Prostaglandin Intracameral Implants for Ocular Hypertension and Open-Angle Glaucoma

Abstract

Background: Sustained-release prostaglandin intracameral implants are new targeted treatment options for open-angle glaucoma or ocular hypertension that lower intraocular pressure (IOP) and reduce or eliminate the need for topical eye drops. Objective: To summarize evidence supporting prostaglandin intracameral implants for treatment of ocular hypertension or open angle glaucoma and identify patient populations most likely to benefit from these treatments. Data sources: A PubMed search (1/1/2016 to 10/1/2024) was conducted to identify randomized, controlled clinical trials for bimatoprost 10-μg and travoprost 75-μg intracameral implants. Manufacturer prescribing information, formulary dossiers, Food and Drug Administration (FDA) clinical reviews and glaucoma clinical treatment guidelines were also reviewed. Study selection and data extraction: English-language randomized controlled trials involving bimatoprost 10-μg or travoprost 75-μg intracameral implants were included. Data synthesis: Bimatoprost and travoprost intracameral implants demonstrated noninferior IOP reduction compared to timolol eye drops in phase 3 trials, with sustained effects up to 12 and 36 months, respectively. The FDA-approved implants are limited to a single administration to the affected eye to minimize corneal risks. The travoprost implant contains a titanium reservoir and requires surgical placement, while the bimatoprost implant is biodegradable and can be placed in a clinic setting. There are no studies directly comparing the safety and efficacy of the two intracameral implants. Conclusions: Prostaglandin intracameral implants are a novel approach to reducing medication burden while delivering sustained IOP reducing effects. Pharmacists should be aware of efficacy and safety considerations of these implants relative to available topical treatments for ocular hypertension or open angle glaucoma.

Background

Glaucoma is a group of chronic, degenerative optic neuropathies associated with elevated intraocular pressure (IOP) that can cause permanent damage to the optic nerve and progressive vision loss. It is the leading cause of irreversible blindness worldwide.^1,2 While the exact cause is unknown, risk factors for the development of glaucoma include advanced age (over 60 years), family history, ocular trauma, prolonged exposure to systemic or topical corticosteroids, and presence of comorbidities such as diabetes mellitus, hypertension, and cardiovascular disease.^3,4 Furthermore, African Americans and individuals of Asian or Native Alaskan descent are at higher risk than Caucasians to develop this condition. The most common form of glaucoma, primary open-angle glaucoma, affects more than 50 million individuals globally, and prevalence is expected to more than double by 2040. ³

Glaucoma treatments include pharmacologic therapies, laser trabeculoplasty, glaucoma drainage devices, and/or incisional surgery that all aim to lower IOP to within normal range (8-22 mm Hg).^1,2 Topical prostaglandins are widely used as first-line therapy because they are effective, well-tolerated, and require just once daily dosing.^1,2 Other classes of ophthalmic drops can be added or substituted to help achieve target IOP (Table 1).

Table 1.

Topical Ophthalmic Solutions for Lowering Intraocular Pressure in Patients With Open-Angle Glaucoma and Ocular Hypertension.

Mechanism of action	Pharmacologic class	Generic name	Brand name	Usual dose, instilled in affected eye(s)
Reduce aqueous humor production	Alpha-2 agonist	Apraclonidine	Iopidine	1 to 2 drops 3 times daily
		Brimonidine a	Alphagan P	1 drop 3 times daily
	Beta blocker	Betaxolol	Betopic-S	1 drop twice daily
		Carteolol	generic	1 drop twice daily
		Levobunolol	generic	1 to 2 drops once or twice daily
		Timolol	Timoptic, generic	1 drop once daily
	Carbonic anhydrase inhibitor	Brinzolamide	Azopt	1 drop 3 times daily
		Dorzolamide	generic	1 drop 3 times daily
Increase aqueous humor outflow	Cholinergic agonist	Pilocarpine	generic	1 drop up to 4 times daily
	Prostaglandin	Bimatoprost	Lumigan	1 drop once daily in the evening
		Latanoprost	Xalatan, Xelpros, Iyuzeh
		Latanoprostene bunod	Vyzulta
		Omidenepag isopropyl	Omlonti
		Tafluprost	Zioptan
		Travoprost	Travatan Z
	Rho kinase inhibitor	Netasudil	Rhopressa
Additive effects based on individual ingredients	Combination products	Brinzolamide/brimonidine	Simbrinza	1 drop 3 time daily
		Brinzolamide/timolol	Combigan	1 drop twice daily
		Dorzolamide/timolol	Cosopt, Cosopt PF	1 drop twice daily
		Latanoprost/timolol	generic	1 drop once daily
		Netarsudil/latanoprost	Rocklatan	1 drop once daily in the evening
		Travoprost/timolol	generic	1 drop once daily

^aBrimonidine also increases uveoscleral outflow.

Consistent and correct application of eye drops is essential for topical glaucoma medications to be effective; however, adherence to glaucoma treatments is known to be suboptimal. ⁵ Studies suggest that up to 80% of patients with glaucoma or ocular hypertension (OHT) do not follow their prescribed medication regimens. ⁵ Factors contributing to nonadherence include forgetfulness, difficulty instilling eye drops, frequent dosing, medication costs, and side effects.^6,7 Consequently, there is a need for alternative treatment modalities that can deliver therapeutic IOP-lowering effects.

Bimatoprost 10-µg intracameral implant (Durysta; Allergan) and travoprost 75-µg intracameral implant (iDose TR; Glaukos) received Food and Drugs Administration (FDA) approval in March 2020 and December 2023, respectively. They were developed to improve management of open angle glaucoma (OAG) or OHT by delivering continuous prostaglandin-mediated IOP reduction without requiring patient or caregiver administration of daily topical eye drops.

Objective

The purpose of this review is to (1) summarize evidence supporting the use of currently marketed prostaglandin intracameral implants for treatment of OHT or OAG and (2) identify patient populations most likely to benefit from these treatments.

Data Sources

Two authors (CR and JC) conducted a PubMed search (1/1/2016 to 10/1/2024) using search terms “bimatoprost AND implant,” “travoprost AND implant,” “bimatoprost intracameral implant,” “travoprost intracameral implant,” “iDose,” and “Durysta.” The search was limited to randomized controlled studies. References of retrieved articles were reviewed for additional studies. Manufacturer’s prescribing information and glaucoma clinical treatment guidelines were reviewed to assess the drugs’ place in therapy. Authors also examined available AMCP format 5.0 formulary dossiers and FDA clinical reviews for the implants.

Study Selection and Data Extraction

Six randomized controlled trials (three for bimatoprost implant and three for travoprost implant) demonstrated the efficacy and safety of prostaglandin intracameral implants. FDA clinical reviews were available for both Durysta and iDose TR. Only Durysta had an AMCP 5.0 dossier and FDA clinical review available. Treatment guidelines for open-angle glaucoma were published either before or around the time of intracameral prostaglandin implant approvals and thus do not mention them.^1,2

Data Synthesis

Bimatoprost 10-µg Intracameral Implant (Durysta)

Durysta is a biodegradable, sustained-release, preservative-free rod-shaped intracameral implant containing 10-µg of the prostaglandin analog bimatoprost. ⁸ It is designed to release bimatoprost slowly and continuously to aqueous outflow tissues for 4 to 6 months. ⁹ The duration of IOP lowering may extend beyond the time that intraocular bimatoprost levels are no longer detectable. ⁹ The implant is preloaded into a single-use applicator for insertion into the anterior chamber wall of the eye during a slit lamp procedure.

The APOLLO study was a phase 1/2 randomized, double-blind, paired-eye, dose-ranging study that evaluated the efficacy and safety of sustained release bimatoprost implant in 75 adults with OAG. ¹⁰ All participants received intracameral bimatoprost SR implants (6, 10, 15, or 20 µg) in one eye (study eye) and topical bimatoprost 0.03% once daily in the contralateral eye (fellow eye). A single repeat administration of the implant was permitted. The primary endpoint was IOP change from baseline through 24 months. At 24 months, mean IOP reduction from baseline was 7.5, 7.3, 7.3, and 8.9 mm Hg following treatment with 6, 10, 15, or 20 µg bimatoprost implants, respectively, compared to 8.2 mm Hg in eyes treated with bimatoprost drops. Intraocular pressure was controlled without additional medications in 51 (68%), 30 (40%), and 21 (28%) of study eyes at 6, 12, and 24 months, respectively. There were no significant differences in change in corneal thickness from baseline between study eyes and fellow eyes. Conjunctival hyperemia was more common in implant-treated eyes, typically appearing within 2 days of the implant procedure, which authors attribute to preprocedure application of ophthalmic povidone-iodine. After the postprocedure period (i.e., more than 2 days after implant placement), there were no significant differences between groups in overall incidence of adverse events. At the 24-month follow-up, 82.9% of patients across all implant doses expressed high likelihood (extremely or very likely) of undergoing another implant procedure if given the opportunity. Furthermore, 88.6% of patients indicated that they would recommend the procedure to others with the same eye condition.

FDA approval of the bimatoprost 10-µg intracameral implant was based on two phase 3, randomized, double-blind, 20-month clinical trials with identical designs known as ARTEMIS 1 and ARTEMIS 2.^11,12 In both trials, adults with OAG or OHT were assigned to 1 of 3 treatment arms: bimatoprost 10-µg implant, bimatoprost 15-µg implant, or twice daily ophthalmic timolol maleate 0.5%. Subjects assigned to either bimatoprost implant group could have the implant readministered at month 4 and month 8. Subjects were followed through month 20 or for at least 12 months after the last bimatoprost implant or timolol administration. Primary endpoints were mean IOP and mean change from baseline IOP through week 12. In both studies, the 10-µg and 15-µg doses of bimatoprost implant met the predefined criteria for statistical and clinical noninferiority to timolol (Table 2).^11,12 Notably, more than 90% of subjects assigned to an implant arm in either trial received repeat bimatoprost implants at 4-month intervals. A phase 3b study of 203 patients from the ARTEMIS studies evaluated the longevity of IOP control after single administration of the 10-µg implant and estimated that probability of IOP control was 75% at 6 months and 56% at 12 months. ¹³ In addition, the probability of not requiring rescue treatment after single administration of the bimatoprost 10-µg implant was 97% at week 12, 74.6% at 6 months, 65.1% at 8 months, and 55.5% at 12 months. ¹³

Table 2.

Phase 3 Non-Inferiority Clinical Studies of Bimatoprost Intracameral Implant.

Study	Study time point	Bimatoprost intracameral implant		Timolol 0.5% twice daily
		10 µg	15 µg
ARTEMIS-1 11
Efficacy
N		198	198	198
Recipients of 2 implants (%)		14 (7%)	18 (9%)	-
Recipients of 3 implants (%)		174 (88%)	151 (76%)	-
Mean diurnal IOP a , mmHg	Baseline	24.0	24.2	23.9
	12 weeks	17.2	17.0	17.5
	52 weeks	18.1	17.9	17.2
Mean IOP reduction from baseline, mm Hg b	12 weeks	6.8-7.5	7.2-7.7	6.4-6.8
% participants not requiring non-study IOP-lowering treatment	52 weeks	84%	73%	86%
Safety
Participants with ≥20% loss of corneal endothelial density	80 weeks or at study exit	20 (10.2%)	42 (21.8%)	-
Participants with ocular adverse events leading to implant removal		7 (3.6%)	16 (8.3%)	-
ARTEMIS-2 12
Efficacy
N		176	176	176
Recipients of 2 implants (%)		13 (7%)	20 (11%)	-
Recipients of 3 implants (%)		152 (87%)	142 (81%)	-
Mean diurnal IOP a , mmHg	Baseline	23.7	23.9	23.9
	12 weeks	16.9	16.7	17.5
	52 weeks	17.8	17.1	17.2
Mean IOP reduction from baseline, mm Hg b	12 weeks	6.2-6.3	6.6-6.7	6.8-6.9
% participants not requiring non-study IOP-lowering treatment	52 weeks	82%	78%	84%
Safety
Participants with ≥20% loss of corneal endothelial density (%)	80 weeks or at study exit	14 (8.1%)	43 (24%)	1 (0.6%)
Participants with ocular adverse events leading to implant removal (%)		5 (2.9%)	19 (10.8%)	-

^aMeasured at 8 am and 10 am. ^bNoninferiority to timolol in change in IOP from baseline was achieved if the upper limit of the 95% CI of the difference in IOP between implant groups and timolol was <1.0 mm Hg for all time points and ≤ 1 mmHg at three or more time points.

The most common ocular treatment emergent adverse events (TEAEs) in both studies were conjunctival hyperemia, conjunctival hemorrhage, foreign body sensation, and eye pain, all of which occurred with higher frequency among implant recipients compared to groups treated with timolol.^11,12 Most of the TEAEs in implant-treated eyes occurred within 2 days after implant administration which authors attributed to the implant placement procedure. In addition, rates of ≥20% loss in corneal endothelial density (CECD) were most frequently observed with subjects treated with bimatoprost 15 µg and/or after repeated implant administrations of either dose. More subjects in the bimatoprost 15 µg group also experienced ocular TEAEs that led to implant removal.

Overall, the risk benefit assessment in these studies favored the 10 µg bimatoprost implant, and this was the formulation that ultimately received FDA approval in 2020 for lowering IOP with OAG or OHT. ⁸ Pooled results from the ARTEMIS trials showed that by 52 weeks, 82% of the implants had either biodegraded completely or were reduced to ≤25% of their initial size. This effect was observed in 95% of implants by 20 months. ¹⁴

Travoprost 75-µg Intracameral Implant (iDose TR)

The iDose TR implant contains 75-µg of travoprost in a rod-shaped biocompatible titanium reservoir preloaded into a single-dose inserter. ¹⁵ The implant requires surgical insertion into the trabecular meshwork and anchoring to the sclera during an operating room procedure.

An initial multicenter, randomized, double-blind phase 2 study of 154 adults with OAG or OHT investigated the safety and efficacy of iDose TR (travoprost) compared to timolol ophthalmic solution in reducing IOP over 36 months. ¹⁶ Patients received either a fast-eluting (FE) implant, slow-eluting (SE) implant, or twice daily timolol 0.5% ophthalmic solution. Throughout the study, all treatment groups experienced statistically significant IOP reductions from baseline (P < .0001). However, a higher percentage of patients in the implant groups (FE and SE) acheived well controlled IOP at 36 months on the same or fewer topical IOP-lowering medications compared to their baseline medication use (FE-implant vs timolol, P = .1545; SE-implant vs timolol, P = .0548). There were similar incidences of adverse drug events across all treatment groups with the most frequent being cataracts, decreased visual acuity, conjunctival hemorrhage, and eye pain.

This study was followed by two identically designed multicenter, randomized, double-blind, parallel group phase 3 studies (GC-010 and GC-012) that evaluated the safety and efficacy of travoprost FE implant, SE implant or twice daily timolol 0.5% ophthalmic drops in patients with OAG or OHT.^17,18,19 The primary endpoint was mean change in IOP from baseline at day 10, week 6, and month 3. Noninferiority was achieved if the upper limit of the 95% confidence interval [CI] of the difference between the implant groups and the timolol group was <1.5 mm Hg at all time points and <1 mm Hg at a minimum of 3 time points. Both FE and SE implants met noninferiority criteria at 3 months; the SE intracameral implant also demonstrated noninferiority to timolol at 12 months while the FE intracameral implant demonstrated noninferiority to timolol at 9 months. In combined analyses of both trials, a greater proportion of implant-treated eyes (89.9% of FE and 93.0% of SE) compared with timolol-treated eyes (66.9%) required the same or fewer topical IOP-lowering medications at 12 months compared to baseline (P < .0001). ¹⁸ In addition, 77.6% of eyes with the FE implant and 81.4% of eyes with the SE implant did not require topical IOP-lowering medications at the 12-month mark. ¹⁸

The most common TEAEs (incidence > 2%) were increased IOP, iritis, and conjunctival/ocular hyperemia. There were no TEAEs of corneal endothelial cell loss in any group based on a predefined threshold of a confirmed ≥30% reduction from baseline (Table 3). Notably, this threshold was higher than the CECD threshold used in the bimatoprost implant studies.

Table 3.

Phase 3 Noninferiority Clinical Studies of Travoprost Intracameral Implant.

Study	Study time point	Travoprost intracameral implant		Timolol 0.5% twice daily
		Fast eluting	Slow eluting
GC-010 (NCT03519386) 17,18
Efficacy
N		200	197	193
Mean diurnal IOP a , mmHg	Baseline	24.2	24.0	24.1
	Day 10	15.8	15.6	16.7
	6 weeks	16.7	16.6	17.2
	12 weeks	17.6	17.4	17.5
Mean IOP reduction from baseline, mmHg b	12 weeks	6.6	6.6-6.7	6.5-6.7
Safety
Participants with ≥30% loss of corneal endothelial density	12 weeks	0	0	0
GC-012 (NCT03868124) 18,19
Efficacy
N		176	176	176
Mean diurnal IOP a , mmHg	Baseline	23.7	23.9	23.9
	Day 10	16.9	16.7	17.5
	6 weeks	17.8	17.1	17.2
	12 weeks
Mean IOP reduction from baseline, mmHg b	12 weeks	6.2-6.3	6.7-6.8	6.8
Safety
Participants with ≥30% loss of corneal endothelial density	12 weeks	0	0	0

^aMeasured at 8 am and 10 am. ^bNoninferiority to timolol in IOP change from baseline was achieved if the upper limit of the 95% CI of the difference between the implant groups and the timolol group was <1.5 mm Hg at all time points and <1 mm Hg at 3 or more time points.

Conclusions

Topical prostaglandins are considered first-line therapies for OAG due to their superior efficacy in lowering IOP compared to beta-blockers, carbonic anhydrase inhibitors, and alpha-adrenergic agonists when used consistently and correctly. Despite their efficacy, adherence to topical glaucoma medications can be challenging for some patients due to factors such as side effects, complex dosing regimens, or underlying health conditions (e.g., tremors, limited mobility, and cognitive impairment). Sustained-release intracameral prostaglandin implants may offer an alternative treatment modality for these individuals. Pharmacists can play an important role in optimizing glaucoma management by staying informed about novel therapeutic options such as prostaglandin intracameral implants. By actively communicating these advancements to both patients and healthcare providers, pharmacists can contribute to the development of personalized treatment plans that better address individual patient needs while optimizing therapeutic response. Furthermore, pharmacists should be aware that patients with a diagnosis of OAG or OHT may have received an intracameral implant, particularly if topical prostaglandins are not listed in their medication records.

Both FDA-approved prostaglandin intracameral implants provide IOP-lowering support that can delay the need for surgery and/or reduce medication burden for patients requiring multiple topical treatments. In addition, since iDose TR requires surgical placement, it may be used adjunctively in patients undergoing planned surgery for glaucoma; this combined approach can reduce the number of surgical procedures patients may need for optimal and sustained IOP control. As the treatment landscape for OHT and OAG evolves, earlier consideration of intracameral implants may become increasingly common. ²⁰

Clinical studies have shown the bimatoprost 10-µg intracameral implant to have similar IOP reductions as twice-daily timolol eye drops for three months, with more than half of patients experiencing sustained effects through 12 months following a single implant.^11-13 Similarly, the travoprost 75-µg slow-eluting intracameral implant has demonstrated noninferior to twice-daily timolol eye drops in reducing IOP for three months, with one study showing sustained effects for up to 36 months in most patients. ¹⁶

The main limitation of intracameral prostaglandin implants is they can cause corneal adverse reactions including endothelial cell loss, endophthalmitis and iritis. Clinical studies have demonstrated the efficacy of implants formulated with higher doses, faster release kinetics, and repeated implant administrations. However, these approaches were associated with an increased risk for corneal adverse events. Thus, current approved prostaglandin intracameral implants are limited to the bimatoprost 10-µg (Durysta) and travoprost 75-µg slow eluting (iDose TR) implants, and both are licensed only for single administration per eye.^8,15 In addition, efficacy may be limited in severe glaucoma, as randomized controlled studies excluded patients with IOP greater than 36 mm Hg in the study eye and/or significant visual field loss.^{10,11,12,16,17,19,21}

Owing to the titanium content, intracameral travoprost implants are categorized as “MR conditional,” meaning they can only be used in specific magnetic resonance imaging (MRI) environments with certain safety precautions. Patients with travoprost implants should carry a patient ID card to alert healthcare providers to presence of the implant. In contrast, the bimatoprost implant is biodegradable, designed to dissolve within 6 months. Regular monitoring of IOP is essential to assess need for additional therapies given that the duration and degree of pharmacologic effect may vary among implant recipients.

Overall, the studies have shown that a sustained release prostaglandin implants can be a valuable treatment option for OAG or OHT by mitigating the shortcomings of traditional IOP-lowering ophthalmic drops, including the need for frequent administration and topical side effects that can negatively impact treatment adherence and effectiveness. Continued advancements in glaucoma treatments offer hope for improved patient outcomes and overall glaucoma care.