Industry develops creative approaches to help increase patient medication adherence
glaucoma drug-delivery future
Prescribing eye drops to patients with the expectation that they will be instilled correctly and the required number of times each day has always been a pipe dream for ophthalmologists hoping to control a disease that has no symptoms.
Recognizing that patients do not adhere to treatment regimens for myriad reasons, the pharmaceutical industry began to develop creative approaches to treat glaucoma.
Here are some of the highlights from a panel discussion of industry leaders at the annual Glaucoma 360 meeting that was guided by Michael Robinson, MD, vice president and Therapeutic Area head, Allergan; and James C. Tsai, MD, MBA, chair, Department of Ophthalmology, Icahn School of Medicine at Mount Sinai.
Ocular Therapeutix Inc.
The company has developed a bioresorbable intracameral implant, OTX-TIC, containing travoprost (Travatan Z, Novartis Pharmaceuticals) that is injected into the anterior chamber to deliver preservative-free drug for from 4 to 6 months. The device is implanted through a 27-gauge needle into the inferior angle.
In a phase 1 clinical trial, patients with glaucoma were randomized to either device implantation or topical travoprost drops in one 1 eye. Michael Goldstein, MD, MBA, chief medical officer, Ocular Therapeutix, Inc., reported that the interim data from 2 patient cohorts that received different drug concentrations showed that in the eyes that received the device, the drug effect was longer than expected and the results with the two 2 routes of administration were similar in their intraocular pressure (IOP)–-lowering capabilities.
“There has been a clinically meaningful decrease in IOP with one 1 insert, a drug duration of 9 months in many patients, and the device is fully bioresorbable. No movement of the implant has been seen and it has been gentle on the corneal endothelium,” Goldstein noted. The company is currently investigating the use of a smaller insert.
The company has designed micro-fluidic delivery systems for use in minimally invasive glaucoma surgeries and modified the systems for long-term drug delivery, explained Jane Rady, MS, MBA, senior vice president of strategy and business development, Glaukos Corporation.
One device, iDose Travoprost, is a small titanium implant that is inserted through a clear corneal incision into the trabecular meshwork and anchored in the sclera. The device [continuously] elutes the drug over the long term, which can translate to “many years,” she said.
A phase 2 clinical study compared the device with topical timolol drops at fast and slow elution rates.
“The 12-month data indicated that both iDose Travoprost devices lowered IOP by 8 to 8.5 mmHg compared with a 7.5-mm Hg reduction by timolol,” she said.
No adverse events that are associated with topical medications occurred when the device was implanted.
A phase 3 clinical trial is currently enrolling patients to determine the noninferiority of the iDose device to timolol at 3 months and safety at 12 months.
Bimatoprost SR is a biodegradable implant inserted into the inferior angle using a 28-guage needle. This implant is used in patients with glaucoma that has been assessed in 2 phase-3 clinical trials.
In the 20-month trials, more than 1,000 patients were randomized to bimatoprost SR (10 or 15 mcg) or topical timolol twice daily. The device was inserted 3 times, once every 4 months, according to Felipe Medeiros, MD, PhD, professor of ophthalmology and vice-chair for Technology, Department of Ophthalmology, Duke University, Durham, NC.
“The results showed a 7.7-mm Hg IOP decrease with the 10-mcg dose of bimatoprost SR, which was a 32% decrease compared with baseline and met the noninferiority endpoint compared to timolol,” he said. After the third implant, 80% of patients were medication-free up to 1 year.
“This is a remarkable result,” he commented and hypothesized that higher drug concentrations in the target tissue may lead to higher matrix metalloproteinase expression with greater changes in the extracellular matrix.
Another finding was slower visual field changes in the 10-mcg bimatoprost SR group compared with timolol. The implant was generally well tolerated.
A subconjunctival device has been envisioned that can contain one 1 or more glaucoma medications individualized to patients and is inserted into a small conjunctival incision, according to Kimberly Cockerham, MD, FACS, consultant to 3T Ophthalmics. The drugs can penetrate the sclera steadily for 2 years, requiring infrequent patient return appointments.
“This device provides robust delivery to all areas of the eye not deliverable by other means,” she commented. In addition, it is minimally invasive, with no need for needles and no infection risk.
Besides treating glaucoma, the device is customizable for use in treating retinoblastoma, macular edema, and inflammatory processes.
The device is currently in an oncology trial in which it was inserted to treat tumors that were refractory to any treatment and has achieved highly substantial results.
“The 3T Ophthalmics device is a paradigm shift. It is simple, truly noninvasive, and can be removed or replaced. We have exciting human data in 6 subjects,” she said. The company is currently seeking funding.
The AcuStream hand-held device was designed to maximize the delivery of topical drugs to the eye. “We have a novel electromagnetic activation procedure that provides a micro-dose of topical preservative-free ophthalmic solution that is equivalent to about 10% to 20% of a normal eye drop,” said Casey Dougan, MBA, chief commercial officer and vice president of operations, Kedalion Therapeutics.
An important advantage for patients with glaucoma patients is that the drugs can be delivered precisely from in front of the eye and there is no need for the patients to tip their head back to instill drops, thus improving patient ergonomics, aiming, and comfort. The device can deliver multiple doses of drugs in 10-μLmicroliter doses to avoid overdosing.
The phase 1 study results showed that the micro-dose is equivalent to instilling topical drops in terms of duration and intensity of the effect, he noted. The phase 2 study is expected to begin soon.
The company is developing a biodegradable drug delivery platform that incorporates a biopolymer approach, said Michael Nash, chief commercial officer, Re-Vana Therapeutics. The implant is photo-crosslinked with polyglycolic acid and poly(lactic-co-glycolic) acid and he reported promising results in early-stage delivery of large- and small-molecule drugs.
“Photocrosslinking facilitates a very high percentage of drug loading—i.e., more than 50% of the implant weight and we can tailor the release profile to this. If zero-order kinetics or burst mode is important, we can accomplish that,” he said.
Two versions of the platform are available, EyeLief and OcuLief. The former is a traditional filament approach seen with a biodegradable delivery system that is a novel sustained-release photo-crosslinked preformed implant that can release therapeutics for 4 to 6 months or longer; the latter, the second-generation system, is a gel-type solution that is injected into the eye and photo-crosslinked at that time.
The company is developing a product that is specific to glaucoma and will deliver latanoprost (Xalatan, Pfizer), which has demonstrated to have shown good in vitro release profiles.
The company’s technology involves an ultra-long-term zero-order drug delivery system that originated at the University of California San Francisco. “This is a depot system in which the drug or biologic is encapsulated in a unique bioerodable highly engineered membrane, which can tailor the release of small molecules and biologics,” said Murty Vyakarnam, PhD, chief executive officer, Zordera, Inc.
This product distinguishes itself because it is designed to deliver therapeutics for 6 months or longer; in addition, zero-order drug delivery is the most efficient from a therapeutic standpoint, resulting in a smaller payload and size, and the implant is resorbable, he noted.
The device is injected using a 25- or 30-gauge needle. Minimal inflammatory responses have been associated with the device. Vyakarnam reported that in a normotensive rabbit model, the device lowered the IOP for longer than 6 months. Investigators also reported IOP reductions when 2 IOP-lowering drugs were combined in the device.