EyeWorld India March 2016 Issue

Glaucoma treatment March 2016 23 EWAP SECONDARY FEATURE problem, which was that this was something in the eye that could slide across the cornea,” Dr. Novack said. This could be a real problem, particularly if people were driving. Now new options are being developed. Dr. Kahook thinks that it is a very exciting stage in drug delivery for glaucoma. “We have all these different methods, whether they’re devices that are inside or outside of the eye, or these drug depots underneath the conjunctiva or inside the eye,” Dr. Kahook said. When weighing this long-term technology, his preferences range from less invasive to more invasive approaches. “If we had a way to insert a punctal plug that delivers an active ingredient over a long period of time, all else being equal, that would be better than methods that require invasive injection or implantation,” he said. “I would prefer a subconjunctival implant over an intraocular implant if it gave me the same efficacy.” Still, he would accept a more invasive delivery system in or around the eye if it ensured safety and efficacy. It’s still too early to decide which approach works best. “Unfortunately, right now it seems as if the less invasive versions have a lot of variability that requires further development,” Dr. Kahook said. “Meanwhile, we still need to prove that the duration of delivery from long-term depots and/or devices would be sufficient enough to outweigh the risk of the invasiveness.” For punctal plugs dispensing medication, there are two big issues. “First is that most of the punctal plug platforms I am aware of don’t have a big enough reservoir to deliver a drug for long enough,” he said. “Second is that the devices fall out at a high rate.” A practitioner is not going to want to insert a punctal plug to dispense glaucoma medication in an eye and tell the patient to come back in 3 months only to have the plug fall out after 2 weeks, perhaps unknowingly leaving the patient without necessary therapy for the duration. Meanwhile, there are also challenges with more invasive therapy, with questions lingering. Dr. Kahook thinks that more long- term data is needed to show that such depots continue delivering medication for months at a time with consistent lowering of IOP. “If I can give an injectable that delivers drug for 4 to 6 months, I think that’s a big win,” he said. “We just need more insight from ongoing clinical trials so we can make data driven decisions.” Dr. Novack thinks that there are pluses and minuses to all of the long-term systems. He cited the popular prostaglandin analogues. “Unlike pilocarpine, which is the early one, there is a question about something I call, ‘Is more better?’” Dr. Novack said. “We know from eye drops that twice-a-day prostaglandins are actually less effective than once a day.” For long-term systems of prostaglandins, there is a question of whether this is going to be as effective as a pulsatile delivery such as eye drops, he explained. Dr. Lewis pointed out that prostaglandins are the biggest agents in glaucoma right now. “The concentrations [needed] are so low that you can get away with putting a small amount in there, but it lasts a long time,” Dr. Lewis said. “Drugs that are less potent would take up so much more volume that you probably couldn’t get much duration, so I think at least at this stage the prostaglandins make more sense.” Dr. Novack has been studying a subconjunctival liposomal nanoparticle formulation of the prostaglandin latanoprost (Peregrine Ophthalmic Pte Ltd, Singapore) together with Tina Wong, MD, PhD, Singapore National Eye Center. “We show a good pressure drop in patients for 3 months similar to what you might expect from an eye drop,” Dr. Novack said, adding that this, however, isn’t a comparative study. Finding success Ultimately, to be successful, any of these long-term approaches needs to be able to deliver enough medication to last for several months, Dr. Novack thinks. He likens it to a backpacking adventure where travelers must take along a certain amount of food and supplies but can only carry so much at a time. “I think that most people would feel that you need at least 3 months of delivery from an injectable or an implanted system,” he said, adding that this is how often patients feel it is worth coming into an ophthalmologist’s office and having such a procedure done. However, for a less invasive approach such as the ForSight Vision 5 Helios insert (Menlo Park, Calif.), which simply rests on the surface of the eye under the lids and slowly releases the drug bimatoprost, the length of time this would need to last could be less, he thinks. Dr. Kahook pointed out that the amount of efficacy demanded by these systems is congruent with the amount of risk. “If a punctal plug was available that ensures 100% adherence but that might be slightly less effective than some of the topical drops that have 50% adherence, I’d be OK with recommending it for my patients—I think that’s a good tradeoff,” he said. “But for the more invasive approaches, I think they should have efficacy that’s congruent with what is available on the market today.” Gaining FDA approval for such long-term systems is slightly different than the pathway practitioners are familiar with for a new drug, Dr. Novack said. “If it’s a delivery system of an already approved product, in the U.S. that’s called a 505(b)(2) route,” Dr. Novack said. “Typically only one pivotal clinical trial is required for a 505(b)(2) as opposed to a 505(b)(1).” However, there are additional hurdles that must be surmounted in the 505(b)(2) route. While the active pharmaceutical ingredient is the same in these long-term systems, the product used for dispensing this is different. So in such cases it’s important to assess the performance characteristics of the system as well as the safety, he stressed. Dr. Novack finds that it takes about 3 years from when a glaucoma product enters phase 3 FDA trials until it can be approved. Dr. Kahook pointed out that there are companies that are in phase 2 and phase 3 for long-term drug delivery using noninvasive approaches similar to punctal plugs. “If all goes well with those trials, there is the potential to see drugs on the market from a punctal plug standpoint in 2017–2018,” Dr. Kahook said, adding that there are other drugs that are being investigated as injectables, such as bimatoprost sustained-release (Allergan) and travoprost sustained release (Envisia, Triangle Park, NC), that are making steady progress toward FDA approval in the coming years. EWAP Editors’ note: Dr. Kahook has financial interests with Alcon (Fort Worth, Texas) and Allergan. Dr. Lewis has financial interests with Aerie Pharmaceuticals (Irvine, Calif.), Allergan, and Envisia. Dr. Novack has financial interests with Peregrine Ophthalmic. Contact information Kahook: malik.kahook@ucdenver.edu Lewis: rlewiseyemd@icloud.com Novack: gary_novack@pharmalogic.com