Promising avenues could simplify glaucoma management – just in time

Researchers are working to develop new interventions for glaucoma s the disease burden is expected to increase with an aging global population. Image credit: ©yana136 – stock.adobe.com

The disease burden of glaucoma is expected to increase with an aging global population. Development of newer procedures and technologies for effective management of glaucoma is the need of the hour. Promising developments have emerged recently that will be interesting to explore further in 2024.

Deviceless glaucoma surgery

One of the most interesting trends that emerged in 2023 is in the field of minimally invasive glaucoma surgery (MIGS). There is a move toward implant-free or deviceless MIGS, such as laser trabeculotomy (eg, the ELIOS and ViaLase systems), ab-interno canaloplasty (eg, the iTrack and iTrack Advance devices), or combined canaloplasty and trabeculotomy (the OMNI system). Due to the absence of implants, these deviceless techniques have attractive benefits such as decreased risk of corneal endothelial cell loss, surgical trauma, postoperative inflammation, and implant-specific adverse events.¹ 

Canaloplasty (ABiC) is gaining favour; it lowers IOP and medication burden^2,3 by improving aqueous humour outflow across the entire conventional drainage pathway. Performed via an ab-interno technique it is a MIGS that preserves the conjunctiva, the sclera, and the trabecular meshwork for potential subsequent interventions; leaves no implant or stent behind in the eye; and requires no suture to maintain patency of the Schlemm canal. It had a reputation of having a steep learning curve, but recently, the FDA approved the second generation of the iTrack family—the iTrack Advance (Nova Eye Medical)—which features an ergonomic, easy-to-use handheld injector to enable the smooth microcatheter insertion into the Schlemm canal. This device can contribute to spreading canaloplasty and has already been in use in Europe for a few years, particularly in Germany.⁴

Among the subconjunctival MIGS, a newly introduced, stent-free alternative is the novel minimally invasive micro sclerostomy (MIMS) procedure (Sanoculis Ltd). It utilises a rotating needle to carve a permanent tunnel near the corneoscleral junction, connecting the anterior chamber with the subconjunctival space. Data from an early clinical trial showed short-term IOP lowering similar to that achieved with subconjunctival-filtering MIGS.⁵

Deviceless MIGS have proven to be effective at lowering IOP in the short term.^6,7 However, the long-term outcomes of different deviceless MIGS is an area that is currently being explored.

Deviceless MIGS that involve trabecular meshwork cutting or ablation may be affected by the mode and amount of trabecular tissue removal. More destructive techniques, such as trabecular meshwork excision, could cause more scarring in the long term, which contributes to suboptimal IOP control compared with less damaging modalities such as laser trabeculotomy. For example, the ELIOS trabeculotomy device (Elios Vision, Inc) uses an excimer laser, which is a ‘cold’ laser that causes less thermal damage and minimises tissue fibrosis.⁸ The technique is still under investigational use in the United States. Femtosecond laser trabeculotomy by the ViaLase device (ViaLase, Inc) has also been found to cause little to no collateral thermal damage to surrounding tissues.⁹ This was demonstrated clinically in recently published findings from a pilot study by absence of a significant healing response or channel closure at 24 months.¹⁰ 

Advanced glaucoma

Advanced glaucoma is a challenging condition to manage. Standard guidelines require target IOPs to be as low as possible in these cases, in the low teens to even in the single digits and, so far, trabeculectomy is the gold standard procedure capable of lowering IOP to such levels. Tube shunts are increasingly becoming the preferred alternatives, but there is a scarcity of data comparing the long-term efficacy of these modalities with that of trabeculectomy in advanced glaucoma. There has been limited innovation in this area over the years, the main players being the Ahmed Glaucoma Valve and Baerveldt Glaucoma Implants, which were first commercialised in the early to mid 1990s. The Paul Glaucoma Implant (Advanced Ophthalmic Innovations, Singapore) is an updated version of the valveless glaucoma drainage device that features a tube with a significantly reduced lumen compared with its predecessors, at 127 µm internal diameter and 426 externally (cf 300 µm and
640 µm, respectively, for the Ahmed and Baerveldt).¹¹ In theory this should reduce the risk of corneal endothelial loss and erosion, simply because of the smaller tube. However, early experience suggests that the reduced lumen diameter also improves the predictability of early IOP control, which, if proven, should provide a welcome advance in this difficult area.

Suprachoroidal space MIGS could be the most effective procedure in regard to raw IOP reduction, as the suprachoroidal and supraciliary outflow is not limited by downstream episcleral venous pressure. In theory, this could produce greater IOP lowering.¹²

The MINIject (iSTAR Medical) is currently the only commercially available supraciliary MIGS implant. At present, it is undergoing clinical trials in patients with mild to moderate glaucoma. Early results show promising IOP lowering over 24 months with few adverse events.¹³ In general, the main limitation of suprachoroidal stents is their susceptibility to scarring and fibrosis.¹² The MINIject aims to prevail over this limitation by using biocompatible medical-grade silicone material, as it has demonstrated good biointegration and preserved drainage in early clinical trials.¹³ Should it be deemed effective and safe, it may be particularly useful in severe, advanced glaucoma.

Innovations in medical therapy

Although rho kinase inhibitors have been the most promising new class of antiglaucoma medications developed in recent years, patients struggle with long-term adherence owing to a relatively high incidence of conjunctival hyperemia. Rho kinase inhibitors have yet to demonstrate noninferiority to latanoprost and timolol maleate in most cases.¹⁴ Hence, they are currently secondary or tertiary choices in medical management
of glaucoma.

There do not seem to be any drug classes on the horizon that could suddenly supplant prostaglandin analogues. What is discernible, however, is true potential for improving outcomes of already available medical therapies with improved drug delivery. At present, achieving sustained medication delivery should take precedence over searching for novel medications.

A major limitation of drug delivery systems is getting sufficient drug in, and for it to elute evenly over a period of time rather than discharge most of the medication at the start and then slowly run out (or dose dumping). Intraocular implants, although invasive, are more effective at providing sustained and localised drug release. A bimatoprost intracameral implant (Durysta; Allergan) is the first of two FDA-approved sustained-release implants. Unfortunately, it cannot—yet—be the solution in a chronic disease needing lifelong therapy, as its drug delivery lasts approximately 4 to 6 months.

Travoprost intracameral implant (iDose TR; Glaukos) received FDA approval in December 2023. Results from phases 2 and 3 showed a good safety profile and noninferiority to topical timolol in regard to IOP reduction. Phase 2B data indicated that the implant had robust IOP-lowering results; it also reduced the burden of topical IOP-lowering medications for up to 36 months.

A major disadvantage of intracameral implants is the surgical intervention required to implant and extract the device. Even if the device were to maintain efficacy for 1 year, an annual visit to the operating room for the patient is not optimal. As such, it needs to be addressed with a focus on developing longer-lasting implants, or else the inconvenience for patients is not justified. Nonetheless, it is crucial to consider the cost of procedure, surgical trauma to the patient, and potential adverse effects.

Subconjunctival MIGS

Subconjunctival MIGS procedures, or minimally invasive bleb-involving surgery (MIBS) procedures, have not yet matched the efficacy of trabeculectomy, despite being proven to produce decent IOP lowering with a good safety profile.¹⁵ In a randomised controlled trial comparing PreserFlo MicroShunt (Santen Pharmaceutical Co, Ltd) and trabeculectomy, interim results at the end of year 1 showed a mean IOP reduction to 14.3 mm Hg in the PreserFlo group, whereas the mean IOP reduction was 11.1 mm Hg in the trabeculectomy group.¹⁶ However, by year 1, there were fewer postoperative interventions required for the PreserFlo group (40.8%) than for the trabeculectomy group (67.4%). Although the PreserFlo did not match the IOP lowering of trabeculectomy in that particular study, it is worth noting that the PreserFlo arm of the study still experienced a substantial reduction in IOP after 1 year. Additionally, it is likely that with the higher doses of antifibrotic agents used in regular clinical practice than were used in that particular study, the IOP-lowering effects of PreserFlo would likely be closer to those of trabeculectomy.

New innovation in subconjunctival MIGS include the Calibreye System under development by Myra Vision, which is a novel device with titrable outflow control that aims to achieve maximum IOP reduction in moderate open-angle glaucoma. It has multiple control channels that can be utilised to reduce or elevate IOP as needed. The first-in-human clinical study of the Calibreye System was announced in the second half of 2023.

MIBS procedures have several potential advantages over trabeculectomy; they are less traumatic, faster to perform, and require less postoperative follow-up. The subconjunctival scarring is what limits their success rate and ability to match the efficacy of trabeculectomy. Several efforts have been made to inhibit wound healing in filtration surgeries, including augmentation with intracameral bevacizumab.¹⁷ This area is prime for innovation with the potential to revolutionise surgical management of glaucoma.

Safety profile

Much of the potential success of the innovations mentioned above lies in their safety profile, which is another area that must be improved. Mitosol is the only FDA-approved formulation of mitomycin-c for ophthalmic use, but mitomycin-c carries risks of leakage or spread of cytotoxicity outside the treatment area.¹⁸ Beta radiation can become an effective addition to conventional scar prophylaxis regimens for trabeculectomy, tube shunt surgery, and subconjunctival MIGS.¹⁹ Prominent experts, such as my colleagues Peng Tee Khaw and Ian Murdoch, have pioneered research on beta radiation. Moreover, Murdoch et al recently published the 20-year results of Moorfields Eye Hospital patients, showing that beta radiation is safe in the long term and that trabeculectomy outcomes using beta irradiation had similar success rates to using antimetabolites while having no risk of leakage, as liquid antimetabolites do.²⁰ Despite a promising profile, beta radiation has not yet translated into a readily available device— this is currently being developed by Radiance Therapeutics.

Conclusion

Promising alternatives for medical and surgical treatment of glaucoma are on the horizon. Minimally invasive interventions and deviceless MIGS seem to be the path ahead for safer and more effective glaucoma management. Research must be focused on refining existing modalities rather than finding breakout therapies.

References

1. Vinod K, Gedde SJ. Safety profile of minimally invasive glaucoma surgery. Curr Opin Ophthalmol. 2021;32(2):160-168. doi:10.1097/ICU.0000000000000731

2. Koerber N, Ondrejka S. Clinical outcomes of canaloplasty via an ab-interno surgical technique using the iTrack device: a narrative review. Int Ophthalmol. 2022;43(6):2017-2027. doi:10.1007/s10792-022-02601-1

3. Gallardo MJ. 36-Month Effectiveness of Ab-Interno Canaloplasty Standalone versus Combined with Cataract Surgery for the Treatment of Open-Angle Glaucoma. Ophthalmol Glaucoma. 2022;5(5):476-482. doi:10.1016/j.ogla.2022.02.007

4. Koerber N, Ondrejka S. 6-Year Efficacy and Safety of iTrack Ab-interno Canaloplasty as a Standalone Procedure and Combined with Cataract Surgery in Primary Open-Angle and Pseudoexfoliative Glaucoma. J Glaucoma. Published online September 12, 2023. doi:10.1097/IJG.0000000000002311

5. Geffen N, Kumar DA, Barayev E, et al. Minimally Invasive Micro Sclerostomy (MIMS) Procedure: A Novel Glaucoma Filtration Procedure. J Glaucoma. 2022;31(3):191-200. doi:10.1097/IJG.0000000000001955

6. Mosaed S, Dustin L, Minckler DS. Comparative outcomes between newer and older surgeries for glaucoma. Trans Am Ophthalmol Soc. 2009;107:127-133.

7. Thein T, Christopher T, Sarrafpour S, Liu J. Comparison of Short-term Surgical Outcomes Between Ab Interno Canaloplasty (ABiC) and Gonioscopy Assisted Transluminal Trabeculotomy (GATT) in Primary Open Angle Glaucoma (POAG) Management. Invest Ophthalmol Vis Sci. 2023;64(8):4293.

8. Durr GM, Töteberg-Harms M, Lewis R, Fea A, Marolo P, Ahmed IIK. Current review of Excimer laser Trabeculostomy. Eye Vis (Lond). 2020;7:24. doi:10.1186/s40662-020-00190-7

9. Mikula ER, Raksi F, Ahmed II, et al. Femtosecond Laser Trabeculotomy in Perfused Human Cadaver Anterior Segments: A Novel, Noninvasive Approach to Glaucoma Treatment. Transl Vis Sci Technol. 2022;11(3):28. doi:10.1167/tvst.11.3.28

10. Nagy ZZ, Kranitz K, Ahmed IIK, De Francesco T, Mikula E, Juhasz T. First-in-Human Safety Study of Femtosecond Laser Image-Guided Trabeculotomy for Glaucoma Treatment: 24-month Outcomes. Ophthalmology science. 2023;3(4):100313. doi:10.1016/j.xops.2023.100313

11. Koh V, Chew P, Triolo G, et al. Treatment Outcomes Using the PAUL Glaucoma Implant to Control Intraocular Pressure in Eyes with Refractory Glaucoma. Ophthalmol Glaucoma. 2020;3(5):350-359. doi:10.1016/J.OGLA.2020.05.001

12. Gigon A, Shaarawy T. The Suprachoroidal Route in Glaucoma Surgery. J Curr Glaucoma Pract. 2016;10(1):13-20. doi:10.5005/jp-journals-10008-1197

13. Denis P, Hirneiß C, Durr GM, et al. Two-year outcomes of the MINIject drainage system for uncontrolled glaucoma from the STAR-I first-in-human trial. Br J Ophthalmol. 2022;106(1):65-70. doi:10.1136/bjophthalmol-2020-316888

14. Clement Freiberg J, von Spreckelsen A, Kolko M, Azuara-Blanco A, Virgili G. Rho kinase inhibitor for primary open-angle glaucoma and ocular hypertension. Cochrane Database of Systematic Reviews. 2022;2022(6). doi:10.1002/14651858.CD013817.pub2

15. Beckers HJM, Aptel F, Webers CAB, et al. Safety and Effectiveness of the PRESERFLO® MicroShunt in Primary Open-Angle Glaucoma: Results from a 2-Year Multicenter Study. Ophthalmol Glaucoma. 2022;5(2):195-209. doi:10.1016/j.ogla.2021.07.008

16. Baker ND, Barnebey HS, Moster MR, et al. Ab-Externo MicroShunt versus Trabeculectomy in Primary Open-Angle Glaucoma: One-Year Results from a 2-Year Randomized, Multicenter Study. Ophthalmology. 2021;128(12):1710-1721. doi:10.1016/j.ophtha.2021.05.023

17. Kopsinis G, Tsoukanas D, Kopsini D, Filippopoulos T. Intracameral Bevacizumab Versus Sub-Tenon’s Mitomycin C as Adjuncts to Trabeculectomy: 3-Year Results of a Prospective Randomized Study. J Clin Med. 2021;10(10):2054. doi:10.3390/jcm10102054

18. Kirwan JF, Constable PH, Murdoch IE, Khaw PT. Beta irradiation: new uses for an old treatment: a review. Eye. 2003;17(2):207-215. doi:10.1038/sj.eye.6700306

19. Kirwan JF, Cousens S, Venter L, et al. Effect of β radiation on success of glaucoma drainage surgery in South Africa: randomised controlled trial. BMJ. 2006;333(7575):942. doi:10.1136/bmj.38971.395301.7C

20. Murdoch I, Puertas R, Hamedani M, Khaw PT. Long-Term Safety and Outcomes of β-radiation for Trabeculectomy. J Glaucoma. 2023;32(3):171-177. doi:10.1097/IJG.0000000000002144

Editor's note: A previous version of this article erroneously stated that travoprost intracameral implant (iDose TR; Glaukos) was still under FDA review at the time of publication in early February. The FDA issued approval in December of 2023. The article has been updated to reflect this approval, and to correct results cited from the Phase 2b study.