A silicone punctal plug-based system for sustained delivery of ophthalmic medications (Evolute, Mati Therapeutics) is versatile technology which can be implemented across multiple therapeutic categories and shows promise for improving efficacy and safety relative to conventional topical drop therapy.
The non-invasive sustained delivery platform is comprised of a non-biodegradable/non-bioerodable punctal plug with a drug-eluting core that is sealed along the sides and at the distal end. Drug delivery occurs only to the tear film and at a predictably precise rate for a predetermined duration. Therefore, the system avoids under- or overdosing.
In addition, because drug is not released into the nasolacrimal duct, the punctal plug system minimizes the potential for systemic absorption and related adverse events. The device has an ocular safety advantage as well because the drug load is in a solid state which obviates the need for any preservative.
Clinical development of the technology was initiated using latanoprost. Results from testing completed through multiple phase II trials in 179 patients showed the modality was effective in providing IOP-lowering. In addition, device retention, tolerability, comfort, and patient acceptance were excellent.
The company is finalizing plans to launch a phase II trial of a sustained-release travoprost punctal plug. In addition, phase II trials investigating systems for delivery of three other candidate medications--nepafenac, difluprednate, and olopatadine--may also begin in 2017.
“This technology is being developed as a long needed replacement for topical drops due to its ability to deliver greatly increased compliance, a reduction in potential systemic side effects, and desirable patient convenience,” said Christopher A. Muller, chief commercial officer and co-founder, Mati Therapeutics.
The company is also considering the development of plugs loaded with other classes of IOP-lowering medications and therapeutics for dry eye.
“The development of alternative modalities for ophthalmic drug delivery is something of great interest for both physicians and patients considering that traditional drops are accompanied by issues of convenience and voluntary as well as involuntary nonadherence,” said Edward J. Holland, MD, director of cornea services, Cincinnati Eye Institute, Cincinnati, OH, and an investigator in clinical trials for the device.
“An alternative to drops that has proven safety and efficacy and reasonable cost would be appealing to most patients,” he said. “[The device] is a very promising approach to alternative drug delivery. Its design maximizes device retention while assuring targeted delivery to the ocular surface and minimizing systemic absorption.”
In addition, the investigators found the plug easy to insert and replace, Dr. Holland said.
In contrast to other platforms being developed for sustained topical ophthalmic drug delivery, this system is distinguished as the only one that delivers all of its medication to the tear film, does so at a constant rate, and is cosmetically invisible yet easily identifiable.
“Patient acceptance is important for adoption of these systems, and aesthetics as well as comfort are important attributes for patients,” Muller said.
A non-bioerodable delivery system was developed because it could incorporate all therapeutics and assure predictable medication release, said Robert Butchofsky, chief executive officer and founder, Mati Therapeutics.
“Our system can be used to deliver any medication whether it is hydrophobic or hydrophilic, and the matrix of the drug-containing core can be tailored to the specific therapeutic to deliver a desired rate of release and duration,” he said. “For example, we can create a flat elution curve for a constant delivery rate desirable for more chronic conditions, or it can be adjusted to deliver an initial burst with higher doses and subsequent downward titration often needed for more acute conditions.”
Since the plug does not dissolve and maintains its physical configuration while in the punctum, it eliminates the potential for interindividual variability which can affect the release profile and retention rates, he added.
In the studies completed using the plug, the retention rate has been consistently high, between 92% and 96%, Muller reported.
“The high retention rate is an important advantage of our system,” Muller said. “Retention becomes a problem using plugs that erode, and retention rates for standard punctal pugs are generally in the 50% to 60% range. We invested a lot of time and effort into designing our platform to ensure a high retention rate, and the available data show that we were successful.”
Easy insertion is another benefit of the delivery system. The plug has an L-shaped design which facilitates its placement while improving retention. The placement procedure has a minimal learning curve and is completed in one to two minutes.
“After verifying that the plug is oriented in the proper direction, it can be slipped easily into the nasolacrimal duct, just like a piece into a puzzle,” Muller said.
Although the device is cosmetically invisible, it is colored and readily seen when the lower lid is retracted. Therefore, it is easy for the physician to identify the plug when it is time for it to be removed and also for the physician, patient, or caregiver to confirm that the plug is still in place during the treatment period.
In phase II testing, the latanoprost-loaded punctal plug provided 5 mm Hg to 5.5 mm Hg IOP-lowering over the study’s 12-week duration. The decision for transitioning to development of a travoprost-loaded system was based on the fact that travoprost is more potent than latanoprost and so has the potential to provide even greater IOP-lowering.
“Relative potency is an important consideration when delivering a very low concentration of medication,” Muller said. “In animal models of glaucoma, we found that compared with latanoprost, a travoprost plug was associated with an additional 1.5 mm Hg to 2 mm Hg of IOP lowering.”
Safe and high satisfaction
Data from clinical trials also show that the device was safe and met with high patient satisfaction.
Patients were asked to rate comfort on a visual analogue scale of 0 (best) to 100 (worst). Mean scores at baseline were typically 18 or 19, increased a few points in the first week after device insertion, and then returned to baseline.
“Even though the device sits in the punctum, epiphora was not a problem,” Butchofsky explained. “If anything, patients may feel their eyes are more comfortable after the plug is placed because of improved tear retention.
“In the associated patient demographic, the majority of patients are likely to have mild-to-moderate dry eye and feel the benefit of the improved tear retention. When the study was completed, patients stated they preferred the device over conventional drops and were disappointed to have to return to using their previous therapy,” he added.
Butchofsky pointed out that he has worn the plug for one year.
“Other than experiencing a mild foreign body sensation transiently after insertion, I have no real awareness that the plug is present, and it seems to be virtually impossible to dislodge despite eye rubbing,” he said.