Nyxol® Eye Drops to Begin Phase 3 Development through the 505(b)(2) Pathway
Nyxol® is a preservative-free ophthalmic solution containing 1% phentolamine mesylate, a nonselective alpha adrenergic antagonist that inhibits the contraction of smooth muscle of the iris. Nyxol® effectively decreases the size of the pupil, resulting in better contrast sensitivity and visual acuity. Nyxol® is being developed for dim or night vision disturbances (NVD), reversal of pharmacological mydriasis, and presbyopia. Ocuphire believes that the results from Nyxol’s three Phase 1 and four Phase 2 trials totaling over 230 patients supports its current development plan.
Phentolamine mesylate is also the active pharmaceutical ingredient in two FDA-approved drugs, REGITINE® and OraVerse®. Nyxol® is being developed under the 505(b)(2) pathway.
Multiple Indications with Large Market Potential
Nyxol® 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
Dim light or 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.
Vision at night or in dim light conditions is different from daytime vision in several important ways. Most notably, at night, the pupils dilate to allow more light into the eye. Because of this dilation, light also passes through the periphery of the cornea and lens. Any imperfections or aberrations present on the periphery cause light to reach the retina in a non-focused and scattered way, creating glare, halos, starbursts, ghosting and a loss of contrast sensitivity (CS).
Individuals with peripheral imperfections or aberrations experience glare and streaky vision, as well as a “halo” or “starburst” effect. These visual disturbances can be debilitating to a variety of everyday activities, especially driving. The light emitted by traffic lights and other cars scatters and obscures most of the visual field, making driving in dim light conditions hazardous.
Diminished night vison is a natural part of aging as well as a common side effect of several conditions and procedures. Night vision disturbances are induced by a variety of causes, including night myopia, cortical cataracts, post-intraocular lens (IOL) implants, LASIK, and keratoconus.
The effects of NVD can be reduced or eliminated by reducing the pupil size to a 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 “moderate” pupil reduction properties. In clinical trials, Nyxol® resulted in improvement in contrast sensitivity and visual performance at night and during the day.
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 (NCT04004507, NCT01703559).
Building on these results, we plan to launch Phase 3 study LYNX-1 in the fourth quarter of 2020.
Reversal of Pharmacologically Induced Mydriasis
An estimated 200 million comprehensive eye exams take place globally each year, including 80 million in the United States. Most involve pharmacologically induced dilation, or mydriasis, of the pupils. In addition, 4 million eyes are dilated for surgical procedures.
Side effects of mydriasis include sensitivity to light and blurred vision, which make it difficult to read, work, and drive. Also, many drops cause cycloplegia, the temporary paralysis of the muscle which allows the eye to focus on near objects. For this reason, many patients may request to avoid dilation, limiting the eye care provider’s ability to conduct a comprehensive exam.
Pharmacological mydriasis is achieved either by stimulating the iris dilator muscle with the use of alpha adrenergic agonists (e.g., phenylephrine), or by blocking the iris sphincter muscle with the use of muscarinic antagonists (e.g., tropicamide), or a combination of both mydriatic agents. Such pharmacologically-induced mydriasis can last from a few hours (typically 6 hours) up to 24 hours, depending on the pigmentation of the iris, one’s age, and other factors.
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. According to the FDA, 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 fourth quarter of 2020.
Presbyopia is an age-related condition that commonly appears in people over 40 years old. As the eye ages, loss of lens elasticity results in an inability to focus on nearby objects (farsightedness). Because of the ubiquity of the condition, presbyopia represents a large market both in the United States and abroad, totaling over 2 billion presbyopia patients. It is estimated that 100 million Americans have presbyopia and this number is expected to grow as the population above the age of 45 increases.
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 can 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 is a clinical development area of focus. In previous clinical trials, Nyxol alone demonstrated the ability to moderately reduce pupil diameter and improve near visual acuity. Further decreasing the pupil size with Nyxol combined with a low-dose pilocarpine agent may achieve the “pinhole effect” that results in improved depth of focus and improved near reading 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 pilocarpine in presbyopia, in the first quarter of 2021.
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, 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 lowering of IOP.
At this time, Ocuphire is only planning to evaluate Nyxol as a second-line add-on to standard of care in glaucoma with a partner.
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.