WITH SO MANY PHARMACOLOGIC TREATMENTS BEING DEVELOPED FOR TREATING PATIENTS WITH PRESBYOPIA, DIFFERENCES BETWEEN THE FINAL PRODUCTS WILL BE IMPORTANT. WE ASKED THREE COMPANIES THAT WE BELIEVE ARE LIKELY TO BE NEXT-TO-MARKET TO DISCUSS IMPORTANT PROPERTIES OF THEIR PRODUCT CANDIDATE.

Orasis Pharmaceuticals – CSF-1 (0.4% pilocarpine HCl with a proprietary formulation)

Orasis Pharmaceuticals is developing CSF-1, a corrective eye drop for the treatment of presbyopia as an alternative to reading glasses. CSF-1 was purposefully designed with the patient in mind with a minimally effective dose at 0.4% pilocarpine HCl (more than 1/3 less than the currently available presbyopia drop) coupled with a proprietary formulation that has demonstrated efficacy, safety and comfort.

Orasis announced conclusion of Phase 3 clinical trials, NEAR-1 and NEAR-2, earlier this year, which demonstrated consistent results to their Phase 2b clinical trial. The NEAR-1 and NEAR-2 Phase 3 studies are multi-center, double-masked, parallel-group clinical trials in the U.S. enrolling approximately 600 participants. Phase 3 NEAR-1 and NEAR-2 clinical trials, which evaluated the efficacy and safety of CSF-1, its novel eye drop candidate, met their primary and key secondary endpoints.

In both trials, CSF-1 met its primary and key secondary endpoints on Day 8, achieving statistically significant 3-line or more gain in distance-corrected near visual acuity (DCNVA), and no loss of 1-line or more in distance visual acuity. Pooled across the two studies, 40% and 50% of participants demonstrated these gains 1-hour post-dose 1 and 1-hour post-dose 2 respectively (P<0.0001). CSF-1 also achieved statistically significant 3-line improvement at all measured time points on Days 1 and 15. On Day 15, participants achieved statistically significant 3-line or more improvement in DCNVA as early as 20 minutes and up to 8 hours post-dose 1. In addition, CSF-1 demonstrated an excellent tolerability and safety profile, with comparable redness and comfort versus vehicle, validating the preservative-free presentation and proprietary formulation of CSF-1. The most common treatment-related adverse events of headache and instillation site pain occurred in only 6.8% and 5.8% of participants, respectively. Of all CSF-1 participants, only 2.6% reported moderate treatment-related adverse events. All other adverse events were mild.

These results were achieved with a minimum effective dose of pilocarpine hydrochloride at 0.4%, which is less than one-third the concentration of the commercially available treatment. With a proprietary vehicle, CSF-1 is formulated preservative-free and provides for dosing flexibility with a comfort and safety profile that does not compromise distance or night vision.

Eyenovia – MicroLine (proprietary pilocarpine formulation), and the Optejet dispenser

Pilocarpine has been used in ophthalmology for over a century and is well characterized in millions of patients. Pilocarpine is a cholinergic muscarinic agonist acting on the smooth muscle of both the iris sphincter and ciliary body to target muscle contraction. The constriction of the ciliary body may be responsible for the brow ache often seen with pilocarpine drops. The constriction may also cause an anterior displacement of the lens that in turn may transfer tractional forces on the retina placing the tissue at risk of detachment.

The presence of brow ache may be a marker for increased risk of retinal detachment, and both are related to the same mechanism. The typical eye drop bottle delivers 35µl to 50µl leading to overdosing and overflow to contralateral tissues, increasing the risk of undesirable adverse effects.

The Optejet device is designed differently by precision dosing of an ~8µl horizontal spray made up of individual microdroplets that evenly and directly coat the corneal surface. In clinical studies, patients using a 2% pilocarpine ophthalmic spray delivered by the Optejet reported fewer than 2% brow/headache. This is noticeably less than the approximate 15% rate seen historically with pilocarpine drops. If there is a relationship between incidence of brow ache and risk of retinal detachment, we believe that patients would be best served with a product with the lowest incidence of this adverse event.

As a reminder, the Optejet is not a drop.

Lenz Therapeutics – aceclidine

Miotics were and are used in glaucoma to reduce intraocular pressure (IOP) by increasing the outflow through the trabecular meshwork. The specific method to achieve a lowered IOP varies by miotic. The mechanism of action (MOA) for both pilocarpine and carbachol lower IOP by stimulating the ciliary muscle to pull on the scleral spur, opening the trabecular meshwork to improve outflow. Aceclidine has a different MOA to open the trabecular meshwork with negligible effect on the ciliary muscle. While this makes aceclidine a less potent hypotensive than either carbachol or pilocarpine, it has some advantage for its use as a miotic.

Research has shown that aceclidine targets the iris sphincter with almost no stimulation of the ciliary muscle. As such, it is the only one of the three miotics that has been shown to be pupil selective, allowing it to constrict the iris to a sub 2mm pupil without creating the myopic shift that occurs with pilocarpine- or carbachol-induced ciliary muscle stimulation and consequent zonular laxity. Aceclidine without induced myopia will allow miosis to occur with little to no effect on distance acuity and appeals to a much larger market in terms of refractive range and age. ■