From improvements in medication targeting and delivery, to neuroprotection and advances in surgical techniques, this review outlines treatments on the horizon in our fight against the silent thief of sight.
The last decade has seen some of the most exciting developments in the management of glaucoma, the leading cause of irreversible blindness worldwide. Although its pathogenesis has yet to be fully elucidated, lowering intraocular pressure (IOP) remains at the forefront in preventing its onset and progression.
Poor adherence to eye drops is a common cause of progression in glaucoma
ADVANCES IN GLAUCOMA MEDICATIONS
Sustained Release Bimatoprost
Poor adherence to eye drops is a common cause of progression in glaucoma and is often multifactorial due to forgetfulness, difficulty with drop instillation, complex dosing regimens and adverse effects. Bimatoprost sustained-release (SR) implant (Durysta, Allergan), is a biodegradable, sustained-release drug delivery system containing the prostaglandin analogue bimatoprost. The implant is administered intracamerally with a prefilled 28-gauge applicator and provides a non-pulsatile, sustained release of bimatoprost over a 90-day period.1 It was approved by the Food and Drug administration (FDA) in March 2020 for open angle glaucoma (OAG) or ocular hypertension (OHT). IOP lowering effects from baseline have been shown to be comparable to those of topical bimatoprost.1
Initial results from phase I/II clinical studies (APOLLO trial) demonstrated a mean overall IOP reduction of 7.2–9.5mmHg at four months in all dose strengths (6, 10, 15, and 20 μg). This IOP-lowering effect was shown to persist after a single administration in 68% of patients at six months, 40% at 12 months, and 28% at two years.1 The mean IOP reduction at 24 months ranged from 5.7–7.4mmHg across the various bimatoprost SR dose strengths (6, 10, 15, and 20 μg ) in patients. The treatment was reported to be safe and well-tolerated: the most common adverse effect was conjunctival hyperaemia which occurred in 34.7% within two days after implant administration and was thought to be procedure-related. Of note, 82.9% of patients reported being extremely or very likely to undergo another bimatoprost implant procedure if given the choice.1
The outcomes of consecutive administrations of bimatoprost SR at four-month intervals is currently being evaluated in phase III trials. The bimatoprost implant is not yet approved for use in Australia.
Rho Kinase Inhibitors
Rho-associated protein kinase is a serinethreonine kinase involved in the regulation of cytoskeletal activities and calciumdependent smooth muscle contraction.2 It lowers IOP by decreasing aqueous production, increasing trabecular outflow, and decreasing episcleral venous pressure.3
Netarsudil Ophthalmic Solution 0.02%
Netarsudil ophthalmic solution 0.02% (Aerie Pharmaceuticals, Irvine, Calif) has been approved in various countries for the treatment of OAG or OHT. It is administered as a once daily buffered aqueous solution eye drop.
The Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2) randomised patients with bilateral OAG or OHT to netarsudil 0.02% (dosed either once daily or twice a day) or timolol 0.5% (dosed twice daily).4 Both dosing forms of netarsudil were found to be non-inferior to timolol with mean IOP reduction from baseline of 3.3-4.6mmHg (16-21%) and 4.1-5.4mmHg (22-24%) for netarsudil daily and twice daily respectively, versus 3.7- 5.1mmHg (18-23%) in the timolol group. The most common adverse event was conjunctival hyperaemia occurring in 50- 59% of patients, with the twice daily dosing associated with increased frequency of adverse events and rate of discontinuation.4
Ripasudil is not yet registered in Australia but is available under the Special Access Scheme.
Fixed Combination Netarsudil/ Latanoprost
Fixed combination netarsudil 0.02% and latanoprost 0.005% (Rocklatan, Aerie Pharmaceuticals, Inc., USA) uses the IOPlowering actions of the rho-kinase inhibitor netarsudil in combination with prostaglandin analogue latanoprost, which increases uveoscleral outflow. Rocklatan received FDA approval for treatment of OAG and OHT in 2019, and is dosed once daily.
The MERCURY study randomised patients with bilateral OAG or OHT to netarsudil 0.02%/latanoprost 0.005% fixed-dose combination (FDC), single-agent netarsudil 0.02%, or single-agent latanoprost 0.005%. The percentage reductions of mean IOP from baseline were 30.9–36.7%, 21.8–24.9%, and 23.3–28.8%, respectively. Netarsudil/latanoprost FDC lowered IOP by an additional 1.8–3.0mmHg over netarsudil only, and an additional 1.3– 2.5mmHg over latanoprost (p<0.0001).5 The main side effect was mild conjunctival hyperaemia, noted in 48–60% of patients. Other adverse effects include perilimbal small subconjunctival haemorrhages, corneal verticillata, and eyelid erythema.2 No significant systemic side effects have been reported.
The past decade has seen significant developments in the space of minimally invasive glaucoma surgery
Fixed combination netarsudil/latanoprost is not yet approved for use in Australia.
Nitric Oxide Compounds
Latanoprostene bunod (LBN) is a nitric oxide-donating prostaglandin F2α analogue, which is rapidly metabolised to latanoprost acid and butanediol mononitrate, releasing nitric oxide. Nitric oxide activates the nitric oxide-guanylate cyclase-1- cGMP cascade, relaxing the trabecular meshwork and Schlemm’s canal, thereby increasing aqueous humour outflow, while latanoprost acid increases uveoscleral outflow. Latanoprostene bunod ophthalmic solution 0.024% (Vyzulta, Bausch & Lomb Incorporated, Rochester, New York, USA) was approved by the FDA in November 2017 for use in OAG and OHT. Several clinical studies have shown that LBN was more effective than latanoprost 0.005% alone or timolol 0.5% twice daily in reducing IOP; analysis of pooled results from phase 3 studies demonstrated a significantly greater proportion of LBNtreated patients had a mean IOP ≤18mmHg and IOP reduction ≥25% from baseline compared to timolol (P<0.001). Its safety profile is also comparable to that of prostaglandin analogues.6
Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for the generation of ATP in mitochondria, and a potent mediator of axon neuroprotection. Increasing retinal NAD+ levels has been shown to provide long-term neuroprotection, preservation of retinal ganglion cell function and reversal of age-related transcriptomic changes in a mouse model of glaucoma.7 Further, serum nicotaminide levels have been reported to be lower in patients with POAG.8,9 The first clinical trial of nicotinamide supplementation in glaucoma participants was carried out in Melbourne. Participants were randomised to receiving either nicotinamide or placebo first, using a dose acceleration method (1.5g/day for six weeks followed by 3g/day for six weeks). Hui et al reported improvements in inner retinal function measured using electroretinography in early to moderate glaucoma compared to placebo. Furthermore, a trend for improved visual field mean deviation was also observed. Larger studies are needed to evaluate long-term neuroprotective effects in glaucoma. More can be read on Dr Hui’s research into Vitamin B3 on page 77 of this mivision issue.
ADVANCES IN LASER TREATMENTS
Micropulse Cyclodiode Laser
Micropulse transscleral cyclophotocoagulation (mTSCPC) is a variation of the continuous-wave form of cycloablation which is used in advanced glaucoma refractory medical management.11 Micropulse laser uses repetitive micropulses of diode laser energy delivered with the Cyclo G6 Glaucoma Laser System (Iridex Corporation, Mountain View, CA). A continuous beam of 810nm wavelength diode laser is segmented into repetitive active pulses interspersed by idle cycles, thereby controlling thermal elevation. Unlike traditional cyclodiode, which is associated with significant adverse effects from excessive damage to surrounding tissues, micropulse laser has significantly reduced overheating and collateral damage.10 The exact mechanism of action is unclear, but could be due to subthreshold cell damage of the pigmented and nonpigmented ciliary epithelium, decreasing aqueous production.
Evidence comparing micropulse to continuous wave cyclodiode laser is limited, but shows that micropulse has similar efficacy and a superior safety profile compared to the latter. A retrospective single-surgeon review, of 73 eyes of 62 patients with POAG, neovascular or pseudoexfoliation glaucoma, demonstrated an average IOP reduction of 46% and a 19% reduction in the number of medications at one year.11 Additionally, 76% had an IOP reduction of at least 20%. The IOP reduction was found to be associated with power used. Of note, there were no instances of phthisis or macular oedema from the procedure. Individual characteristics of the population such as age, glaucoma type and severity, ethnicity and degree of pigmentation may affect results of micropulse laser, making it difficult to determine the ideal energy level which offers the best balance between therapeutic and adverse effects.10
Micropulse Laser Trabeculoplasty
Laser trabeculopasty was first introduced in 1979 in the form of Argon Laser Trabeculoplasty. This was superseded by selective laser trabeculoplasty (SLT) introduced by Latina et al in 1995, which provided a more targeted treatment and less damage to surrounding tissues.12
Micropulse laser trabeculoplasty (MLT) was introduced in 2008 and similar to mTSCPC, allows tissue cooling between pulses. This potentially decreases damage to surrounding tissues. In a clinical trial of patients randomised to 360° MLT or SLT, the authors reported a similar reduction in IOP from baseline up to one year. Although there were more treatment failures in the micropulse group, this was found to be not significant. Patients in the MLT cohort also reported less pain during and after the procedure.12 Robust studies evaluating the efficacy of MLT are however, lacking, possibly due to the established efficacy and safety profile that SLT already offers. To our knowledge MLT is not widely used in Australia.
MINIMALLY-INVASIVE GLAUCOMA SURGERY
The past decade has seen significant developments in the space of minimally invasive glaucoma surgery (MIGS). With longer term safety and efficacy profiles becoming available, its role in the glaucoma treatment paradigm continues to evolve. The MBS item (42504) for MIGS as a standalone procedure became available in May 2020, which will improve patient access in Australia.
The iStent (Glaukos Corporation, Laguna Hills, CA, USA) is a trabecular micro-bypass stent that is implanted into Schlemm’s canal. The second generation (iStent inject) includes two stents and recently, further modifications have been made to include a widened flange at its base (iStent Inject-W) as well as a change to the injector trocar and viewing windows to improve the predictability of implantation. A two-year prospective random control trial (RCT) of iStent inject had more eyes achieving ≥20% reduction in IOP from baseline compared to cataract surgery alone (75.8% vs. 61.9%, p = 0.005) and a greater percentage of patients were medication free. 17 In a Cochrane review, a summary estimate from two of four RCTs reported iStent in combination with cataract surgery were 1.38 times more likely to be off medications between six and 18 months compared to cataract alone.18 As a standalone procedure, an RCT comparing iStent inject versus two ocular hypotensive agents reported similar IOP reductions.19 Similarly, a single-site RCT comparing two first-generation stents vs. once-daily topical travoprost reported similar IOPs between the groups at five years, although fewer iStent eyes required additional medication (17% vs. 44%, p = 0.017). They also reported treatment success (IOP 6–18mmHg without further additional medications or surgery) was achieved in more eyes with the iStent (77% vs. 53%, p = 0.04).20 The Royal Australian and New Zealand College of Ophthalmology (RANZCO) currently recommends iStents as an intermediary intervention between first line therapies (laser and medications) and glaucoma filtration surgery.21
The hydrus microstent (Ivantis, Inc., Irvine, CA, USA) is an 8mm long nickeltitanium scaffold with three windows that is implanted into Schlemm’s canal. It dilates approximately three clock hours of the canal, providing direct aqueous access to the collector channels. The threeyear results from the HORIZON study,15 comparing cataract surgery with Hydrus vs. cataract surgery alone in mild-to-moderate POAG, found 73% of Hydrus patients remained medication-free compared to 48% in the cataract-only arm (p < 0.001). It also reported lower cumulative probability of incisional glaucoma surgery in the Hydrus group (0.6% vs. 3.9%, p = 0.02). The recent COMPARE study16 of 152 eyes randomised to Hydrus or 2-iStent procedure, showed a greater rate of complete surgical success (defined as freedom from repeat glaucoma surgery, IOP ≤ 18mmHg and no glaucoma medications) and reduced medication use in the Hydrus group at 12 months. However, a greater proportion of iStent subjects in this study (3% vs 22%, 7:1 ratio) did not undergo the 12-month medication washout, which may have favoured the Hydrus results. The international SPECTRUM registry for Hydrus, the largest single device registry in ophthalmology with nearly 3,000 eyes, completed enrolment in November 2019 and will provide ‘real-world’ data on the safety and efficacy of the device as a combine or standalone procedure.
The Preserflo (previously known as InnFocus Microshunt, Santen, Osaka, Japan) is an 8.5mm long biocompatible, synthetic tube. It is implanted using an ab-externo approach to divert aqueous from the anterior chamber to subconjunctival space. A small feasibility study (n=21) reported complete success (defined as an IOP of six to 21mmHg, with at least a 20% IOP reduction without medication). This was achieved in 82.6% of patients at the end of five years. The mean number of medications was reduced from 2.4±1.0 at baseline to 0.8±1.3.20 A retrospective study comparing Xen Gel implant (Allergan, Dublin, Ireland) to Preserflo reported similar results in terms of IOP-lowering and safety profile.21 A large RCT comparing Preserflo to trabeculectomy has recently been completed and will shed greater light on its efficacy (NCT01881425). The Preserflo is currently awaiting US FDA approval and is not yet available in Australia.
Xen Gelstent Implant
The Xen implant (Allergan, Dublin, Ireland) is a 6mm stent made of biocompatible porcine collagen that is inserted ab interno into the subconjunctival space, bypassing the conventional outflow pathway. A prospective, non-randomised trial22 demonstrated reductions in IOP and medication burden with Xen as a standalone procedure or combined with cataract surgery. At two years, the clinical success rate was 65.8% (eyes with ≥ 20% IOP reduction from baseline on the same or fewer medications without a second surgical intervention) and 44.7% were medication free. A retrospective cohort study showed similar surgical success and safety profiles between Xen and trabeculectomy, although trabeculectomy was more effective in lowering IOP at 12 months.23 A voluntary recall of the Xen was made in late 2019 due to trace amounts of polishing compounds being detected in a small number of unreleased units. There have also been a series of case reports of endophthalmitis related to implant erosion and extrusion, or associated with bleb needlings.24-26 Longer term safety studies are further required to examine its role.
Ab Interno Canaloplasty with iTrack Microcatheter
Gonioscopy-assisted transluminal trabeculotomy (GATT) involves an ab interno placement of an illuminating micro-catheter device (iTrack, Ellex, Freemont CA) into Schlemm canal following a 360° viscodilation to stretch the inner wall.27 A study of 198 patients with POAG who underwent the GATT procedure demonstrated a mean IOP decrease of 9.2mmHg (37.3%) at 24 months and mean decrease of 1.43 glaucoma medications. Complications were transient and included hyphaema, steroid induced IOP spike, and iridodialysis.27 Outcomes appear to be equivalent to ab externo circumferential trabeculotomy. The awareness and use of iTrack surgical system is growing in Australia.
Several exciting developments in glaucoma treatment have shown promise in early clinical studies to date, and can hopefully provide a useful addition to our armamentarium in managing this challenging condition. With some already approved for use overseas, these are expected to be available for use in Australia in the near future. As technology advances, we are fortunate to have a wide variety of novel approaches to preventing glaucoma related blindness in our patients.
Dr Jeremy Tan BSci, MD, MMed graduated from the University of New South Wales and undertook RANZCO accredited ophthalmology training at the Prince of Wales Hospital, Sydney, where he is the current Professorial Senior ophthalmology registrar. He has a research interest in glaucoma imaging techniques.
Dr Jessica Tang BMedSc, MBBS (Hons), PhD completed her PhD in Glaucoma at the Centre for Eye Research Australia and University of Melbourne. She is currently a RANZCO accredited ophthalmology registrar at the Prince of Wales Hospital, Sydney. A/Prof. Ashish Agar MBBS (Syd), PhD (UNSW), FRANZCO is a Glaucoma consultant and surgeon at the Prince of Wales and Sydney Eye Hospitals, and is a Partner with Marsden Eye Specialists in Sydney. He is a conjoint Senior Lecturer at the University of New South Wales, engaged in clinical studies and laboratory research into glaucoma, being awarded a PhD in this field, and was Fellowship trained in Oxford.
A/Prof Agar is involved in aid projects and educational programs in South East Asia and India. He works in Far Western New South Wales with the Outback Eye Service and is the Director of the Ophthalmology Service at Broken Hill Hospital. He is President of Australian Society of Ophthalmologists, Co-Chair and New South Wales lead of the IRIS program, and Chair of the RANZCO Indigenous Committee.
- Craven E.R., Walters T., Christie W.C., Day D.G., Lewis R.A., Goodkin M.L., et al. 24-Month Phase I/II Clinical Trial of Bimatoprost Sustained-Release Implant (Bimatoprost SR) in Glaucoma Patients. Drugs. 2020;80(2):167-79.
- Cvenkel B., Kolko M. Current Medical Therapy and Future Trends in the Management of Glaucoma Treatment. Journal of ophthalmology. 2020;2020:6138132.
- Conlon R., Saheb H., Ahmed, I.I. Glaucoma treatment trends: a review. Canadian journal of ophthalmology Journal canadien d’ophtalmologie. 2017;52(1):114-24.
- Serle J.B., Katz L.J., McLaurin E., Heah T., Ramirez-Davis N., Usner D.W., et al. Two Phase 3 Clinical Trials Comparing the Safety and Efficacy of Netarsudil to Timolol in Patients With Elevated Intraocular Pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2). American journal of ophthalmology. 2018;186:116-27.
- Asrani S., Robin A.L., Serle J.B., Lewis R.A., Usner D.W., Kopczynski C.C., et al. Netarsudil/Latanoprost Fixed-Dose Combination for Elevated Intraocular Pressure: Three- Month Data from a Randomized Phase 3 Trial. American journal of ophthalmology. 2019;207:248-57.
- Weinreb R.N, Ong T., Scassellati Sforzolini B., Vittitow J.L., Singh K. Kaufman P.L. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study. The British journal of ophthalmology. 2015;99(6):738-45.
- Williams P.A., Harder J.M., Foxworth N.E., Cochran K.E., Philip V.M., Porciatti V., et al. Vitamin B(3) modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science (New York, NY). 2017;355(6326):756-60.
- Hui F., Tang .J, Williams P.A., McGuinness M.B., Hadoux X., Casson R.J., et al. Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: A crossover randomized clinical trial. Clinical & experimental ophthalmology. 2020;48(7):903-14.
- Nzoughet K.J., de la Barca C.J.M., Guehlouz K., Leruez S., Coulbault L., Allouche S., et al. Nicotinamide Deficiency in Primary Open-Angle Glaucoma. Investigative ophthalmology & visual science. 2019;60(7):2509-14.
- Sanchez F.G., Peirano-Bonomi J.C., Brossard Barbosa N., Khoueir Z., Grippo T.M. Update on Micropulse Transscleral Cyclophotocoagulation. Journal of glaucoma. 2020;29(7):598-603.
- Sarrafpour S., Saleh D., Ayoub S., Radcliffe N.M. Micropulse Transscleral Cyclophotocoagulation: A Look at Long-Term Effectiveness and Outcomes. Ophthalmology Glaucoma. 2019;2(3):167-71.
- Abramowitz B., Chadha N., Kouchouk A., Alhabshan R., Belyea D.A., Lamba T. Selective laser trabeculoplasty vs micropulse laser trabeculoplasty in open-angle glaucoma. Clinical ophthalmology (Auckland, NZ). 2018;12:1599-604.
- Samuelson T.W., Sarkisian S.R., Jr., Lubeck D.M., Stiles M.C., Duh Y.J., Romo E.A., et al. Prospective, Randomized, Controlled Pivotal Trial of an Ab Interno Implanted Trabecular Micro-Bypass in Primary Open-Angle Glaucoma and Cataract: Two-Year Results. Ophthalmology. 2019;126(6):811-21.
- Le JT, Bicket A.K., Wang L., Li T. Ab interno trabecular bypass surgery with iStent for open-angle glaucoma. Cochrane Database of Systematic Reviews. 2019(3).
- Fea A.M., Belda J.I., Rękas M., Jünemann A., Chang L., Pablo L., et al. Prospective unmasked randomized evaluation of the iStent inject versus two ocular hypotensive agents in patients with primary open-angle glaucoma. Clin Ophthalmol. 2014;8:875-82.
- Fechtner R.D., Voskanyan L., Vold S.D., Tetz M., Auffarth G., Masood I., et al. Five-Year, Prospective, Randomized, Multi-Surgeon Trial of Two Trabecular Bypass Stents versus Prostaglandin for Newly Diagnosed Open-Angle Glaucoma. Ophthalmology Glaucoma. 2019;2(3):156-66.
- RANZCO. Guidelines for the Use of Trabecular Micro-bypass Glaucoma Stents (MBGS) 2020 [Available from: https://ranzco.edu/wp-content/uploads/2020/05/ RANZCO-Guidelines-for-the-Use-of-Trabecular-Microbypass- Glaucoma-Stents-MBGS-002.pdf.
- Ahmed I.I.K., Rhee D.J., Jones J., Singh I.P., Radcliffe N., Gazzard G., et al. Three-year findings of the HORIZON trial: a Schlemm canal microstent for pressure reduction in primary open angle glaucoma and cataract. Ophthalmology. 2020.
- Ahmed I.I.K., Fea A., Au L., Ang R.E., Harasymowycz P., Jampel H.D., et al. A Prospective Randomized Trial Comparing Hydrus and iStent Microinvasive Glaucoma Surgery Implants for Standalone Treatment of Open- Angle Glaucoma: The COMPARE Study. Ophthalmology. 2020;127(1):52-61.
- Batlle J.F., Corona A., Albuquerque R. Long-term Results of the PRESERFLO® MicroShunt in Patients with Primary Open-angle Glaucoma from a Single-center Nonrandomized Study. J Glaucoma. 2020.
- Scheres L.M.J., Kujovic-Aleksov S., Ramdas W.D., de Crom R., Roelofs L.C.G., Berendschot T, et al. XEN(®) Gel Stent compared to PRESERFLO MicroShunt implantation for primary open-angle glaucoma: two-year results. Acta Ophthalmol. 2020.
- Karimi A., Lindfield D., Turnbull A., Dimitriou C., Bhatia B., Radwan M., et al. A multi-centre interventional case series of 259 ab-interno Xen gel implants for glaucoma, with and without combined cataract surgery. Eye (Lond). 2019;33(3):469-77.
- Wagner F.M., Schuster A.K., Emmerich J., Chronopoulos P., Hoffmann E.M. Efficacy and safety of XEN-Implantation vs. trabeculectomy: Data of a “real-world” setting. PLoS One. 2020;15(4):e0231614.
- Olgun A., Imamoğlu S., Karapapak M., Düzgün E., Kaçar H. Endophthalmitis After XEN Gel Stent Implantation: 2 Cases. J Glaucoma. 2018;27(12):e191-e4.
- Karri B. Gupta C., Mathews D. Endophthalmitis Following XEN Stent Exposure. J Glaucoma. 2018;27(10):931-3.
- Buffault J., Baudouin C., Labbé A. Is the Xen Gel Stent really minimally invasive? Am J Ophthalmol Case Rep. 2020;19:100850-.
- Grover D.S., Smith O., Fellman R.L., Godfrey D.G., Gupta A., Montes de Oca I., et al. Gonioscopy-assisted Transluminal Trabeculotomy: An Ab Interno Circumferential Trabeculotomy: 24 Months Follow-up. Journal of glaucoma. 2018;27(5):393-401.