Future ocular allergy drug delivery methods may eliminate compliance issues

“Eye drops are about as far from the ideal drug delivery mechanism as you can get,” John A. Hovanesian, MD, FACS, a specialist in cornea, external ocular disease and refractive and cataract surgery, said in an interview.

The bioavailability of ocular drugs topically applied in eye drops is poor, according to Zielinski and Sullivan. A significant amount of the topically applied drug is immediately diluted in tears, and excess fluid can spill over the lower eyelid or drain into the nasolacrimal duct, they wrote.

“Corneal contact time has been estimated to be in the order of only a couple of minutes or less, with drug bioavailability dropping to as low as 10%,” according to the researchers.

Drops expose the eye to an overwhelmingly high dose of medication for an underwhelmingly short amount of time and are quickly gone with a blink, Hovanesian, also a Primary Care Optometry News Editorial Board member, said.

“What we are trying to do is achieve a steady state of disease treatment with a very high pulsatile dosing regimen. Many of [the new treatment methods] are designed to mitigate that,” he said.

New treatment delivery methods such as depots and emulsions have the potential to eradicate patient compliance issues with eye drops while delivering a steady dose of sustained medication.

“With allergy or any other chronic disease, it never gets better. You can control the disease, but you can’t cure it,” Bruce Onofrey, OD, RPh, FAAO, clinical professor at the University of Houston College of Optometry and PCON Editorial Board member, said in an interview. “At the end of the day, if someone doesn’t have a maintenance plan in place that they can comply with, which is safe and effective for a long period of time, the symptoms will return.”

Image: Sutton BM

“In general terms, you’re looking for something to deliver a controlled dose of medication over a period of time,” Brad M. Sutton, OD, FAAO, clinical professor at the Indiana University School of Optometry and service chief of Indianapolis Eye Care Center, told PCON. The ideal ocular allergy drug would “take compliance out of the equation and be affordable – it might be much lower than taking drops every day. There is definitely a need for something that delivers that controlled dose over an extended period of time.”

The propensity of eye drops, “speaks to a lack of other options,” Hovanesian said. “The trend is toward extending treatments ... to drugs that have longer modes of action and treatment strategies.”

Depots may solve compliance issues

One drug that may improve compliance by removing patient responsibility altogether is Dextenza from Ocular Therapeutix. Dextenza is administered by a physician as a bioresorbable intracanalicular depot for release of dexamethasone to the ocular surface for up to 30 days, according to a company press release.

In late January, Ocular Therapeutix resubmitted a new drug application to the FDA for Dextenza for treatment of ocular pain after ophthalmic surgery, according to a release. In clinical trials, Dextenza met the two primary efficacy endpoints of absence of ocular pain on day 8 and absence of ocular inflammation on day 14 as compared to placebo and met the secondary endpoint of absence of anterior chamber flare superior to placebo.

The company has also begun a phase 3 trial to assess the efficacy of Dextenza compared with placebo for allergic reactions.

The drug offers one-time administration by a physician, “and a release profile that avoids the peaks and valleys associated with topical dosing,” Carolyn Repke, MD, principal investigator, said in a company press release.

“This drug is the closest to FDA approval to my knowledge,” Hovanesian said. “It has been shown in several clinical studies on over 500 patients to deliver a consistent dose of steroid at safe levels. It’s an important product because it’s likely to be the first approved.

“When treating ocular inflammation, whether it’s related to surgery, allergy or dry eye, we want to have an adequate level of drug delivered in a sustained way and avoid side effects,” he continued. “Steroids produce side effects when they are given in high doses, and steroids in suspension can deliver widely varying levels of drug to the eye. The problem goes away with Dextenza because it melts away slowly over time.”

The plug is retained in the eyes of nearly 100% of patients, he said.

“If patients are looking for it, they can see the plug, but it is not obtrusive,” Hovanesian added.

In the study of Dextenza following cataract surgery, pressure spikes were not an issue, as the drug is delivered in such a low, steady state of concentration that it never reaches a high peaking dose, he said.

“In many conditions where you have an inflamed eye, like dry eye and in postsurgical patients, plugging the puncta provides additional lubrication, so you get a secondary benefit and with nothing to remove, like a contact lens depot would require,” he continued.

“I think the sustained release depot products are the most interesting treatments being worked on with respect to ocular allergy,” Harry M. Green, OD, PhD, FAAO, assistant clinical professor at the University of California Berkeley School of Optometry, told PCON. “Allergies represent a chronic and ongoing inflammatory process. Having something that is sustained release and offering relief over time, over a spray or drops, is most exciting for me in that area.”

Green said one area where depots could have a big impact is with mast-cell stabilization.

Generally, drops require 4 to 6 weeks of therapy for a full sustained effect, he said. In depot systems that deliver continual therapy, mast-cell stabilization may be achieved at a much faster rate.

“That would make a big difference for chronic allergy sufferers,” Green said.

With a drop, “you get a certain amount of tissue absorption within the first 15 minutes,” he said. “With the depot, there is a possibility with sustained therapy over time that the particular effect may control mast-cell degranulation.

“Only clinical studies with these devices will tell the tale in the end,” Green said.

He added that the actual concentration of the drug would need to be lower with a depot, as the therapeutic is constantly available.

He is concerned about patients developing an allergy to the platform as well as potential deleterious effects to the ocular surface.

Onofrey said one big barrier that Ocular Therapeutix needs to overcome is establishing efficacy for itching.

“The phase 3 trial did show benefit for allergy, but the Holy Grail for allergy is to stop itching,” he said.

He feels the company will want to make the claim that the agent stops itching and redness.

‘The new ointments’

Onofrey is most excited about emulsions, which are available now. Emulsions provide the benefits of ointments without being oily, he said. They are made of an oil-soluble drug suspended in a water-soluble vehicle.

Restasis (cyclosporine ophthalmic emulsion, Allergan), which is dissolved in castor oil and then micro-emulsified and put in a water vehicle, is easy to apply, Onofrey said. He uses the treatment off-label in place of or after short-term steroid use for maintenance management of atopic allergic eye disease.

“You get the benefit of the active drug, but the tear film itself is an emulsion. Water and mucin bind with water and oil and emulsify into tears,” he said. “Not only does the delivery system of the drug bring greater viscosity and greater duration of drug on the eye, but it dissolves into the tear film.”

Gels and emulsions increase the residence time of the drug on the surface of the eye and maintain a high concentration of the drug in the tears, he said.

“I call emulsions the new ointments,” Onofrey added.

Dosing platforms for liquids, powders

The VersiDoser and VRx2 are alternate delivery platforms from Mystic Pharmaceuticals Inc.

The VersiDoser delivers liquid products, while the VRx2 is designed for powder delivered as powder or reconstituted at the time of administration and delivered in liquid form, according to the company’s website. The VRx2 system can be configured to deliver two or more drugs packaged individually and automatically combined at time of administration.

The manufacturing process packages drugs in proprietary unit dose blisters and can accommodate a variety of drugs and dose volumes starting at 10 mL, according to Mystic. Each unit dose blister incorporates a novel VJet nozzle that is optimized for the specific drug or biologic contained in the system.

The VJet controls the dose volume and characteristics of the dispensed spray such as droplet or particle size, particle distribution, spray angle and velocity, the company says.

Onofrey believes this type of system would be helpful for those with shaky hands, where drop instillation is difficult.

“It’s interesting, because you can adjust the dose, you could go from 10 µL to 30 µL in a spray format, and it also counts the number of doses given,” he said. “As a doctor, you can see if the patient used it or not and get an exact count of what the patient did or didn’t do ... you could kick up the drug to see if the patient would get a better response from it, or dial it down.”

Drug-eluting contacts

Drug-eluting contact lenses have been under study for years, but with no product releases on the market.

“This is a great mechanism to deliver medication long-term, but the question is how effective it will be from a practical standpoint,” Sutton said. “Patients have to wear them successfully, and the medication or solution cannot irritate the corneal surface.

“There are definitely reasons why there have been a lot of trials and a lot of work in this area but nothing has hit the market yet,” Sutton added. “There are barriers, no question.”

Alex Hui, OD, PhD, FAAO, a lecturer at the School of Optometry and Vision Science, University of New South Wales, Sydney, researches drug-eluting contact lenses.

“In general, from our results in the laboratory (in vitro), we are able to show that commercially available lenses are able to take up and release significant amounts of many drugs, including anti-allergy agents such as ketotifen fumarate,” Hui said. “The hope is that simply by including a commercial contact lens on the ocular surface we can increase the ocular residence time, as evidenced by some of the work with contact lenses, ketotifen and rabbits.”

Companies are actively investigating anti-allergy agents and contact lenses, Hui explained. Vistakon has completed a phase 3 clinical trial in humans investigating a proprietary ketotifen-releasing lens versus a placebo, he said.

“Some of the results have been published on www.clinicaltrials.gov, and hopefully a peer-reviewed paper will be published so we can see all of the results,” Hui said.

“The trial recruited participants age 8 years or older, so it would be quite easy to envision the use of these lenses to control allergic conjunctivitis in children and to design it in a way that can be used in a daily disposable context so that cleaning and maintenance of the lenses become less of an issue,” he added.

Nonionic surfactant vesicles

Nonionic surfactant vesicles are lamellar structures made up of amphiphilic molecules surrounded by an aqueous compartment, according to Ku in BioMed Research International. Vesicular systems provide sustained and controlled release of medication at the corneal surface and prevent metabolism of the drug at the tear/corneal epithelium surface by various enzymes, Ku wrote.

“What we’re trying to do at the end of the day is increase the bioavailability to the eye ... in a lipid-soluble envelope that doesn’t damage the surface of the eye but can get through the epithelium,” Onofrey said.

The drug amount can be reduced, and these also have a repository effect; “they hang around longer in the tears and they match the substance of the tears, like emulsions,” he added.

However, this delivery system has some challenges. It is difficult to produce as it is a complex system, Onofrey said.

“New delivery systems could improve compliance, but cost could be out of reach for many people. Insurance companies may not cover it,” he added.

Giving Eastern medicine a chance

Michael S. Cooper, OD, a private practitioner with Windham Eye Group in Willimantic, Conn., encourages certain allergy sufferers to try acupuncture, after seeing success in symptom relief for his own grandmother.

His grandmother developed allergies when she moved from the East to the West Coast, and she tried “everything that was available at the time: loratadine, drops and saline washes,” he said. Nothing traditional seemed to work for her.

After doing acupuncture, “she experienced quite the relief,” Cooper said in an interview.

“I then decided for my own practice that if drops were not illustrating symptomatic improvement in an appropriate time frame from the patient perspective or the doctor’s expectations, a referral to an allergist would be standard of care to pursue a systemic solution. If the patient has exhausted all of their medical options, I would recommend acupuncture,” he said.

“What can be gleaned from the literature in several studies is that acupuncture modulates itch at the hormonal level of cytokines and other anti-inflammatory mediators by stimulating the release of beta endorphin and adrenocorticotrophic hormone,” Cooper explained. “This does beg the question as to the role neurogenic inflammation may play in the discussion, too. The paralimbic and limbic systems seem to be modulated with acupuncture with neuroimaging of the amygdala, anterior cingulate and insular cortices. Transparently, I am not sure whether this a case of which came first – the chicken or the egg. What I mean by this assertion is whether the brain is stimulating the hormonal response or vice versa or a combination thereof.”

Over the years he has referred between 100 and 200 patients to local acupuncturists.

“Patients are satisfied that they were able to achieve this relief of symptoms by balancing their concerns surrounding medication cost and chronic medical therapy that may have an undesirable side effect profile,” he said.

He noted that he has seen success with dry eye disease patients as well.

As with medical therapy, consistency is important, Cooper said.

“Patients cannot do acupuncture just once or twice,” he added.

Cooper said many of his patients who originated from Southeast Asia and mainland China desire an alternative treatment and are comfortable trying acupuncture. He also recommends the therapy to American patients who have exhausted other options and want to try something different.

“The more Westernized the individual, the more surprised the patient is with the results,” he said.

He noted that 75% of his patients are satisfied with the results from acupuncture treatment, but that patients experience fewer symptoms, not fewer signs.

“The ocular allergy cascade is a small piece of the puzzle of what they are actually experiencing, which is really systemic in nature,” Cooper said. “The eye is an endpoint for exposure to extrinsic factors such as pollen, industrial pollution and cigarette smoke, which potentially advance an immunological feedback loop in the system, causing the patient to exhibit those allergy symptoms.”

He suggests that practitioners keep an open mind when it comes to alternative treatments.

Therapy must be individualized

When treating ocular allergy, a “one-size-fits-all” approach cannot be applied, our sources said.

“In my experience, if there is an ocular allergy in any amount from chronic and severe, practitioners often prescribe the same drug at the same dose. I don’t believe that is necessary,” Green said.

With so many different drugs to treat allergy, “we should be determining how often the patient has problems and what they are allergic to,” he continued. “ODs don’t refer to allergists enough. They just treat the symptoms rather than finding out what the person is allergic to and doing something about avoiding the allergy altogether. Avoidance is the best therapy.”

Green has patients who have one bad allergy day a month or five a year, and he does not prescribe a multimodal drug for them.

“I recommend an over-the-counter antihistamine drop,” he said. “If they use those drops maybe four times during one bad day, I think that’s better for cost and quality of life to take care of something that happens only 5 times a year.”

Better tools

Hovanesian quoted the popular phrase: “Technology reaches its peak when it is invisible.”

When technology works seamlessly, without much or any patient interaction, is when a new drug or treatment method will be effective and patient-compliant, he said.

“Eye drops require an interruption in your day and are an unpleasant activity that most patients do not perform very well,” he said. “A drug delivery mechanism that requires no patient effort is ideal. It’s like an airbag in your car. You don’t think about it until you need it, and it works for you.

“The good news is that we’ve had good evolution of topical drugs,” Hovanesian added. “We have better tools today than we did even 2 years ago.” - by Abigail Sutton

• References:
• Gaudana R, et al. Pharmaceutical Research. 2009;doi:10.1007/s11095-008-9694-0.
• Ku R, et al. BioMed Research International. 2014;doi:10.1155/2014/263604.
• Soluri A, et al. Optom Vis Sci. 2012;89:1140-1149. doi:10.1097/OPX.0b013e3182639dc8.
• Tieppo A, et al. J Control Release. 2012;157:391-397. doi:10.1016/j.jconrel.2011.09.087.
• Zielinski WL and Sullivan TR. Touch Briefings. Ophthalmic drug therapy – Challenges and advances in front-of-the-eye delivery. 2007. http://www.mysticpharmaceuticals.com/OphthalmicDrugTherapySpecial%20Report.pdf.

• For more information:
• Michael S. Cooper, OD, is adjunct professor at the Massachusetts College of Pharmacy and Health Sciences and the Chicago College of Optometry-Midwestern University and is in private practice at Windham Eye Group in Willimantic, Conn. He can be reached at: coopadre@gmail.com.
• Harry M. Green, OD, PhD, FAAO, is assistant clinical professor at the University of California Berkeley School of Optometry. He can be reached at: hgcomm@gmail.com.
• John A. Hovanesian, MD, FACS, is a specialist in cornea, external disease and refractive and cataract surgery with Harvard Eye Associates in Laguna Hills, Calif., a clinical instructor at UCLA Jules Stein Eye Institute and a member of the Primary Care Optometry News Editorial Board. He can be reached at: johnhova@gmail.com.
• Alex Hui, OD, PhD, FAAO, is a researcher and lecturer at the School of Optometry and Vision Science, UNSW Sydney. He can be reached at: alex.hui@unsw.edu.au.
• Bruce Onofrey, OD, RPh, FAAO, is clinical professor at the University of Houston College of Optometry and a member of the Primary Care Optometry News Editorial Board. He can be reached at: beonofre@central.uh.edu.
• Brad M. Sutton, OD, FAAO, is clinical professor at the Indiana University School of Optometry and service chief of Indianapolis Eye Care Center. He can be reached at: brsutton@indiana.edu.

Disclosures: Green, Hui, Onofrey and Sutton reported no relevant financial disclosures. Cooper is a consultant for Alcon, Allergan, Bausch + Lomb, BioTissue, Johnson & Johnson Vision Care and Shire. Hovanesian is a consultant for Alcon and clinical investigator for Ocular Therapeutix and Icon Bioscience. He is also a medical advisory board member and has a small equity interest in Ocular Therapeutix.