ICAM-1 expression is increased in both diabetic animal models and in human patients (McLeod et al. 1995; Miyamoto et al. 1999). ICAM-1 also plays an important role in VEGF-induced vascular permeability (Miyamoto et al. 2000). Inhibition of ICAM-1 was shown to block leukostasis in diabetic rats via the use of a blocking antibody (Miyamoto et al. 1999). More recently, a small molecule inhibitor of the ICAM-1 ligand, LFA-1, was shown to block leukostasis as well (Rao et al. 2010). This is of particular interest as this ophthalmic therapeutic, SAR 1118, has been used in clinical trials formulated as eye drops (NCT00882687) in the treatment of allergic conjunctivitis.

In other lines of study, it has been demonstrated that processes of Müller glia penetrate the vascular walls of the capillary bed, primarily on the arterial side (Kern and Engerman 1995; Bek 1997b; Bek 1997a). Loss of capillary perfusion leads to a signal to initiate the proliferation of vascular endothelium indicative of neovascularization. The appearance of new blood vessels in either the retina or the optic disc heralds the progression of diabetic retinopathy into the proliferative stage and so is referred to as PDR. Here, the pathophysiology is no longer restricted to the retina. New blood vessels, often associated with fibrous material, emerge from the retina to grow on the posterior surface of the vitreous and even move into the vitreous gel (Chew 2000).

21.3.2.2  Therapeutics Either in Current Use or in Clinical Trials

Although one might consider general antidiabetic therapeutics as prophylactic agents for blocking the development of ocular complications, a discussion of this vast area is beyond the scope of this chapter. For this reason, we will limit our discussion to therapeutics targeting retinopathy specifically. We will divide this section into a discussion of therapeutics for DME followed by a discussion of therapeutics for PDR. A list of the current therapeutics either in use or in clinical trial for the treatment of DME is given in Table 21.2 while trials of therapeutics involving PDR or DR (without concern for whether the patient is suffering from DME or PDR) are given in Table 21.3.

Therapeutics for Diabetic Macular Edema (DME)

Corticosteroids:  Edema is often a consequence of inflammation and corticosteroids, powerful anti-inflammatory drugs, have been found to be efficacious in the treatment of DME. A discussion of the mechanism of action of the corticosteroids is provided earlier in this chapter. TA, dexamethasone, and FA are administered, primarily by either intravitreal injection or by intravitreal implant. Efficacy has been established in multiple clinical trials [for review see Kiernan and Mieler (2009)].

Antiangiogenic therapeutics:  In addition to their role as blockers of neovascularization, VEGF inhibitors also have the property of decreasing vessel permeability. This class of drug has been discussed extensively earlier. Pegaptanib has been investigated in several clinical trials. For example, intravitreal injections of 0.3 mg pegaptanib were found to improve both vision and mean central macular thickness in approximately 30% of patients (Querques et al. 2009). Bevacizumab has also been investigated.

In a randomized prospective study, bevacizumab was compared with laser coagulation for the treatment of DME (Michaelides et al. 2010). An intravitreal dose of 1.25 mg was administered from 3 to 9 times every 6 weeks and ETDRS letters assessed at the 12-month time point. Vision was improved in approximately 30% of patients as compared to 8% for the laser treatment group. Ranibizumab, likewise has been examined. A randomized trial was performed examining intravitreal injections of ranibizumab in combination with laser treatment (either immediate or deferred) as compared to TA in combination with laser treatment (Elman et al. 2010). Results were reported after 1 year and showed that ranibizumab with prompt laser treatment was superior to triamcinolone. The most recent addition to the VEGF blocking armamentarium: aflibercept (VEGF Trap-Eye) has also been examined in an exploratory study (Do et al. 2009). Five patients with DME were given a single dose of aflibercept and examined at 6 weeks. The drug was well tolerated and four of the five showed improvement. All of the trials completed so far have been of short duration. Clinical trials are ongoing for all of these therapeutics. Phase 3 trials are in process for bevacizumab and ranibizumab (examples include NCT00417716, NCT00997191, NCT00473330, NCT00473382, and NCT00444600).

As mentioned earlier, PAI-1 appears to play an important role in events that occur within the ECM, including VEGF signaling. It has been reported that choline fenofibrate markedly decreases the expression of PAI-1 via the activation of SHP (small heterodimer partner) and the AMP-activated protein kinase (AMPK) (Chanda et al. 2009). SHP is a transcription factor (part of the nuclear receptor superfamily) involved in many aspects of cell growth and survival via the regulation of cholesterol and glucose metabolism. AMPK is known for its involvement in the regulation of energy metabolism and more recently has been appreciated as a mediator of vascular responses to stress (Nagata and Hirata 2010). Use of this therapeutic is currently under investigation in a phase II clinical trial sponsored by Abbott Pharmaceuticals (NCT00683176).

Modulators of intracellular signal transduction:  Activation of PKC is a consequence of VEGF receptor engagement and block of PKC activity has been shown to reduce VEGF-mediated vascular permeability (Aiello et al. 1997). Ruboxistaurin, an orally active PKC-b inhibitor underwent an initial clinical trial in which 41 patients with DME were followed for 18 months (Strom et al. 2005). This small trial found that patients with the greatest amount of leakage showed the most improvement. A much larger trial was performed involving 685 patients receiving either 32 mg ruboxistaurin per day or placebo for 36 months (Davis et al. 2009). ETDRS (early treatment of diabetic retinopathy study) visual acuity and fundus photographs were taken every 3–6 months. While both groups lost visual acuity over time, the ruboxistaurin group declined at about half the rate of the placebo group, indicating some clinical efficacy.

PKC interacts with a number of other signal transduction cascades creating a complex network. Within this network there exist certain points of intersection at which significant regulatory activity may occur. One such point of regulation may be found in the protein termed mTOR (mammalian target of rapamycin). Pathways involving PKC, PLC, AKT, and MAPK as well as others converge on this protein

making it a target of great interest. The mTOR signaling pathway plays an important role in the proliferation, differentiation, growth, and survival of many different cell types (Foster and Fingar 2010). Rapamycin, known clinically as sirolimus, was first used as an immunosuppressive drug and subsequently for the treatment of cardiac artery stent restenosis. It is the sensitivity of the mTOR2 complex to growth factors that has directed interest in this protein as a therapeutic target for DME. Cell culture studies have shown that HIF-1a, the ischemia sensitive transcription factor responsible for upregulating VEGF gene expression, is stimulated through an mTOR-mediated process. While no clinical data have been published, a phase II clinical trial examining sirolimus in the treatment of DME, sponsored by the National Eye Institute, is currently in progress (NCT00711490).

Anti-inflammatory therapeutics:  Elevated prostaglandin levels, associated with inflammation, will disrupt the tight junctions of perifoveal retinal capillaries (Tranos et al. 2004). NSAIDs inhibit the enzyme, cyclooxygenase, and so block prostaglandin production. There exist two isoforms of cyclooxygenase: COX-1 and COX-II. Studies with isoform specific inhibitors have determined that COX-II, the isoform associated with inflammation signaling, is primarily responsible for diabetes-mediated prostaglandin production (Ayalasomayajula et al. 2004). NSAIDS, used for many different ocular conditions, are also useful for the treatment of DME. Using PLGA encapsulation, a single dose of celecoxib is capable of blocking diabetes-induced vascular leakage (Ayalasomayajula and Kompella 2005; Amrite et al. 2006). Interestingly, inhibition of COX-II (but not COX-I) in diabetic rats decreases VEGF production demonstrating that inflammation underlies neovascularization in this case (Ayalasomayajula and Kompella 2003). Most recently, intravitreal diclofenac has been examined for the treatment of macular edema from multiple etiologies including DME (Soheilian et al. 2010). This small pilot study examined five patients with DME, treating them with a single intravitreal dose. The results were moderate. Two out of five patients improved, one worsened, and two remained the same. A separate study examined the combination of oral celecoxib and laser coagulation (Chew et al. 2010). Again the results were equivocal. A slight improvement over placebo was observed but there was no improvement over laser coagulation. A clinical trial examining bromfenac sodium in DME patients, sponsored by ISTA Pharmaceuticals, is in progress (NCT00491166).

Inhibition of retinal detachment.  Microplasmin, discussed earlier, has applications to DME. A study of the efficacy of Microplasmin in DME, sponsored by Thrombogenics (NCT00412451), is currently underway.

Therapeutics for Diabetic Retinopathy and Progressive Diabetic Retinopathy.

Therapeutic agents that block VEGF have been covered in detail previously. Many of them are being assessed for the treatment of diabetic retinopathy. A large number of clinical trials are ongoing. A list of the current therapeutics excluding VEGF blockade either in use or in clinical trial for the treatment of diabetic retinopathy and progressive diabetic retinopathy is given in Table 21.3.

Modulators of intracellular signal transduction:  In addition to treating DME, ruboxistaurin is also being considered for more advanced forms of diabetic retinopathy.

The concept was tested in a multicenter randomized double-masked placebo controlled clinical trial involving 252 subjects with mild non-PDR (PKC-DRS- Study-Group 2005). Unfortunately, the trial showed no statistical benefit for the experimental group.

Angiotensin II inhibition:  It has been known for some time that tight blood pressure control, along with glycemic control, reduces the incidence and severity of diabetic retinopathy (UK-Prospective-Diabetes-Study-Group 1998b; UK-Prospective- Diabetes-Study-Group 1998a). Angiotensin II is one of several targets, the inhibition of which, achieves the goal of decreased blood pressure. Candesartan cilexetil, a small molecule inhibitor of angiotensin II produced by AstraZeneca, has been shown to block retinal damage in a rat model of diabetes (Sugiyama et al. 2007). A large clinical trial (the DIRECT trial, NCT00252720 and NCT00252733) has just been completed examining the effects of candesartan cilexetil on the development and severity of diabetic retinopathy in both type 1 and type 2 diabetes patients. While a report of the baseline characteristics of the study has been published (Sjolie et al. 2005), the results of the trial have not been made available as of this writing.

Somatostatin:  Somatostatin is a pleiotropic neurohormone which plays a role in retinal physiology. Electrophysiological studies have suggested that somatostatin plays diverse roles as a neurotransmitter, a neuromodulator, and a trophic factor (Ferriero and Sagar 1987; Zalutsky and Miller 1990; Ferriero et al. 1992; Akopian et al. 2000). An antiangiogenic function for somatostatin in the retina was first reported in 1997 (Smith et al. 1997). The mechanism involves the inhibition of IGF-1 (see Sect. 21.3.3). Others have confirmed these results using various tools including the somatostatin mimetic: octreotide (Higgins et al. 2002; Dal Monte et al. 2003). Novartis has sponsored several recently completed clinical trials examining the safety of octreotide administered in a microsphere formulation to patients with diabetic retinopathy (NCT00248157, NCT00248131, NCT00131144, and NCT00130845). Results from these studies have not been released as of this writing.

Clearance of vitreal hemorrhage:  Vitreous hemorrhage in PDR contributes to decreased vision and also obscures the retinal pathology, making accurate diagnosis difficult. Clinicians often wait to see if the hemorrhage resolves (watchful waiting). If it does not resolve and the clinician feels that it is necessary to remove it then vitreoretinal surgery is performed. Several therapeutics which have the capability of clearing the hemorrhage material are currently being investigated. Hyaluronidase helps to break down the vitreous by cleaving glycosidic bonds of hyaluronic acid, thus increasing the ability of cells to diffuse through this medium and for lysed red blood cells to be phagocytosed. The results of two phase III trials (sponsored by ISTA Pharmaceuticals) were reported in 2005 demonstrating that the treatment is safe (Kuppermann et al. 2005b) and efficacious (Kuppermann et al. 2005a). Patients with PDR received a single dose of purified ovine hyaluronidase (Vitrase) and were observed for several months. Within 1 month 30% of patients had cleared enough of the hemorrhage to allow diagnosis and this population increased to 45% by the third month. A current phase III trial of a related therapeutic, Vitreosolve (Vitreoretinal Technologies, Inc.) is currently underway (NCT00908778).