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Sustained-release therapies remove patient factor from glaucoma treatment
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Sustained delivery devices that take glaucoma therapy out of patients’ hands may be the answer to the many issues related to adherence, with significant benefits for patients and physicians.
Not yet available on the U.S. market, these technologies fall under the broad category of guided administration of pharmaceuticals (GAP), ranging from injectable sustained-release formulations, to drug-eluting rings and contact lenses, to punctal plug reservoirs. Many are in the pipeline, undergoing phase 2 or nearing phase 3 trials.
“GAP is an umbrella term for several technologies that have three points in common: They are patient-independent, physician-administered and device-guided,” OSN Glaucoma Board Member Malik Y. Kahook, MD, said. “The patient is taken out of the equation, and there is 100% adherence.”
Adherence is a major issue with medical therapy in glaucoma. Barriers can range from simple forgetfulness to physical limitations, such as the inability to identify the correct bottle, squeeze the bottle, see the tip or aim the drop to the eye. In patients who are on multiple medications, there might be confusion regarding which bottle to use or which medication to take.
Drug-eluting rings
For a long time, manufacturers have been looking into ways to improve adherence, mainly in the form of reminders and eye drop guides for self-administration. What these strategies have not addressed is “the human factor,” Kahook said.
“There is very good evidence that reminders increase adherence for a short period of time, typically 6 to 8 weeks, and then patients revert back to their initial habits. Physical aids still have a patient factor; patients find ways to miss the eye,” he said.
GAP therapy is a different therapeutic approach wherein the physician administers and monitors the effect of the drug and the burden of daily administration is overcome by passive sustained release.
Of the three categories of GAP devices in the pipeline — drug-eluting rings, injectable reservoirs and punctum plugs — rings are the easiest, least invasive and most promising, according to James D. Brandt, MD.
Brandt was principal investigator in the phase 2 trial of the bimatoprost-eluting ring, originally from ForSight Vision and now Allergan. The device is made of a silicone polymer and can potentially contain nearly any drug or drug combination. It is inserted under the eyelid and sits in the fornix, where it provides sustained drug delivery for 6 months.
“It looks like a cumbersome device, but the vast majority of patients find it comfortable. Just like patients who are new contact lens wearers, they feel a slight foreign body sensation in the eye for a few days, then get used to it and don’t even remember it’s there,” Brandt said.
The first phase 2 trial showed a mean IOP decrease of 20% that did not fully meet the noninferiority criteria compared with timolol drops. Brandt believes that it will do so in larger clinical trials, but more importantly in real-world usage it will have the advantage of doing away with compliance issues.
“Another important aspect is that if it gets dislodged or falls out, the patient will be aware of it. We had over 90% rate of the device staying in without having to be repositioned or reinserted by a clinician, and we had no cases where it fell out and the patient was unaware of it,” he said.
Punctal plugs, injectable reservoirs
One disadvantage of punctal plugs is that the patient may not realize if a plug inadvertently pops out.
“If the punctal plug has disappeared, you don’t know whether it fell out 2 days before the visit or a week after it was put in,” Brandt said. In those cases, the physician cannot know how long the patient has gone without glaucoma medication.
Punctal plugs currently undergoing evaluation are the OTX-TP (Ocular Therapeutix) containing travoprost and the Evolute (Mati Therapeutics) containing latanoprost.
The small size of punctal plugs poses limitations in terms of capacity of the drug reservoir and therefore duration of the therapeutic effect, which so far is up to 3 months.
“I don’t see that punctal plugs, as well as injectable devices, will ever be able to provide anything other than pure monotherapy. In the Ocular Hypertension Treatment Study, half of our patients ended up needing more than one drug to achieve the study’s modest 20% IOP-lowering target. With monotherapy GAP platforms, we’ll have to add drops, which sort of defeats their purpose,” Brandt said. A bimatoprost-timolol drug-eluting ring is in phase 1 studies, and other drug combinations are being considered for development, he said.
Currently tested biodegradable implants include ENV515 (Envisia Therapeutics), providing extended-release travoprost, and Bimatoprost SR (Allergan). The iDose (Glaukos) is a titanium implant filled with travoprost, and it can be removed and replaced after depletion. All three implants are injected into the anterior chamber.
Because injectable drugs require either hydrolysis or enzymatic breakdown of the polymer, there may be interindividual variability in terms of how fast erodible implants break down and how long the effect lasts in the eye.
“This is speculation on my part, but it’s something people will have to watch closely in the phase 3 studies. If in some patients the effect wears off more quickly than expected, they run the risk of being uncovered for maybe a month or two,” Brandt said.
Another concern physicians share is the potential risk for endophthalmitis or other severe infection.
“My biggest personal concern is that the vast majority of patients, especially with early disease, are unlikely to go blind from their glaucoma if we monitor and treat them properly. By injecting a device, we expose them to the chance, however small, to go blind. I am not sure the benefit is worth the risk. We regularly inject AMD patients, but since in that case they would really go blind without the treatment, the risk-benefit calculation is very different,” Brandt said.
Open questions
Adjustments will be needed to integrate GAP therapies into practice once they become available, Kahook said.
“We have to think of how they are going to affect patient flow. Injectables could require not one but two consecutive appointments spaced days or weeks apart, as we are not likely to do the procedure bilaterally in one session. Also, since the duration of the effect may vary and may last 3 to 4 months in one patient and 6 to 8 months in another patient, we may need to monitor patients every 3 months instead of every 6 months as we do now in most cases,” he said.
Another issue is whether the injections will be performed in the office or in a procedure room, which may require extra space, equipment and sterility measures. The impact of these new therapeutic options on individual and social costs also needs to be clarified.
Many other questions are still open.
“We need to figure out where each GAP therapy might fit. Do we offer them as first-line therapy or where medications have failed? If a patient is on two medications and the injectable only offers one of the two, should we still do it, even though the patient will still be using drops? Should we do it before laser or after laser has failed? Should we do it in patients who have failed with trabeculectomy or drainage devices if they have to go back on medical therapy? These are all things we need to tease out as the platforms become available to our patients,” Kahook said.
What he is confident about is that GAP therapies will play a significant role in the care of glaucoma patients. In a survey performed in his clinic, 45% of patients said they would welcome alternatives to eye drops, including more invasive procedures such as intraocular injections and punctal plugs. – by Michela Cimberle
- References:
- Brandt JD, et al. Ophthalmology. 2016;doi:10.1016/j.ophtha.2016.04.026.
- Kass MA, et al. Arch Ophthalmol. 2010;doi:10.1001/archophthalmol.2010.20.
- For more information:
- James D. Brandt, MD, can be reached at UC Davis Eye Center, 4860 Y St., Suite 2400, Sacramento, CA 95817; email: jdbrandt@ucdavis.edu.
- Malik Y. Kahook, MD, can be reached at Department of Ophthalmology, University of Colorado School of Medicine, Anschutz Medical Campus, 1675 Aurora Court, Mailstop F-731, Aurora, CO 80045; email: malik.kahook@gmail.com.
Disclosures: Brandt reports he receives research support and travel support from ForSight Vision and owns stock in Glaukos. Kahook reports he is a consultant for Alcon, Allergan and New World Medical.