Medication adherence and compliance is a main barrier to controlling glaucoma. Patients have a hard time taking their eye drops properly, dealing with side effects, and even paying for their medication. In a 2015 study of more than 1,200 newly diagnosed glaucoma patients who were started on topical therapy, just 20% had persistently good treatment adherence at 1 year, and only 15% did at 4 years.¹ Addressing medication compliance is crucial, because poor compliance can lead to fluctuating intraocular pressure (IOP). Studies such as the Advanced Glaucoma Intervention Study (AGIS) have found that advanced open-angle glaucoma (OAG) patients who fluctuated more than 4 mmHg in IOP throughout the study had a higher risk of progression than those who had less than 4 mmHg fluctuation. Another study from 2019 revealed short-term IOP fluctuation as a risk factor for glaucoma progression on visual field (VF).²

The Benefits of Reducing Drops

Reliable data support the positive impact of reducing the postsurgical drop burden on patients’ quality of life (QOL) and progression of disease after selective laser trabeculoplasty (SLT) or MIGS procedures. The LiGHT trial, which compared first-line SLT to topical latanoprost, demonstrated less risk for progressing to incisional glaucoma surgery in the SLT group vs latanoprost group despite similar IOP reductions. No SLT patients required glaucoma surgery to reduce IOP, compared with 11 patients who required surgery in the eye drop group. The SLT group needed fewer topical drops to achieve target IOP, which ended up saving the UK’s National Health Service money as well. The SLT group also had a lower likelihood of eventually needing cataract surgery, which made researchers question whether glaucoma medications might increase the risk of cataract formation.³

The 5-year data of the HORIZON trial, which compared cataract surgery alone to cataract surgery with the Hydrus Microstent (Ivantis/Alcon) in patients with OAG, also revealed less medication burden in the Hydrus group and a 60% lower chance of mild to moderate patients progressing to needing incisional glaucoma surgery (such as trabeculectomy or tube surgery) than the cataract surgery alone group. In addition, the Hydrus Microstent lowered the rate of visual field loss by 47% vs cataract surgery alone.⁴

A 2021 study of the pivotal trial for the Istent Inject (Glaukos) found that not only did the device reduce IOP and the need for topical medication, but also a higher percentage of patients who received Istent Inject showed meaningful improvements in QOL scores, when compared with patients who received cataract surgery alone. Patients who were drop-free had the greatest improvement in QOL scores. This is the first time that a MIGS procedure has been shown to positively affect patient QOL compared to cataract surgery alone.⁵

New Sustained-release Medications

With the importance of reducing the drop burden established, where do sustained-release glaucoma medications fit into the paradigm? Since June 2020, physicians have had access to Durysta (Allergan/Abbvie), which has allowed us to decrease the drop burden in a variety of patients. Durysta is approved as a single intracameral implant that releases 10 μg of bimatoprost — a prostaglandin analog (PGA) — over 4 months, but the duration of effect has been seen for up to 2 years in up to 25% of patients.⁶

Several other sustained-release devices are in development, including a travoprost intracameral implant (OTX-TIC; Ocular Therapeutix), a latanoprost microdose device (Microprost; Eyenovia), and a travoprost-latanoprost punctal plug (Evolute; Mati Therapeutics). However, the next drug delivery product likely to be approved is the Idose TR intracameral travoprost-releasing implant from Glaukos.

Anecdotal Experience With Idose

I was a principal investigator for both the phase 2 and phase 3 clinical trials for Idose TR. The device is a 1.8 mm x 0.5 mm biocompatible titanium implant that releases a proprietary formulation of travoprost inside the anterior chamber.^7,8 Like Durysta, eluting a PGA inside the eye bypasses the corneal surface permeability issues, allowing for a consistent 24-hour delivery of the active drug over time without the significant side effects of topical PGAs on the surface and extraocular tissues. The implant has 3 parts: a scleral anchor that passes through the trabecular meshwork (TM) and sits within the scleral wall; the body of the device, which serves as the drug reservoir; and the elution membrane, which allows for the consistent release of travoprost over time.

We implanted Idose TR in our sterile in-office surgical suite, but most surgeons performed the procedure at an ambulatory surgery center or hospital. This standalone implantation procedure was efficient and intuitive — the process will seem familiar to surgeons who have implanted an Istent Inject. We created a 2.2-mm incision and filled the anterior chamber with a cohesive viscoelastic. We then rotated the head and scope nasally, and with a gonioprism and viscoelastic on the cornea we viewed the nasal angle in the same way as our MIGS procedures. We then introduced the ergonomic Idose loader and aimed it at the TM. We then applied direct perpendicular pressure to anchor the implant into the scleral wall and released the prongs. We confirmed its stability by using the loader to nudge the device from side to side and made sure the device was not pointing down towards the iris. We used manual irrigation and aspiration to remove viscoelastic and hydrated the wounds with balanced salt solution.

Idose Clinical Trial Results

The phase 2 trial enrolled 154 patients with open-angle glaucoma or ocular hypertension (OHT). Patients in the study were randomly assigned to receive a fast-elution implant, a slow-elution implant, or sham surgery followed by twice-daily topical timolol maleate 0.5%. Postprocedure IOP was measured over 12 months. At 3 months, mean IOP reductions for both Idose groups and the control group were similar, ranging from 8.5 mmHg (a 33% decrease from baseline) in the fast implant group, 8 mmHg (32% decrease) in the slow implant group, and 7.6 mmHg (30% decrease) in the timolol group. IOP was controlled without additional medications in 82% of the 2 Idose groups and 74% in the control group. At 12 months, IOP in both Idose groups remained around 32% below baseline. IOP in sham (patients treating with topical medications) was similar at around 30%.

Safety outcomes were favorable, as there were no serious adverse events. Through 12 weeks, there was no increased conjunctival hyperemia in either treatment arm, and travoprost was not detected in any study patient’s blood serum. In addition, the mean number of glaucoma medications ranged from 0.54 to 0.56 at 12 months in the fast and slow elution Idose TR groups, respectively, compared to 0.72 mean medications in the timolol group.⁹

The recently reported phase 2b results are based on an analysis conducted at 36 months for all 154 subjects randomized into the trial. Subjects in the Idose TR arms received a single intracameral implant, while the subjects randomized to the timolol active comparator received twice-daily eye drops over the 36-month evaluation period, which equates to approximately 2,190 eye drops per eye, per protocol. In the fast- and slow-release Idose TR arms, 70% and 68% of subjects, respectively, were well controlled, with the same or fewer IOP-lowering topical medications at 36 months vs screening, compared to 46% of subjects in the timolol control arm. In this responder group, average IOP reductions from baseline observed at 36 months were 8.3 mmHg and 8.5 mmHg in the fast- and slow-release Idose TR arms, respectively, vs 8.2 mmHg in the timolol control arm. Overall, Idose TR subjects performed similarly to timolol subjects at 36 months in terms of mean IOP reductions with fewer topical medications vs timolol. The 36-month phase 2b data also continued to demonstrate a favorable safety profile for Idose TR, with no clinically significant corneal endothelial cell loss, no serious corneal adverse events, and no adverse events of periorbital fat atrophy or conjunctival hyperemia reported to date in either elution arm.¹⁰

The ongoing Idose TR phase 3 trial compares Idose TR devices at both fast and slow elution rates to twice-daily topical timolol. The phase 3 trials randomized a total of 1,150 subjects across 89 clinical sites, most of which are in the United States.¹¹ The phase 3 trial results are expected to support Glaukos’s targeted NDA submission in 2022, with FDA approval for Idose TR in 2023.

Looking to the Future

Although the Idose is not yet approved, surgeons are already thinking about how to incorporate this device into clinical practice. One of the key benefits is the length of time for release of medication and duration of effect, but the insertion procedure does involve opening the eye and using viscoelastic. Therefore, when will it be used? Will this be done at the same time as a combined cataract and MIGS surgery? Will it be done at the same time as our standalone MIGS, allowing us to hedge our bets to keep the patient drop free for longer? How about using it with a glaucoma tube surgery to control IOP until the nonvalved tube opens up? Will we feel comfortable implanting this as a standalone device?

Another question is, will it be approved for reimplantation after the implant reservoir is empty and the effect wears off? Glaukos has studied the removal and reimplantation of another Idose implant, which ended up being rather straightforward. One could always leave the expended implant in place since it is biocompatible and removing it later, when another surgery is indicated.

There has been a paradigm shift in the management of glaucoma over the last decade, and we are fortunate to be treating patients in this new environment. With sustained-release drug delivery and other interventions, we are now able to reduce IOP earlier and more effectively in our glaucoma patients while maintaining a high QOL. GP

I. Paul Singh, MD, practices at the Eye Centers of Racine and Kenosha in Wisconsin. He reports consultancy to Allergan, Glaukos, New World Medical, Sight Sciences, Istar Medical, Bausch + Lomb, Zeiss, Ivantis/Alcon, Nova Eye Medical, and Elios. Reach him at ipsingh@amazingeye.com.

References

1. Newman-Casey PA, Blachley T, Lee PP, Heisler M, Farris KB, Stein JD. Patterns of glaucoma medication adherence over four years of follow-up. Ophthalmology. 2015;122(10):2010-2021. doi:10.1016/j.ophtha.2015.06.039
2. Matlach J, Bender S, König J, Binder H, Pfeiffer N, Hoffmann EM. Investigation of intraocular pressure fluctuation as a risk factor of glaucoma progression. Clin Ophthalmol. 2018;13:9-16. doi:10.2147/OPTH.S186526
3. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al; LiGHT Trial Study Group. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet. 2019;393:1505-1516. Erratum in: Lancet. 2019;6;394(10192):e1. doi:10.1016/S0140-6736(18)32213-X.
4. Ahmed IIK, De Francesco T, Rhee D, et al; HORIZON Investigators. Long-term outcomes from the HORIZON randomized trial for a Schlemm’s canal microstent in combination cataract and glaucoma surgery. Ophthalmology. 2022:S0161-6420(22)00160-9. doi:10.1016/j.ophtha.2022.02.021. Epub ahead of print.
5. Samuelson TW, Singh IP, Williamson BK, et al. Quality of life in primary open-angle glaucoma and cataract: an analysis of VFQ-25 and OSDI from the iStent inject pivotal trial. Am J Ophthalmol. 2021;229:220-229. doi:10.1016/j.ajo.2021.03.007.
6. Craven ER, Walters T, Christie WC, et al; Bimatoprost SR Study Group. 24-month phaseI/II clinical trial of bimatoprost sustained-release implant (Bimatoprost SR) in glaucoma patients. Drug. 2020;80(2):167-179. doi:10.1007/s40265-019-012428-0
7. Ibach M. Interim results of a prospective phase II study of travoprost intraocular implants. Paper presented at: the American Academy of Optometry Annual Meeting; November 9, 2018; San Antonio, Texas.
8. Ibach M. Interim results of a prospective phase II study of travoprost intraocular implants. Paper presented at: the American Academy of Optometry Annual Meeting; November 9, 2018; San Antonio, Texas.
9. Prospective, randomized phase II study comparing two elution rates of Glaukos travoprost intraocular implants to timolol maleate ophthalmic solution, USP, 0.5%. ClinicalTrials.gov identifier: NCT02754596. Updated April 30, 2021. Accessed April 20, 2022. https://clinicaltrials.gov/ct2/show/NCT02754596
10. Glaukos press release. Glaukos’ iDose TR demonstrates sustained IOP reduction and favorable safety profile over 36 months in phase 2b study. January 11, 2022. Accessed April 21, 2022. https://investors.glaukos.com/investors/news/news-details/2022/Glaukos-iDoseTR-Demonstrates-Sustained-IOP-Reduction-and-Favorable-Safety-Profile-Over-36-Months-in-Phase-2b-Study/default.aspx
11. Prospective, randomized phase III study comparing two models of a travoprost intraocular implant to timolol maleate ophthalmic solution, 0.5%. ClinicalTrials.gov identifier: NCT03519386. Updated April 30, 2021. Accessed April 20, 2022. https://clinicaltrials.gov/ct2/show/NCT03519386 .