Open-angle glaucoma (OAG) treatment has focused on lowering IOP by decreasing aqueous humor production or increasing its outflow.^1-4 First-line monotherapy of OAG has centered on once-daily administration of topical prostaglandins.⁵ Mechanistically, prostaglandins are thought to alter the activity of matrix metalloproteinases in the extracellular matrix of the trabecular meshwork (TM) and ciliary body, thereby increasing outflow through both the conventional and unconventional pathways.^6-8

Due to the progressive nature of optic nerve damage in OAG, ideal management involves long-term, uninterrupted treatment. However, as with many chronic diseases, adherence remains a significant obstacle to achieving optimal outcomes.^9,10 Documented barriers to adherence have included patient difficulties with administration, forgetfulness and adverse effects associated with preservatives.^11,12 Consequently, treatment innovation has sought to introduce novel drug delivery systems that effectively lower IOP while bypassing these difficulties. This review aims to analyze and compare a select number of drug delivery systems currently in development. (For additional comparison of the treatments discussed below, see Table.)

BIMATOPROST SR IMPLANT

The Bimatoprost SR (Durysta, Allergan) consists of bimatoprost embedded in a poly-D,L-sustained lactide-co-glycolide (PLGA) polymer matrix, which degrades to lactic acid and glycolic acid.¹³ The intracameral implant is injected into the anterior chamber in a clinic setting and has a targeted duration of 3 to 4 months.

Phase 1/2 trials enrolled 75 patients with bilateral OAG or ocular hypertension (OHT).^13,14 These studies compared Bimatoprost SR at a dose of 6, 10, 15 or 20 mcg in the study eye to topical bimatoprost 0.03% once daily in the control eye, measuring IOP over 24 months. When averaged over the first 4 months, mean IOP reductions for all implant doses were similar to that for topical treatment. However, at the timepoint of week 16, mean IOP reductions for all implant doses were less than that for topical treatment at a statistically significant level. Overall, at 4, 6, 12 and 24 months, IOP was controlled without rescue or re-administration in 91%, 68%, 40% and 28% of study eyes, respectively. As for biodegradability, the implant had completely degraded at month 24 in only 26.5% of the patients evaluated by gonioscopy.

Central endothelial cell density, a safety consideration, was similar in study and control eyes at baseline but was slightly decreased in study eyes at month 24. Adverse events (AE) were more common in study eyes and included conjunctival hyperemia, foreign body sensation and eye pain, which resolved after several days and were thought to be related to the implantation procedure.

The Phase 3 trial compared Bimatoprost SR at a dose of 10 or 15 mcg administered at 4-month intervals over a 12-month period (at day 1, week 16, week 32) in the study eye to topical timolol 0.5% twice daily in the control eye.^15,16 Press releases focused on the lower dose, which is now commercially available. At 3 months, IOP reduction in the Bimatoprost SR 10 mcg cohort was over 30%. At 12 months, after three administrations, IOP was controlled in 80% of study eyes one year after the last injection. Consistent with Phase 1/2 findings, average loss of endothelial cells was about 5% after 20 months.

IDOSE TRAVOPROST IMPLANT

The iDose (Glaukos) is a titanium implant with three main elements: a scleral anchor that inserts into the inner wall of the sclera through the TM, a body that serves as the drug reservoir and a membrane that elutes a proprietary formulation of travoprost intracamerally.¹⁷ This implant is placed in a surgical setting and has a targeted duration of 6 to 12 months.

The Phase 2 trial enrolled 154 patients with OAG or OHT.^18,19 It compared the iDose at either a fast or slow elution rate to topical timolol 0.5% twice daily, measuring IOP over 12 months. At 3 months, mean IOP reductions for both iDose groups and the control group were all similar, at about 8.0 mm Hg (32%). IOP was controlled without additional medications in 82% of both iDose groups and 74% in the control group. At 12 months, IOP in both iDose groups remained at 32% below baseline. No AEs were reported.

ENV515 TRAVOPROST EXTENDED-RELEASE

The ENV515 (Envisia Therapeutics) consists of a biodegradable polymer system that delivers a proprietary formulation of travoprost.²⁰ The intracameral implant is injected into the anterior chamber in a clinic setting and has a targeted duration of 6 to 12 months.

The Phase 2 trial was comprised of multiple cohorts with intention for design optimization. The first cohort enrolled 21 patients with OAG.²⁰ It compared the ENV515 with topical travoprost 0.004% once daily, measuring IOP over 25 days. Mean IOP reductions in the ENV515 and topical groups were similar, at about 6.6 mm Hg (28%). The second cohort enrolled five patients with bilateral OAG and compared the ENV515 in the study eye with topical timolol 0.5% twice daily in the control eye, measuring IOP over 11 months. When averaged over 11 months, mean IOP reductions in study and control eyes were similar at about 6.9 mm Hg (26%). The most common AE was conjunctival hyperemia associated with the procedure. Subsequent cohorts will investigate the efficacy and safety of higher dosing and different implant shapes and sizes.

BIMATOPROST PERIOCULAR RING

The Bimatoprost Ocular Ring (Allergan) contains bimatoprost embedded in a silicone matrix with an inner polypropylene support structure.^21,22 Sizing is based on intercanthal distance, with diameters ranging from 24 mm to 29 mm. It is designed to be manually inserted into the upper and lower fornices and worn for 6 months.

The Phase 2 trial enrolled 130 patients with OAG or OHT.²¹ It compared the bimatoprost ring with a topical placebo to a placebo ring with topical timolol 0.5% b.i.d., measuring IOP over 6 months. The bimatoprost ring met the study definition of non-inferiority at two of nine time points. Retention of either the bimatoprost or placebo ring at 6 months was 88.5%. AEs included eye discharge and conjunctival hyperemia.

OTX-TP TRAVOPROST INTRACANALICULAR PLUG

The OTX-TP (Ocular Therapeutix) is a polyethylene glycol resorbable hydrogel rod with polylactic acid microparticles containing travoprost.²³ The intracanalicular insert is placed in a clinic setting and has a targeted duration of 90 days.

The Phase 3 trial enrolled 554 patients with OAG or OHT. It compared the OTX-TP with a placebo insert, measuring IOP over 12 weeks.²⁴ Results showed that mean IOP reductions of OTX-TP failed to meet the primary efficacy endpoint of non-inferiority at all measured time points. The most common AEs were dacryocanaliculitis and lacrimal structure disorder.

DISCUSSION

Of all novel drug delivery systems currently in development, Durysta is the only FDA-approved sustained release platform. The Durysta implant is remarkable in its innovative design, continued IOP-lowering effect over time and potential for causing a landmark shift in treatment paradigms. However, although Bimatoprost SR may be comparable to topical bimatoprost for up to 3 months, a need for additional medication or repeated implant administration is likely by 12 months. For patients with newly diagnosed OAG or OHT, a topical prostaglandin remains favorable as first-line treatment. The Bimatoprost SR implant may be considered for patients with adherence difficulties or poor IOP control. However, it is currently approved for only a single administration. Further studies looking at multiple dosing may help address the possibility of chronic treatment with this technology.

The next device furthest in development is the iDose (Glaukos). Phase 3 trials are ongoing, set for completion in 2023. An important design difference is that insertion and removal or exchange require a clean room setting, which increases total cost and may complicate workflow. Notably, a limitation of both the Phase 3 trial of Bimatoprost SR and the Phase 2 trial of iDose is that the control intervention was timolol, a beta blocker, instead of a prostaglandin, though timolol is the historical comparator for FDA trials. However, Phase 2 data shows that the Bimatoprost SR achieves a similar IOP reduction to bimatoprost 0.03% drops. Previous studies have shown that topical timolol has substantially less IOP-lowering effect than topical bimatoprost.²⁵

SUMMARY

As patients with glaucoma continue to experience difficulties with treating their vision-threatening disease, innovation in drug delivery systems remains a worthwhile pursuit. It must balance the need for efficacy with the needs for safety, tolerability and feasibility.

The Bimatoprost SR is commercially available, while the iDose is in Phase 3 clinical trials. They have both been shown to provide a sustained IOP-lowering effect. With an improved strategy for monitoring and re-administration and a clearer understanding of long-term efficacy and safety, they may become valuable adjuncts to existing treatment approaches to glaucoma. OM

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About the Authors

Arsham Sheybani, MD, is an associate professor of ophthalmology, at Washington University School of Medicine in St. Louis, Mo. He is a consultant for Allergan, Glaukos, Ivantis and Santen.

Tiffany Wu, BS, is currently a third-year medical student at Washington University School of Medicine in St. Louis, Mo. She is from southern California and received her BS in Physiology & Neuroscience from the University of California, San Diego.