Retinal diseases such as neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO) can lead to severe central vision loss. Treatments with vascular endothelial growth factor antagonists (anti-VEGF), given as intravitreal injections, are currently considered the standard of care, as they can suppress disease progression through the inhibition of angiogenic pathways. However, given that they do not cure the disease, treatments are oftentimes ongoing, which consist of frequent intravitreal injections over several years, often at monthly or bimonthly intervals. This can result in a significant socioeconomic burden on the patient, their families, physicians, and the health care system.1–3 Current impressive clinical trial results are not replicated in routine clinical practice, which has been demonstrated in several real-world studies.4–6 Alternative drug delivery methods and differing routes of administration have been explored, aiming to provide minimally invasive delivery and/or provide sustained exposure to therapeutics over longer periods of time. These longer-lasting or continuous treatment options are more likely to translate to long-term visual benefits in routine clinical practice.
The route of administration and therapeutic formulation are 2 major considerations in assessing novel drug delivery systems.7 In terms of delivery routes, the posterior segment of the eye can be reached via multiple routes, including topical, systemic, and periocularly via the suprachoroidal space (SCS) and intraocular injections.8 Regarding novel therapeutic formulations, advances in biomaterials and nanotechnology enable the ocular delivery of drugs via sustained-release implants, depots using prodrugs, microparticles, and hydrogels, surgically implanted reservoirs, and gene therapy. Current clinical trials assess whether the delivery of ocular pharmacologic agents via these novel delivery methods supports more durable retinal therapy while maintaining the efficacy and safety of currently available intravitreal therapies. In this review, we present recent advances in novel posterior segment drug delivery, focusing on exudative macular diseases (Fig. 1).
BARRIERS TO ENTRY FOR POSTERIOR SEGMENT DRUGS
The anatomy of the eye presents a major challenge in delivering therapeutic agents, particularly for retinal diseases. The inner segment of the blood-retinal barrier (BRB) consists of tight junctions between the endothelial cells of the retinal capillaries while the outer component consists of junctional complexes of the retinal pigmented epithelium (RPE) and the pigment epithelial cells of the pars plana. In addition, the barrier is selectively permeable to more lipophilic molecules.9 Although the BRB prevents pathogens from reaching ocular tissues, it may also limit systemic pharmacologic agents from reaching potential ocular tissue targets. Intravitreal injections, given through the pars plana, bypass the BRB, delivering medications directly within the vitreous space. However, there may still be barriers at the vitreoretinal interface or related to drug clearance that needs to be considered.10
Efforts to improve the durability of intravitreal medications have been made to reduce burdens associated with injection frequency. Dose escalation of 2 mg ranibizumab injections compared with standard 0.5 mg in HARBOR and SAVE trials identified longer VEGF suppression in patients treated with higher doses of ranibizumab but no significant visual benefit.11,12 There are also 2 ongoing phase 3 trials, PHOTON (DME) and PULSAR (AMD), to investigate the efficacy, safety, and durability of aflibercept 8 versus 2 mg.13
Recently, brolucizumab became the first anti-VEGF drug approved for 12-week dosing.14 Brolucizumab is a small-size (26 kDa) single-chain antibody fragment without a fragment crystallizable (Fc) portion, which is responsible for the increased migration of molecules through the BRB.15 It has a high affinity to VEGF-A isoforms, thereby preventing VEGF-A from binding to its VEGF receptor-1 (VEGFR-1) and receptor-2 (VEGFR-2), and its small size may be responsible for greater tissue penetration and more durable result.16 However, the greater risk of intraocular inflammation and occlusive vasculitis, which was seen soon after the drug was approved for usage by the US Food and Drug Administration (FDA), needs to be considered.17
In contrast, larger molecules such as conjugate-modified drug delivery are known to potentially enhance intraocular stability and prolong intravitreal half-life.18 Recently, Kodiak Sciences developed KSI-301 (950 kDa), an anti-VEGF antibody biopolymer conjugate. After demonstrating its safety, efficacy, and durability in its phase 1a/1b studies in treatment-naive nAMD, DME, and RVO patients,19,20 phase 2/3 trials comparing 5 mg of KSI-301 to aflibercept 2 mg demonstrated varied results. DAZZLE study (NCT04049266) aimed at evaluating the safety, efficacy, durability, and pharmacokinetics of KSI-301 and aflibercept in treatment-naive patients with nAMD, randomizing patients into 2 arms.21 The KSI-301 (5 mg) arm was administered by intravitreal injection at 12-, 16-, and 20-week intervals as specified in the study protocol, while the aflibercept (2 mg) arm was administered into the study eye every 4 weekly for 3 months, followed by every 8 weeks. This study was terminated early as it failed to meet the primary endpoint of mean change in best-corrected visual acuity (BCVA) at 1 year; the aflibercept arm had higher BCVA gains of average of 7 letters compared with 1 letter for the KSI-301 arm.22 Subsequently, phase 3 of DAYLIGHT study (NCT04964089) was designed with monthly dosing of 5 mg KSI-301 in patients with nAMD.23 KSI-301 is the subject of other ongoing phase 3 trials, including BEACON (NCT04592419) of bimonthly treatment in RVO and GLEAM and GLIMMER studies (NCT04611152, NCT04603937) of every 8–24 weekly treatments.24–26 Overall, KSI-301 clinical trials demonstrated the potential value of the anti-VEGF biopolymer conjugate platform in retinal diseases.
Faricimab is the first bispecific antibody that inhibits VEGF-A and angiopoitin-2 (Ang-2) inhibitors. Ang-2 levels are elevated in patients with AMD, DME, and RVO, and blocking Ang-2 reduces inflammation and leakage.27 Similar to brolucizumab, it has a modified Fc domain to reduce systemic absorption. LUCERNE (NCT03823300) and TENAYA (NCT03823287) were multicenter phase 3 trials for nAMD, demonstrating the safety, efficacy, and durability up to 16 weeks for intravitreal faricimab.28 Similarly, YOSEMITE and RHINE were 2 phase 3 trials that evaluated the efficacy and durability of faricimab compared with aflibercept in patients with DME.29 Noninferiority for vision gains and anatomic improvements with faricimab were reported with adjustable dosing up to every 16 weeks. Currently, BALATAN and COMINO are phase 3 clinical trials evaluating faricimab for RVO. Faricimab was approved for clinical usage in the setting of AMD and DME in the United States in early 2022, and patterns of usage are still being identified.
INTRAVITREAL DELIVERY SYSTEM
Sustained-release Intravitreal Implants
Ocular implants eliminate the need for repetitive treatments by administering drug for a prolonged period of time. Currently, sustained-release intravitreal implants, Ozurdex and Iluvien are approved by the FDA for treatment of DME and macular edema secondary to RVO.
Iluvien is a fluocinolone acetate intravitreal implant using Durasert technology, designed for the treatment of DME. Durasert (EyePoint Pharmaceuticals) is a solid polymer implant with a drug core with one or more surrounding polymer layers that can release small molecules for predetermined periods ranging from days up to 3 years.30 Iluvien is a small cylindrical (3.5 ×0.37 mm) polyimide tube that is injectable through a 25-gauge inserter. It releases a low dose of fluocinolone acetonide (0.23–0.45 μg/d) for 18–36 months. It is a nonbiodegradable implant. Therefore, patients requiring repeat injections may end up with multiple devices within the vitreous cavity.31
Ozurdex is a dexamethasone intravitreal implant and has FDA approval for the treatment of macular edema secondary to RVO and chronic pseudophakic DME. The implant contains 0.7 mg dexamethasone in a biodegradable, solid poly lactic-co-glycolic acid (PLGA) drug delivery system and is preloaded into a single-use, specially designed 22-gauge applicator to facilitate injection of the rod-shaped implant directly into the vitreous cavity.32 Although it has a relatively short duration of action between 1 and 3 months, the therapeutic effect oftentimes lasts longer, as seen in a phase 2 clinical study where therapeutic effects persisted at 180 days in some eyes.25
RIPPLE-1 (NCT04576689) is a phase 2 and multicenter study currently recruiting patients with DME and macular edema due to RVO to evaluate the safety and efficacy of the prodrug intravitreal implant, IBE-814.33 Unlike Ozurdex and Iluvien, IBE-814 does not contain polymeric carriers but it consists entirely of prodrug. The implant contains 10% of the dexamethasone dose (70 μg) used in Ozurdex and the absence of a polymeric matrix results in a much smaller implant. This enables injection through a 30-gauge applicator. Furthermore, lower drug load may contribute to less drug-related adverse events such as increased intraocular pressure and cataracts. The preclinical studies demonstrated zero-order dexamethasone delivery out to 6 months.33,34 RIPPLE-1 is currently recruiting patients to evaluate the safety and efficacy of 2 administrations of prodrug implants containing 70 or 140 μg dexamethasone. Primary outcome measures will include BCVA, central subfield thickness (CST), and drug-related adverse events at 6 months.
Brimonidine drug delivery system (BRIMO DDS), an intravitreal implant containing brimonidine in a biodegradable polymer matrix, has been developed for the potential treatment of geographic atrophy (GA) secondary to AMD.35 Brimonidine, an alpha2-adrenergic agonist, has demonstrated cytoprotective and neuroprotective activity in cultured cells and a variety of animal models of retinal and optic nerve disease.36–38 BRIMO DDS containing a dose of 132 or 264 μg brimonidine can be administered via intravitreal injection using a 22-gauge needle. Brimonidine diffuses out of the implant into the vitreous humor over a period of several months as the polymer matrix degrades.29 BRIMO DDS phase 2 trial (NCT00658619) established the safety and efficacy of the implant, and the implant was well tolerated.39 The GA lesion growth at 12 months was reduced in patients with baseline GA lesion ≥6 mm2. A larger phase 2b study, BEACON (NCT02087085), evaluated a more potent formulation of the implant, BRIMO DDS Gen 2 400 μg, administered at 3-month intervals.40 This trial was terminated at interim analysis as the rate of GA lesion progression was significantly reduced (1.6 mm2/y) in the enrolled population.41 On the basis of the result, phase 3 trials (IMAGINE and ENVISION) are in development.
Encapsulated Cell Technology
Encapsulated cell technology (ECT) utilizes genetically modified cell lines to secrete therapeutic agents locally. Genetically modified human RPE cells are encapsulated in a semipermeable membrane capsule that allows exchanges of nutrients, waste, and therapeutics while preventing the efflux or influx of cells.42,43 This prevents host cell rejection, avoiding the need for suppression of the host immune system.44
Neurotech Pharmaceuticals Inc. (Cumberland, RI) developed intraocular ECT implant to deliver ciliary neurotrophic factor (CNTF), known as NT-501 (Renexus), for the potential treatment of retinitis pigmentosa (RP) and dry AMD. CNTF is a growth factor protein that demonstrated neuroprotective effect on photoreceptors in a broad range of animal models with retinal degeneration.45–47 However, a bolus injection of CNTF into intravitreal cavity is not ideal given its potent cytokine nature and extremely short intraocular half-life (1–3 minutes).48,49 To bypass these limitations, NT-501, an implantable polymeric capsule device, was developed to facilitate controlled and sustain delivery of CNTF directly to the neurosensory retina.50 Genetically modified human RPE cells secrete recombinant human CNTF and are packaged in a hollow tube capsule consisting of a semipermeable membrane surrounding a scaffold of 6 strands of polyethylene terephthalate yarn. Two ends of the polymer section are sealed, and a titanium loop is placed on the anchoring end, which is implanted at the pars plana and anchored to the sclera. Despite its invasive implantation and surgical removal procedure, clinical trials have not reported any serious adverse events.43
Early clinical trials demonstrated the safety of the implant and stable production of CNTF over a 2-year period.43 Although the original phase 2 trials did not demonstrate therapeutic benefit in RP or dry AMD, the implant demonstrated reduced progression of retinal degeneration in patients with macula telangiectasia (MacTel) type 2.51–53 In addition, reading speed was stabilized in patients receiving NT-501. Phase 3 trials investigating MacTel type 2 are currently ongoing (NCT03319849 and NCT03316300).54 The primary outcome will be the rate of change in ellipsoid zone loss at 24 months.
Nanoparticles (10 nm to 1 µm) and microparticle (1–1000 µm) systems are produced as capsules or spheres that contain drugs that are either encapsulated or dispersed within a polymer matrix.55 Nanospheres are solid monolithic spheres composed of a dense solid polymeric network, and nanocapsules are reservoirs consisting of a central core surrounded by a polymeric membrane in which drug molecules may be dissolved in an oily core or absorbed to the surface interface.54 Nanoparticles have a high ratio of inner and outer surface area to volume, hence ideal for carrying various drugs as well as attaching to drug targets. It is possible to improve the solubility, target the retina, enhance cellular uptake of the drugs, improve the drug transport through biological barriers, and increase the residence time.56
A variety of nanostructures such as nanoparticle size, shape, material, and surface properties need to be considered for the drug formulation for retinal diseases. When delivered intravitreally, particles sized 200 nm were evenly distributed in the vitreous cavity and the inner limiting membrane while larger particles (2 µm) were found to remain in the vitreous cavity and smaller particles (50 nm) were still detected in the retina after 2 months postinjection.57 Regardless of the particle size, nanoparticles with surface charge are unable to effectively diffuse through vitreous humor, yet charged particles have been shown to diffuse effectively to the retina when dispersed in the appropriate polymer material.58 Positively charged polyethyleneimine nanoparticles cannot diffuse through the vitreous humor when injected intravitreally.59 However, nanoparticles based on glycosylated chitosan (200–500 nm) have their positive charge marked by the glycol groups and can reach the retina when injected intravitreally.57 Synthetic, biodegradable polymers are commonly used as they are biocompatible and hydrolytically degradable.55 The particles are versatile as it can encapsulate both hydrophilic and hydrophobic molecules, and its polymer and other compositions can be modified to meet specific drugs and applications.60 However, major challenges for particle systems are low protein encapsulation efficiency (usually <30% for nanoparticles and <60% for microparticles), high initial bursts (20%–50% of encapsulated protein in first 24 hours), incomplete release of the entrapped proteins, and potential loss of protein drug bioactivity during the release process.61–63
GrayBug Vision Inc. (Redwood City, CA) has developed GB-102, an injectable form of sunitinib maleate, a tyrosine kinase inhibitor (TKI). Sunitinib maleate is multitargeted TKI with activity against pan-VEGF and platelet-derived growth factors pathways, resulting in potent antiangiogenesis. Once injected, GB-102 forms a depot in the inferior vitreous cavity, which gradually biodegrades over time and its durability is demonstrated to be lasting for up to 6 months. ADAGIO (NCT03249740) was a phase 1/2a, single-dose, multicenter study on GB-102 in nAMD patients. Each of the 4 treatment arms received a single dose of either 0.25, 0.5, 1, or 2 mg of GB-102. The safety and tolerability were successfully met, and BCVA and CST were improved in all treatment arms. However, the 2 mg cohort had microparticle dispersion to the anterior chamber, resulting in a decrease in visual acuity. A new formula was developed to minimize the microparticle burst and incomplete aggregation. ALTISSIMO (NCT03953079) is a larger phase 2b, randomized, multicenter study on GB-102 for choroidal neovascularization (CNV) lesions in previously treated nAMD patients. Three cohorts of patients were each given either 1 mg or 2 mg of GB-102 or 2 mg aflibercept. The GB-102 group received initial doses 6 monthly while the aflibercept group received the doses every 2 months. At 12 months, BCVA was reduced in patients who received GB-102 while BCVA improvement was observed in the aflibercept group.64 In this phase 2a trial, GB-102 failed to demonstrate the safety, tolerability, and efficacy in patients with DME and RVO (NCT04085341). Overall, the majority of the study participants experienced adverse events, including macular edema and deterioration in both BCVA and CST. Given the extensive types of nanotechnology used in drug delivery, relevant reviews of nanoparticles should be reviewed.65,66
Hydrogel Delivery Systems
Although injectable polymeric nanoparticles and microparticles provide controllable and sustained drug release, one of the challenges is to localize them to the injection site or desired location in the eye. It has been shown that normal eyes can clear microparticles within 50 days and vitrectomized eyes can clear microparticles within 14 days.67 To limit particle movement in the eye and to maintain a longer treatment effect, injectable hydrogels can be good candidates as a secondary carrier for nanoparticles and microparticles to provide localized and extended drug release after injection.68
Hydrogels are 3-dimensional polymer networks that can encapsulate relatively large concentrations of drugs. For intraocular drug delivery, hydrogels can be administered in a liquid state via intravitreal injection and are subsequently transformed in situ into a solid-like gel state through crosslinking by either temperature, light, or pH. Hydrogels can also be injected in a dehydrated fiber form, which hydrolyzes over time. Hydrolysis of the hydrogel complex slowly releases drug compounds over time. Due to the low aqueous solubility of the vitreous in the eye, the duration of drug release can be controlled through the composition of the hydrogel crosslinking density for a sustained and controlled release. The major advantages of hydrogels are sustained drug delivery, biocompatibility, and biodegradability.
There are currently no approved therapies utilizing hydrogel technology for retinal diseases, though a phase I clinical trial is currently investigating the safety of OTX-TKI in subjects with nAMD (NCT03630315).69 OTX-TKI is a dried polyethylene glycol-based hydrogel fiber containing dispersed microcrystals of axitinib, a small molecule TKI with antiangiogenic properties. OTX-TIK has been reported to degrade over 9 to 10.5 months, and signs of durability have been seen up to 13 months postinjection.56 Although this technology seems effective, safety and biocompatibility need to be further investigated.
Several studies have examined various types of thermoresponsive hydrogels.70 Thermoresponsive hydrogels are a particularly attractive means of extended drug delivery, as once injected into the vitreous space, it employs temperature change as a trigger for gelation and swelling. At room temperature, these hydrogels are designed as a solution or have a fluid-like consistency. After injection into the eye, they solidify into a solid form upon reaching body temperature.71,72 Kang-Mieler and colleagues have developed a polymer-based thermoresponsive hydrogel using biodegradable material.73,74 Their thermoresponsive system has been shown to be capable of localizing the release of bevacizumab or ranibizumab for about a month and induced no long-term effects on retinal function.61,75 Further studies in nonhuman primates have shown safety and efficacy in a model of CNV for up to 6 months. Additional studies by Kang-Mieler and colleagues have shown that this biodegradable thermoreversible model is also capable of encapsulating 2 different molecules (dexamethasone and aflibercept) and releasing the 2 agents independently (see below under the Composite Drug Delivery section).
Wang and colleagues have developed copolymer-based biodegradable thermoresponsive hydrogels for the extended release of bevacizumab. They demonstrated biocompatibility in vitro and in vivo with a human RPE cell line in a rabbit model for 2 months. Bioactive bevacizumab from hydrogels for 1 month in vitro was established, although no in vivo efficacy data on animal models have been reported.70
Composite Drug Delivery System
This composite DDS, a combination of polymeric nanoparticles and microparticles and hydrogel, offers advantages by further extending release and reducing initial burst.76,77 Recently, Kang-Mieler and colleagues have incorporated PLGA microspheres into their thermoresponsive hydrogel to create a microsphere-hydrogel composite.76,78–80 This combined system reduced the initial burst typically seen with microparticles following direct injection by ~75% and was able to provide sustained release of PLGA for 200 days.66 Subsequently, this system was able to contain and release anti-VEGF agents such as ranibizumab and aflibercept over 196 days.66,67 Safety of the aflibercept microsphere-hydrogel DDS has been demonstrated in nonhuman primates, where no morphologic and functional abnormalities were seen over the 6 months after the injection.69 In addition, in vivo efficacy has been demonstrated in a laser-induced CNV rat model, where a single intravitreal injection of the aflibercept microsphere-hydrogel DDS was able to reduce lesion size through 6 months.81 Most recently, a combination composite DDS containing both aflibercept and dexamethasone-loaded microparticles has been investigated, showing that additional therapeutic effect can be achieved without influencing the release kinetics of the 2 agents.82
Port Delivery System (Susvimo)
The port delivery system (PDS) is a permanent, nondegradable, refillable eye implant, which is surgically implanted into the vitreous (Fig. 2). A self-sealing septum in the center of the implant allows the refill of the drug reservoir without the need to remove the implant. One of the biggest advantages of PDS is that on-demand refills can be performed in an in-office procedure using a customized exchange needle. One of the major initial challenges was reported to be the higher rate of surgical complications such as conjunctival bleb leak and endophthalmitis as surgeons gained experience.84 Careful management of both the conjunctiva and Tenon capsule during the opening and closing steps of the implant insertion procedure mitigated the risk of conjunctival retraction and reduced the risk of endophthalmitis.
Roche Genentech unit developed a customized formulation of ranibizumab (100 mg/mL) that diffuses passively down a concentration gradient from the implant reservoir into the vitreous. The passive diffusion is controlled through a porous metal release control element specifically designed for ranibizumab. It is designed to continuously deliver ranibizumab up to 6 months. LADDER, a phase 2 trial, investigated 3 formulations of ranibizumab (10, 40, or 100 mg/mL) delivered via PDS in comparison to monthly intravitreal injections of 0.5 mg ranibizumab. Among the PDS group, 6 months or longer medication-refill–free period was achieved in 63.5%, 71.3%, and 80% of patients at ranibizumab dose of 10, 40, and 100 mg/mL, respectively. Superior formulation of ranibizumab was 100 mg/mL with patients requiring a mean of 2.4 treatments per patient over 22 months. At 9 months, BCVA improvement was best achieved for PDS 100 mg/mL group with a gain of 5.0 letters. ARCHWAY (NCT03677934), a phase 3 trial, demonstrated noninferior improvements in BCVA and CST with PDS 100 mg/mL formulation compared with monthly 0.5 mg ranibizumab.72 Patients received either 100 mg/mL refills every 24 weeks or 0.5 mg intravitreal injections every 4 weeks. At 36 and 40 weeks, BCVA gain was similar at 0.2 and 0.5 letters in the PDS and monthly ranibizumab group, respectively. At week 36, CST change from baseline was superior in the PDS group with a reduction of 10.3 μm while the monthly arm had an average reduction of 4.4 μm. It should be pointed out that new sales of this device in the United States were suspended in October 2022 due to the concerns of endophthalmitis (2.5%), along with dislodgement of the drug release internal septum. It is hoped that the device will be returned to the market within the next year or in the near future.
VELODROME (NCT04657289) is a phase 3b and multicenter trial currently recruiting patients to assess 100 mg/mL ranibizumab delivered every 36 weeks in comparison to 24 weeks.85 PORTAL (NCT03683251) is an active long-term safety and tolerability study of the PDS, involving patients who completed the LADDER, ARCHWAY, or week 24 visit of VELODROME.86 No study updates have been released from VELODROME or PORTAL. PAVILION (NCT04503551) and PAGODA (NCT04108156) are more recent phase 3 trials investigating PDS in patients with DME.87,88
NONINTRAVITREAL DELIVERY SYSTEM
There is an unmet need for noninvasive alternatives such as topical drops that can achieve the potency of intravitreal injections while maintaining efficiency. Effective nonintravitreal DDS to targeted retinal tissues is a major challenge due to the complex structure of the eye that inhibits deep drug penetration. In the case of topical application, tear dilution, tear turnover, and lacrimation are major obstacles resulting in decreased drug permeation.89 Further challenges include variable dosage applied by patients’ technique and variable dosage absorption depending on individuals’ anterior surface status.
PAN-90806 (PanOptica) is a TKI topical drop that targets VEGF-2 and platelet-derived growth factor receptors. The initial phase 1/2 trials evaluated PAN-90806 drops and identified reversible punctate keratopathy due to off-target inhibition of corneal epithelial epidermal growth factor receptors.90 A newly formulated PAN-90806 with an improved safety profile demonstrated promising results in naive nAMD patients in a phase 1/2 study (NCT02022540).91 Three concentrations of PAN-90806 (2, 6, and 10 mg/mL) were administered as a daily drop for 12 weeks with rescue therapy permitted after 2 weeks.92–94 Fifty-one percent of the participants successfully completed the study on PAN-90806 monotherapy without rescue therapy until week 16. Improved BCVA and CST were evident in patients who received 6 and 2 mg/mL. At 1-month follow-up postmonotherapy treatment, all patients maintained improvement in BCVA and reduction in CST. PAN-90806 demonstrated improvement in structure and function in naive nAMD patients as monotherapy induced with no serious events or safety issues.
EXN407 is a topical selective serine/arginine-protein kinase 1 (SRPK1) inhibitor that is known to reduce proangiogenic VEGF-A activity. SRPK1 regulates alternative splicing of VEGF-A to proangiogenic isoforms, hence SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels.95–97 EXONATE PQ-110-001 is recruiting patients for its phase ½ study to evaluate the safety and tolerability of EXN407 in patients with center-involved DME.98 The study will assess 3 EXN407 concentration levels (0.5, 0.1, and 1.5 mg/mL) and placebo for 7 days on twice-daily regimen to select the highest well-tolerated dose. The selected dose will be then evaluated in the dose expansion cohort for 84 days.
Systemic delivery of therapeutics is considered an atypical route for ocular indications affecting the posterior segment. The BRB significantly limits access to local retinal targets, with bioavailability of <2%.99 The potential for systemic toxicity is a major challenge, especially when retinal diseases are significantly more common in elderly patients. Pharmacokinetics and pharmacodynamics of drugs should be considered, such as the drug’s protein-bound capacity, excretion pathway, and interactions with other medications.
Currently, verteporfin (Visudyne), given intravenously, is often used as part of the photodynamic therapy to manage CNV and central serous chorioretinopathy.100 Meanwhile, supplementation with the AREDS/AREDS2 antioxidant vitamins and minerals has been recommended to reduce the risk of progression to advanced AMD.101 Oral saffron has also been shown to improve visual function in mild/moderate AMD, though this area of research needs further work.102
The main advantages of systemic delivery over intravitreal injections are the absence of injection-related infections and the reduction in the need for health professionals and equipment in cases such as oral tablets. This can potentially improve treatment adherence and reduce cost and previous serious complications such as endophthalmitis. Systemic delivery is convenient in bilateral disease, further reducing patient burdens. On the other hand, larger drug doses are often required, resulting in off-site adverse effects and drug toxicity and interactions.
Studies demonstrated complement pathway activation and the consequent membrane attack complex play a major pathogenic mechanism in choriocapillaris loss and development of AMD and GA.103–105 This indicates that AMD may be a manifestation of a broader systemic disease, thus systemic therapeutics that target global inflammation may be a viable treatment option. Several completed and ongoing clinical trials have examined the efficacy of complement factor modulation in patients with AMD and GA.
COMPLETE was a phase 2 clinical trial examining the effect of intravenous eculizumab in patients with dry AMD.106 Eculizumab is an immunoglobulin G antibody that inhibits complement component 5 (C5). There was no change in the growth rate of GA compared with placebo after 26 weeks.
Two systemically delivered compounds are currently being investigated in phase 2 clinical studies. Danicopan (ALXN2040) is a complement factor D inhibitor that is formulated as an oral table, and IONIS-FB-LRx is an antisense inhibitor of complement factor B given as a subcutaneous injection.107,108 There are some concerns that IONIS-FB-LRx may increase the risk of thrombocytopenia, however, this is yet to be confirmed in animal or clinical studies. In addition, there have been concerns for an increased risk of infection with systemic complement inhibition, notably Neisseria meningitides. Hence, vaccinations are a requirement for participation in these trials.109,110
Several other systemic therapies are being trialed. Curcumin supplementation is being investigated to reduce drusen in dry AMD in a phase 1 study (NCT04590196); oral sildenafil for choroidal ischemia in vitelliform macular dystrophy, AMD, central serous chorioretinopathy, and RP in a phase 2 study (NCT04356716); oral metformin for the treatment of ABCA4 retinopathy in a phase 2 study (NCT04545736); oral levosulpiride in DME in a phase 2 study (NCT03161652), and oral MS-553 in DME in another study (NCT04187443).111–115
The SCS is an attractive drug delivery site due to the sclera’s high fibrous composition, and large surface area results in less resistance to drug diffusion.116 Studies have shown that molecules up to 70 kDa can readily penetrate the sclera, whereas through the cornea it is less than 1 kDa. The SCS can expand to accommodate higher volume of therapeutics and higher concentrations of therapeutics penetrating the retina, RPE, and choroid with minimal medication exposure to anterior segment, compared with intravitreal method.117,118 This is advantageous in the case of corticosteroids, showing a lower incidence of intraocular pressure spikes and cataract formulation.
The SCS delivery has several advantages over the traditional intravitreal route. As the vitreous is not uniform throughout, molecules of different sizes travel through the vitreous at different rates. The internal limiting membrane also serves as a barrier to penetration via the vitreous. The half-life of therapeutics including steroids and anti-VEGF molecules is also reduced in vitrectomized eyes. Injections into the SCS also alleviate the prevalence of floaters often seen in intravitreal injections. A major challenge of transscleral delivery is that with high drug clearance mechanisms and static, dynamic, and metabolic barriers, an effective drug concentration within the eye may not be readily achieved.119
Clearside Biomedical (Alpharetta, GA) developed a specialized microneedle and injector, CLS-TA, which administers a suprachoroidal injection of corticosteroid triamcinolone acetonide. The depth of the microneedle is 750 μm, which is designed to perforate only the conjunctiva and sclera but avoid penetration deeper than the SCS. The injector allows for consistent insertion of the microneedle into the suprachoroidal space. Thus, this method reduces the risks commonly associated with intravitreal injections, including the potential for retinal damage.120 Due to the small surface area of the microneedle, this system is limited to small molecules, and microneedles cannot always deliver a therapeutic dose. CLS-TA has been trialed in several clinical trials assessing the efficacy of treating RVO and DME.
TYBEE was a phase 2 study assessing the effectiveness of CLS-TA in combination with aflibercept versus aflibercept monotherapy in RVO.121 They found similar results between the active and control groups at 24 weeks. TANZANITE was a phase 2 study similarly assessed CLS-TA in combination with aflibercept, compared with aflibercept monotherapy in DME.122 The group that received combination therapy required significantly less frequent injections compared with the monotherapy group, and both BCVA and CST outcomes were better than the monotherapy group after 3 months. However, the phase 3 studies (SAPPHIRE and TOPAZ) failed to meet study endpoints.
The use of modified microneedles using triamcinolone acetonide (TA) has been investigated in RVO. Nawar et al123 reported that patients who were treated with combination therapy of suprachoroidal TA with ranibizumab required less frequent ranibizumab injections over 12 months and achieved better visual and anatomic outcomes. A case series in vitrectomized eyes using a modified needle TA also found that injections into the SCS were effective. The HULK study assessed TA injection into the SCS for DME and found significantly better BCVA and CST after 3 months.124
Microcannulation or microcatheter was originally designed for canaloplasty, but the technology is now being investigated for ocular drug delivery system to subretinal and suprachoroidal space.125,126 This technically challenging delivery system uses microcatheter to achieve stem cell transplantation into the subretinal space. This approach involves the creation of a sclerotomy, introduction of a specialized cannula into the suprachoroidal space, advancement of the cannula under direct visualization to the desired delivery site, advancement of an internal needle through the choroid into the subretinal space, and delivery of cells.127 The use of a microcatheter to deliver anti-VEGF alone is not a viable option due to the high clearance of agent in the choroidal circulation and limited ability to penetrate the retina. However, subretinal delivery is very useful in delivering genes directly to the RPE and photoreceptor cells.
Human umbilical tissue-derived cells, CNTO 2476 (Palucorcel), were investigated in a phase 1/2 clinical trial for GA secondary to AMD.128 CNTO 2476 provides trophic factors that reduced the rate of retinal degeneration and vision loss in animal models when given to the subretinal space.129,130 In the trial, CNTO 2476 was delivered into the subretinal space near the macular GA using iTrack Model 275 microcatheter.131 They reported that the eyes that received the treatment improved 4–5 letters while the untreated eyes lost 2 letters. They reported a 15% rate of retinal detachment.
RGX-314 is a novel adeno-associated virus vector, which contains a gene that encodes for a soluble anti-VEGF monoclonal antibody fragment, similar to ranibizumab, in transduced retinal cells. The gene can be delivered into the subretinal space via a pars plana vitrectomy approach, placed in the vitreous cavity, or injected into the suprachoroidal space. Its phase 1/2 suprachoroidal trial in nAMD reported no drug-related adverse events, stability in visual acuity and retinal thickness, and overall positive reduction in treatment burden.132 The phase 2/3 clinical trial, ATMOSPHERE (NCT04704921), is currently recruiting patients.133 Patients will be enrolled across 2 RGX-314 dose arms versus ranibizumab, and the primary endpoint will be noninferiority to ranibizumab based on BCVA at 1 year.
In 2022, the global ophthalmic pharmaceutical market was valued at $33.81 billion, and the biggest portion was ophthalmic drugs in retinal diseases.134 This figure is expected to grow at a compound annual growth rate of 7.80% from 2023 to 2030, reflecting the huge potential scope of increasing research and opportunities in launching novel ophthalmic drug delivery systems in macular diseases.
Nanotechnology has the potential to add innovative functionality and provide superior therapeutic efficacy over intravitreally delivered anti-VEGF treatments. Intravitreal nanoparticle drug delivery systems combined with controlled drug release technologies utilizing safe, biodegradable, and natural polymers and hydrogels are actively being investigated. There is still a need for further research to explore nanotechnology and biomaterials that are more stable and safer in the vitreous while releasing drugs at a steady and predictable rate.
Given the limitations of currently available intravitreal treatments for retinal diseases, alternate drug delivery systems with increased durability while maintaining current (or more effective) treatment efficacy and safety are required. Each of the novel drug delivery modalities described in this review has its advantages and disadvantages. Intravitreal therapies remain the current gold standard. Delivery via sustained-release intravitreal implants, polymeric nanoparticles, microparticles, hydrogel, and composite drug delivery systems have the potential to produce more prolonged therapeutic effects, but the safety profile, particularly relating to intraocular inflammation, needs to be considered. Encapsulated cell technology is an exciting area of development that may allow the delivery of cells that produce neurotrophic agents in diseases that currently do not have treatments. Posterior segment gene therapy delivery is being attempted by a number of different delivery approaches, and this treatment offers promise for the future. The PDS has demonstrated prolonged efficacy up to a half year and reduced the need for regular intravitreal injections by allowing an in-office setting for refill of the drug reservoir. However, it still requires surgical implantation of the device, and initial complications such as endophthalmitis and dislodging of the drug release septum within the device have been reported. Some of these concerns may arise from a high surgeon learning curve. Sales of the device at the present time in the United States have been suspended for the above-noted concerns. Nonintravitreal drug delivery systems offer promise but there are no approved therapies for retinal diseases using these approaches at present. Delivery by topical application is limited in the amount of effective drug that is able to reach the posterior segment. Although permeability enhancers may make this route of delivery more effective in the future, additional research and clinical trials are needed to demonstrate their efficacy. Systemic delivery, while appealing in concept, is limited by the blood-ocular barrier and systemic side effects.
Overall, with the advancement in drug development, biomaterials, gene therapy, and nanotechnology, there is great promise for novel ocular drug delivery systems to significantly improve the standard of care for macula disease in the near future. Robust clinical trials and postmarketing surveillance are required to ensure these treatments are safe for our patients.
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