macular edema therapy using dexamethasone nanoparticle suspension
PURPOSE
To determine the effectiveness and safety of a new topical nanoparticle dexamethasone ophthalmic suspension OCS-01 (Oculis SA, Lausanne, Switzerland) in the treatment of diabetic macular edema (DME).
STUDY BACKGROUND
Diabetic macular edema (DME) is the main cause of visual impairment in patients with diabetic retinopathy (DR). DME is the result of the breakdown of the blood-retinal barrier (BRB), due to the imbalance between inflammatory and angiogenic factors of the retinal epithelium and the vitreoretinal surface. Among these, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and interleukin 1B are the important ones. Clinical evidence has shown that the lower vitreous concentration of the pigment epithelium-derived anti-angiogenic factor (PEDF) is also related to DME.
A little more than a decade ago, laser therapy and intravitreal anti-VEGF medications were considered the go-to treatments for reestablishing BRB in patients with DME. The efficacy of these therapies in DME has been demonstrated by several studies. However, they come with significant treatment burdens for patients and their caregivers. Anti-VEGF treatment requires multiple injections that are difficult to transpose to clinical setting. It has been demonstrated that repeated intravitreal injections carry the risk of endophthalmitis. Over time, some patients develop anxiety, cataracts and glaucoma. In fact, studies show that about 20% to 60% of patients with DME do not respond to intravitreal injections. Cost implications are another major limitation of this treatment. Thus, only fewer injections are administered in real life clinical setting than in clinical trials. Therefore, the results of clinical trials have been difficult to replicate in real life. A relatively safe treatment that reduces the risk of severe adverse effects might be beneficial.
Findings from systematic reviews and animal models highlight the potential of topical therapies for DME. They are cost-effective, improve patient comfort and safety, are highly accessible, and allow for individualized dosing. Moreover, they are an interesting alternative treatment option for patients in whom anti-VEGF injections do not work. However, while certain studies demonstrated favorable results for eye drops for DME, others were still more heterogeneous in their findings. Anatomical and physiological barriers of the eye prevent the drugs from entering the posterior segment. Thus, topical ocular drug delivery mostly results in low ocular bioavailability.
OCS-01, the novel topical dexamethasone ophthalmic suspension, is formulated using solubilizing nanoparticle technology to ensure a longer residence time, thereby enhancing the bioavailability of the drug in both the anterior and posterior segments of the eye. Results from small pilot studies and case series suggest OCS-01 had a significant effect on improving central macular thickness (CMT) and visual acuity in patients with DME. In these studies, the investigators also noted that intraocular pressure (IOP), the most common adverse event, quickly decreased after the end of treatment.
This vehicle-controlled phase II study evaluates the efficacy and safety of OCS-01 eye drops in patients with DME.
METHODS
This phase II, multicenter, double-masked, randomized clinical trial was conducted at 27 clinical sites in 6 countries in the European Union. All patients (aged 18–85 years) enrolled in the study had DME for less than three years, BCVA ranging from 20/40 to 20/320, central macular thickness ≥310 μm, and glycated hemoglobin (HbA1c) of ≤12.0%. Patients were excluded if they had macular edema or decreased visual acuity due to any cause other than DME, or had macular ischemia, ETDRS high-risk proliferative diabetic retinopathy, or other ocular disorders. Patients who had a history of intravitreal, subtenon, or periocular corticosteroid treatment were also excluded. Out of 184 patients screened, 144 were randomly assigned to receive OCS-01 (n = 99) or a vehicle (n = 45) three times daily for 12 weeks. Efficacy was evaluated as a change from baseline to ETDRS letters at Week 12 and central macular thickness (CMT). The primary analysis used a linear model with baseline ETDRS letters as a covariate and treatment as the main effect factor. Multiple imputation pattern mixture models were used to impute missing data. If the one-sided p-value was less than 0.15 and the difference in the mean change from baseline in the ETDRS letters was greater than zero, the active treatment was deemed superior to the vehicle.
RESULTS
- Compared with the vehicle group, higher proportions of patients treated with OCS-01 demonstrated gains of ≥10 ETDRS letters (14% vs 5%) and ≥15 ETDRS letters (5% vs 0%).
- At Week 12, mean CMT showed a statistically significant decrease from baseline in the OCS-01 group than the vehicle (−53.6 vs −16.8 μm, p= 0.0115), and at all post-baseline points up to Week 12. Mean CMT also showed statistically significant differences between groups at all visits from Weeks 2 to 12.
- At baseline, all patients in both treatment groups had an IOP of <30mmHg. The adverse event review showed that at Week 12, 14% of patients treated with OCS-01 had an increase in IOP from baseline. IOP increased in the OCS-01 group during the 12 weeks by a mean of 4.53mmHg but, at week 16, 4 weeks after the end of the observation period, IOP returned to the baseline level.
- Treatment-emergent adverse events (AEs) were higher in the OCS-01 group than in the vehicle group (70% vs 53%). The most frequent AE was the IOP increase, and all were treatment-related. Though there was no severe IOP increase observed, two patients discontinued due to these AEs. Influenza, nasopharyngitis, and diabetic retinal edema were the other common AEs reported in both treatment groups.
- Severe adverse events (SAEs) were reported by 11% and 2% of patients in the OCS-01 and vehicle groups, respectively. Only one patient in the OCS-01 group reported retinal detachment and an ocular SAE. Most SAEs affect the cardiovascular system. In the OCS-01 group, two patients had cardiac arrest, two had atrial fibrillation, and one had the peripheral arterial occlusive disease. One patient in the control group had a myocardial infarction. Diabetes mellitus, diabetic ulcer, influenza, urinary tract infection, and respiratory distress were among the other SAEs reported.
DISCUSSION
Several clinical trials involving different combinations of treatment modalities for DME have been conducted, including laser therapy, and intravitreal injection of triamcinolone acetonide, bevacizumab, or ranibizumab. However, these combination therapies have not proved more flexible, safer, less expensive, or easily accessible than topical therapy.
This first vehicle-controlled phase II study showed that OCS-01 has the potential to be the first clinically validated topical therapy for DME. The topical dexamethasone ophthalmic suspension OCS-01 had a significant effect on improving CMT, compared to vehicle-treated eyes. Specifically, DME patients with lower baseline best corrected visual acuity (BCVA) benefited more from OCS-01 eye drops. In an exploratory post-hoc analysis, both BCVA and CMT showed statistically significant improvements from baseline in patients with baseline BCVA ≤65 letters. The results also showed that the OCS-01 group improved by 3.8 letters compared with 0.9 letters in the vehicle group. However, this improvement in BCVA was not as large as that reported by Nguyen et al. and Korobelnik et al.
The authors noted OCS-01 was well tolerated, with increased IOP being the most common adverse event, as expected with dexamethasone. The increased IOP of ≥10 mmHg from baseline at week 12 was proof that OCS-01 penetrated well to achieve a good concentration inside the eye. The return to normal IOP at the end of the observation period indicates that the drop can be stopped immediately if any side-effect occurs. That is a benefit of topical therapies compared with intravitreal injections.
In conclusion, this study showed that topical therapy with OCS-01 was more effective than vehicle eye drops in improving CMT in patients with DME. Visual acuity was better in patients with lower baseline vision. A phase 2/3 study is required to confirm the findings within a larger patient population.
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