Nyxol

Indications for Nyxol

We are focused on developing therapies to treat a variety of ophthalmic disorders. Nyxol®, a once-daily ophthalmic solution containing phentolamine mesylate, is our lead drug candidate and is currently being developed for night vision disturbances (NVDs), reversal of mydriasis, and presbyopia. Each indication has a precedent pathway to approval or primary endpoints agreeable to the FDA. Nyxol is an investigational drug candidate that is being tested in clinical trials and has not yet been approved by the FDA or other regulatory bodies for commercial sale.

Night Vision Disturbances

Night Vision Disturbances (NVDs) is a new indication with no approved therapies, despite an estimated 4 million people in the United States and 7 million worldwide (Europe and Japan) affected by the condition. In dim light conditions, the pupil dilates to allow more light to enter the eye. However, because of this dilation, light also passes through the periphery of the cornea and lens. As light passes through the periphery of the eye, any imperfections or aberrations cause light to scatter before it reaches the retina. Individuals with peripheral imperfections or aberrations experience glare and streaky vision, as well as a “halo” or “starburst” effect.

Night vision disturbances are induced by a variety of causes, including night myopia, cortical cataracts, post-intraocular lens (IOL) implants, LASIK, and keratoconus. NVDs can be debilitating and interfere with a variety of everyday activities, most notably driving. The light emitted by traffic signals and other cars makes driving in dim light conditions difficult and unsafe. The effects of NVDs can be reduced or eliminated by reducing the pupil size to a smaller diameter that prevents the scattering effect without impeding the ability to see at night.

Nyxol could be a first-line treatment for night vision disturbances based on its optimal pupil reduction properties and consequent improvement in contrast sensitivity and visual performance at night and during the day. Nyxol’s alpha-1 blocking activity relaxes (i.e., inhibits contraction of) the iris dilator muscle, resulting in a smaller pupil size.

ORION-1 (NCT03960866), a recently completed randomized, double-masked, placebo-controlled, crossover, multiple-dose Phase 2b study with evening dosing, demonstrated statistically significant and clinically relevant reduction in pupil diameter, which was sustained through 36 hours post-dose. For more information about our previously completed Phase 2 studies on night vision disturbances, please visit clinicaltrials.gov (NCT04004507NCT01703559).

Building on these results, we plan to launch Phase 3 study LYNX-1 in the first half of 2020.

Reversal of Mydriasis

More than 80 million comprehensive eye exams are performed each year in the United States, during which the pupils are dilated (i.e., mydriasis), increasing sensitivity to light and impairing vision for four to eight hours afterwards. Also, many mydriasis-inducing drugs cause cycloplegia, the temporary paralysis of the muscle responsible for focusing the eye on nearby objects. Mydriatic reversal after eye exams would therefore be beneficial.

Pharmacologically-induced mydriasis is achieved either by contracting the iris dilator muscle with the use of alpha adrenergic agonists (i.e., phenylephrine) or by blocking the iris sphincter muscle with the use of cholinergic antagonists (i.e., tropicamide).  Typically, induced mydriasis dilates the pupil to 7-8mm, a size suitable for ophthalmic examination of the retina and other structures of the eye’s interior.

Dapiprazole, an alpha-1 antagonist, was approved by the FDA in 1990 to reverse pharmacologically-induced mydriasis and was marketed under the trade name Rev-Eyes. Rev-Eyes was withdrawn from the market for reasons other than safety and efficacy, and since then no other drug has been approved for reversal of mydriasis.

Nyxol has been shown to reduce pupil size by relaxing the iris dilator muscle in normal eyes. To counteract mydriatic drugs, Nyxol could be instilled in the eyes to rapidly reverse mydriasis, thereby relieving post-exam side effects and discomfort.

MIRA-1 (NCT04024891) Phase 2b results showed statistically significant and clinically relevant reductions in pupil diameter (PD) at 1 hour, 2 hours, and 4 hours post-treatment compared to placebo. Nyxol also returned more subjects to baseline vision (accommodation) and PD within 2 hours compared to placebo.

Building on these results, we plan to launch Phase 3 study MIRA-2 in the first half of 2020.

Presbyopia

Presbyopia is an age-related condition that commonly appears in people aged 40 to 50. As the eye ages, loss of lens elasticity results in an inability to focus on nearby objects. Presbyopia affects close to 2 billion worldwide, including over 100 million people in the United States. Presbyopia’s prevalence is expected to rise as the average age of the population increases over time.

Individuals with presbyopia use reading glasses, contact lenses, and in some cases, surgical interventions, but there are no currently approved drug therapies for presbyopia. There are several drawbacks to reading glasses. For example, presbyopia only affects near vision, so reading glasses must be put on and taken off throughout the day. Contact lenses for presbyopia may cause eye strain, night vision disturbances, and other side effects. Eye drops are considered to be the “holy grail” alternative to corrective devices for presbyopia.

Presbyopia is a large unmet market, where pupil modulation, such as Nyxol’s approach, is an intense area of focus. Nyxol is a potential treatment alone or in combination for presbyopia, based on its ability to reduce pupil diameter and improve visual acuity. The goal is to achieve a target pinhole size, which will result in clearer near vision.

In ORION-1 (NCT03960866), a recently completed Phase 2b study, Nyxol as a single agent showed statistically significant improvement of 1 or more lines from baseline in near visual acuity, with a trend of 2 or more lines at multiple time points.

We are finalizing a fixed-dose combination of 1% Nyxol and a miotic to treat presbyopia, and plan to begin the Phase 2 study VEGA-1 in the first half of 2020.

Other Indications: Glaucoma

Glaucoma is a progressive, age-related disease and the leading cause of irreversible vision loss, affecting 60 million people worldwide, including 3 million people in the United States. Glaucoma is the result of increased intraocular pressure (IOP) due to a buildup of aqueous humor in the eye. Sustained elevated IOP damages the optic nerve, resulting in loss of vision and blindness. There are currently five classes of approved glaucoma medications. U.S. spending on glaucoma medications in 2016 totaled $2.8 billion, yet almost half of patients in treatment for glaucoma do not reach normal IOP goals. Second-line treatments, especially for patients in normotensive range, are needed to decrease patients’ IOP levels. A potential mechanism of action of IOP lowering is through episcleral venous pressure.

We are looking for a partner for this program for continued Phase 2 development.

Nyxol Product Profile

In summary, Nyxol once-daily preservative-free eye drops are an investigational 505(b)(2) ophthalmic solution containing phentolamine mesylate, a reversible non-selective alpha-1 and alpha-2 adrenergic blocker. Nyxol has been tested in more than 150 subjects over the course of seven randomized, double-blind, placebo-controlled Phase 1 and 2 studies, demonstrating promising evidence of safety, tolerability, and efficacy in our targeted indications. Phentolamine mesylate was previously FDA-approved as an IV formulation for lowering blood pressure in pheochromocytoma and an intramuscular formulation to speed recovery from dental anesthesia and was shown to be tolerable and efficacious. In our two recently completed Phase 2b studies, Nyxol was well-tolerated with no burning, ptosis, no tachyphylaxis, no rebound, and no other AEs or SAEs.

We believe that Nyxol possesses a differentiated product profile compared to other therapies on the market and in clinical development. Nyxol’s safety and tolerability profile makes it an ideal candidate that uniquely addresses a cross-section of front-of-the-eye indications. If approved, clinicians could utilize Nyxol as either a first-line intervention or as adjunct therapy for patients in need of further improvement. Nyxol’s ability to improve both daytime and night vision would also help mitigate the adverse side effects of other treatments with the convenience of once-daily dosing at or near bedtime.

Publications/Presentations

Ocuphire Pharma is dedicated to publishing the results of Nyxol studies in peer-reviewed medical journals and presenting them at leading eye care conferences around the world. Nyxol’s active pharmaceutical ingredient, phentolamine mesylate, is in the alpha-adrenergic antagonist class and has a long history in the literature.

Please check our News page for key papers and presentations.