Mr. Joseph Papa reports

BAUSCH + LOMB AND NICOX ANNOUNCE FDA APPROVAL OF VYZULTA (LATANOPROSTENE BUNOD OPHTHALMIC SOLUTION), 0.024%

First Prostaglandin Analog with one of its Metabolites Being Nitric Oxide Approved to Provide Consistent and Sustained IOP Reduction Through 12 Months

Valeant Pharmaceuticals International Inc.'s wholly owned subsidiary, Bausch + Lomb, a leading global eye health company, and Nicox S.A., an international ophthalmic company, have received U.S. Food and Drug Administration (FDA) approval for the new drug application (NDA) for Vyzulta (latanoprostene bunod ophthalmic solution, 0.024 per cent). 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 (1).

"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 humour 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 humour 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 CEO 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 humour outflow through the trabecular meshwork and Schlemm's canal. Studies have also demonstrated that patients with glaucoma have reduced levels of NO signalling 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, MD, 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 licence agreement.

Vyzulta comprehensive clinical trials

Vyzulta versus Timolol study: non-inferior and superior to Timolol 0.5 per cent (32-per-cent mean diurnal IOP reduction)

The efficacy and safety of Vyzulta were evaluated in two randomized, multicentre, double-masked, parallel-group phase 3 studies, Apollo and Lunar, comparing Vyzulta with Timolol maleate ophthalmic solution 0.5 per cent in subjects (N equals 831) with open-angle glaucoma or ocular hypertension. The primary objective of these studies was to demonstrate that the mean IOP reduction over three months of treatment with Vyzulta once daily (QD) in the evening was non-inferior to Timolol 0.5 per cent twice daily (BID). A secondary objective was to demonstrate the superiority of Vyzulta QD to Timolol 0.5 per cent BID. In both studies, Vyzulta met the primary efficacy end point. Vyzulta also demonstrated significantly greater IOP lowering than Timolol 0.5 per cent throughout the day at three months of treatment resulting in a reduction in mean diurnal IOP of 32 per cent from baseline (2) (3) (4). The most common ocular adverse events included conjunctival hyperemia (6 per cent), eye irritation (4 per cent), eye pain (3 per cent) and instillation site pain (2 per cent) (1). No unexpected safety concerns were raised as a result of any of the ocular sign assessments or vital sign measurements (2) (3).

Vyzulta versus Latanoprost study: greater mean IOP reduction versus 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 per cent) 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 per cent, showed greater IOP reduction compared with Xalatan (latanoprost ophthalmic solution 0.005 per cent), with the differences reaching 1.23 millimetres mercury (Hg) (p equals 0.005) for Vyzulta. In addition, 68.7 per cent of subjects treated with the FDA-approved dose for Vyzulta (latanoprostene bunod ophthalmic solution), 0.024 per cent, compared with 47.5 per cent of subjects treated with Xalatan (latanoprost ophthalmic solution 0.005 per cent), achieved a mean diurnal IOP of 18 millimetres Hg (p less than 0.05) (5).

52-week safety study: Vyzulta reduced mean IOP to 14.4 millimetres Hg in subjects with mean low baseline IOP of 19.6 millimetres Hg

The long-term safety of Vyzulta was assessed in Jupiter, a single-arm, multicentre, open-label phase 3 study of one-year duration in Japanese subjects (N equals 130) with open-angle glaucoma (including normotensive, pigmentary and pseudoexfoliative glaucoma) or ocular hypertension. The efficacy end points 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 millimetres Hg. Treatment with Vyzulta resulted in a 22-per-cent mean reduction in IOP at week 4 which was sustained through week 52. Mean IOP was 14.4 millimetres Hg at week 52, representing a 26-per-cent 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 per cent dosed BID in reducing IOP measured over a 24-hour period in subjects with open-angle glaucoma or ocular hypertension (N equals 25). The results of this randomized, single-centre, open-label, two-month crossover study demonstrated that Vyzulta lowered IOP over 24 hours, with a significantly greater nocturnal IOP reduction versus Timolol (p less than 0.004). The study also compared ocular perfusion pressure (OPP) in Vyzulta-treated subjects with Timolol-treated subjects over a 24-hour period. Vyzulta improved daytime OPP versus baseline (p less than 0.001) and nocturnal OPP versus Timolol 0.5 per cent (p equals 0.01) (7)

Important risk information about Vyzulta

Indication and usage

Vyzulta (latanoprostene bunod ophthalmic solution), 0.024 per cent, is a prostaglandin analog indicated for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Important safety information

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 are usually reversible upon treatment discontinuation.

Most common ocular adverse reactions with incidence equal to 2 per cent are conjunctival hyperemia (6 per cent), eye irritation (4 per cent), eye pain (3 per cent) and instillation site pain (2 per cent).

Please see the full prescribing information on the Bausch + Lomb website.

About Valeant Pharmaceuticals International Inc.

Valeant is a multinational specialty pharmaceutical company that develops, manufactures and markets a broad range of pharmaceutical products primarily in the areas of dermatology, gastrointestinal disorders, eye health, neurology and branded generics.

References

(1) Vyzulta (prescribing information); Bridgewater, N.J.; Bausch & Lomb, 2017.

(2) Weinreb RN, Scassellati Sforzolini B., Vittitow J., Liebmann J. Latanoprostene bunod 0.024 per cent versus Timolol maleate 0.5 per cent in subjects with open-angle glaucoma or ocular hypertension: the Apollo study; ophthalmology, 2016.

(3) Medeiros FA, Martin KR, Peace J. et al., comparison of latanoprostene bunod 0.024 per cent and Timolol maleate 0.5 per cent in open-angle glaucoma or ocular hypertension: the Lunar study; Am J Ophthalmol, 2016.

(4) Kaufman PL. Latanoprostene bunod ophthalmic solution 0.024 per cent for IOP lowering in glaucoma and ocular hypertension; Expert Opin Pharmacother, 2017.

(5) Weinreb RN, Ong T., Scassellati Sforzolini B. et al., a randomized, controlled comparison of latanoprostene bunod and latanoprost 0.005 per cent in the treatment of ocular hypertension and open-angle glaucoma: the Voyager study; Br J. Ophthalmol, 2015.

(6) Kawase K., Vittitow JL, Weinreb RN, Araie M. for the Jupiter study group, long-term safety and efficacy of latanoprostene bunod 0.024 per cent in Japanese subjects with open-angle glaucoma or ocular hypertension: the Jupiter study; Adv Ther, 2016.

(7) Liu J., Slight JR, Vittitow JL et al., efficacy of latanoprostene bunod 0.024 per cent compared with Timolol 0.5 per cent in lowering intraocular pressure over 24 hours; Am J Ophthalmol, 2016.

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