The use of intraocular corticosteroids

Background: Diabetic macular edema (DME), cystoid macular edema (CME), age-related macular degeneration (AMD), retinal vascular occlusion (RVO) and uveitis are responsible for severe visual impairment worldwide. In some patients with these conditions, treatment with intraocular corticosteroids may be beneficial. Although off-label use of these agents has occurred for many years, novel agents including preservative-free and sustained-release intravitreal implants are currently being studied in clinical trials (CTs). Objective: To review the use of intraocular corticosteroids. Methods: Literature review. Results: Used alone, intravitreal corticosteroids may benefit disorders such as DME, RVO and uveitis compared with standard therapy or observation. Patients with AMD may benefit more from combination treatment with photodynamic therapy, intravitreal corticosteroid and intravitreal anti-VEGF injections. Intraoperative use of these agents may assist in visualization and manipulation of fine retinal structures. Sustained-release intraocular implants have been approved for severe posterior uveitis, and have shown benefits in ongoing CTs. Conclusion: Although intraocular corticosteroid injections have a limited duration of action requiring frequent re-treatment, and significant side effects including cataract and glaucoma development, intraocular injections may be of benefit in certain ocular disorders. Corticosteroid implants are emerging as potential treatments for macular edema due to uveitis, DME or RVO.     

Intraocular corticosteroids for posterior segment disease: 2012 update

Introduction: Diabetic macular edema (DME), cystoid macular edema (CME), age-related macular degeneration (AMD), retinal vascular occlusion (RVO) and uveitis are responsible for severe visual impairment worldwide. In some patients with these conditions, treatment with intraocular corticosteroids may be beneficial. Although off-label use of these agents has occurred for many years, novel agents including preservative-free and sustained-release intravitreal implants are currently being studied in clinical trials (CTs).

Areas covered: This paper reviews the use of CTs for vitreoretinal (VR) diseases including choroidal neovascularization, CME, DME, RVO and posterior uveitis. It also discusses the use of corticosteroids for treating VR disease, including dexamethasone, fluocinolone acetonide, intravitreal implants and triamcinolone acetonide.

Expert opinion: Used alone, intravitreal corticosteroids may benefit disorders such as DME, RVO and uveitis compared with standard therapy. Cases of exudative AMD non-responsive to standard treatment may benefit from combination therapy, including usage of intravitreal corticosteroid injections. Intraoperative use of these agents may aid visualization of retinal structures. Sustained-release intraocular implants have been approved for posterior uveitis and RVO associated with macular edema. In spite of this, most intraocular corticosteroids have a limited duration of action along with significant side effects, including cataract and glaucoma. Currently, intravitreal corticosteroid usage for DME is considered off-label.     

Nonbiological pharmacotherapies for the treatment of diabetic macular edema

Introduction: During the past decade, there have been significant advances in the pharmacotherapies for the treatment of diabetic macular edema (DME). Among the presently available treatment options, anti-vascular endothelial growth factors (anti-VEGF) agents are the most favored agents due to their efficacy and safety. The index review focuses on nonbiological therapies that have entered in phase 3 clinical trials for DME.

Areas covered: An extensive review of the literature was performed to identify various nonbiological immunotherapies i.e., drugs other than ‘-mAbs’ (monoclonal antibodies including anti-VEGF agents), ‘-mibs’ (proteasome inhibitors), ‘-NAbs’ (nanoparticle albumin-bound), and ‘-nibs’ (small molecule inhibitor/tyrosine kinase inhibitors), among others. Extended-release low-dose corticosteroid devices have been recently approved for the treatment of DME. Other compounds such as non-steroidal anti-inflammatory drugs, antibody mimetic proteins, nonbiological growth factor inhibitors, and inhibitors of protein kinase C have been described.

Expert opinion: A number of therapies are under development for the pharmacological management of DME. Due to the rising healthcare costs associated with anti-VEGF agents, a number of alternate treatment options have been explored recently. Some of these agents have reached phase 3 in clinical trials and appear to have a promising role in the management of DME. As further research is conducted, the role of each individual agent will become more defined, alone or in combination therapy.     

Pharmacotherapy for diabetic retinopathy

Background: Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) continue to cause significant visual loss among patients with diabetes mellitus. In some patients unresponsive to standard laser techniques, as well as improved control of blood pressure and blood sugar, pharmacologic treatment may be beneficial. Although no agent is now approved by the FDA for this purpose, many agents are now being studied in randomized clinical trials (RCTs). Objective: To review concisely the chief pharmacotherapies for diabetic retinopathy available at present. Methods: Literature review and synopsis. Results: Used alone, intravitreal triamcinolone acetonide (IVTA) seems to have some short-term efficacy against DME, but longer-term outcomes (≤ 3 years) using IVTA monotherapy showed a lesser benefit than focal/grid laser treatment in a prospective RCT done by the Diabetic Retinopathy Clinical Research Network. Intravitreal anti-VEGF agents have demonstrated some short-term efficacy against DME, and continuing RCTs will evaluate combination therapies (anti-VEGF and laser) for both DME and PDR. Other agents are being evaluated in pilot studies and Phase II RCTs. Conclusion: Pharmacotherapies for DME and PDR have potential for vision stabilization or improvement. Continuing RCTs will provide evidence-based data on their role in clinical practice. A potential role for pharmacotherapy in the prevention of DME and PDR is also emerging.     

Fluocinolone acetonide for the treatment of diabetic macular edema

Introduction: Fluocinolone acetonide intravitreal implant is a non-erodible implant approved for the treatment of diabetic macular edema (DME) insufficiently responsive to available therapies.

Areas covered: The injectable intravitreal implant releases fluocinolone acetonide at an average rate of 0.2 µg/day for at least 36 months. The two pooled pivotal FAME trials showed that, in patients with DME previously treated with laser photocoagulation, fluocinolone acetonide intravitreal implant was more beneficial than sham injection when looking at the proportion of patients with an improvement from baseline in visual acuity of more than 15 letters at 24 months and at 36 months. Cataract (82%) and intraocular pressure (IOP) elevation (37%) were the most common adverse events. Raised IOP was mostly treated with IOP-lowering medications, with <5% of eyes requiring incisional IOP-lowering surgery. FAME trial program results are confirmed by a series of real-world studies in eyes with chronic/recalcitrant DME.

Expert opinion: data indicate that fluocinolone acetonide intravitreal implant is a useful second-line option for the treatment of DME.     

Treatment of diabetic macular edema with sustained-release glucocorticoids: intravitreal triamcinolone acetonide,dexamethasone implant,and fluocinolone acetonide implant

Introduction: Diabetic macular edema (DME) can be treated with intravitreal glucocorticoids, particularly triamcinolone acetonide, dexamethasone (DEX), and fluocinolone acetonide (FA).

Areas covered: The pathophysiology of DME includes multiple growth factors such as VEGF and also inflammatory mediators. Glucocorticoids act on DME through multiple pathways, and current research into their efficacy, safety, and therapeutic potential when administered intravitreally is discussed.

Conclusion: The intravitreal route of administration minimizes systemic side effects of glucocorticoids. Furthermore, sustained-release low-dose delivery via the DEX implant or the FA implant will limit frequent intravitreal injection and possibly some cost associated with intravitreal anti-VEGF therapy. In addition, the durable action of these treatments facilitates combination therapy. Patients can receive these implants as foundational therapy, and then receive additional treatment with laser or intravitreal anti-VEGF agents as combination therapy, which may conceivably provide some synergistic benefit. While the FA implant lasts much longer than the DEX implant, potentially decreasing the visit and treatment burden on patients and their families, the FA implant appears to have a greater risk of inducing ocular hypertension and cataract. However, these modalities have not been directly compared in a clinical trial and there is insufficient evidence to draw more elaborate conclusions.     

Sirolimus for the treatment of noninfectious uveitis

Introduction: Noninfectious posterior uveitis (NIPU) remains a significant burden of legal blindness. Because of its immune mediated and chronic recurrent nature, common therapy includes (systemic) corticosteroids and immune modulatory agents. Most treatments bear the risk of significant adverse effects. Therefore efforts are made to administer therapeutic agents directly into the vitreous cavity. The purpose of this article is to identify the role of intravitreally applied sirolimus as a recently approved therapeutic option in NIPU.

Areas covered: A MEDLINE database search was conducted through August 2015 using the terms: intravitreal injection, pharmacology, sirolimus, treatment and uveitis. To provide ongoing and future perspectives in treatment options, also clinical trials as registered at ClinicalTrials.gov were included. Sirolimus (Opsiria) was in licensed from SANTEN in 2015 and approved in Phase III registration trials in the US, Europe and other countries for NIPU. Current information results mainly from registration and Phase III trials.

Expert opinion: Intravitreal sirolimus appears to be an interesting option in the treatment algorithms of NIPU because of its highly targeted molecular effects, nonsteroidal nature and good safety profile. It has the advantage to avoid systemic side effects, but this has to be balanced against the fact that treatment covers one eye only and bears the risks of any intraocular procedure. Nevertheless a careful evaluation of this agent has to be made, as current experience is almost exclusively based on registration trials and long-term effects still have to be explored.     

Upcoming therapeutic advances in diabetic macular edema: an intravitreal dexamethasone drug delivery system

Introduction: Diabetes mellitus, through its ophthalmic complications diabetic retinopathy and diabetic macular edema (DME), is a leading cause of vision loss in industrialized countries.

Areas covered: This review covers laser treatment, which is a standard treatment strategy that has proven efficacy and safety through large clinical trials in DME. Several intravitreal drug applications currently being investigated are also discussed.

Expert opinion: First results suggest that the administration of anti-VEGF compounds is effective for DME. However, frequent injections may compromise safety. In order to enhance patient compliance, sustained delivery systems are being evaluated as potential treatment approaches. So far, only steroids have been included as active in such non-biodegradable or biodegradable delivery systems. Non-biodegradable systems are more complicated to administer as surgery is required and they need to be retrieved at the end of treatment. Also, in some cases safety issues have arisen, especially around intraocular pressure control. A new biodegradable dexamethasone delivery system seems to show promising efficacy results in addition to a more favorable safety profile, which will potentially improve patient compliance. All new therapeutic approaches, alone and in combination, will need to demonstrate their efficacy and safety in DME in future trials.     

Innovative therapies for neovascular age-related macular degeneration

ABSTRACT

Introduction: Investigational anti-VEGF treatments for neovascular age-related macular degeneration (nAMD) aim to improve visual outcomes and reduce treatment burden; these include long-acting agents, combination strategies, topical agents, sustained-release, and genetic therapies.

Areas covered: The authors provide a comprehensive review of investigational therapies for nAMD, focusing on therapies currently in clinical trial.

Expert opinion: Long-acting anti-VEGF agents have demonstrated promising results in phase 3 studies, and include Brolucizumab, a single-chain antibody fragment, and Abicipar, a designed ankyrin repeat protein (DARPin). Other unique anti-VEGF agents in current trials include Conbercept – a fusion protein of the VEGF receptor domains, KSI-301 – an anti-VEGF antibody biopolymer conjugate, and OPT-302 – an inhibitor of VEGF-C/D. Strategies to activate the Tie-2 receptor, some in combination with VEGF inhibition, are of interest, with recent trials of Faricimab, ARP-1536, and nesvacumab. Topical anti-VEGF ± anti-PDGF agents, such as pazopanib, squalamine lactate, regorafenib, and LHA510 have shown limited efficacy and/or have not been advanced, although PAN-90806 continues to advance with promising initial results. Sustained-release anti-VEGF treatments, to address treatment burden, include the ranibizumab Port Delivery System, GB-102, NT-503, hydrogel depot, Durasert, and ENV1305. Similarly, genetic therapies, including RGX-314 and ADVM-022, aim to provide sustained anti-VEGF expression from the retina.     

Extended duration strategies for the pharmacologic treatment of diabetic retinopathy: current status and future prospects

ABSTRACT

Introduction: Intraocular pharmacotherapy (vascular endothelial growth factor [VEGF] inhibitors and corticosteroids) has become first-line therapy for diabetic retinopathy (DR). A series of intraocular injections is usually required before disease modulation decreases the treatment burden in some patients, but others with chronic diabetic macular edema may require intensive longer-term therapy.

Areas covered: Recent studies showing successful pharmacologic treatment of proliferative DR will probably lead to increased use of pharmacotherapy, thereby further emphasizing the need for longer duration drugs. Recently approved anti-VEGF drugs (aflibercept) and corticosteroids (dexamethasone and fluocinolone inserts) provide extended durations of action. Longer action anti-VEGF molecules, sustained release devices and pumps, and encapsulated cell technology, may further decrease treatment burden, though regulatory approval may not occur for at least 5 years. Oral medications (danazol and minocycline) and modified topical drugs (loteprednol) will require daily administration but may decrease the frequency of visits to physicians’ offices. Intravitreally administered drugs that target different biochemical pathways are being developed as monotherapy and combination therapy, and their effects on durability remains to be seen.

Expert opinion: The rich development pipeline promises to provide improved therapeutic options in addition to drugs and devices with longer duration of action.     

Pharmacotherapy for treatment of retinal vein occlusion

Introduction: Retinal vein occlusion (RVO) is a common vascular condition, which may cause blindness and impaired vision as a result of the development of macular oedema. The management of macular oedema due to RVO is complex and a multidisciplinary approach is required in order to limit disease progression and achieve a better clinical outcome.

Areas covered: An update and a brief review on the current treatment strategies were provided in patients with macular oedema following RVOs. Evidence available from prospective, multicentre clinical studies evaluating the use of VEGF inhibitors and steroids and from a selective literature search is reported.

Expert opinion: For many years, laser photocoagulation has been considered the standard of care for the treatment of branch RVO. However, new treatment modalities have been evaluated through randomised controlled trials. Recently, anti-VEGF agents and corticosteroids have been shown to be efficacious options in the treatment of RVO.     

Integrin antagonists as potential therapeutic options for the treatment of Crohn’s disease

Introduction: Anti-integrin therapy for the treatment of patients with Crohn’s disease is rapidly evolving. Two agents, natalizumab and vedolizumab, are approved by the United States Food and Drug Administration for the treatment of Crohn’s disease, with vedolizumab the primary anti-integrin used due to a more favorable safety profile. Several other anti-integrins are in various stages of development.

Areas Covered: This review discusses the current state of anti-integrin therapy as well as suggestions for positioning of these agents in clinical practice. Emerging anti-integrin therapies, their underlying mechanisms of action, and available safety and clinical data are also reviewed.

Expert Opinion: Anti-integrins are effective for the treatment of Crohn’s disease, even in patients refractory to other therapies. Their use should be considered in patients with Crohn’s disease who do not respond to, develop non-response to, or have contraindications to anti-TNF therapy. Anti-integrin therapies can be offered as a first biologic therapy, in particular for older patients, patients with concurrent multiple sclerosis (natalizumab only), and in patients with contraindications to anti-TNF therapy. In patients with more severe symptoms, providers should consider co-induction with corticosteroids if possible to hasten remission.     

Current concepts of pharmacotherapy of diabetic macular edema

ABSTRACT

Introduction: Diabetic macular edema (DME) is a sight threatening disease and a major cause for blindness for people in working age. The pathogenesis is multifactorial and complex. The pharmacotherapy of DME addresses both the inhibition of vascular endothelial growth factor (VEGF) by the intravitreal injection of VEGF inhibitors and inflammatory processes by the intravitreal application of steroids. Several trials have been published reporting on the efficacy and safety of these treatments.

Areas covered: This review discusses original research articles including basic science and clinical studies as well as review articles focusing on the role of inflammation and VEGF expression in DME. It discusses newly published clinical trials on intravitreal pharmacotherapy for DME. The literature was searched using Medline/PubMed and was selected given its relevance for the topic to be discussed.

Expert opinion: Our knowledge regarding the pathophysiology of diabetic macular edema has significantly increased. Some of these insights have been successfully transferred into current treatment strategies already including VEGF suppression or anti-inflammatory treatments using steroids. The identification of additional pathophysiological aspects and their relevance as potential treatment targets will be a future challenge in the treatment of DME. A better knowledge on the complex pathophysiology will also help to establish combination strategies.     

玻璃体腔内注射曲安奈德联合激光光凝治疗糖尿病黄斑水肿

目的观察玻璃体腔内注射曲安奈德联合激光光凝治疗糖尿病黄斑水肿的疗效并进行分析。方法30例41眼经眼底检查、荧光素眼底血管照影(FFA)检查确诊的糖尿病黄斑水肿患者21眼行玻璃体腔内注射曲安奈德(TA)联合激光光凝,20眼单纯激光光凝,随访6个月,观察治疗前后患眼视力、眼底情况、眼压以及眼底荧光素血管照影的变化。结果联合治疗组治疗后平均视力为0.36±0.21,与治疗前(0.10±0.07)比较,P<0.001,差异有统计学意义,水肿减轻17眼(80.95%);单纯光凝组治疗后平均视力为0.12±0.09,与治疗前(0.11±0.07)比较,P>0.05,差异无统计学意义;水肿减轻7眼(35.00%)。两组水肿减轻差异显著(χ2=8.91,P<0.005)。结论激光光凝治疗糖尿病黄斑水肿时联合玻璃体腔内注射曲安奈德可促进水肿吸收和视力改善,且安全方便,是一种有效可行的方法。     

Road to remission: a comprehensive review of therapy in uveitis

Introduction: Although uveitis remains the third leading cause of preventable blindness in the US, the care and management of patients with uveitis and ocular inflammatory disease sit poised to make evolutionary if not revolutionary changes in the years ahead. This review serves to highlight important advances in the pharmacologic options available for the treatment of uveitis and ocular inflammation.

Areas covered: Advances in steroid therapy (both topical and extended delivery), updates in the clinical safety of systemic immune modulation, and the emerging therapies for uveitis and ocular inflammatory disease are some of the areas covered in this review.

Expert opinion: Corticosteroids have been the mainstay in the care of patients with ocular inflammatory disorders for many years. Indeed, some physicians still use only steroids for treating inflamed eyes. However, the mission is remission of all corticosteroids in order to prevent the complications associated with long-term corticosteroid use. The goal is to achieve quiescence through aggressive use of corticosteroids to extinguish the fire and then move along to achieve steroid-free remission through immunosuppressant agents.     

Update on the pharmacotherapy for myelodysplastic syndromes

Introduction: For many decades, myelodysplastic syndromes (MDS) were a poorly understood disease group with no approved therapies, and patient management largely relied upon supportive care and intensive chemotherapy. The last decade has seen many scientific and therapeutic advances culminating in the US FDA approval of three drugs for the treatment of these complex malignancies: lenalidomide, azacitidine and decitabine.

Areas covered: This review summarizes the major prognostic risk models that guide treatment decisions and examines the available literature on the mechanism of action and efficacy of each of the approved agents. The authors also discuss evidence supporting the use of other therapies that have entered the standard of care including growth factors, immunosuppressive therapy and stem-cell transplantation.

Expert opinion: While significant progress has been made in understanding the molecular basis of MDS, much of this has yet to translate into therapeutic benefit. Each of the available treatment modalities has shortcomings, and both combination strategies and novel agents are under investigation in clinical trials to improve outcomes.     

Pharmacological management of hypertensive emergencies and urgencies: focus on newer agents

Introduction: Hypertensive crises are categorized as hypertensive emergencies and urgencies depending on the presence of acute target-organ damage; the former are potentially life-threatening medical conditions, requiring urgent treatment under close monitoring. Although several short-acting intravenous antihypertensive agents are approved for this purpose, until recently little evidence from proper trials on the relative merits of different therapies was available.

Areas covered: This article discusses in brief the pathophysiology, epidemiology and diagnostic approach of hypertensive crises and provides an extensive overview of established and emerging pharmacological agents for the treatment of patients with hypertensive emergencies and urgencies.

Expert opinion: Agents such as sodium nitroprusside, nitroglycerin and hydralazine have been used for many years as first-line options for patients with hypertensive emergencies, although their potential adverse effects and difficulties in use were well known. With time, equally potent and less toxic alternatives, including nicardipine, fenoldopam, labetalol and esmolol are increasingly used worldwide. Recently, clevidipine, a third-generation dihydropyridine calcium-channel blocker with unique pharmacodynamic and pharmacokinetic properties was added to our therapeutic armamentarium and was shown in clinical trials to reduce mortality when compared with nitroprusside. In view of such evidence, a change in pharmacological treatment practices for hypertensive crises toward newer and safer agents is warranted.     

Sustained-release fluocinolone acetonide intravitreal insert for macular edema: clinical pharmacology and safety evaluation

Introduction: Inflammation plays a key role in the pathological processes leading to macular edema. Sustained release, low-dose intraocular corticosteroid delivery devices provide long-term anti-inflammatory therapy. Recently, a novel fluocinolone acetonide intravitreal insert (FAi, Iluvien), has been introduced with promising long-term results in the treatment of macular edema.

Areas covered: An extensive review of the literature in the English language was performed to provide comprehensive information on the pharmacological properties of FAi and its safety and efficacy data from various multi-center randomized clinical trials.

Expert opinion: The FAc, Retisert is a sustained-release device that is surgically implanted in the vitreous and has been approved by the US FDA for the treatment of non-infectious intermediate, posterior or panuveitis. FAi was developed after FAc and is an intravitreal corticosteroid delivery system that allows controlled release of therapeutic levels of fluocinolone acetonide (FA). Initial efficacy and safety data suggest that this delivery system maintains clinical effectiveness for up to 3 years after a single delivery of the device. This second-generation fluocinolone delivery device has shown superior safety results in clinical trials compared to the previous version of the higher dose FAc (0.59 mg). Sustained delivery preparations may help to reduce the treatment burden and its associated risks by decreasing the frequency of intravitreal injections. However, much needs to be learnt from additional clinical trials, post-marketing surveillance and results of extension studies. Concerns of intravitreal corticosteroids, such as cataract and increase in intraocular pressure, remain major challenges for this therapeutic strategy.     

Emerging drugs for renal cell carcinoma

Importance of the field: The treatment of metastatic renal cell carcinoma (RCC) has evolved significantly over the past 5 years and targeted therapy has become the standard of care. However, complete and lasting responses to these drugs are still uncommon. Currently, novel agents are being tested in clinical trials.

Areas covered in this review: We discuss approved targeted agents in RCC and emphasize on emerging therapies. We searched the US National Library of Medicine (PubMed) using the terms ‘renal cell carcinoma’, ‘targeted therapy’ and ‘novel agents’, from 1990 to the present. We also searched for abstracts from the meetings of the American Society of Clinical Oncology and Genitourinary Cancers Symposium from 2007 to the present.

What the reader will gain: This paper provides understanding of the approved treatments for advanced RCC as well as the novel agents and their targeted biological pathways.

Take home message: Despite dynamic and recent advances in the management of metastatic RCC much about the molecular biology of this tumor has yet to be delineated. Even more so, strategies of sequential treatment, combination of targeted drugs, mechanisms of resistance, optimal dosages and scheduling remain areas of potential development interest.