Drops are changing the future of presbyopia treatment

Data support the idea that when drug delivery is optimized, efficiency increases, allowing us to deliver treatment with less exposure and reduced risk.

Inquisitive by nature and eminently human, physicians are constantly on the lookout for something new. When industry representatives walk into our practice, we want to hear about new molecules, modalities, and devices. Meanwhile, novel formulations, delivery vehicles, and platforms are frequently met with skepticism.

In our pursuit of novelty, we sometimes forget that significant treatment breakthroughs have been made thanks to the reformulation or change in treatment delivery. Several years ago, brimonidine tartrate ophthalmic solution 0.1% or 0.15% (Alphagan P; Allergan) was reformulated to brimonidine tartrate ophthalmic solution 0.025% (Lumify; Bausch + Lomb), creating an entirely new aesthetic application for brimonidine. With the identification of a minimal effective concentration through reformulation, resolution of an established effect—eye whitening—became a primary point of efficacy.

Now, reformulated pilocarpine is taking a similar path, creating a novel treatment category—the pharmaceutical management of presbyopia—in the process. Recent development efforts have yielded a concentration that is one-fifth the concentration of the most used glaucoma formulation and one-third the concentration of the only presbyopia drop available on the market today. There is an association among concentration, adverse effects, and lowering of intraocular pressure, which is why in glaucoma management higher concentrations of pilocarpine were often needed. When the goal is reduced pupil size, using a reduced concentration with a revised formulation may allow the medication’s goal to be achieved with few adverse effects.

Although pilocarpine has been a part of our clinical armamentarium for many years, there are compelling reasons to look closer at the established benefits of reformulation.

Minimum effective dose control

As clinicians, we strive to find the minimum effective dose for our patients. Arriving at a minimal effective dose can provide salient benefits, both in terms of efficacy and reducing adverse events. In the case of brimonidine tartrate ophthalmic solution 0.025%, for example, the active ingredient has been known to cause red eyes at higher concentrations. But when it was reformulated to achieve a minimum effective dose, the molecule was found to reduce eye redness instead.

The next generation of pilocarpine-based treatments will try to take advantage of this core benefit of reformulation, providing desirable efficacy while reducing adverse events. CSF-1 (Orasis Pharmaceuticals), a pilocarpine compound currently in development, is showing an adverse event profile significantly lower than the one traditionally associated with older formulations used to manage glaucoma.1 For patients interested in using drops to manage their presbyopia symptoms, an offering with fewer adverse events will undoubtedly prove attractive. More generally, this early data indicate that reformulation efforts are already translating into real-world, empirical improvements in this treatment domain. The CSF-1 clinical studies, for instance, showed that modifying pilocarpine’s concentration and formulation can reduce pupil size without lowering the intraocular pressure.

Formulation is key when it comes to optimizing a pharmaceutical product for its intended use. Animal studies indicate that calibrating pH with pilocarpine to improve bioavailability can significantly improve drug delivery, potentially improving outcomes.2 A near-neutral pH can allow pilocarpine to be formulated at a minimum effective dose owing to the improved bioavailability upon installation at a neutral pH.

Targeted presbyopia treatment

Whenever a new treatment category reaches our practice, we must carefully consider the ideal patients: those who stand to benefit
the most given the product’s inherent advantages and limitations.

In the case of drops used to manage presbyopia, this new type of treatment likely offers us an excellent option for treating patients with early to moderate presbyopia. At this stage, their natural lens is still relatively well functioning. The addition of drops affords them a level of control over their symptoms, allowing them to fine-tune management of symptoms based on day-to-day situations and needs. Implementing drops into the clinical algorithm is also relatively easy, as many patients with early-stage presbyopia are amenable to trying something flexible and acute before committing to a more permanent solution.

Given that presbyopia management represents a lifestyle category, patient expectations are especially high. Potential trade-offs between symptom relief and possible adverse effects are weighed heavily because the treatment category is both elective and paid for out of pocket. By matching solutions formulated to achieve the minimum effective dose with the patients positioned to benefit the most, we can improve patient satisfaction and minimize treatment roadblocks.

A well-known example here is the success story behind onabotulinumtoxinA (Botox Cosmetic; Allergan), where the arrival of a minimum effective concentration delivered a safe, sustainable effect with an acceptable risk profile. Just like with Botox, a novel category is being created to treat presbyopia. It will be exciting to see how the presbyopia market unfolds as CSF-1 (0.4% pilocarpine) enters the market next with a novel low-dose reformulation.

The future of formulation

Pilocarpine is one of the most recent molecules to undergo reformulation, but it is far from the last we’ll see. Formulation evolution will continue to create new utility and new categories of disease treatment. Although new molecules possess an undeniable allure, it’s important that we also consider new takes on tried-and-true treatments. Data support the idea that when drug delivery is optimized, efficiency increases, allowing us to deliver treatment with less exposure and reduced risk. To integrate appropriate treatments and deliver our patients the best results possible, we must keep an open mind and follow the data wherever they lead.

References

1. Lighthizer N, Garlich J, Coats J, Lang J, Dunbar M. CSF-1 (0.4% pilocarpine hydrochloride ophthalmic solution) demonstrated safety and efficacy in participants with presbyopia. Poster presented at: American Academy of Optometry Annual Meeting; October 26-29, 2022; San Diego, CA.

2. Weaver ML, Tanzer JM, Kramer PA. Salivary flow induction by buccal permucosal pilocarpine in anesthetized beagle dogs. J Dent Res. 1992;71(11):1762-1767. doi:10.1177/00220345920710110101