Editors’ Note: We asked Jay Pepose, MD, PhD, chief medical advisor of Ocuphire Pharma and a member of the company’s board of directors, to differentiate Nyxol from other pharmacologic options being developed.

A Unique Mechanism of Action and Differentiated Product Profile

PHENTOLAMINE OPHTHALMIC solution, 0.75% (POS; Nyxol, Ocuphire) is a novel, preservative- and EDTA-free, stable, reversible, nonselective α-1 and α-2 antagonist packaged in a single-use vial. It competes with norepinephrine (or phenylephrine) binding to the α-1 receptors on the iris dilator muscle, thereby moderately decreasing pupillary diameter. POS has been evaluated in 12 completed clinical trials, (of which 4 were phase 3 FDA registration trials), and it is being developed for 3 proposed indications: treatment of presbyopia (~128 million prevalence in the United States), reversal of pharmacological mydriasis (~100 million dilated examinations annually in the United States), and treatment of night vision disturbances (~36 million patients in the United States).

The iris has 2 opposing muscles that modulate pupillary diameter—the radial iris dilator muscle activated by adrenergic agents, and the iris sphincter muscle, activated by muscarinic parasympathetic agents (Figure 1). A distinct advantage of Nyxol is that it does not engage the ciliary muscle, as do cholinergic miotic drugs, such as pilocarpine, to varying degrees. This obviates concerns of Nyxol increasing the risk of accommodative spasm, retinal tears^1,2 or detachment, or vitreofoveal traction,³ which has been reported with the use of Vuity (1.25% pilocarpine, Allergan) in some patients with pre-existing retinal risk factors. While a causal relationship has not been definitively proven, the potential for increased retinal risks and the expanded warning on the directions for use are thought to relate to the mechanism of pilocarpine-induced shallowing of the anterior chamber and associated vitreous traction. In August 2022, the FDA label for Vuity was updated in consideration of postmarket reports about these adverse events, which were not observed in the two Gemini phase 3 trials that lasted only 30 days and did not include myopes greater than -4D.

Another distinguishing attribute of Nyxol is its durable effect—pupil reduction for ≥24 hours. This offers a unique advantage to presbyopic subjects who instill Nyxol before bedtime, affording improvement in near vision that will be evident the moment they awaken, whereas other agents will require some time for onset of action. As detailed below, the moderate decrease in pupil diameter of around 1.5 mm improves near vision and distance vision, as well as contrast sensitivity and mesopic low contrast vision at night. Nyxol has a favorable safety profile, with no headaches; no systemic side effects, such as changes in heart rate or blood pressure; only mild, transient reversible eye redness (an on-target effect on the smooth muscle in conjunctival blood vessels), which is gone by morning with nighttime dosing; and mild instillation site discomfort.

Nyxol Alone or as an Adjunct to Low-dose Pilocarpine for Treatment of Presbyopia

Nyxol’s unique mechanism of action allows for differentiation on safety, tolerability, and durability, whether used alone or in combination with low dose 0.4% pilocarpine (LDP) in the large, expanding presbyopia population. With regard to efficacy, in VEGA-1, a phase 2, US multicenter, placebo-controlled trial, 29% of subjects had a ≥3 line improvement in distance corrected near vision (DCNVA) without loss of 5 letters or more in best corrected distance vision (BCDVA) compared to 12% with placebo (P=.02). At 12 hours postdose, 53% of subjects achieved ≥2 line gains in DCNVA (P=.005 vs placebo). In this VEGA-1 phase 2 study with inclusion criteria of 20/50 DCNVA or worse studying Nyxol as a single drop, 56% of presbyopia subjects achieved 20/40 or better DCNVA at 12 hours postdose. The combination, Nyxol with adjunctive LDP, demonstrated greater efficacy, with 61% of subjects having a ≥3 line improvement in DCNVA without losing 5 letters or more of BCDVA (P=.003 vs placebo) and 79% achieving ≥2 line gain in DCNVA (P=.005 vs placebo). In addition, 84% of subjects using Nyxol with adjunctive LDP achieved 20/40 or better vision at 1 hour post-LDP dose or 13 hours post-Nyxol dose. In addition, a durable response of Nyxol vs placebo on DCNVA was seen at 12 and through 18 hours. Similar efficacy was seen in patients with light and dark colored irises, in all ages, and across a range of baseline pupil diameters. Importantly, the dynamic pupillary light response was maintained in patients with Nyxol and Nyxol plus LDP.

Nyxol for Night Vision Disturbances

Night vision disturbances describe a decrease in the quality of vision secondary to glare disability, with decreased contrast sensitivity and consequential image degradation. Glare, halos, and ghosting are common components of night vision disturbances and decreased mesopic visual function. These symptoms are common in millions of patients with complex corneas and irregular astigmatism and residual ametropia, such as patients with keratoconus, pellucid marginal degeneration, status post-LASIK, penetrating refractive keratotomy or refractive keratotomy, anterior membrane dystrophy, dry eye, and other conditions, as well as multifocal or extended depth of focus (EDOF) intraocular lenses (IOLs). Dim light disturbances are contributed to by higher-order aberrations (which impact light distribution on a small angular distance), ocular scattering (which causes uniform distribution of light across a wide region of the retina), internal reflections within an IOL, or from superimposed, out-of-focus retinal images in patients with multifocal or EDOF IOLs.

The larger the pupil, the more unfocused peripheral rays of light negatively impact retinal image quality in patients with large amounts of higher order aberrations, which is reduced with moderate pupil reduction that selectively allows for passage of the more centrally focused rays. Too much reduction of the pupil size degrades image quality due to the effects of diffraction and reduced retinal neural contrast sensitivity, which is a consequence of low retinal illumination. While miotics, such as pilocarpine, have been tried in the past for the treatment of night vision disturbances, these have the aforementioned increased risks of retinal detachment or tears in patients with a history of retinal pathology and may also cause dimming of vision if the pupil diameter is too small, thereby diminishing retinal illumination. Brimonidine has been utilized occasionally, but tachyphylaxis has been demonstrated, with many patients experiencing rebound mydriasis after a month and some developing follicular conjunctivitis.

In a randomized, double-masked, phase 2 trial of Nyxol, 24 subjects with severe night vision disturbances were randomized 2:1 to receive Nyxol or placebo⁴. Mean contrast sensitivity with glare in Nyxol-treated subjects improved significantly post-treatment at spatial frequencies 3, 6, 12, and 18 cycles per degree (P≤.03), as well as in the number of letters read for mesopic and photopic, high- and low-contrast visual acuity (LCVA). Importantly, a statistically greater proportion of Nyxol-treated eyes registered mesopic LCVA 5-letter gain (69% vs 31% in control, P=.029) and 10-letter gain (34% vs 6% control, P=.04), which was even higher in subjects with a baseline mesopic pupil diameter ≥6 mm. Nyxol was well tolerated with the only reported side effect being a mild, transient conjunctival hyperemia.

LYNX-1 was a first pivotal, randomized, double-masked, placebo-controlled, US multicenter phase 3 trial of Nyxol in 145 subjects with night or dim light disturbances randomized 1:1 between Nyxol and placebo, with daily near bedtime dosing for 14 days. The study achieved its primary endpoint, with 15% of subjects treated with Nyxol gaining ≥3 lines of mesopic LCVA at day 8 vs 3% on placebo (P<.05). Key secondary endpoints were also met, especially with longer dosing with 21% of subjects treated with Nyxol gaining ≥3 lines of mesopic LCVA at day 15 vs 3% on placebo (P<.01) and 44% vs 23% placebo gaining ≥2 lines of mesopic LCVA at day 15 (P<.05). Significant improvement in photopic LCVA was also observed. There were no headaches, serious adverse events, or evidence of tachyphylaxis.

Other Clinical Programs: Mydriasis Reversal

Optometrists and ophthalmologists conduct more than 100 million dilated eye examinations per year in the United States to achieve an optimal view of anterior segment (eg, lens) and posterior segment (eg, peripheral retina, vitreous) structures or as part of ophthalmic procedures. Regardless of the initial pupil diameter, pharmacological mydriasis generally dilates the pupil to 6-8 mm. Dilation can last up to 24 hours depending on the mydriatic drugs, iris pigmentation, age of patient, and other factors. Just as miosis decreases the impact of higher order aberrations, pharmacological dilation unmasks them, and patients may experience ocular discomfort, loss of accommodation, inability to work, lower image quality, impaired driving performance, and nighttime headlight-induced glare. Currently, there are no commercially available therapeutic agents to reverse pharmacologically induced mydriasis.

MIRA-2⁵ and MIRA-3 were 2 phase 3, randomized, double-masked, placebo-controlled, US multicenter FDA registration studies of a total of 553 subjects aged 12 to 81 years old randomized between Nyxol and placebo for the reversal of pharmacological mydriasis (using the most commonly employed agents—phenylephrine, tropicamide, and Paremyd (hydroxyamphetamine hydrobromide/tropicamide, Akorn). MIRA-4 was a similar study using a single drop of Nyxol in 23 pediatric subjects 3 to 11 years old. Across these pivotal phase 3 studies, Nyxol demonstrated a rapid return to baseline pupil diameter with statistically significant difference from placebo starting at 1 hour and durable effects lasting up to 24 hours. Nyxol was effective across commonly used mydriatic agents, iris colors, and ages, with time savings of ~4 hours to return to within 0.2 mm of baseline pupil diameter.

Summary

In conclusion, given Nyxol’s differentiated mechanism of action, durable effect, and favorable safety profile, it is being studied in FDA registration trials for potential use for 3 indications: treatment of presbyopia, treatment of night vision disturbances, and the reversal of pharmacological mydriasis. ■

References

1. Eton EA, Zhao PY, Johnson MW, Rao RC, Huvard MJ. Rhegmatogenous retinal detachment following initiation of pilocarpine hydrochloride ophthalmic solution 1.25% for treatment of presbyopia. Retina Cases Brief Rep. 2022 Aug 12. [Online ahead of print]
2. Al-Khersan H, Flynn HW Jr, Townsend JH. Retinal detachments associated with topical pilocarpine use for presbyopia. Am J Ophthalmol. 2022;242:52-55.
3. Amarikwa L, Michalak SM, Caul S, Mruthyunjaya P, Rahimy E. Vitreofoveal traction associated with pilocarpine for presbyopia. Ophthalmic Surg Lasers Imaging Retina. 2022;53(7):410-411.
4. Pepose JS, Hartman PJ, DuBiner HB, et al Phentolamine mesylate ophthalmic solution provides lasting pupil modulation and improves near visual acuity in presbyopic glaucoma patients in a randomized phase 2b clinical trial. Clin Ophthalmol. 2021;15:79-91.
5. Karpecki PM, Foster SA, Montaquila SM, et al. Phentolamine eye drops reverse pharmacologically induced mydriasis in a randomized phase 2b trial. Optom Vis Sci. 2021;98(3):234-242.

Dr. Pepose is a specialist in refractive surgery and in corneal and external diseases. He is the founder and medical director of the Pepose Vision Institute and a professor of clinical ophthalmology and visual sciences at Washington University School of Medicine in St. Louis, MO.

Disclosures
Dr. Pepose is a member of the board of directors and chief medical advisor of Ocuphire Pharma. He is a consultant to Acufocus, Azura, Bausch + Lomb, Brim Biotech, J & J Vision, Mimetogen, Ocuphire Pharma, Stuart Therapeutics, Sun Pharma, Telios Pharma, and Thea Pharma.