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 (NVD), reversal of mydriasis, and presbyopia. Each indication has a precedent pathway to approval or primary endpoints discussed with 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 (NVD) is a new indication with no approved therapies, despite an estimated 15-20 million people in the United States with moderate-to-severe NVD and an addressable NVD market of approximately 4 million US adults. 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. NVD 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 NVD 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 has the potential to 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 multi-center, randomized, double-masked, placebo-controlled, multiple-dose Phase 2b study with evening dosing, demonstrated statistically significant reductions 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 and more than 4 million ophthalmic surgical dilations 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. A more rapid 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 6-8mm, a size suitable for ophthalmic examination of the retina and other structures of the eye’s interior.

There are no drugs currently approved for the reversal of mydriasis. 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 discontinued from the market for reasons other than safety and efficacy.

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 more rapidly reverse mydriasis, thereby potentially relieving post-exam side effects, visual impairment, eye strain and discomfort.

MIRA-1 (NCT04024891) Phase 2b results showed statistically significant 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 a clinical development area of focus. Nyxol is a potential treatment alone or with a low dose miotic for presbyopia, based on efficacy data that demonstrated its ability to reduce pupil diameter and improve near visual acuity. The goal is to achieve a target pinhole size, which may 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 of improvement at multiple time points.

We plan to begin the Phase 2 study VEGA-1, which will study the effects of 1% Nyxol with a low dose miotic in presbyopia, 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.

In NYX-01a2 (NCT01703559), a Phase 2 NVD study with subjects with normal IOP baseline, a single dose of 1% Nyxol resulted in a statistically significant IOP lowering of 2.4 mmHg in 2 hours (p=0.001). A potential mechanism of action of IOP lowering is through episcleral venous pressure.

We are looking for a partner for Nyxol for continued Phase 2 development as a second-line drug candidate after prostaglandin therapy or normal tension glaucoma patients.

Nyxol Product Profile

Nyxol is a 1% ophthalmic solution of phentolamine mesylate, a non-selective α1 & α2 adrenergic antagonist. Phentolamine mesylate is a small molecule that was approved in 1952 for intravenous systemic use to treat surgical hypertension, and in 2008 for intraoral submucosal injection to reverse the effects of dental anesthesia. Nyxol is a first-in-class ophthalmic formulation targeting multiple front of the eye indications, including NVD, RM and Presbyopia. Nyxol’s product candidate profile is shown below, reflecting the treatment to date of over 150 subjects in 7 completed Phase 1 and 2 trials. 1% Nyxol is intended to be a preservative-free, EDTA-free, once-daily chronic evening or acute eye drop, with a tolerable and durable profile, that moderately reduces pupil diameter.


Mechanism of Action

Nyxol inhibits α1 which relaxes the iris dilator, thereby reducing the pupil diameter. Decreasing the larger pupil size at night blocks the light scatter by aberrations on the corneal periphery that cause NVD. Similarly, rapidly decreasing the pupil size to normal levels re-establishes normal vision in RM. For Presbyopia, decreasing the pupil size below 2mm with Nyxol + low-dose pilocarpine may create a “pinhole effect” for improved depth of focus, thereby improving near reading vision.

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.