Presbyopia &Topical Therapies

Presbyopia &Topical Therapies

September 24, 2021

Ophthalmology News - “The word ophthalmos, “οφθαλμος”  from which the term ophthalmology is derived, appears often in Homer’s epic poetry: “Athena aimed the arrow towards the nose, near the ophthalmos [eye] and pierced the white teeth” [Il 5.291].”

Presbyopia is a common age-related vision disorder characterized by a progressive inability to focus on near objects. If uncorrected or under-corrected, presbyopia can significantly impact patients’ quality of life.

Presbyopia represents an area of considerable unmet need due to its rising prevalence worldwide as the population ages, the high proportion of under-treated individuals in some parts of the world, and the limitations of currently available corrective methods.

Progressive or bifocal spectacles are associated with peripheral blur, a restricted visual field and impaired depth perception, which have been linked to an increased risk of falls in the elderly.

Contact lens options can be difficult to maintain due to the development of age-related dry eye symptoms and reduced manual dexterity.

Other corrective methods involve surgical interventions that modify the optics of the cornea, replace the crystalline lens, or attempt to restore active accommodation.

While patients undergoing surgery report satisfactory outcomes post-operatively, many of them eventually require reading glasses.

Topical Therapies

Topical agents that temporarily treat presbyopia without affecting other aspects of vision are on the cusp of becoming approved and available for widespread use.

Presbyopia literally means ‘old eye’ and results in a gradual decrease in lens accommodation, leading to a significant lack of functional near vision.

It affects the majority of people over the age of 40, with a target population of 30 to 40 million in the United States, and we have no approved pharmacologic treatment.

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Over the years, many surgical approaches to the correction of the condition have been attempted, but none has yet become widely adopted for patients without significant cataract.

A review of available and emerging treatments for presbyopia was recently published. Finding the ultimate solution for this problem has long been the target of ophthalmology because the demand— and the potential rewards—are great.

Companies have begun testing topical therapies for the temporary correction of presbyopia. Several of these drugs may be approved over the next 1 to 3 years, opening a new treatment avenue for patients who wish to be less dependent on reading glasses.

Most of the drops being evaluated aim to modulate the pupil for better near vision. There are likely to be significant differences among them in duration, tolerability and other factors.

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Candidates & Trial Results

There are various topical agents and clinical results available to date, discussed as follows.

PILOCARPINE

Pilocarpine is a cholinergic muscarinic receptor agonist well established in managing pupillary miosis and is the most employed agent in emerging presbyopia therapeutics.

What distinguishes the emerging presbyopia formulations from currently available generic pilocarpine is the lower concentration (in most cases, ≤ 1% vs up to 6% in generic pilocarpine) and that the investigational agents rely on sophisticated delivery vehicles that are better at modulating how much of the active ingredient reaches the ocular tissues.

Ophthalmology News - “The word ophthalmos, “οφθαλμος”  from which the term ophthalmology is derived, appears often in Homer’s epic poetry: “Athena aimed the arrow towards the nose, near the ophthalmos [eye] and pierced the white teeth” [Il 5.291].”

Several companies have pilocarpine-based drops in clinical trials:

AbbVie/Allergan (AGN-190584) Two Phase 3 clinical trials (Gemini I and II) with a total of 750 participants have been completed.

No published studies are available, but public reports note that primary endpoints in both studies were met, with more patients in the treatment group vs the vehicle-controlled group gaining three or more lines of mesopic high contrast binocular distance-corrected near visual acuity (DCNVA) at 3 hours over 30 days of bilateral single-dose use.

Headache, conjunctival hyperaemia, blurred vision and eye pain were each reported by 3% or fewer of the patients treated with AGN-190584. A New Drug Application has been submitted to the US Food and Drug Administration (FDA) and approval is anticipated in late 2021.

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Orasis (CSF-1) A Phase 2 study5 with 166 participants was completed in 2019, with reportedly good tolerability of the drop and statistically significant gains of three or more lines of DCNVA when dosed twice daily.

There was no impact on distance or night vision. A Phase 3 study of 300 participants has recently begun.

Eyenovia (Microline) This company has a novel microdose dispenser (Optejet) that sprays the drug at the eye.

A Phase 3 trial in which 84 subjects’ DCNVA were tested 2 hours after treatment with 1% or 2% pilocarpine1 showed that a statistically significant proportion of patients treated had a three-line or more increase in DCNVA vs placebo in low light 2 hours after treatment.

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PILOCARPINE + PHENTOLAMINE

Ocuphire Pharma is evaluating a kit that combines a moderate and long-acting evening dose of the non-selective a-1/a-2 adrenergic antagonist phentolamine 0.75% with a morning dose of pilocarpine 0.4%.

Synergistically activating the iris sphincter muscle while inhibiting the iris dilator muscle allows for lower concentrations of the active ingredients and may reduce the likelihood of adverse reactions.

A Phase 2 study in 152 patients whose NVA was tested for up to 6 hours post-dose met its primary endpoint with statistical significance at 1 hour.

More than half (61%) of patients treated with Nyxol plus lowdose pilocarpine gained 15 letters (three lines) in near VA.

Ophthalmology News - “The word ophthalmos, “οφθαλμος”  from which the term ophthalmology is derived, appears often in Homer’s epic poetry: “Athena aimed the arrow towards the nose, near the ophthalmos [eye] and pierced the white teeth” [Il 5.291].”

ACECLIDINE

Similar to pilocarpine, aceclidine is also a parasympathomimetic cholinergic muscarinic receptor agonist.

A Phase 2 study of an aceclidine-based miotic treatment for presbyopia in 58 participants was completed by Presbyopia Therapies in 2018.

At the time, the company reported that 47% of study eyes gained three or more lines of near vision and 92% gained at least two or more lines 1 hour after instillation, a statistically significant benefit over placebo.

Approximately half the eyes maintained a two-or-greater line improvement for up to 7 hours. Little information has been released about the drop since and no additional studies have been registered, although the company has reorganised and is moving forward under its new name, Lenz.

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FIXED-COMBINATION CARBACHOL/ BRIMONIDINE TARTRATE

Brimochol is a fixed combination of carbachol and brimonidine invented by Dr Herbert Kaufman and now under development by Visus Therapeutics for the treatment of presbyopia.

Carbachol has previously been shown to be a more potent cholinergic miotic than pilocarpine. Combining it with brimonidine, which prevents pupil dilation and may inhibit ciliary muscle contraction, achieves synergistic effects, and may reduce the severity of adverse effects.

Brimonidine also whitens eyes, which may prevent the redness typically associated with miotics. Four peer-reviewed studies evaluating this combination have been published in the literature, though using different formulations than are currently being tested by the company.

One of these demonstrated superiority of the fixed combination over the individual components, something that is essential for FDA approval of any fixed-combination drop.

Results of the most recent study, in 2019, showed a 12-hour duration of effect on near vision in 57 participants without any reported symptoms of headache or brow ache.

A Phase 2 crossover study in 45 phakic and pseudophakic patients dosed once daily with one of two different Brimochol formulations or carbachol monotherapy has recently begun.

Ophthalmology News - “The word ophthalmos, “οφθαλμος”  from which the term ophthalmology is derived, appears often in Homer’s epic poetry: “Athena aimed the arrow towards the nose, near the ophthalmos [eye] and pierced the white teeth” [Il 5.291].”

LIPOIC ACID CHOLINE ESTER CHLORIDE

Unlike the other drops that act by modulating the pupil, Novartis is developing UNR844, a lipoic acid choline ester chloride that acts on disulphide bonds between crystalline lens proteins.

The idea is that by hydrolysing the disulphide bonds, this drug would soften the lens and restore some accommodative ability.

Results of an early Phase 1/2 study found an improvement in DCNVA of 8.1 letters in the treated group vs 4.3 letters in the placebo group.

A Phase 2 controlled trial evaluating safety and efficacy after 3 months of twice-daily dosing treatment in early presbyopes (aged 45–55) has also been completed, with an improvement of 6.1 letters in the treatment group vs 4.5 letters in the placebo group.

In addition, 25% of the treatment group vs 16% of the placebo group achieved 75 or more letters in total. The most common adverse events reported were dysgeusia and headache, in 5% and 3% of treated participants, respectively.

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Thus far, study sponsors have reported only functional effects on vision from this lens-softening agent, rather than any lens outcomes such as change in accommodation.

Also, as trials are attempting to reverse presbyopic lens changes, it seems likely that such a drop would be used in younger individuals to prevent lenticular changes in the first place.

This would increase the burden of proving that the lens is safe for long-term use. This is a fascinating therapeutic category, but I think ophthalmologists are going to want to see a great deal more data, including whether these drops work consistently across the entire lens.

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Important Factors

As presbyopia-correcting drugs come to market, one of the most important factors for both physician and patient acceptance will be efficacy – how well the patient can read and use a computer.

Everybody likes to see J1 clinical trial results, but most individuals do not actually need to be able to read J1.

A drop that can provide J6 or better for 8–12 hours, which would cover most of a person’s working hours, would be a big advancement for patients.

Ophthalmology News - “The word ophthalmos, “οφθαλμος”  from which the term ophthalmology is derived, appears often in Homer’s epic poetry: “Athena aimed the arrow towards the nose, near the ophthalmos [eye] and pierced the white teeth” [Il 5.291].”

Although most of the pupilmodulating drops in development are being tested for use in both eyes, patients may experiment with using the drops monocularly and binocularly.

The newer drops will likely have vehicles that are kinder to dry eyes or will make use of sustained delivery nanomicelle technology.

Some presbyopia-correcting drops may be available in preservativefree formulations, which will make them more comfortable for patients with pre-existing ocular surface disease.

This was true for glaucoma patients who had been on 4% or 6% pilocarpine for years, which had a high concentration of the active ingredient and were preserved, but it may not be an issue with the much lower concentrations of pilocarpine that are being developed for presbyopia.

Although there are quite a few presbyopia-correcting drops in development, there will probably be room for all—or at least several—of them. It will be relatively easy for patients to try several types and for practitioners to customise drop choice to patients’ lifestyles and ocular needs.

Ophthalmology News - Inflections of Vision-Illumination-Emanation! Intersection of the energies streaming from the infinite dimensions and intelligent infinity. 

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