Pending presbyopia treatments edge closer to disrupting the marketspace

Pharmacologic treatments could fill the unmet need for vision correction in presbyopic patients who want to see well without spectacles or contact lenses but do not opt for a surgical solution.

Presbyopia affects more than 1.8 billion people worldwide, including more than an estimated 11 million in the U.S. For those patients who do not want to wear corrective lenses, there is a host of management options, all surgical and all elective: excimer laser ablation, femtosecond laser intrastromal correction, multifocal and accommodating IOLs, and intracorneal inlays.

Some companies are coming at the problem from a different direction, with eye drops.

Source: Mitchell A. Jackson, MD

The marketspace is in its infancy, similar to the MIGS market a decade ago when multiple companies flocked to develop the devices, OSN Refractive Surgery Section Editor John P. Berdahl, MD, said.

Although data available for the pharmacologic therapies thus far are limited and mostly anecdotal, “When there is a convergence of companies working on something all at once, there is going to be a real market that comes out of it,” Berdahl said.

Presbyopia Therapies, Alcon, Allergan and Orasis Pharmaceuticals have all converged on the marketspace, with drug candidates in clinical trials.

“There is a huge unmet need because there are so many patients affected by presbyopia who want to spend less time wearing reading glasses, yet are either not candidates for surgery or do not want to have surgery. Having pharmacologic therapies become available to help provide patients with the ability to read without glasses would be a huge innovation,” OSN Technology Section Editor William B. Trattler, MD, said.

The drops in development are a “perfect solution” for patients in the 40- to 55-year age range who have yet to develop cataracts, OSN Refractive Surgery Board Member Mitchell A. Jackson, MD, said.

Mechanisms of action

Allergan, Orasis Pharmaceuticals and Presbyopia Therapies all have miotic treatments in development, which reduce the pupil to create a “pinhole effect,” allowing for greater depth of field. Alcon’s eye drops, however, target presbyopia by restoring crystalline lens flexibility and allowing the lens to focus on nearby objects.

Either of these pharmacologic approaches would provide an important treatment paradigm that would allow ophthalmologists to treat a broader spectrum of dysfunctional lens syndrome without surgery, OSN Technology Board Member George O. Waring IV, MD, FACS, said.

Patients in the first stage of dysfunctional lens syndrome, defined as the loss of accommodation, showcase the first symptoms of presbyopia but still have a clear crystalline lens. They may be dependent on spectacles but may prefer a non-surgical intervention, particularly in the earliest stages, he said.

“Patients who want help but who may not be suited for or want a surgical solution may be interested in this as an option,” Waring said. “Monofocal patients who didn’t invest in an advanced presbyopia-correcting lens may also find some of these therapies to be beneficial.”

PRX-100

In a phase 2b trial, Presbyopia Therapies’ eye drop candidate PRX-100 demonstrated a three-line or greater improvement in monocular distance corrected near acuity in patients aged 48 to 64 years.

The randomized, double-masked, placebo-controlled study included 58 subjects who received either PRX-100 or a placebo. One hour after treatment with PRX-100, 47.2% of patients gained at least three lines and 91.7% gained at least two lines of improvement in near vision, both statistically significant improvements.

One-half of study eyes maintained a two-line or greater improvement for up to 7 hours. Pupil size ranged from 1.5 mm at 30 minutes to 1.9 mm at 7 hours. The drug was well-tolerated, there were no serious adverse events, and PRX-100-treated eyes did not experience any statistically measurable loss of monocular best corrected distance visual acuity.

PRX-100, a topical ophthalmic solution containing aceclidine alone in one arm and aceclidine and low-dose tropicamide in another, is intended to induce strong miosis and create a pinhole effect without using pilocarpine, Gerald Horn MD, chief scientific officer and founder of Presbyopia Therapies, said.

PRX 2b data suggest it is the first true non-accommodative depth of field topical, with potential to be effective throughout most of the full presbyopic age range, Horn said. The reversible nature and potential for binocular dosing also offer the possibility of equal or greater near vision than for either eye monocularly.

“What we are intending to do is to create a ‘pinhole filtered’ enhanced depth of field, high depth perception, non-accommodative and binocularly dosed, and reversible continuum of sharp vision from about 16 inches to infinity,” Horn said. “Pilocarpine, due to its high ratio of accommodation for equivalent miosis, is difficult to achieve a non-accommodative equal depth of field with, but ideal for an accommodative effect with minimal depth of field at lower concentrations. A predominantly accommodative mechanism then may result in pupils greater than 2 mm with reduced depth of field and greater effect in younger 40- to 49-year-old presbyopes, best distance sharpness for increments of baseline hyperopia, and for baseline emmetropes and low myopes, risk of exponentially additive myopic blur for each baseline –0.25 D increment of myopic spherical equivalent.”

The onset of action for PRX is less than 30 minutes, and best corrected visual acuity photopic distance and distance with 3 lux of ambient light (low luminance) was sufficient to result in no statistical difference versus placebo. Both active arms were equivalent to each other with no significant adverse events.

Miotic therapy challenges

Principles of optics and physics are at work in miotic-based drops. If the aperture decreases, the depth of focus increases. But miotic therapies historically come with challenges for some patients, Berdahl said.

“By combining a miotic with another medication or by using a different miotic or a different dosage of miotic, we may be able to exploit the positive optical principles of miotics without the side effect profile of headache or decreased contrast sensitivity or other issues. There is no doubt the optics and the physics work, but we’re trying to limit the downside,” he said.

One of those downsides is limited peripheral night vision. Even in combination with other treatments, miotic-based agents may not be the best option for the person who spends time driving at night, according to Jackson.

CSF-1

Orasis Pharmaceuticals’ CSF-1 drop, a parasympathomimetic agent with a nonsteroidal anti-inflammatory in an oil-based formulation, is another miotic-based therapy in development.

The privately held company closed on $13 million Series B financing in June 2018 to be used through the completion of its phase 2b clinical trial and for preparation of its phase 3 trial.

The clinical trials have demonstrated significant improvements in near vision and a positive safety profile. The treatment is designed to provide an alternative to reading glasses and surgical procedures.

The presbyopia treatment is not only designed to improve near visual acuity, but also to generate additional benefits such as a fast onset of action, long duration and comfort during administration, Elad Kedar,CEO of Orasis Pharmaceuticals, told Ocular Surgery News at the Ophthalmology Innovation Summit at AAO in Chicago.

Presbyopia eye drops should also be able to provide alternative treatments for other conditions as well, Trattler said.

“These technologies will certainly play a second role,” he said. “They won’t just be for presbyopia, but for patients with keratoconus, irregular astigmatism or other corneal problems.”

Any of these miotic-based candidates will provide a patient with a smaller aperture and “reduce the quantity of information’” coming into the eye and retina that is out of focus, he said. This will result in improvement in vision for these patients.

Allergan’s candidates

Allergan has two miotic-based drop candidates, AGN-199201 and AGN-190584, in development. Early data assessing safety and efficacy have been published for both agents.

Three hundred participants are expected to be enrolled in a phase 3 multicenter, double-masked, randomized, vehicle-controlled, parallel-group study evaluating the safety and efficacy of AGN-190584 in participants with presbyopia.

In a phase 2 trial, Allergan evaluated the safety and efficacy of AGN-199201 alone, AGN-190584 alone and the two candidates combined in patients with presbyopia. The trial included 65 participants.

From baseline to day 3, uncorrected visual acuity was assessed without corrective lenses in the participants’ nondominant eye, and the percentage of patients with at least a two line or more improvement was noted.

More than 70.6% of participants who received one drop of AGN-190584 ophthalmic solution followed by one drop of AGN-199201 vehicle in the nondominant eye and two drops of AGN-199201 vehicle in the dominant eye experienced a two line or more improvement. Additionally, 68.8% of participants treated with a combination of one drop of AGN-199201 ophthalmic solution followed by one drop of AGN-190584 in both eyes once or twice daily for 3 days experienced a two line or more improvement.

Combination therapies

One of the hot trends in topical therapy is combination therapy. It would not be surprising if patients eventually use a combination of agents in a single drop to address the disease state in different modalities, Waring said.

“There are a number of drops at various stages of the innovation pipeline with different mechanisms of action, which is fairly typical of a new treatment modality. Whether it’s femtosecond lasers or presbyopia-correcting lens implants, they each have their own merits and may have a different place in the treatment algorithm,” he said.

The combination of one of the miotic candidates with the non-miotic candidate currently being developed by Novartis may improve accommodation and give patients the benefit of miosis, Berdahl said.

The non-miotic drop candidate Novartis is developing is designed to “enhance lens elasticity” and provide a solution more to the source of the problem, Waring said.

EV06

Novartis’ EV06 ophthalmic solution 1.5% (lipoic acid choline ester) is a novel topical therapy that targets presbyopia by restoring crystalline lens flexibility, allowing the lens to focus on nearby objects. The chemical entity targets the increase in the formation of disulfide bonds between the crystalline proteins within lens fiber cells. The drop is intended to break these bonds and restore elasticity.

“If breaking disulfide bonds does allow actual accommodation to be improved, then we have something that is a unique mechanism that can be very helpful,” Berdahl said.

Novartis evaluated the therapy in a phase 1/2 clinical study. After 3 months of twice-daily treatment with 50 participants receiving one drop of EV06 and 25 participants receiving a placebo, participants who received EV06 demonstrated improvement in all distance corrected near vision acuity (DCNVA) measurements.

By day 91, 82% of participants in the EV06 group had 20/40 DCNVA compared with 48% of participants in the placebo group. Additionally, 60% of patients in the EV06 group had 20/32 DCNVA or better by day 91 compared with 24% in the placebo group, and 36% of EV06 participants had combined DCNVA scores of 20/20 and 20/25 compared with 16% of placebo participants.

At day 91, EV06 patients experienced a significant improvement from baseline in DCNVA from 0.397 logMAR at baseline to 0.206 logMAR compared with 0.408 logMAR at baseline to 0.313 logMAR for placebo patients.

The drop breaks up the excessive disulfide bond formation in the human lens to restore lens flexibility and improves accommodation, Jackson said.

“There is oxidation-induced disulfide bond format between crystalline proteins. The lens stiffening that occurs compromises accommodation. This is really breaking those bonds and softening those lenses in a patient,” he said.

Out-of-pocket costs

It is likely that the drops would not be covered by insurance, according to Berdahl.

“What models are going to be used? What are patients going to be willing to pay for the convenience of not having to use reading glasses or bifocals? I think it will be a fascinating experiment in behavioral economics,” he said.

This will be the same decision patients must make regarding laser vision correction, laser lens replacement or presbyopia-correcting lenses at the time of cataract surgery. These are all self-pay procedures that have a meaningful benefit regarding quality of life, and patients must decide if the improvement in quality of life is worth the investment, Waring said.

Waring encourages his patients to use his practice’s cost calculator to examine the lifetime costs of purchasing glasses, bifocals or contacts lenses compared with investing in an elective vision surgical procedure.

More times than not, patients find spectacles, contact lenses and contact lens solution costs far exceed that of an elective vision procedure. While glasses and contacts can be covered to varying degrees by insurance, patients tend to purchase designer frames, high index lenses, blue blocking filters and transitional lenses, which are all out-of-pocket costs and quickly add up, usually exceeding the out-of-pocket cost for an elective vision procedure, Waring said.

“If you just look at this from a comparative cost calculation, I would not be surprised if the cost of drops ends up being less than glasses or contacts over time, but it’s really the quality of life that you can’t put a price tag on,” he said. – by Robert Linnehan

• References:
• A safety, efficacy and pharmacokinetic study of AGN-199201 and AGN-190584 in patients with presbyopia. clinicaltrials.gov/ct2/show/NCT02780115. Accessed Jan. 24, 2019.
• A study of the concurrent use of AGN-190584 and AGN-199201 in participants with presbyopia. clinicaltrials.gov/ct2/show/NCT02595528. Accessed Jan. 21, 2019.
• A study to evaluate the safety and efficacy of EV06 ophthalmic solution in improving vision in subjects with presbyopia. clinicaltrials.gov/ct2/show/results/NCT02516306. Accessed Jan. 21, 2019.
• CSF-1 overview. www.orasis-pharma.com/our-solution/csf-1-overview/. Accessed Jan. 22, 2019.
• Encore Vision announces successful phase I-II study of topical EV06 for the treatment of presbyopia. www.prnewswire.com/news-releases/encore-vision-announces-successful-phase-i-ii-study-of-topical-ev06-for-the-treatment-of-presbyopia-300263690.html. Accessed Jan. 22, 2019.
• Fernández J, et al. J Ophthalmol. 2018;doi:10.1155/2018/4318405.
• Fricke TR, et al. Ophthalmology. 2018;doi:10.1016/j.ophtha.2018.04.013.
• Orasis completes financing for development of drop to treat presbyopia. www.healio.com/ophthalmology/ophthalmic-business/news/online/%7B27f779f1-9286-4199-a728-2ea745e8bab3%7D/orasis-completes-financing-for-development-of-drop-to-treat-presbyopia. Accessed Jan. 22, 2019.
• Phase 3 efficacy study of AGN-190584 in participants with presbyopia. www.clinicaltrials.gov/ct2/show/NCT03804268. Accessed Feb. 21, 2019.
• Presbyopia Therapies announces primary safety and efficacy endpoints met in a phase IIb study of its topical PRX ophthalmic solution for the treatment of presbyopia. www.prnewswire.com/news-releases/presbyopia-therapies-announces-primary-safety-and-efficacy-endpoints-met-in-a-phase-iib-study-of-its-topical-prx-ophthalmic-solution-for-the-treatment-of-presbyopia-300688070.html. Accessed Jan. 23, 2019.
• Renna A, et al. Eye Vis (Lond). 2017;doi:10.1186/s40662-017-0068-8.
• Safety and efficacy of AGN-199201 and AGN-190584 in patients with presbyopia. clinicaltrials.gov/ct2/show/results/NCT02197806. Accessed Feb. 5, 2019.
• VIDEO: Presbyopia-correcting eye drop formulation progresses in clinical trials. www.healio.com/ophthalmology/refractive-surgery/news/online/%7b54043d14-e6ad-4528-9577-8751bab800a7%7d/video-presbyopia-correcting-eye-drop-formulation-progresses-in-clinical-trials. Accessed Feb. 2, 2019.

• For more information:
• John P. Berdahl, MD, can be reached at Vance Thompson Vision, 3101 W. 57th St., Sioux Falls SD 57108; email: john.berdahl@vancethompsonvision.com.
• Gerald Horn, MD, can be reached at LASIKPlus, 3021 Butterfield Road, Suite 200, Oak Brook, IL 60523; email: visionxcl@aol.com.
• Mitchell A. Jackson, MD, can be reached at Jacksoneye, 300 N. Milwaukee Ave., Suite L, Lake Villa, IL 60046; email: mjlaserdoc@msn.com.
• William B. Trattler, MD, can be reached at Baptist Medical Arts Building, 8940 N. Kendall Drive, Suite 400-E, Miami, FL 33176; email: wtrattler@gmail.com.
• George O. Waring IV, MD, FACS, can be reached at Waring Vision Institute, 735 Johnnie Dodds Blvd., Suite 101, Mt. Pleasant, SC 29464; email: gwaring@waringvision.com.

Disclosures: Berdahl reports he is a consultant for Allergan, Orasis Pharmaceuticals and Novartis. Horn reports he is the chief scientific officer and founder of Presbyopia Therapies. Jackson reports he is a consultant for Alcon and Allergan. Trattler reports he is a consultant for Alcon and Allergan and has a financial interest in Orasis Pharmaceuticals. Waring reports he is an investigator, consultant and on the medical advisory board for Allergan.

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