This roundtable discussion series about sustained-release drug delivery for glaucoma includes Steven R. Sarkisian, Jr., MD, founder and CEO of Oklahoma Eye Surgeons, PLLC, in Oklahoma City, Oklahoma; Jacob Brubaker, MD, from Sacramento Eye Consultants in Sacramento, California; and E. Randy Craven, MD, FACS, Chief of Wilmer Eye Institute, Bethesda Location, Vice Chair for Wilmer Network of Locations, and an associate professor at Johns Hopkins University in Baltimore, Maryland. The second part of this series addresses the data behind the sustained-release glaucoma therapies that are being or have been tested in late-phase clinical trials.

Dr. Sarkisian: Dr. Craven, can you discuss the Allergan Bimatoprost SR data, when the implant might be available, and how you think it will fit in the paradigm?

Dr. Craven: I was one of the first to implant a Bimatoprost SR. It was a brave new world at the time. My general impression after I first used it was that this method of drug delivery would work. What we’ve seen from the phase 1 data is that a single implant will control pressure in most patients for 6 months.¹ At 1 year, a little less than half of patients have pressure control, but they still have pressure control from a single implant, and it doesn’t seem to be dose related, so it’s not related to the concentration. At 24 months, about 28% of the patients who had a single injection with no rescue, nothing else being done, still had a pressure that’s down at levels such that they don’t require rescue.² If you look at the mean IOP, although it’s a very small number of people, their pressures are in the low teens. So, it seems that putting a small amount of bimatoprost in the eye does decrease the IOP for more time than expected, as based on our experience with drops; the most likely mechanism is the outflow of aqueous is altered over what drops achieve. So, doing something in the eye may have a different mechanism of action than what the drops do externally.

Bimatoprost SR will likely be available by the end of this year or early 2020. That depends upon FDA approval, but all the data are closed and they’re reviewing all the efficacy and safety data and talking to the FDA. So, it’s not too long away, in my opinion.

Dr. Brubaker: I also participated in the phase 2 trial. In that study, patients were receiving Bimatoprost SR in one eye and bimatoprost drops (Lumigan) in the other eye, and they were comparable as far as efficacy was concerned. As Dr. Craven was saying, the longevity is something that was a little bit surprising, with some people lasting quite a while with just a single implant.

Dr. Sarkisian: So how do you think that we’re actually going to be using this then, Dr. Craven, based on the data that we have so far?

Dr. Craven: Despite having been somewhat of a cowboy, I tend to be conservative. I probably will inject one, watch and see how they do with it, tolerate maybe a little higher pressure, and use supplemental medicines until a period of time has gone by. After that, I’ll reinject them and place a second implant. I don’t think I’m going to be doing multiple injections myself. My feeling is that it’s better to have a single implant, let it go away, and then look at doing the dosing later.

Dr. Sarkisian: Data presented at the 2019 American Glaucoma Society meeting showed that 86% of the patients treated with bimatoprost SR made it a year without drops.³ How did that happen, and how do you expect using the implant given that data?^4,5

Dr. Craven: There was a series of 2 or 3 bimatoprost SR injections that got that 86% drop. There probably will be a series of 2 or 3 injections required to maintain the concentration of the molecule inside the eye to give it that enduring effect and then maybe at a year, depending on their response, maybe another one. And then it remains to be seen after that how often they’re going to need it.

Dr. Sarkisian: Dr. Craven, were these done with a slit lamp, or in a minor procedure room in your office or ASC?

Dr. Craven: Some did them at ASCs, but mostly in minor procedure rooms, usually with the patient flat. The study protocol was that they were laying down. But I think most surgeons don’t have access to a microscope in their office, so I think it’s probable they will do it with a slit lamp. I think patients should be able to tolerate that and it makes it a little easier for the logistics of an office.

Dr. Sarkisian: So, what do you think, Dr. Brubaker? How frequently do you think you’ll be injecting?

Dr. Brubaker: The way the phase 3 trial was designed was to dose initially, again 4 months later, and then after another 4 months they received their final implant. So, patients got a total of 3 doses, 4 months apart. At that point we watched them closely and only rescued them if needed. When we compare the phase 2 trial in which most patients received only one implant to the phase 3, the percentage of patients that had a longer duration of effect following 3 implants compared to a single implant was greater. Given these data, I feel there is a longevity advantage to dosing with 3 implants compared to just 1. Therefore, I believe I would initially follow the phase 3 protocol. We don’t have a lot of data looking at duration of effect after 2 implants, so as I got more comfortable with the device I might consider delaying the third injection if their pressure’s still under control.

Dr. Craven: I’d probably be somewhere in between, where I’d do one, and then if I did lose efficacy and it’s dissipating from the eye, then I’d probably do a second one to load it. I don’t know how I feel about putting in several implants at once. I might be a little slow on that myself.

Dr. Brubaker: The challenge is that the first one will probably take at least 12 months to completely dissolve, if not longer. So even though you’re not putting them all in at the same time, the first one’s still there by the time you get to 4 months. And then by the time you get to another 4 months later, the first one’s probably starting to degrade and dissipate, it’s probably at about 40% to 50% of original volume at that 8 month mark. So by the time you’re putting in that third implant, you probably have 3 implants in the inferior angle. Is that what your concern is, Dr. Craven?

Dr. Craven: Yes, absolutely. At ASCRS, I presented data on how long the implant is observable on gonioscopy. We were able to see the remnants of a single implant on a few patients at about a year out. At 2 years, nearly all patients had no implant visible on gonioscopy.⁶ I don’t want to stack too many things in the angle. I’m concerned about anything that could happen, like inflammation, endothelial cell loss, or cataract formation.

Dr. Brubaker: So far, I don’t think there were any adverse events related to cataract formation, but I agree that damage to the corneal endothelium is a concern.

Dr. Craven: We didn’t see that in the phase 1, but we’ll see what happens with the phase 3 data.

Dr. Sarkisian: So moving on to the iDose, which is different in that it’s not going to be implanted through a tiny stab incision, you need to put viscoelastic in the eye and use an operating microscope and a surgical gonioprism. Where do you see the iDose fitting in to the mix?

Dr. Brubaker: One of the things that’s appealing about the iDose, in my understanding, is the longevity is potentially very good. If you’re making a larger incision and using viscoelastic likely in the OR, I feel I would need something that’s going to last longer than 4 months, and hopefully greater than a year. I also like the idea that it’s tethered, meaning it’s less likely to float around and potentially damage the corneal endothelium.

Dr. Sarkisian: The iDose is in phase 2 and 3 studies. Two of 3 arms in the study have the iDose, but at different elution rates. So, theoretically, it could be several years before the data are ready. If we find that it modulates scleral outflow in a significant way, that it transcends the molecule and there’s lasting effect like we’re seeing with bimatoprost, I believe that patients are going to have some options. They’re going to have a potentially shorter term option with the Bimatoprost SR and potentially a longer term option with the iDose and if they’d be willing to maybe accept a little bit more risk in the beginning rather than having that risk spread out over the same period of time with multiple injections, that would be an option.

The other area where the iDose could play a significant role is combined with other MIGS. Patients who are on multiple medicines and have cataract surgery with MIGS often still have to be on at least one medicine, typically a prostaglandin, to maintain control. It’s great that they got off of some of their medications, but this would be an opportunity to potentially get them off drops completely. I think we’re going to see surgeons being very aggressive in service to their patients with this — for example, doing a canal procedure combined with an iDose — to truly get to the next level of a drop-free situation. So that’s where I see the iDose fitting in. Obviously if you’re going to be in the OR, you could always put in a Bimatoprost SR as well, but if you’re going to bother to make an incision and go to the OR, you’re probably going to want to have the biggest bang for your buck. We did not see cataracts or endothelial cell loss in the phase 2 study, and the phase 3 is ongoing. So that’s going to be very interesting to see. That, of course, is in the phase 3 study, so we’re a few years away from that coming out.

Editor’s note: Dr. Sarkisian reports consultancy to, advisory board membership with, speaker’s fees from, and grant support from Alcon; consultancy to, advisory board membership with, and speaker’s fees from Allergan and Bausch + Lomb; consultancy to and advisory board membership with Beaver-Visitec International, Katena Products, New World Medical, Omeros, and Santen; consultancy to, advisory board membership with, equity ownership with, and grant support from Sight Sciences; and consultancy to, advisory board membership with, and grant support from Glaukos. Dr. Brubaker reports consultancy to Glaukos and Allergan. Dr. Craven reports consultancy to and advisory board membership with Aerie Pharmaceuticals, Alcon, Allergan, Aqueous Biomedical, Ivantis, Santen, and W.L. Gore.

References

1. Lewis RA, Christie WC, Day DG, et al; Bimatoprost SR Study Group. Bimatoprost sustained-release implants for glaucoma therapy: 6-month study results from a phase I/II clinical trial. Am J Ophthalmol. 2017;175:137-147.
2. E. Randy Craven, Jacob W. Brubaker, Thomas Walters, et al. Long-term efficacy of bimatoprost sustained-release implant in lowering intraocular pressure. Paper presented at: American Glaucoma Society Meeting; March 3, 2018, New York.
3. Ahmed IIK, Walters TR, Bejanian M, et al. Extended duration of IOP control with intracameral bimatoprost sustained-release implant (Bimatoprost SR): late-breaking phase 3 clinical trial results. Presented at: American Glaucoma Society Meeting; March 16, 2019, New York.
4. Allergan announces positive topline phase 3 clinical data for Bimatoprost SR (sustained-release) implant for IOP lowering in patients with open-angle glaucoma or ocular hypertension. https://www.allergan.com/news/news/thomson-reuters/allergan-announces-positive-topline-phase-3-clinic.aspx .
5. Allergan announces positive 3-month topline results from second phase 3 study of Bimatoprost SR (sustained-release) implant for lowering intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. https://www.allergan.com/news/news/thomson-reuters/allergan-announces-positive-3-month-topline-result .
6. Chen M, Craven ER, Rhee D, Robinson M, Zhang J. Biodegradation of intracameral bimatoprost sustained-release implant in a 24-month phase I-II study in glaucoma patients. Abstract presented at: ASCRS Annual Meeting; May 2019; San Diego, CA.