In the real-world setting, there is suboptimal compliance with treatments that require frequent administration and assessment visits. This undertreatment frequently has negative consequences in eye disease and carries a real risk to vision. For example, patients with glaucoma risk progression of visual loss even with a small number of missed doses, and patients with neovascular age-related degeneration (nAMD) who fail to attend a bi-monthly clinic appointment to receive an intravitreal anti-vascular endothelial growth factor (VEGF) drug injections may lose the initial vision gains in vision. Protracted regular treatment schedules represent a high burden not only for patients and families, but also healthcare professionals, systems, and ultimately society too. There has been a clear need for longer-acting therapies that reduce the frequency, and therefore the burden, of treatment interventions. Several longer-acting interventions for nAMD, diabetic macular oedema, retinal vein occlusion, uveitis and glaucoma have either been developed or are in late-phase development, some of which employ novel mechanisms of actions, and all of which of promise longer (≥3 month) treatment intervals. This review delivers an overview of anti-VEGF agents with longer durations of action, DARPins, bispecific anti-VEGF/Ang2 therapies, anti-PDGF and anti-integrin therapy, Rho-kinase inhibitors, the Port Delivery System, steroids, gene therapy for retina and uveitis, and for glaucoma, ROCK inhibitors, implants and plugs, and SLT laser and MIGS. The review also refers to the potential of artificial intelligence to tailor treatment efficacy with a resulting reduction in treatment burden.
在现实生活中, 患者的治疗依从性欠佳, 需要频繁进行治疗和评估回访。治疗不足通常会对眼部疾病产生负面影响, 并对视力造成威胁。例如, 青光眼患者即使遗漏少剂量药物使用, 也会有视力丧失的风险; 新生血管性年龄相关性退行性变 (nAMD) 的患者如果未能参加每两个月一次的复诊, 接受玻璃体内抗血管内皮生长因子 (VEGF) 药物注射, 可能会失去最初的视力增益。长期的定期治疗计划不仅对患者和家属, 而且对医疗专业人员、医疗系统乃至整个社会都是一个沉重的负担。
显然, 有必要采用长效疗法, 以减少干预的频率和负担。一些针对nAMD、糖尿病黄斑水肿、视网膜静脉阻塞、葡萄膜炎和青光眼的长效干预措施已经应用于临床或处于研究的后期阶段, 其中一些药物采用了新的作用机制, 所有这些干预措施都有望延长治疗间隔(≥3个月)。
本文对长效抗VEGF药物、DARPins、双特异性抗VEGF/Ang2治疗、抗PDGF和抗整合素治疗、Rho激酶抑制剂、Port传递系统、类固醇、视网膜和葡萄膜炎的基因治疗, 以及青光眼、ROCK抑制剂、眼植入物和栓子, 以及SLT激光和MIG进行了综述。该综述还提及了人工智能在调整治疗效果、减轻治疗负担方面的潜力。
The past two decades have seen significant advances in our ability to treat ocular disease, particularly those of the posterior segment. In particular, the advent of anti-vascular endothelial growth factor (VEGF) drugs has transformed the treatment of retinal diseases such as neovascular age-related macular degeneration (AMD), diabetic macular oedema (DMO), and macular oedema secondary to retinal vein occlusions (RVO). In glaucoma, the introduction of the prostaglandin analogue latanoprost, and more recently, the RhO-kinase (ROCK) inhibitor netarsudil and the nitric oxide (NO) latanoprostene bunod have resulted in significant therapeutic benefits for patients.
However, all of these therapies are associated with a relatively high treatment burden [
Glaucoma is also largely a disease of an ageing population, and although the treatment is primarily topical therapy, this still requires strict compliance. It was estimated in 2020 that glaucoma represents the cause of moderate or severe visual impairment in 4.1 million people and blindness in 3.6 million [
The reality is that patients have busy lives, have other commitments, and other health concerns as they age. They may forget an appointment or to take their eye drops, and with anti-VEGF therapy, may miss injections because of reluctance to be a burden to the relatives or carers who bring them to the appointment, have needle-phobia, or simply become weary of repeated visits to an eye clinic. One approach that should help address these issues is the introduction of longer-acting therapies. Longer-acting therapies—particularly those that require fewer clinic visits for treatment administration—will result in a lower burden for patients (reducing the number of clinic visits means less time spent on travel and hospital appointments, with less disruption to work); for families and carers (who accompany the patient), as well as for overstretched healthcare systems. Therapies with extended durations of action will lessen the risk of forgotten or missed doses. In addition, novel treatments (e.g. gene therapies for inherited retinal disorders), will result in even greater demand for the services of eye care professionals, further increasing the pressure on already stretched health resources. The introduction of longer-acting therapies is therefore welcome and timely.
For the purpose of this review article, we defined ‘long-acting’ therapies as those with a potential treatment effect of more than 12 weeks. We included glaucoma in this review, as longer durations of treatment effects would help resolve issues with patient compliance associated with topically administered anti-glaucoma drug regimens. Innovative drug delivery methods and routes are used to achieve the goal of longer duration of action in the eye (Fig. For retinal disorders intravitreal injections are employed to deliver various antibodies, extended release depot preparations and implants, as well as new biologics and some gene therapy. Subretinal injections (after vitrectomy) are used to deliver gene therapy, suprachoroidal injection route is employed to deliver steroids and has potential for use with other agents. Port delivery system anchored at pars plana is used as a reservoir of therapeutic agent that dissolves in vitreous over time. For glaucoma the options include extended release implants in the anterior chamber, MIGS devices and selective laser trabeculoplasty.
Pegaptanib sodium (MacuGen, Pfizer, New York, NY, USA) was the first anti-VEGF agent approved for ophthalmic use but was superseded by other agents. The next anti-VEGF agent to be approved, ranibizumab, has a posology for neovascular age-related degeneration (nAMD), DMO, PDR and RVO at one injection per month until maximum visual acuity is achieved (or there are no signs of disease activity) and thereafter, the decision when to treat with the next dose is determined by the treating physician based on disease activity, as assessed visual acuity or anatomical parameters [ Long-acting Anti-VEGF pharmacotherapies for nAMD, BRVO, CRVO and DMO. Aflibercept Human recombinant fusion protein; combines the second Ig domain of VEGFR-1 and third Ig binding domain of VEGFR-2 with the constant Fc portion of IgG1 Soluble decoy receptor with high affinity for binding to VEGF-A and PlGF nAMD, DMO, BRVO, CRVO, myopic CNV nAMD: Initially q4w for 3 doses, then q8w, then T&E BRVO/CRVO: q1m DMO: Initially q4w for 5 doses, then q4w for rest of first year, then T&E Brolucizumab Humanised, single-chain variable fragment (scFv) antibody Soluble decoy receptor with high affinity to neutralise all VEGF-A isoforms nAMD nAMD: Initially q4w for 3 doses, then q8w (if disease activity is present) or q12w (if disease activity is not present). Conbercept Human recombinant fusion protein; second Ig domain of VEGFR-1 and the third and fourth Ig domain of VEGFR-2 with the Fc portion of human IgG1. Soluble decoy receptor with high affinity for binding to VEGF-A and PlGF N/A Monthly for three doses, then q3m or T&E or PRN dosing for up to q12m Abicipar Designed ankyrin repeat protein (DARPin)-based therapy Binds all VEGF isoforms N/A q12w dosing regimens were evaluated; development discontinued. Faricimab Bispecific antibody: modified Fc portion of humanised IgG with one anti-Ang2 Fab and one anti-VEGF-A Fab Blocks VEGF-A and angiopoietin-2; modified Fc portion reduces both systemic absorption and potential for ocular inflammation N/A q4w, q8w, q12w and q16w dosing regimens and PDS under evaluation KSI-301 Bioconjugate: humanised anti-VEGF monoclonal antibody and phosphorylcholine-based polymer added to prolong duration of molecule in eye Blocks all VEGF isoforms N/A nAMD trials: q3m to q5m regimen evaluated. RGX-314 Gene therapy, encodes an anti-VEGF Fab AAV8 encoding anti-VEGF-A similar to Ranibizumab N/A Single dose (potentially) ADVM-022 Gene therapy: encodes aflibercept AAV encoding anti-VEGF-A similar to aflibercept nAMD Single dose (potentially)
Recently, two studies, ALTAIR [
Ziv-aflibercept (Zaltrap, Sanofi, Paris, France, indicated to treat colon cancer via systemic infusion) contains the same active molecule (aflibercept) but in a different buffer, and is supplied in 4 mL/100 mg and 8 mL/200 mg vials. Ziv-aflibercept can be prepared in a similar manner to bevacizumab for intravitreal injection, and its off-label use to treat nAMD, macular oedema secondary to RVO and DMO, is reviewed elsewhere [
In 2020, brolucizumab (Beovu, Novartis Pharma AG), another humanised monoclonal single-chain antibody fragment that targets VEGF-A, was approved for the treatment of nAMD, and is currently undergoing late-phase clinical investigation for other retinal diseases, including PDR (NCT04278417), DMO (NCT04058067), and RVOs (NCT03802630 and NCT03810313). In nAMD, brolucizumab is administered monthly for the first three doses, thereafter the dosing regimen is decided by the treating physician based on visual acuity/anatomical parameters, with the EMA-approved posology being ‘in patients without disease activity, treatment every 12 weeks (3 months) should be considered. In patients with disease activity, treatment every 8 weeks (2 months) should be considered.’ The Phase III brolucizumab HAWK and HARRIER studies [
Nevertheless, multiple brolucizumab dosing regimens are currently under investigation for diabetic retinopathy in Phase 3 trials. These include three 6-weekly loading injections, followed by 12 weekly maintenance doses for PDR (NCT04278417); and for DMO, five loading doses with ‘subsequent doses per protocol-specified maintenance schedule’ up to 12 weekly dosing (NCT03481660; NCT04079231, NCT03481634) and monthly dosing (NCT03917472). Similarly, the TALON study (NCT04005352) is currently evaluating brolucizumab in extended treatment interval (treat-and-extend fashion) compared to aflibercept in patients with nAMD.
Conbercept (Lumitin, Chengdu Kanghong Biotech Co., Ltd., Sichuan, China), like aflibercept, is a VEGF receptor 1 and 2 fusion protein, which has undergone or is currently undergoing Phase III clinical evaluations for indications including nAMD, (NCT03577899, NCT03630952) DMO (NCT02194634), uveitic macular oedema (NCT04296838), and macular oedema following RVO (NCT03108352), but is currently only approved for the treatment of nAMD in China and Mongolia. The Phase III PANDA-1 trial that compared 8- and 12 weekly conbercept doses with 8-weekly aflibercept doses in patients with nAMD failed to meet its primary endpoint at 1 year (NCT03577899), and it and the PANDA-2 trial (NCT03630952) have now closed. The Phase 3 PHOENIX study, performed in patients with choroidal neovascularisation secondary to AMD, employed a dosing regimen of three monthly doses, followed by quarterly (q3m) dosing for the rest of the 12-month study period [
Finally, another anti-VEGF agent, OPT-302 (Ophthea, South Yarra, Australia) which blocks the C and D isoforms of VEGF has completed a series of Phase I and II trials in wet AMD and DMO (NCT02543229, NCT03345082, NCT03397264). Phase III trials in nAMD (NCT04757610, NCT04757636) are currently underway, but only a 4-week dosing interval is currently being investigated.
It is worth noting that there are multiple anti-VEGF ‘biosimilars’ in development (Table Anti-VEGF biosimilars in developmenta. Company Compound name Registered clinical trials Phase Aflibercept biosimilars Amgen ABP 938 NCT04270747 III Alteogen ALT-L9 NCT04058535 I Coherus Biosciences CHS-2020 – Formycon FYB203 NCT04522167 III Momenta/Mylan MYL-1701P NCT03610646, NCT04674800 III (both) Samsung Bioepis SB15 NCT04450329 III Ranibizumab biosimilars Coherus Biosciences/Bioeq FYB201 NCT02611778 III Lupin LUBT010 NCT04690556 III Samsung Bioepis SB11 NCT03150589 III Xbrane Xlucane NCT03805100 III Bevacizumab biosimilars Outlook therapeutics ONS-5010 NCT03834753 III Pfizer Bevacizumab-bvzr/Zirabev Currently only oncology indications Amgen/Allergan Bevacizumab-awwb/MVASI Currently only oncology indications aDuration of efficacy to be determined.
Abicipar pegol (Allergan/Abbvie, Dublin, Ireland), is a designed ankyrin repeat protein (DARPin)-based therapy that binds all VEGF isoforms [
The bispecific antibody faricimab (Roche, Basel, Switzerland) targets not only VEGF-A, but also angiopoietin (Ang)-2. The Ang-tyrosine kinase endothelial receptor (Ang-Tie) pathway is responsible for regulating vascular homoeostasis through Tie-2 receptor, the breakdown of which leads to vascular permeability, inflammation, and angiogenesis. In a healthy state, Ang1 binds the Tie-2 receptor, the pathway becomes activated, and this maintains vascular health. Under the pathological conditions found in AMD or DMO, however, Ang2 acts as a competitive antagonist of Ang1, and inhibits the activation of the Tie-2 receptor, destabilising the retinal vasculature and making it more susceptible to the effects of pro-inflammatory cytokines and VEGF [
Faricimab has been evaluated in two Phase II trials (STAIRWAY [
Another anti-VEGF/Ang2 bispecific antibody in development is BI 836880 (Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany), which is currently undergoing a Phase I dose-ranging clinical trial (NCT03861234) for the treatment of nAMD. The future might see more biphasic antibodies that target disease-causing or disease-exacerbating cytokines, with the development of a platform to create dual targeting fragment antigen-binding region (DutaFab) molecules. This approach has already been used to create DutaFabs that bind both VEGF-A and platelet-derived growth factor (PDGF)-BB with high affinity [
Another method of producing longer-acting therapies is to bind therapeutic molecules covalently to lipid or polymer carrier molecules in a process that results in ‘bioconjugate’ drugs [
Tyrosine kinases are a family of enzymes that phosphorylate and activate numerous receptors. Tyrosine kinase inhibitor (TKI) drugs can therefore inactivate certain receptors (e.g. VEGF receptors) that are responsible for driving the pathologies involved in many retinal diseases. One such TKI is sunitinib maleate, which has activity against both VEGF-A and PDGF and is being developed as GB-102 (GrayBug Vision, Inc., Redwood City, CA, USA) for use as an nAMD and DMO therapy. The drug has an extended-release formulation; sunitinib is encapsulated within bioerodable and slowly degradable polymer nanoparticles designed to release clinically effective sunitinib concentrations over a 6-month period, meaning the drug can be administered by intravitreal injection every 6 months [
OTX-TKI (axitinib intravitreal implant, Ocular Therapeutix Inc., Bedford, MA, USA) is a dried polyethylene glycol-based hydrogel fibre-containing dispersed microcrystals of the small molecule tyrosine kinase inhibitor axitinib, which is designed to deliver therapeutic concentrations of the drug over the course of a year in order to enable 12-monthly dosing in patients with nAMD. Axitinib inhibits VEGF1-3, c-KIT and the PDGF receptor. Preliminary findings from a Phase I trial of OTX-TKI presented at the 2020 Retina Society meeting suggested that the durability of therapy ‘was up to 4.5 months’ and that the ‘implant biodegraded in all subjects in cohort 1 by 9–10.5 months’ [
Several of the drugs mentioned above target PDGF, and this action is important, as the response to anti-VEGF therapy can wear off over time. This is because the new blood vessels start to become covered with pericytes that protect the new vessels and nourish them with several cell survival cytokines, including VEGF. PDGF is one molecule that recruits the pericytes to the vessels, and thus blocking PDGF could improve outcomes by enhancing the effect of anti-VEGF. Anti-PDGF therapy has been tried in combination with ranibizumab in the past as a naïve nAMD therapy. A 32-mer pegylated DNA aptamer that binds PDGF-BB and PDGF-AB homodimers and heterodimers agent pegpleranib (Fovista, Ophthotech, New York, NY, USA) was evaluated in a pair of Phase III trials (NCT01944839 and NCT01940900) but ultimately failed to show any superiority over ranibizumab alone [
GEM103 (Gemini Therapeutics, Cambridge, MA, USA) is a recombinant human complement factor H (CFH) molecule that is currently under Phase II clinical trial investigation for both neovascular (NCT04684394) and dry AMD (NCT04643886) using monthly and every other month dosing regimens. CFH plays a central role in regulating the immune system’s alternative pathway in terms of protecting host cells during an inflammatory/immune response. Over-activation of the innate immune system is thought to be one of the factors that can lead to the pathology in dry AMD. Lampalizumab (Roche) was a humanised Fab that binds to complement factor D, and 4-weekly and 6-weekly dosing regimens were under investigation in Phase III clinical trials for the treatment of geographic atrophy (GA; NCT02745119, NCT02247531, and NCT02247479). However, the trials were terminated due to failure of the drug to meet the trial’s primary endpoints.
Pegcetacoplan (Apellis Pharma, Waltham, MA, USA) a synthetic peptide-polyethylene glycol polymer conjugate that binds and inhibits complement proteins C3 and C3b. It is currently under Phase III clinical investigation for the treatment of GA secondary to AMD (NCT04770545, NCT03525600) using 4-weekly and 8-weeky dosing regimens. Twenty-four-month data from an earlier Phase 1b APL2-103 (NCT03777332) in 13 patients (where the eye with the worst BCVA received the study drug) revealed that GA lesions pegcetacoplan-treated eye had a growth rate that was 46% lower than the untreated fellow eye (
Risuteganib, (Luminate, ALG-1001, Allegro Ophthalmics, San Juan Capistrano, CA, USA), targets integrins αvβ3, αvβ5, and α5β1, all of which are receptors involved with angiogenesis. Risuteganib has completed four Phase 3 trials: one for dry AMD (NCT03626636); one for nAMD (NCT01749891), one for DMO (NCT02348918) trials; and one for the treatment of vitreomacular adhesion (NCT02153476). Results have been published for the DMO trial, DEL MAR, in which four doses of risuteganib were compared with bevacizumab [
Rho-kinase inhibition has become an attractive therapeutic target in ophthalmology. The upregulation of the Rho-kinase (ROCK) pathway has been shown, in diabetes, to promote angiogenesis and vasculopathy, thus inhibiting ROCK signalling could have beneficial effects in treating neovascular diseases of the retina, either alone, or in combination with other therapies. It also has a role in glaucoma therapy: netarsudil (Aerie Pharmaceuticals, Inc., Irvine, CA, USA) is a ROCK inhibitor marketed in Europe as Rhokiinsa, (and Rhopressa in North America) that is available as a 0.02% ophthalmic solution that is used to lower the IOP in ocular hypertension or open-angle glaucoma [
It has been observed that synonymous single nucleotide polymorphisms (SNPs) in the gene,
A different method of delivering effective drug doses over an extended period is to use a slow-releasing intraocular device such as the PDS device (Roche). The PDS is a permanent, refillable implant that is placed in the eye through a small incision in the sclera and pars plana. The PDS has a self-sealing septum in the centre of the implant flange which allows clinicians to refill the implant reservoir. The drug present in the PDS passively diffuses along a concentration gradient from the implant reservoir to the vitreous cavity, via a porous metal release control element. This approach is currently under investigation with not only ranibizumab [
Corticosteroids are a powerful tool for controlling ocular inflammation and act by reducing the expression of a wide range of pro-inflammatory and pro-angiogenic cytokines (including VEGF), and have successfully been used in treating DMO and uveitis. Their use in DMO is typically second-line to anti-VEGF therapy, as intravitreal steroid application can be associated with increases in IOP in some patients and accelerated cataract development in most patients who still have their natural crystalline lens [
An extended-release intravitreally implanted formulation of dexamethasone (Ozurdex, Allergan/ Abbvie, Irvine, CA, USA) was approved by the European Medicines Agency for the treatment of DMO in pseudophakes or patients who are considered insufficiently responsive to, or unsuitable for non-corticosteroid therapy, macular oedema following either branch or central RVO, or inflammation of the posterior segment of the eye presenting as non-infectious uveitis [
A second steroid-releasing intravitreal implant, in this case, one that contains fluocinolone acetonide (Iluvien, Alimera Sciences, Alpharetta, GA, USA) is also available, and is reported to release fluocinolone acetonide for a period of up to 36 months. Its approved indications in Europe are ‘the treatment of vision impairment associated with chronic DMO considered insufficiently responsive to available therapies’ and the ‘prevention of relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye.’ [
Suprachoroidal administration of triamcinolone acetonide is associated with the drug diffusing through the suprachoroidal space, which concentrates the drug mostly in the sclera, choroid and retina, and minimises the amount of drug that accumulates in the anterior chamber, lens and vitreous [
A propriety, preservative-free formulation of triamcinolone acetonide for suprachoroidal administration, CLS-TA (XIPERE, Clearside Biomedical, Alpharetta, GA, USA), has undergone late-phase clinical evaluation for the treatment of DMO, and macular oedema secondary to non-infectious uveitis and RVO.
A Phase III trial of CLS-TA comparing CLS-TA in combination with aflibercept with aflibercept monotherapy was performed in 460 patients with RVO and macular oedema (SAPPHIRE, NCT02980874) was terminated after 8 weeks as no additional benefit of the combination therapy was seen at that point [
A 12 weekly dosing of CLS-TA (or sham treatment, randomised in a 3:2 ratio) was evaluated in 160 patients with macular oedema secondary to non-infectious uveitis for a 24-week period in the Phase III PEACHTREE trial (NCT02595398). Suprachoroidally administered CLS-TA was significantly better than sham treatment at achieving ≥15 letter BCVA gains from baseline (47% vs. 16%,
Many patients with non-infectious uveitis affecting the posterior segment will receive systemic corticosteroid therapy, particularly in the acute setting. This can be very effective, but typically multiple systemic side effects accumulate as the duration of therapy lengthens. Local steroid treatment as described above can become an option for some patients, but immunosuppressant drugs are also an option that can help reduce long-term corticosteroid dependence. These agents include antimetabolites, T-cell inhibitors, alkylating agents, and biologics targeting B- and T-cell activation, interferon therapy, and the use of drugs that interfere with the action of interleukin-6. Many of these therapies require frequent dosing and so are outside the scope of this review, but some require infrequent administration, for example, rituximab (MabThera, Rituxan, Roche) and alemtuzumab (Campath/Lemtrada, Sanofi, Paris, France).
Rituximab is a chimeric monoclonal antibody which blocks CD20, a cell surface marker found on B-lymphocytes [
Alemtuzumab is a monoclonal antibody that binds CD52 (a protein that is expressed on mature lymphocytes) and targets these lymphocytes for destruction. Its principal indications are for the treatment of B-cell chronic lymphocytic leukaemia, and as a third-line treatment for relapsing-remitting multiple sclerosis [
However, these therapies are not licensed in the United Kingdom, nor are they funded for use in the National Health Service, and it is important to note that in 2018, alemtuzumab was subject to a FDA Safety Announcement, that noted ‘rare but serious’ instances of stroke and blood vessel wall tears in patients with multiple sclerosis, some of which were fatal, and most of which occur within 1 day of treatment initiation [
Gene therapy holds considerable and transformative potential for the development of therapies that could significantly reduce treatment burden. For example, gene therapy can potentially be used to generate long-term therapeutic biological molecule production in the eye. The complexity of retinal disease pathogenesis can make the therapy more challenging to be administered, and for treatment to be successful, several factors need to be addressed including the definition of the therapeutic window, safe and efficient vectors, identification of a suitable target gene, and a reliable means of regulating transgene expression, as well as patient selection and outcome measurement.
RGX-314 is a one-time, subretinal gene therapy that uses an adenoviral vector to introduce a monoclonal antibody fragment into the eye. The antibody neutralises VEGF to reduce or eliminate abnormal blood vessel growth, has been shown to reduce anti-VEGF treatment burden, and appears to be well-tolerated as a subretinal injection [
GT005 is another potential AAV-2 based gene therapy, this time for dry AMD. It is delivered as a one-time treatment into the suprachoroidal space in patients with GA secondary to dry AMD. GT005 upregulates complement factor I (CFI), which counters inflammation caused by an overactive complement system. The HORIZON trial (currently recruiting) will randomise patients to receive either GT005 (medium or high dose) or no treatment, thus evaluating the efficacy of a potential single-dose treatment for dry AMD [
The combination of the plethora of treatment options under development, and the fact that many of them have novel (and even multiple) mechanisms of action can make choosing the optimal treatment option for patients challenging. There is much interest in the potential application of artificial intelligence (AI) in terms of automated diagnostic screening. Further to the benefits that this will bring, an additional key step in optimising treatment in these different conditions will be to integrate the prediction of the best personalised treatment plans by analysing response to agents used, evaluating dosing regimens in big datasets. This will enable us to achieve the best possible outcomes with the lowest patient and healthcare system burden [
Glaucoma is a common, currently irreversible cause of vision loss, characterised by optic nerve head excavation and loss of visual field. The mainstay of glaucoma therapy remains medical treatment in the form of eye drops, although adherence and persistence (i.e. continued correct compliance) have been found to be suboptimal, even when compared with other chronic medical conditions. As a result, longer-acting therapies for glaucoma are of significant interest (Table Non-anti-VEGF long-acting retina and glaucoma pharmacotherapies. Dexamethasone (Ozurdex) Glucocorticoid Agonist of the glucocorticoid receptor DMO, RVO, uveitis Single-use biodegradable implant lasting 3–4 months Fluocinolone acetonide (Iluvien) Glucocorticoid Agonist of the glucocorticoid receptor DMO, uveitis Single-use biodegradable implant lasting ≤36 months Triamcinolone acetonide (CLS-TA; Xipere) Glucocorticoid Agonist of the glucocorticoid receptor N/A 12 weekly dosing for the treatment of noninfectious uveitis. Risuteganib (Luminate) Anti-integrin peptide Targets integrins αvβ3, αvβ5, and α5β1 nAMD, DMO nAMD: Initially q4w for three doses, then at week 20 as needed GB-102 Sunitinib maleate polymer nanoparticle extended-release formulation Tyrosine kinase inhibitor N/A nAMD: 6-monthly dosing OTX-TKI Axitinib intravitreal implant, suprachoroidally administered Tyrosine kinase inhibitor N/A nAMD: 12-monthly dosing PAN-90806 Topically administered tyrosine kinase inhibitor suspension that reaches the retina via the trans-scleral vascular route. Tyrosine kinase inhibitor N/A Daily topical drops (which may extend anti-VEGF intravitreal injection intervals to ≥3 months). GT005 Recombinant non‐replicating AAV vector encoding human complement factor I (CFI) Addresses depletion in CFI levels causing complement dysfunction N/A nAMD: single-dose under evaluation Bimatoprost Implant (Durysta) Analogue of prostaglandin F2α Ester prodrug; increases outflow of aqueous fluid from the eye; does not act on any known prostaglandin or prostamide receptor; believed to work via trabecular meshwork and uveoscleral pathways Glaucoma Single-use biodegradable implant lasting 3–4 months under evaluationa Travoprost XR Analogue of prostaglandin F2α Ester prodrug; increases outflow of aqueous fluid from the eye; does not act on any known prostaglandin or prostamide receptor; believed to work via trabecular meshwork and uveoscleral pathways Glaucoma Single-use biodegradable implant lasting 3–4 months under evaluation; single-use punctal plug lasting 90 days under evaluation aFDA-approved regimen; not yet approved by the European Medicines Agency.
One approach has been the development of biodegradable implants, such as Bimatoprost SR (Durysta; Allergan, Dublin, Ireland) [
Travoprost has also been utilised in drug-eluting intracameral implants. Travoprost XR (Aerie Pharmaceuticals, USA) is a biodegradable implant that uses novel sterile nanoparticle replication engineering technology to provide continuous release of travoprost. A 12-month study of 15 patients with POAG demonstrated noninferiority to twice-daily timolol maleate 0.5% at 11-month follow-up, with a mean IOP reduction of 6.7 ± 3.7 mmHg [
A travoprost eluting punctal plug, OTX-TP (Ocular Therapeutix, USA) is a hydrogel rod that swells to fit the canalicular space and continuously releases travoprost over a 90-day period. A placebo-controlled multicentre Phase III trial found OTX-TP treated eyes had statistically significant IOP reduction in eight of nine time points over 20-weeks of follow-up, with only transient and minor adverse effects, most commonly dacyrocanaliculitis [
Longer-term IOP-lowering can also be achieved by laser treatment, most commonly as selective laser trabeculoplasty (SLT). First approved by the FDA in 2001, today SLT is widely used, more recently also as a first-line treatment option following the publication of the LiGHT study in 2019 [
Finally, over the past decade, a series of novel surgical approaches to glaucoma have aimed to provide long-acting alternatives to topical medications for glaucoma, called minimally invasive glaucoma surgeries (MIGS). MIGS were intended to bridge the gap between medical or laser therapy and more invasive filtering surgery in mild-to-moderate glaucoma. They are meant to have a favourable safety profile ensuring prompt postoperative recovery and a reliable (but more modest) IOP reduction than that of traditional filtering surgery. Given that most of these devices have been introduced within the last 5 years, there is a lack of long-term data regarding their effectiveness, with most published evidence being limited to nonrandomised studies and uncontrolled retrospective comparisons, with few high-quality randomised controlled trials.
Longer-acting glaucoma treatments have the potential to address well-known adherence and persistence issues, reduce burden and cost on healthcare providers and remove the need for daily dosing for patients with glaucoma. More widespread usage of SLT appears likely going forward, given its low adverse effect profile. Intracameral drug-eluting systems hold promise, although concerns over damage to the corneal endothelium persist.
Many new long-acting treatment options are currently in the pipeline, and although not all molecules will make it to the market, it is likely that in the next 5 years a number will do so, and will offer the promise of 12 weekly or longer treatment intervals, translating to around four treatments per year for patients. This reduced treatment burden is clearly going to benefit patients, healthcare providers and healthcare systems—and ultimately society too. Gene therapy holds a real potential to provide long-term benefits for patients, although there are several technical and cost hurdles that need to be overcome before this approach becomes widely available. We also need to address the fact that fewer clinic visits for treatment can also mean fewer opportunities for monitoring disease progress—particularly in fellow eyes—and also for recognising any ocular side effects that might be associated with these new agents. This is an issue that may be dealt with by creating imaging hubs or self-monitoring devices to provide regular assessments. It is anticipated that this would be supported by AI implementation in reading centres to assess the risk of disease activity or progression and treatment would be tailored accordingly. The advent of longer-acting therapies brings new treatment options to the horizon, many of which employ novel mechanisms of action. Finally, in addition to improving patients’ regimen compliance, the personalisation of these long-acting treatments to patients’ own specific disease biomarkers should allow better vision outcomes to be achieved, all with a lower treatment burden for all.
This document, and its development, were independent of the funder. None of the authors have received any funding for contributing to the development of this paper. The Group retained final control of all the content and editorial decisions. Editorial assistance for this review was supported by Allergan via an independent and unrestricted research grant. Allergan had the opportunity to review the final version of the manuscript to address any factual inaccuracies or request the redaction of information deemed to be proprietary or confidential and ensure that study support was disclosed.
Editorial assistance was provided to the authors by Dr Mark Hillen, BSc, Ph.D., through an unrestricted grant, funded by Allergan International plc, Dublin, Ireland. Publication costs were also provided through an unrestricted education grant from Allergan International at the request of the lead author. All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship and authors retained full control over the paper.
FG: Institutional research grants from: Allergan, Bayer, Boehringer Ingelheim, Chengdu Pharma, Clearside, Novartis, Roche. Travel Grants from Allergan, Bayer, Novartis. Lecture fees from: Allergan, Alimera, Heidelberg, Bayer, Novartis, Roche, Ad board/Consultancy for Allergan, Alimera, Apellis, Bayer, Boehringer Ingelheim, Novartis, Roche. Editorial board member for