Valeant Pharmaceuticals International, wholly owned subsidiary, Bausch + Lomb, a leading global eye health company, and Nicox S.A., an international ophthalmic company,  announced that the US Food and Drug Administration (FDA) has approved the New Drug Application (NDA) for Vyzulta (latanoprostene bunod ophthalmic solution, 0.024%). Vyzulta, the first prostaglandin analog with one of its metabolites being nitric oxide (NO), is indicated for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

"With today's approval of Vyzulta, our customers and their patients with glaucoma now have a new treatment option that can help provide consistent and sustained IOP lowering, the only modifiable risk factor that can help slow down the progression of the disease," said Joseph C. Papa, chairman and chief executive officer, Valeant. "We expect to make this new advancement available for those who suffer with glaucoma before the end of the year."

Following topical administration, Vyzulta, a once daily monotherapy with a dual mechanism of action, works by metabolizing into two moieties, latanoprost acid, which primarily works within the uveoscleral pathway to increase aqueous humor outflow, and butanediol mononitrate, which releases NO to increase outflow through the trabecular meshwork and Schlemm's canal.  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.

"Vyzulta represents the first FDA-approved therapy developed through our proprietary NO-donating research platform," said Michele Garufi, chairman and chief executive officer of Nicox. "We look forward to continuing to leverage our platform in the development of additional innovative ophthalmic compounds."

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.

"The safety and efficacy of Vyzulta has been well-established through multiple clinical studies, which have demonstrated positive results, including statistically significant differences in IOP lowering compared to timolol and latanoprost," said Robert N. Weinreb, M.D., chairman and distinguished professor of Ophthalmology and director, Hamilton Glaucoma Center at the University of California San Diego. "As one molecule with a dual mechanism of action, Vyzulta provides a new treatment option that works to reduce IOP by increasing the outflow through both the trabecular meshwork and the uveoscleral pathways."

Vyzulta was licensed on a global basis to Bausch + Lomb from Nicox. As a result of this approval, Nicox will receive $17.5 million from Bausch + Lomb and will make a $15 million payment to Pfizer under a previous license agreement.

Vyzulta vs. Timolol Study: Non-Inferior & Superior to Timolol 0.5% (32% Mean Diurnal IOP Reduction) 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. The most common ocular adverse events included conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site pain (2%). No unexpected safety concerns were raised as a result of any of the ocular sign assessments or vital sign measurements.

Vyzulta vs. Latanoprost Study: Greater Mean IOP Reduction vs. Latanoprost
In the phase 2 VOYAGER study, designed to identify the appropriate dose of Vyzulta for the reduction of IOP in addition to assessing safety and efficacy, 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).

52-Week Safety Study: Vyzulta Reduced Mean IOP to 14.4 mm Hg in Subjects with Mean Low Baseline IOP of 19.6 mm Hg 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.

24-hour IOP Lowering Study: Vyzulta Demonstrated Better 24-hour IOP Control than Timolol
Another 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).