Presbyopia-Correcting Eye Drops for Pseudophakic Patients

Presbyopia, a common age-related disorder mainly affecting those over 40, involves progressive inability to focus on near objects. Worldwide, 1.8 billion are affected by presbyopia as of 2019.¹ In the United States, the prevalence of presbyopia is 80% by age 45–55, 16% of whom are not receiving adequate correction.² With the demographics of the United States population trending towards older age, the number of affected individuals will increase.

Despite ongoing debate regarding the exact mechanism of accommodation—or the eye's ability to change the crystalline lens's refractive power via contraction and relaxation of the ciliary muscle to bring objects into focus at various distances—³presbyopia is hypothesized to occur by one of two mechanisms. First, due to the weakening of the ciliary muscles and, second, a loss of lens elasticity prevents changes in focal point.⁴

Recent research suggests that the primary mechanism is an increase in lens rigidity due to disulfide bond linkage.⁵ Both ciliary muscle strengthening and lens softening are drug targets currently being explored for presbyopia treatment.

Topical treatment options

Pupillary miotics

Pupillary miotics are muscarinic agonists that cause the ciliary muscle to contract and increase crystalline lens thickness; consequently, this provides increased depth of focus and field via the pinhole effect. Muscarinic agents, however, can cause chronic inflammation with posterior synechiae and spasmodic contractions of the iris. For this reason, topical Non-Steroidal Anti-Inflammatory drugs (NSAIDs) are often combined with miotics, as they inhibit cyclooxygenase activity thereby decreasing risks of posterior synechiae and spasmodic ciliary contraction.⁶

The only currently US Federal Drug Administration-approved agent to treat presbyopia is the miotic agent VUITY™ (Allergan, Irvine CA), a daily eyedrop specifically designed for presbyopia that can improve near and intermediate vision without impacting distance vision and lasts up to 6 hours.⁷

https://covalentcareers3.s3.amazonaws.com/media/original_images/Vuity.png

Vuity is a combination of pilocarpine and Allergan’s proprietary eye care therapeutic pHast^TM technology that allows Vuity to adjust the physiologic pH of the tear film. There were no serious adverse events observed during clinical trials, and the most common adverse events were headache and eye redness.⁷

For more on doctors' perspectives on VUITY.

Other miotic drugs currently in phase 3 trials include MicroLineTM and CSF-1. MicroLine^TM (Eyenovia, New York, NY) is a proprietary pilocarpine formulation designed with the Optejet® dispenser. It allows patients to adjust their doses as needed, preventing the complication of overdosing with traditional eyedroppers, thereby reducing systemic exposure and toxicity. All symptoms reported were mild, with fewer than 3% reporting headaches.⁸

CSF-1, licensed by Orasis (Herzliya, Israel), has completed phase 3 trials⁹ with no reported results. Results from phase 2b trials indicate statistically significant improvement in distance corrected near vision (DCNVA) of 3 lines or greater with no reduction in distance or night vision.¹⁰

Miotics in phase 2 trials include PRX-100, which sustained a three-line improvement in near visual acuity with rapid onset in clinical trials.¹¹ Nyxol® Ocuphire Pharma, Farmington Hills, MI) is a non-selective alpha-1and alpha-2 adrenergic antagonist combined with pilocarpine, completed phase 2 trials in 2021.¹² Subjects in phase 2 trials gained 3 lines of near vision that lasted at least 6 hours with only mild ocular side effects. Nyxol with pilocarpine will advance to phase 3 trials in the near future.¹³

The second class of drugs is less explored than pupillary miotics and is aimed at lens softening. This mechanism of action mitigates lens stiffening— and loss of elasticity—by acting on oxidation and subsequent cross-linking of adjacent lens proteins.⁶ The antioxidant lipoic acid has been shown to reduce these disulfide bonds in the lens, resulting in increased refractive power.¹⁴

Topical drops targeting crystalline lens softening

The only drug candidate targeting crystalline lens softening as a treatment for presbyopia in clinical trials is UNR844, which has entered phase 3 trials.¹⁵ Reported treatment-emergent adverse events (TEAEs) were either mild or moderate in intensity with no discontinuation or severe TEAEs reported during the study.¹⁶ In previously completed phase 2 trials, statistically significant improvements in DCNVA were not associated with any adverse ocular effects or systemic complications.

Current treatments for presbyopia

Refractive correction with spectacles and contact lenses

The continued development of presbyopia eye drops is crucial to addressing current shortcomings in care that patients face. Current treatment options, while numerous, each have gaps in coverage that eye drop formulations can address. Despite many growing accustomed to daily use for those who wear glasses or bifocals, others do not and discontinue their use.¹⁷

Additionally, there is no current treatment that can fully restore a patient’s full range of accommodation via glasses.⁴ Similarly, contacts can also offer a restricted range of accommodation. For most patients, a single-vision contact lens is used, requiring additional correction with reading glasses, which poses the same inconvenience as those who only utilize glasses. Another major limitation noted in contact use is the reduction in stereopsis and contract sensitivity which are critical for tasks such as driving.²

Surgical options

Options involving surgery are also available to those with presbyopia, including corneal procedures such as laser vision correction and refractive cataract surgery. While these options are typically effective and produce good outcomes, some patients may not be able to reap the full benefits due to existing ocular comorbid diseases, such as corneal ectasia, glaucoma, and macular disease.¹⁸

Considerations for prescribing

For pseudophakic patients, a unique set of challenges present for presbyopia, as corneal scars and residual irregularities from prior incisions may present difficulties. Aberrations of pseudophakic intraoacular lenses may alter distance and near vision. In addition, a significant proportion of pseudophakic patients have increasing dry eye symptoms, which can cause visual fluctuations and slow healing rates.¹⁹

Billing and coding challenges

Vuity is currently not covered under most patient insurance plans.²⁰ For a 30-day prescription, the out-of-pocket cost for patients is approximately $88. For providers, since current treatment options for evaluating and managing presbyopia are included in current coding paradigms, this transition to having presbyopia eye drops as a bona fide treatment option should allow for payer inclusion.

Conclusions

Topical presbyopia treatment provides unique management opportunities for a wide range of patients. This is especially true in pseudophakic patients as many of the miotic eye drops include NSAIDs, which may effectively address some of the issues with inflammation and ocular surface disease that these patients face. The use of eye drops will likely be incorporated into existing billing and coding practices to minimize out-of-pocket cost hardship to patients.

References

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A Dose-ranging Study to Evaluate the Safety and Efficacy of UNR844 in Subjects With Presbyopia. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04806503. Updated February 8, 2022.
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