Reversal of Pharmacologically Induced Mydriasis
About Reversal of Pharmacologically Induced Mydriasis
In the United States, an estimated 100 million comprehensive eye exams take place each year that involve pharmacologically induced dilation (or mydriasis) of the pupils.
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.
Market Landscape
100M
In-office eye dilations per year in the U.S.
How Phentolamine Ophthalmic Solution 0.75% Can Help Pharmacologically Induced Mydriasis
Across multiple clinical trials, Phentolamine Ophthalmic Solution 0.75% alone has shown the ability to reduce pupil size by relaxing the iris dilator muscle in normal eyes. To counteract mydriatic drugs, Phentolamine Ophthalmic Solution 0.75% could be instilled in the eyes to more rapidly reverse mydriasis, thereby potentially relieving post-exam side effects, visual impairment, eye strain, and discomfort.
Clinical Trial
Building on the results of MIRA-1 and MIRA-2, we have launched a second Phase 3 registration trial (MIRA-3) and a Pediatric safety study (MIRA-4) in the fourth quarter of 2021 with data from both studies expected near the end of Q1 2022.
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. Phentolamine Ophthalmic Solution 0.75% also returned more subjects to baseline vision (accommodation) and PD within 2 hours compared to placebo.
MIRA-2 (NCT04620213) and MIRA-3 (NCT05134974) both Phase 3 studies met their primary endpoint at 90 minutes and multiple secondary endpoints. Effect was seen starting at 1 hour and lasting up to 24 hours. Phentolamine Ophthalmic Solution 0.75% demonstrated a faster return to baseline compared to placebo at 90 minutes and accommodation and shortened recovery time from dilation on average by 4 hours.
Presbyopia
About Presbyopia
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 128 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 and contact lenses, and in some cases receive 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.
Market Landscape
120M
in the US. Expected to grow to 150+M by 2034
How Phentolamine Ophthalmic Solution 0.75% Can Help Presbyopia
Presbyopia is a large unmet market, where pupil modulation is a clinical development area of focus. Two labels are being pursued for presbyopia: Phentolamine Ophthalmic Solution 0.75% alone and Phentolamine Ophthalmic Solution 0.75% with low-dose (0.4%) pilocarpine. In previous clinical trials, Phentolamine Ophthalmic Solution 0.75% alone demonstrated the ability to moderately reduce pupil diameter and improve near visual acuity. Further decreasing the pupil size with Phentolamine Ophthalmic Solution 0.75% combined with a low-dose miotic agent may achieve the “pinhole effect” that results in improved depth of focus and improved near reading vision.
Clinical Trial
VEGA-1 (NCT04675151), a Phase 2 study met its primary endpoint and several key secondary endpoints. Phentolamine Ophthalmic Solution 0.75%+LDP combination treatment showed statistically significant improvement in 3-lines or more from baseline in near visual acuity at multiple timepoints.
In ORION-1 (NCT03960866), a Phase 2b study, Phentolamine Ophthalmic Solution 0.75% 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.
Night Vision Disturbances
About Dim Light or Night Vision Disturbances
Dim light or night vision disturbances (DLD or NVD) is a new indication with no approved therapies, despite an estimated 16 million people in the United States with moderate-to-severe DLD.
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 vision 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.
Market Landscape
38M
Adults suffering from Dim Light or Night Vision Disturbances in the U.S.
How Phentolamine Ophthalmic Solution 0.75% Can Help DLD
The effects of DLD 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. Phentolamine Ophthalmic Solution 0.75% has the potential to be a first-line treatment for night vision disturbances based on its optimal “moderate” pupil reduction properties. In clinical trials, Phentolamine Ophthalmic Solution 0.75% demonstrated improvement in contrast sensitivity and visual performance at night and during the day.
Clinical Trials
ORION-1 (NCT03960866), a recently completed multi-center, randomized, double-masked, placebo-controlled, multiple-dose Phase 2b study with evening dosing, met the primary endpoint and demonstrated statistically significant reductions in pupil diameter, which was sustained through 36 hours post-dose.
Phase 2 Clinical Trial of Nyxol in Elderly Subjects with Glaucoma (NCT03960866)
Severe Night Vision Disturbance Single-Dose Phase 2 Clinical Trial with Nyxol (NCT04004507)
Night Vision Complaints Multiple-Dose Phase 2 Clinical Trial with Nyxol (NCT01703559)
Building on these results, we have launched the Phase 3 study LYNX-1 in the second half of 2020. (NCT04638660)