receive either latanoprostene bunod (various concentrations) or Xalatan (latanoprost ophthalmic solution 0.005%) once a day in the evening for 28 days. Two of the four doses tested, including the FDA approved dose for Vyzulta (latanoprostene bunod ophthalmic solution), 0.024%, showed greater IOP reduction compared with Xalatan (latanoprost ophthalmic solution 0.005%), with the differences reaching 1.23 mm Hg (p=0.005) for Vyzulta. In addition, 68.7% of subjects treated with the FDA approved dose for Vyzulta (latanoprostene bunod ophthalmic solution), 0.024%, compared to 47.5% of subjects treated with Xalatan (latanoprost ophthalmic solution 0.005%), achieved a mean diurnal IOP ≤18 mm Hg (p<0.05).
3. 52-Week Safety Study: The long-term safety of Vyzulta was assessed in JUPITER, a single-arm, multicenter, open-label Phase 3 study of one-year duration in Japanese subjects (N=130) with open-angle glaucoma (including normotensive, pigmentary and pseudoexfoliative glaucoma) or ocular hypertension. The efficacy endpoints of the JUPITER study were to evaluate the absolute IOP level and its reduction from baseline over a 52-week period. The mean baseline IOP in the study eye in the JUPITER study was 19.6 mm Hg. Treatment with Vyzulta resulted in a 22% mean reduction in IOP at Week 4 which was sustained through Week 52. Mean IOP was 14.4 mm Hg at Week 52 representing a 26% reduction from baseline in the study eye.6 The most common ocular adverse events were conjunctival hyperemia, growth of eyelashes, iris pigmentation, blepharal pigmentation, eye irritation, and eye pain.
4. 24-hour IOP Lowering Study: CONSTELLATION compared the effect of Vyzulta dosed QD with timolol maleate ophthalmic solution 0.5% dosed BID in reducing IOP measured over a 24-hour period in subjects with open-angle glaucoma or ocular hypertension (N=25). The results of this randomized, single-center, open-label, 2-month crossover study demonstrated that Vyzulta lowered IOP over 24-hours, with a significantly greater nocturnal IOP reduction vs. timolol (p<0.004). The study also compared ocular perfusion pressure (OPP) in Vyzulta-treated subjects vs. timolol-treated subjects over a 24-hour period. Vyzulta improved daytime OPP vs. baseline (p<0.001) and nocturnal OPP vs. timolol 0.5% (p=0.01).
Some of the adverse events noted in the trials include:
- Increased pigmentation of the iris, periorbital tissue (eyelid), and eyelashes can occur. Iris pigmentation is likely to be permanent.
- Gradual changes to eyelashes, including increased length, increased thickness, and number of eyelashes, may occur. These changes were found to be usually reversible upon treatment discontinuation.
- Most common ocular adverse reactions with incidence ≥2% were conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site pain (2%).
What is Latanoprostene bunod (LBN)?
LBN is composed of latanoprost acid (LA) linked to a nitric oxide (NO)-donating moiety and is the first NO-releasing prostaglandin analog approved in the United States.
The role of latanoprost in increasing uveoscleral outflow of aqueous humor is well established. Pharmacokinetic studies in rabbits and corneal homogenates indicate that LBN is rapidly metabolized to LA and butanediol mononitrate. NO is subsequently released by butanediol mononitrate as shown by increased cyclic guanosine monophosphate (cGMP) levels in (1) the aqueous humor and iris-ciliary body after administration of LBN in rabbits and in (2) human trabecular meshwork (TM) cells after incubation with LBN.
LBN reduced myosin light chain phosphorylation, induced cytoskeletal rearrangement, and decreased resistance to current flow to a greater extent than latanoprost in TM cells, indicating that NO released from LBN elicited TM cell relaxation. LBN also lowered IOP to a greater extent than latanoprost in FP receptor knockout mice, rabbits with transient OHT, glaucomatous dogs, and primates with OHT.
Along with results from a Phase 2 clinical study in which treatment with LBN 0.024% resulted in greater IOP-lowering efficacy than latanoprost 0.005%, these data indicate that LBN has a dual mechanism of action, increasing aqueous humor outflow through both the uveoscleral (using LA) and TM/Schlemm's canal (using NO) pathways.
References: PR Newswire, Journal of Ocular Pharmacology and Therapeutics
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