Innovative delivery: sustained ophthalmic steroids in diabetic macular edema 

Professor Sobha Sivaprasad, Professor of Retinal Clinical Studies, UCL Institute of Ophthalmology, and Consultant Ophthalmologist, Moorfields Eye Hospital, UK discusses unmet needs in DME therapeutics and how they could be addressed by sustained release ophthalmic steroids administered with novel suprachoroidal drug delivery methods. 

Diabetic eye disease is a growing global concern. Between 2019 and 2045, the number of people with diabetes is expected to increase by around 51%, from 463 million to 700 million1.Diabetic retinopathy is a common microvascular complication of diabetes2, and can result in diabetic macular edema (DME), the leading cause of vision loss in the working-age population in the developed world3. Worldwide, there are an estimated 20.6 million individuals with DME4, and the average age at diagnosis is just 50 years5,6. 

Diabetic eye disease can have devastating personal and socioeconomic consequences1. Approved treatment options are available, but these come with a high burden to patients, physicians and caregivers. In particular, individuals with DME are subject to a high level of treatment burden. Once DME manifests, frequent ocular treatments for DME are added to multiple visits to different specialists (diabetologist, diabetes nurse, cardiologist, nephrologist, retinal specialist) as well as their regular appointments at the primary care physician. Professor Laurent Kodjikian of the University of Lyon, France, notes: “It’s important to understand that diabetes is a systemic disease in younger and more active patients. In addition to seeing their ophthalmologist, these patients need to see their primary care physician, diabetologist, cardiologist, nephrologist, and so on – they need many, many health professional visits. There is a huge burden of diabetes, especially for diabetic patients with DME.”  

For younger patients, this can be disruptive to working life, and for more elderly patients with limited mobility the impact extends to their family or caregivers. As a consequence, many patients struggle to attend the necessary appointments. In particular, multiple clinic visits for treatment and follow-up at retinal specialists are required to achieve meaningful visual outcomes in real-life as expected from randomised controlled trial data. 

The Covid-19 pandemic, with recurrent lock-downs impacting hugely on private life and medical care, recently provided additional insights to the challenges of current DME treatments with limited durability. Patients with diabetes are more likely to experience severe clinical outcomes from Covid-19 infection7. Even with the availability of anti-Covid-19 vaccination, the potential for contact with multiple people whilst attending or travelling to and from clinic visits is associated with a high degree of risk for this vulnerable population. For this reason, the use of telemedicine and remote healthcare in the management of these patients has been recommended where possible8,9. Indeed, reports indicate that patient visits to ophthalmologists decreased dramatically during the initial months of the pandemic. As a result of the initial lock-down in the UK in March and April 2020, attendance at the accident and emergency department of Moorfields Eye Hospital NHS Foundation Trust dropped by over 50%, with 57% of cases being addressed by an online consultation service run by the department10. In another example, new patient visits to one retinal clinic in Canada dropped to 30% at the peak of the pandemic, only recovering to 50% of pre-Covid levels by May and 83% in August11. In Italy, the number of intravitreal (IVT) injections for DME decreased by 60–79% in the first lock-down, compared with the previous year12,13 while in Greece, one tertiary reference centre for diabetic eye disease reported that no IVT injections were given during the Covid-19 lock-down from March to May 202014. 

Given these factors, there is a need for new therapies and management strategies to minimise the burden to patients with DME. These should aim to make treatment adherence easier, improving real-world visual outcomes, as the same time as reducing the risk associated with clinic visits. 

Therapeutic options for DME 

While anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for visual impairment associated with DME, not every patient responds to anti-VEGF therapy. In the RIDE and RISE studies of ranibizumab (Lucentis; Genentech, South San Francisco, CA, USA) in 252 patients with DME treated with 0.5 mg ranibizumab for three years, a best-corrected visual acuity (BCVA) gain of ≥15 letters was not achieved in around 60% of patients. Although some of these patients may have been restricted in the amount of visual gain that they could achieve due to having relatively high baseline BCVA (also known as a ‘ceiling effect’), about 40% did not achieve a final visual acuity of at least 20/4015. Similar limitations in vision gains were also observed for the 0.3mg dose of ranibizumab approved by the US FDA for DME. Similarly, in the VIVID and VISTA studies of aflibercept (Eylea; Bayer AG, Leverkusen, Germany) in DME, over 65% of patients in the 2mg-every-eight-weeks arm did not achieve a ≥15-letter BCVA gain at Week 10016 

In addition, the required frequency of anti-VEGF injections for DME can be a barrier to effective treatment. In the Diabetic Retinopathy Clinical Research Network (DRCR.net)’s Protocol T study, comparing anti-VEGF agents in DME, patients (n=660) had meaningful visual gains of 10 to 13 letters in the first year, but required a median of 9 to 10 injections17. 

In real-world practice, non-adherence to recommended injection frequency and follow-up intervals is common and can lead to suboptimal outcomes as fewer injections compared to the approved treatment regimen generally result in more limited or absent vision gains. In an analysis of electronic medical records for 28,658 eyes undergoing anti-VEGF treatment for DME in the USA from 2013 to 2018, 22% received three or fewer anti-VEGF injections in their first year of treatment, and only 50% received at least six injections18. The LUMINOUS observational study of ranibizumab in DME showed that treatment-naïve patients (n=1,063) receiving four or fewer injections in the first year of treatment gained only a mean 0.5 letters, compared with those receiving five or more injections who gained a mean of 6.9 letters from baseline19. 

The investigational anti-VEGF agents faricimab (Roche, Basel, Switzerland) and KSI-301 (Kodiak Sciences Inc, Palo Alto, CA, USA) aim to address the problem of durability targeting less frequent treatments. However, evidence from Phase III studies including 594 patients with DME suggests that in the first year, only around half of patients treated with faricimab according to a personalised treatment interval are able to be maintained on the longest treatment interval of 16  weeks, and a minimum of four monthly loading doses are required20. In a Phase Ib study of KSI-301, 69% of 32 patients with DME could be maintained on a si6 month or longer treatment interval, but again multiple monthly loading doses were needed, and these results need to be verified in later-phase studies with larger patient populations21. 

For those patients who do not achieve satisfactory results from anti-VEGF therapy, alternative treatments may be considered, such as corticosteroids. 

Corticosteroids in DME 

In DME, hyperglycemia is thought to cause abnormalities in different, overlapping metabolic pathways, leading to upregulation of VEGF and various inflammatory cytokines which promote the development of inflammation and retinal hypoxia22. Corticosteroids have both strong anti-inflammatory and anti-edema effects. They act on the inflammatory processes involved in DME pathogenesis, downregulate VEGF expression and inhibit prostaglandin and proinflammatory cytokine production, and reduce blood–retinal barrier permability23. 

Intravitreal use of the corticosteroid triamcinolone acetonide is off-label for the treatment of DME, but has a long history, with the first case being reported in 200124. In 2009, the DRCR.net reported three year outcomes of the prospective Protocol B study comparing IVT triamcinolone with focal/grid photocoagulation for the treatment of DME25. At doses of 1mg and 4mg, long-term results showed nominally poorer BCVA outcomes and a higher incidence of cataract surgery in the triamcinolone group. A later study, DRCR.net Protocol I, showed a benefit of adding triamcinolone to prompt laser in pseudophakic patients, albeit with an accompanying risk of elevated IOP26. Triamcinolone has been recommended for consideration as IVT monotherapy or in combination with laser, in cases of persistent or refractory DME, particularly in pseudophakic eyes27. 

Sustained release formulations of ophthalmic therapeutics for DME offer a number of potential benefits. Less frequent administrations reduce patient and clinic burden. Consistent, gradual release of the active component should reduce fluctuations in retinal thickness and maintain stability. Professor Francesco Bandello of the Scientific Institute San Raffaele, Milan, Italy, comments: “Trying to solve a chronic problem with an acute therapy is not logical. The ideal treatment for DME would release a small amount of drug inside the eye day-by-day.” In addition, reducing the number of invasive procedures that a patient receives lowers their exposure to the risk of injection-related adverse events such as intraocular inflammation or even endophthalmitis.  

A sustained delivery system for anti-VEGF therapy has recently been approved by the FDA for use in patients with neovascular age-related macular degeneration (AMD). The ranibizumab port delivery system (Genentech, South San Francisco, CA, USA) requires surgical implantation, after which the drug reservoir can be refilled with ranibizumab using a specialised needle, with a potential treatment interval of six months. Phase III results in neovascular AMD suggest that visual outcomes are comparable to monthly IVT injections of ranibizumab and that over 90% of patients do not require supplemental treatment prior to the scheduled refills of the reservoir every 24 weeks20. However, there are currently no data available in DME, with a Phase III study scheduled for completion in 2024 (NCT04108156). 

Two sustained release retinal steroids are currently approved for use in DME: the dexamethasone intravitreal implant (Ozurdex; Allergan, Irvine, CA, USA) and the fluocinolone acetonide insert (Iluvien; Alimera Sciences, Atlanta, GA, USA). The 0.7mg dexamethasone IVT implant was approved for use in DME on the basis of the MEAD studies, two randomised, multicentre, masked, sham-controlled, Phase III clinical trials with identical protocols28. In a total of 1,048 patients, the 351 individuals who were treated with the 0.7mg dexamethasone IVT implant were significantly more likely to achieve a ≥15-letter improvement in BCVA at three years than the 350 treated with sham (22% vs 12% , p<0.001), with a mean of 4.1 treatments over three years28. However, only 64% of patients treated with the 0.7mg implant completed the study, and rates of complications were high. In 265 patients who were phakic at baseline, 68% treated with the 0.7mg implant had cataract-related adverse events during the study, compared with 20% of 249 patients in the sham arm. In addition, over 40% of patients treated with the 0.7mg implant required medication to control intraocular pressure (IOP) versus 9% of those in the sham arm. 

A separate, single-centre exploratory study which monitored the effects of the dexamethasone IVT implant on morphological and functional changes using optical coherence tomography (OCT) reported that the greatest effect on retinal thickness was observed at eight weeks, with recurrence of edema noted at 16–20 weeks, and proposed that more frequent treatment than the six months treatment interval provided in the product label might be required29. However, in the absence of an approved option with a better efficacy, tolerability and durability profile, the dexamethasone IVT implant is the standard option for many retinal specialists when treating patients with an inadequate response to anti-VEGF therapy30. 

The fluocinolone acetonide insert is a non-biodegradable implant containing 190µg of the active compound31. In two three-year, randomised, sham injection-controlled, double-masked, multicentre clinical trials, patients treated with high-dose (0.5µg/day) or low-dose (0.2µg/day) fluocinolone were more likely to achieve a BCVA improvement of ≥15 letters compared with sham (28% [n=110/395] and 29% [n=108/376] versus 19% [n=35/185], respectively; p=0.018)31. The maximum benefit of treatment was seen at 30 months, and around 70–75% of patients required only one treatment during the three-year study. However, almost all of the patients in the fluocinolone groups developed cataract: in patients who were phakic at baseline, 87% treated with the high dose required cataract surgery during the study, compared with 27% in the sham arm. Also, incisional glaucoma surgery was required in 5% of patients in the low dose group and 8% of patients in the high dose group.  

The fluocinolone acetonide insert is associated with more frequent, more severe and less easily managed IOP increases than the dexamethasone IVT implant, and so its use is generally limited to patients who have already demonstrated no clinically significant IOP response to a corticosteroid or have undergone prior filtration surgery30. 

Given the limitations of the currently available sustained release formulations of retinal steroids, there exists a high unmet need for long-lasting, well-tolerated, potent anti-inflammatory and anti-edema treatments for DME. 

Innovations in sustained release retinal steroids  

The suprachoroidal space is a route of administration for treating retinal diseases which is currently under evaluation for use across a range of therapeutic modalities, including small molecules, biotherapeutics, and gene therapies. The advantage of drug delivery to the suprachoroidal space is that the choroid, retinal pigment epithelium and retina are targeted with high bioavailability, while low levels of therapeutic agent are maintained elsewhere in the eye32,33. This may permit the use of lower amounts of drug to achieve similar levels of efficacy to traditional routes of administration such as IVT injection and reduce the risk of side effects associated with intraocular drug delivery32,33. 

Dr Mark Wieland, President of Northern California Retina Vitreous Associates, USA, comments: “From an efficacy standpoint, knowing that by injecting into the suprachoroidal space the steroid is working its way back to the macula, and is juxtaposed and flush with the macula, gives me the sense that it is going to have better activity.” Dr Michael Singer of the University of Texas Health Science Center, USA, adds: “I’ve seen a lot of evidence in the literature where steroids are injected more anterior to the lens resulting in higher IOP responses, but I believe the suprachoroidal space may be relatively more protected than the intravitreal space.” 

OXU-001 (Oxular) is a new sustained release drug formulation of dexamethasone which aims to address the current unmet need in DME. OXU-001 consists of dexamethasone incorporated into long-lasting microspheres of biodegradable polymer for administration into the suprachoroidal space. These microspheres are designed to deliver a precise daily amount of dexamethasone to retinal and choroidal tissues for up to 12 months following a single administration. OXU-001 is delivered using a semi-automated ocular administration device. The Oxulumis device contains a microcatheter which it deploys into the posterior region of the suprachoroidal space via a 27-gauge needle inserted in the region of the pars plana. The microcatheter deploys automatically once the tip of the needle reaches the suprachoroidal space advancing posteriorly toward the macula. Illumination of the microcatheter provides trans-scleral visual confirmation of accurate placement prior to drug delivery. The short procedure is minimally invasive, not penetrating the retinal tissues, and is appropriate to be performed in an office setting.  

The administration device has demonstrated impressive early results in the first in-human cases where it was used to deliver 2.4mg triamcinolone suspension (Marc de Smet, personal communication). In a 78-year-old woman with chronic macular edema, suprachoroidal administration of triamcinolone resulted in a decrease in central macular thickness from 616 µm at baseline to 344µm after 10 days and a gain of around four lines of vision, which were maintained at 60 days. “The device was easy to use and performed exactly as we expected. The results in response to a very small dose of triamcinolone were spectacular,” says Professor Marc de Smet of the MicroInvasive Ocular Surgery Center, Lausanne, Switzerland. 

Current evidence for the OXU-001 formulation includes a preclinical study in rabbits in which the pharmacokinetics (PK) of two doses of OXU-001 were compared with the dexamethasone IVT implant over the course of one year34. Suprachoroidal administration of OXU-001 resulted in high choroidal levels that acted as a reservoir to the retina. Therapeutic levels of drug were maintained for approximately one year, compared with approximately one  to two months for the dexamethasone IVT implant (Figure 1). In contrast, levels of drug in the vitreous and lens throughout the study period were extremely low for OXU-001, compared with the dexamethasone IVT implant which peaked at approximately one month (Figure 2). It is expected that this difference in the PK profiles will translate into a favourable safety profile for OXU-001 compared with the dexamethasone IVT implant. Professor Anat Loewenstein from Tel Aviv University, Israel, says: “With the options currently approved for DME, we pay the price for longer duration of action with an increased risk of side-effects. I believe in steroids and use them a lot in my practice, so the prospect of being able to give a steroid just once a year with a good safety profile is very exciting for me.” 

Clinical evidence to support the use of OXU-001 will be provided by an upcoming Phase II randomised clinical study comparing suprachoroidally administered OXU-001 with intravitreally administered dexamethasone IVT implant in patients with DME. 

Conclusion 

DME is a condition associated with a high level of patient burden. Although anti-VEGF therapy is the current standard of care in DME, there is a role for agents with anti-inflammatory and anti-edema activity, particularly corticosteroids, in the management of DME. Sustained release steroids can provide benefit to many patients, and an opportunity for clinicians to reduce treatment burden. However, existing sustained release retinal steroids are associated with limited longevity, and a less-than-optimal safety profile, negatively impacting risk/benefit and limiting visual outcomes. 

An innovative sustained release formulation of dexamethasone currently under investigation for use in DME offers the potential for effective anti-inflammatory treatment with significantly fewer injections and a high likelihood of fewer side effects, as its levels in the vitreous and anterior segment are minimal. This will limit the frequency of IOP elevation and cataract and maintain visual benefits long-term. Once-yearly dosing would reduce the burden of treatment for patients with DME and make maintaining compliance much easier to achieve. The results of an upcoming Phase II clinical trial comparing this new formulation with an existing sustained release dexamethasone implant are awaited with interest. 

Volume 23, Issue 1 – Winter 2021/22

Figure 1: Pharmacokinetics of OXU-001 and the dexamethasone intravitreal implant in the rabbit retina and choroid over an observation period of one year
Figure 2: Pharmacokinetics of OXU-001 and the dexamethasone intravitreal implant in the rabbit vitreous and lens over an observation period of 1 year

About the author 

Professor Sobha Sivaprasad, MBBS, MS, DM, FRCS, FRCOphth, is Professor of Retinal Clinical Studies, UCL Institute of Ophthalmology and Consultant Ophthalmologist, Moorfields Eye Hospital, UK. 

Additional comments are provided by expert contributors Francesco Bandello (Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy), Marc de Smet (MicroInvasive Ocular Surgery Center (MIOS sa), Lausanne, Switzerland), Laurent Kodjikian (Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France; and 2UMR-CNRS 5510 Matéis, Villeurbanne, Université Claude Bernard Lyon 1, University of Lyon, Lyon, France), Anat Loewenstein (Division of Ophthalmology, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Israel), Michael Singer (Clinical Professor of Ophthalmology, University of Texas Health Science Center, San Antonio, TX, USA) and Mark Wieland (Northern California Retina Vitreous Associates, CA, USA). 

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