New and In-development Treatments For Diabetic Macular Edema

ASHISH SHARMA, MD · BARUCH D. KUPPERMANN, MD, PhD

Diabetic retinopathy is a main cause of vision loss in the United States. The prevalence of diabetes in the United States is currently 7%, meaning that approximately 21 million of the 300 million Americans alive today have diabetes.¹ Diabetic macular edema (DME) is a common manifestation of diabetic retinopathy that causes loss of central vision. Data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) revealed that after 15 years of known diabetes, the prevalence of DME is approximately 20% in patients with type 1 diabetes mellitus (DM), 25% in patients with type 2 DM who are taking insulin, and 14% in patients with type 2 DM who do not take insulin. The prevalence of DME among US diabetics approaches 30% in adults who have had diabetes for 20 years or more. In eyes with mild nonproliferative retinopathy, the prevalence of DME is 3%. This rises to 38% in eyes with moderate to severe nonproliferative retinopathy, and reaches 71% in eyes with proliferative retinopathy.^2-5

Although DME is a multifactorial disease, excess uncontrolled blood sugar damages the retinal microvasculature, causing fluid and lipid to leak into the retina. The relative hypoxia associated with this microvascular damage often triggers a vascular endothelial growth factor (VEGF) production cycle.

The ideal treatment for DME is primary prevention, which was demonstrated by the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS). Prevention does not always work, and retinopathy and DME are not only frequently observed despite good glycemic control but are often the initial presenting signs of diabetes. Once clinically significant macular edema (CSME), as defined by the ETDRS trials is observed, treatment is recommended. Treatment modalities, such as focal or grid argon laser photocoagulation, pars plana vitrectomy with and without peeling of the inner limiting membrane (ILM), as well as intravitreal injections using triamcinolone acetonide or novel VEGF inhibitors, are the most common approaches in use today. Among all, focal and grid photocoagulation are the gold standard. However, the increasing availability of new agents raises the possibility of improving the current standard of care for patients with diabetic maculopathy in the near future, if ongoing clinical trials can show significant benefits.

Below, we summarize some of the new treatment approaches in the pipeline for DME.

INTRAVITREAL ANTI-VEGF

Vascular endothelial growth factor has been shown as an important factor in the occurrence of vascular permeability in ocular diseases such as DME.⁶ In DME, the development of microvascular damage leads to an increase in production of VEGF, which increases vascular permeability by a variety of mechanisms, including affecting endothelial tight junction proteins.⁷

Ranibizumab (Genentech)

This is an antibody fragment that binds and blocks the effects of VEGF-A. Ranibizumab (Lucentis) inhibits all isoforms of VEGF-A. Ranibizumab is being utilized in the following clinical trials to evaluate its usefulness in DME.

READ-2 Study. This is a phase 2 randomized, open-label, uncontrolled, parallel-assignment study. The purpose of this study is to assess the safety and efficacy of the intravitreal injection of 0.5 mg of ranibizumab in people with DME. The study consists of a 2-week screening period (Days -14 to 0), a 6-month treatment period with a primary time endpoint, and an 18-month follow-up and treatment period with secondary time endpoints. Enrollment for the READ-2 Study is complete and includes 126 patients who will be followed for 2 years. Six-month endpoint evaluation of the READ-2 clinical trial data are encouraging. On average, the vision of ranibizumab-treated patients improved to 20/63 at month 6 compared with essentially unchanged acuity scores of about 20/80 in both the laser and the combination treatment groups. In addition, patients treated with ranibizumab had a 56% reduction in excess retinal thickness, whereas only an 11% reduction was seen in those receiving laser treatments.⁸

RIDE & RISE Studies. These are 2 phase 3, double-masked, multicenter, randomized, sham injection-controlled studies of the efficacy and safety of intravitreal ranibizumab injection 0.5 mg every 4 weeks for 24 months in patients with CSME secondary to DM (type 1 or 2). This study is currently recruiting participants with estimated enrollment of 366 patients, and the primary endpoint is the proportion of patients with best-corrected visual acuity (BCVA) improvement of 15 letters.^9,10

RESOLVE Study. This is a randomized, double-masked, multicenter, phase 2 study assessing the safety and efficacy of 2 concentrations of ranibizumab intravitreal injections compared with nontreatment control for the treatment of DME with center involvement. This study is being conducted primarily in Germany and is ongoing, but not recruiting participants.¹¹

CAPTURE (DME) Study. This is a phase 1 randomized, open-label, dose-comparison, safety/efficacy study and is currently recruiting participants. This study is designed to assess a combined approach to treatment using ranibizumab and efalizumab (Raptiva, Genentech) for DME. Enrollment is estimated at 72 patients and completion is estimated to be April 2010. This study assesses the role of efalizumab, which inhibits the binding of leucocyte function-associated antigen-1 (LFA-1) to intercellular adhesion molecule-1 (ICAM-1), thereby inhibiting the adhesion of leukocytes to other cell types. Patients are randomized to ranibizumab 0.5 mg intravitreal alone every 4 weeks, efalizumab alone subcutaneously 1 mg/kg weekly, or combination therapy.¹²

Bevacizumab (Genentech)

Bevacizumab (Avastin) is the full antibody to VEGF-A from which ranibizumab is derived. This anti-VEGF molecule is FDA-approved for systemic treatment of metastatic colon cancer, but not for any ophthalmic indications. Its use in conditions such as age-related macular degeneration (AMD), diabetic retinopathy, and DME is currently off-label.

This NEI/DRCRnet-sponsored phase 2 study recently was completed. It was a randomized, double-masked, parallel-assignment, safety/efficacy study with 121 patients. Subjects were randomly assigned to 1 of 5 groups: focal photocoagulation at baseline (N=19, group A), intravitreal injection of 1.25 mg bevacizumab at baseline and 6 weeks (N=22, group B), intravitreal injection of 2.5 mg bevacizumab at baseline and 6 weeks (N=24, group C), intravitreal injection of 1.25 mg bevacizumab at baseline and sham injection at 6 weeks (N=22, group D), or intravitreal injection of 1.25 mg bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (N=22, group E). Central subfield thickness (CST) on optical coherence tomography (OCT) and BCVA were measured at baseline and after 3, 6, 9, 12, 18, and 24 weeks. The results demonstrate that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial.¹³ This study was designed to provide preliminary data on the dose and dose-interval–related effects of intravitreally administered bevacizumab on retinal thickness and visual acuity in subjects with DME to aid in planning a phase 3 trial.

The Pan-American Collaborative Retina Study Group performed an interventional retrospective multicenter study of patients with DME at 6 centers from 6 countries of patients with DME. They reviewed the clinical records of 88 consecutive patients (110 eyes) with DME. Seventy-eight eyes of 64 consecutive patients with a minimum follow-up of 6 months and mean age of 59.7+/-9.3 years were included in this analysis. Patients were treated with at least 1 intravitreal injection of 1.25 mg or 2.5 mg of bevacizumab. Researchers concluded that primary intravitreal bevacizumab at doses of 1.25 mg to 2.5 mg seem to provide stability or improvement in VA, OCT, and fluorescein angiography in DME at 6 months. Follow-up is still short to make any specific treatment recommendations; however, the results appear promising. Evaluation in a multicenter, randomized, controlled clinical trial with longer follow-up is needed.¹⁴

Pegaptanib Sodium (OSI/Pfizer)

Pegaptanib (Macugen) is an anti-VEGF aptamer, a small piece of RNA that self-folds into a shape that binds to and blocks the effects of VEGF₁₆₅, an isoform of the VEGF family of molecules. The drug has already been approved by the FDA for the treatment of AMD and now is in phase 2/3 randomized, controlled, double-masked, multicenter, comparative trial. The trial is ongoing but not recruiting participants. This study will compare the safety and efficacy of intravitreous injections of 0.3 mg pegaptanib sodium, given as often as every 6 weeks for 2 years, to sham injections in subjects with DME involving the center of the macula. Enrollment is estimated at 300 patients and completion is estimated to be February 2010.¹⁵

Bevasiranib (OPKO)

Bevasiranib is a first-in-class small interfering RNA (siRNA) drug designed to silence the genes that produce VEGF, believed to be largely responsible for causation of DME.

The RNAi Assessment of Bevasiranib in DME, or RACE trial, was a pilot phase 2 investigation of the safety and preliminary efficacy of bevasiranib in patients with DME. This 48-patient multicenter, double-masked and randomized trial studied 3 dose levels of bevasiranib. In this pilot study, there was a trend showing a decrease in macular thickness between weeks 8 and 12, where the higher doses result in a larger reduction in thickness than the lowest dose. This trial also showed no detectable levels of bevasiranib in patients at all doses and time-points. These results further support the findings of the CARE study and serve as a confirmation of the safety and biologic activity in a second VEGF-driven ocular condition.¹⁶

VEGF Trap (Regeneron)

The VEGF Trap-Eye is a fully human, soluble VEGF receptor fusion protein that binds all forms of VEGF-A along with the related placental growth factor (PlGF). The VEGF Trap-Eye is a specific and highly potent blocker of these growth factors.

Encouraging results were announced on a phase 1 study of VEGF Trap-Eye in treating DME. In the open-label safety study, the drug was administered as a single 4.0-mg intravitreal injection to 5 patients with longstanding diabetes and multiple prior treatments for DME. The single injection resulted in a marked decrease in mean central retinal thickness and mean macular volume throughout the 6-week observation period. Further larger studies are under way, and the compound is also in phase 3 trials for choroidal neovascularization associated with AMD.¹⁷

TOPICAL DROPS

Topical instillation of ophthalmic drops is the most common method used to administer treatments for ocular disease. However, topical therapy does not penetrate to the posterior segment readily, so drops have rarely been used for retinal diseases. These new drugs are small, have appropriate polarity, and are designed to reach to the posterior segment by transcorneal and/or transconjuctival/transscleral routes.

Mecamylamine (Comentis)

Mecamylamine inhibits endothelial nicotinic acetylcholine (nACh) receptors and decreases angiogenesis and vascular permeability via this novel anti-VEGF pathway. A phase 2 study of the safety and bioactivity of topical ocular mecamylamine for the treatment of DME was recently completed. It was given twice a day in patients with DME and patients were treated for 12 weeks.¹⁸ Results are forthcoming.

BROMFENAC (ISTA)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce vascular hyperpermeability associated with tissue inflammation by inhibiting prostaglandin synthesis, and increased inflammatory markers have been found in diabetic retinopathy in patients treated with NSAIDs.¹⁹ Bromfenac ophthalmic solution (Xibrom) is a potent NSAID with prolonged pharmacokinetics allowing twice daily dosing, and has been FDA-approved for inflammation associated with cataract surgery.

A nonrandomized, open-label, uncontrolled phase 1 pilot study is currently recruiting participants to assess safety and biologic activity of topical bromfenac ophthalmic solution, 0.09%, in subjects with diffuse DME refractory to laser.²⁰

STEROIDS

Increasingly, corticosteroids have been employed to treat macular edema. Corticosteroids control DME by attacking various pathophysiological factors responsible for causation of DME such as inhibition of inflammatory mediators and VEGF with improvement of vascular homeostasis.

Nova63035 (Novagali)

Nova63035 is a unique injectable emulsion allowing the sustained release of the prodrug over 6 to 9 months due to Eyeject technology. The prodrug is converted into the drug by the enzymes that are present in the retina and choroid and absent in the vitreous, which makes this drug safe and specific.

This is a phase 1, nonrandomized open-label, dose-escalation clinical study to assess the safety and tolerability of NOVA63035 in patients with DME secondary to diabetic retinopathy. This study is currently recruiting the participants. Enrollment is estimated at 18 patients and completion is estimated to be February 2010.²¹

Triamcinolone Acetonide (TA)

Intravitreal triamcinolone acetonide (IVTA) has been proposed as an alternative treatment for eyes with DME refractory to laser photocoagulation, and there is growing evidence that it effectively reduces macular thickness and improves visual acuity in DME. There are various trials comparing safety and efficacy of TA with another treatment.

Intravitreal Triamcinolone Acetonide vs Laser for DME. This is an NEI-sponsored phase 2 trial conducted by the DRCRnet, and is a randomized, masked, parallel-assignment, efficacy study. The study compares IVTA and laser photocoagulation for DME. The study was recently completed with enrollment estimated at 693 patients. Data will be available shortly (potentially released by the date of publication of the current article).²²

IBEME Study. This is a phase 1 randomized, prospective study to compare the efficacy and safety of IVTA and intravitreal bevacizumab injection for refractory diffuse DME. Twenty-eight patients were randomly assigned to receive a single intravitreal injection of either 4 mg/0.1 mL TA or 1.5 mg/0.06 mL bevacizumab. Central macular thickness was significantly reduced in the IVTA group compared with the bevacizumab group at weeks 4, 8, 12, and 24.²³

Figure 1. A. Version of Posurdex tested in phase 2. B. Applicator for insertion of Posurdex. C. Version of Posurdex tested in phases 2b and 3.

STEROID-CONTAINING DRUG DELIVERY IMPLANTS

Long-acting intravitreal drug delivery implants can overcome many of the limitations of other therapeutic approaches, such as frequent intravitreal injections or systemic side effects.

Posurdex Implant (Allergan)

The Posurdex implant (Figures 1A, 1B, and 1C) is a sustained-delivery formulation of dexamethasone. This is a biodegradable implant with a polylactic glycolic acid polymer as the delivery vehicle, which undergoes hydrolysis with degradation to lactic acid and glycolic acid, 2 naturally occurring metabolic byproducts that are then further broken down to water and carbon dioxide. Two different dexamethasone dose (350 μg and 700 μg) implants were evaluated in a 6-month, phase 2, multicenter, randomized clinical trial in 315 patients with refractory, persistent macular edema due to various causes and showed positive results.²⁴ At 6 months, 18.1% of patients in the 700-μg group had BVCA improved by 15 letters or more, compared to 14.6% of patients in the 350-μg group and 7.6% of patients in the observation group.

A phase 3, randomized, double-masked, dose-comparison, placebo-controlled, parallel-assignment study is currently underway and recruiting patients. The study is designed to evaluate the safety and efficacy of an intravitreal implant of dexamethasone for the treatment of DME. Enrollment is planned for 860 patients; follow-up is to last a total of 3 years. Completion is estimated to be June 2014.²⁵

A phase 3b, randomized, double-masked, active-control, parallel-assignment study will evaluate the safety and efficacy of the intravitreal implant of dexamethasone with laser treatment vs laser treatment alone in patients with DME. This study is currently recruiting participants. Enrollment is estimated at 250 patients and completion is estimated to be June 2009.²⁶

Retisert Implant (Bausch & Lomb)

The only FDA-approved steroid implant Retisert (Figure 2) contains fluocinolone acetonide (FA) within a small reservoir containing only 0.59 mg of drug, which delivers chronic sustained low levels of the drug (approximately 0.5 μg/day) into the vitreous cavity for up to 3 years. The Retisert implant demonstrated significant efficacy in patients with uveitis and was approved by the FDA for this indication.

A 3-year, randomized, dose-masked, 3-arm, controlled, phase 2 pilot study was conducted to evaluate the safety and efficacy of the intravitreal FA implants (0.59 mg and 2.1 mg), when compared to laser photocoagulation in the treatment of patients with DME. The study was completed with 40 patients.²⁷

Another study was a phase 2/3, multicenter, randomized, masked, parallel-group, controlled study in patients with DME, comparing Retisert (0.59 mg) with control therapy (standard of care: repeat macular grid laser or observation). The objective was to evaluate the safety and efficacy of the intravitreal FA implant in the treatment of patients with DME. The study was completed with 196 patients.²⁸ Pearson and colleagues reported that at 36 months, the implant resolved edema at the center of the macula and produced a 3 or more line improvement in visual acuity in a significant proportion of eyes studied. At 36 months, no evidence of edema was present in 58% of implanted eyes compared with 30% of eyes that received the standard of care (P<.001). Although these are good results, safety concerns have limited the utilization of the Retisert implant in patients with DME. Overall, more than 90% of patients receiving a Retisert implant require cataract surgery, and nearly 40% of patients require glaucoma surgery within 3 years.²⁹

Figure 2. Comparative sizes of Medidur, Retisert, and Vitrasert.

Medidur Implant (Alimera)

This is a similar but smaller fluocinolone-based implant that has 2 formulations — one that delivers 0.2 μg/day and the other 0.5 μg/day. Medidur has 2 models; 1 is designed to last approximately 3 years, and the other lasts approximately 18 months.

Enrollment in the phase 3 FAME (Fluocinolone Acetonide in DME) trial, which is evaluating a daily dose of 0.2 μg and 0.5 μg of FA to the retina, has been completed. FAME is a double-masked, randomized, multicenter study involving more than 900 patients in the United States, Canada, Europe, and India. Safety and efficacy will be assessed at 2 years, and patients will be followed for 3 years. Results from this trial will help to determine if Medidur FA is effective and capable of reducing the steroid-induced side effects seen in the Retisert trial.³⁰

I-vation Implant (SurModics)

The prospective, randomized, double-masked STRIDE (Sustained Triamcinolone Release for Inhibition of Diabetic Macular Edema) trial assesses the safety and tolerability of the I-vation TA implant (Figures 3A, 3B, and 3C) in 30 patients. Dugel and colleagues reported results of a 6-month interim analysis. In the study, patients were randomized to either a slow-release or fast-release implant containing 925 μg of TA. At 6 months, the proportion of patients with BCVA of at least 70 ETDRS letters increased from 14% to 46% in the slow-release group and from 18% to 41% in the fast-release group. Eight percent of patients in the slow-release group and 18% in the fast-release group gained more than 15 letters. Macular thickness improvement was reported with the use of both implants. Mean IOP increased from 13.9 mm Hg to 16.1 mm Hg in the slow group and from 14.3 mm Hg to 16.4 mm Hg in the fast group at 6 months. The patients in the STRIDE study will be followed for 3 years.³¹

SUBCONJUNCTIVAL ADMINISTRATION

This approach to drug delivery is safer and less invasive than intravitreal injection and also offers the potential advantage of localized, sustained-release drug delivery. Drug delivery by this route uses the large surface area of the sclera for drug penetration. However, subconjunctival delivery is associated with greater systemic exposure than intravitreal delivery, due to the presence of conjunctival and orbital blood vessels and tissue.

Sirolimus (MacuSight)

Sirolimus (rapamycin) is a relatively new immunosuppressant drug approved by the FDA for systemic use in renal transplantation. It inhibits the mammalian target of rapamycin (mTOR). According to its developers, this drug acts by immunosuppressive, antiangiogenic, antimigratory, antiproliferative, antifibrotic, and antipermeability mechanisms. This drug is 92% protein-bound with a half-life of 57 to 63 hours.

For the eye, sirolimus is injected either subconjunctivally or intravitreally, and lasts up to 3 months when given subconjunctivally. The drug has shown positive interim data from a phase 1 study in patients with chronic, clinically significant DME. Results from this prospective study of 50 patients demonstrated that sirolimus was safe and well-tolerated in all doses tested with 2 different routes of administration. Additionally, investigators noted improvements in visual acuity and foveal thickness reductions for up to 180 days following a single administration of sirolimus. This finding raises the possibility that sirolimus may be fundamentally changing the course of diabetic retinopathy through its impact on the mammalian target of rapamycin pathway rather than simply reversing macular edema in a more nonspecific way.³²

A phase 2, randomized, double-masked, placebo-controlled, dose-ranging clinical study to assess the safety and efficacy of subconjunctival injections of sirolimus in patients with DME secondary to diabetic retinopathy is currently recruiting participants, with estimated enrollment of 120 patients, and the primary endpoint is the proportion of patients with BCVA improvement by ETDRS. The study has 3 experimental and 1 placebo arm. Two conjunctival injections of 220, 440, and 880 μg will be tested. Completion is estimated to be March 2012.³³

ANTI-TNF-ALPHA

Tumor necrosis factor (TNF, cachexin, or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in inflammation and is a member of a group of cytokines that stimulate the acute phase reaction. Anti-TNF-α could be helpful to reduce inflammation and improve DME.

Figure 3. A. The I-vation insert. B. Where the insert sits inside the eye. C. The size of the I-vation insert.

Infliximab (Johnson & Johnson)

Infliximab (Remicade) is a genetically engineered antibody against a molecule in the body called TNF-α. It neutralizes the effects of TNF-α by binding to it. There is a phase 1, nonrandomized, open-label, single-group assignment study currently recruiting participants. The trial will study safety and tolerability of intravitreal infliximab in patients with refractory DME or choroidal neovascularization secondary to AMD. All subjects will receive 0.5 mg/0.05 mL of infliximab by intravitreal injection at their first treatment visit or the 6 weeks visit if eligible for a repeat injection. Enrollment is estimated at 4 patients and completion is estimated to be December 2008.³⁴

LIPOLYTIC AGENT
Choline Fenofibrate SLV348 (Solvay)

Fenofibrate exerts its therapeutic effects through activation of peroxisome proliferator-activated receptor a (PPARa). This increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III.

This study is not yet open for participant recruitment. This is a phase 2, 1-year, placebo-controlled, randomized study. The purpose of this study is to evaluate the effect of choline fenofibrate (SLV348) on macular edema measured by OCT in subjects with DME. Enrollment is estimated at 106 patients and completion is estimated to be October 2009.³⁵

NONSURGICAL POSTERIOR VITREOUS DETACHMENT
Microplasmin (ThromboGenics)

Vitreous traction is one of the causes for persistence of DME in some cases. Creating a posterior vitreous detachment (PVD) could be of help in these cases. Although instrumentation and techniques for vitreous surgery have greatly improved in recent years, it can still cause complications such as retinal breaks, retinal detachment, and retinal nerve fiber damage.^36,37

Therefore, it would be helpful to have a biochemical agent that could cleave the vitreoretinal interface selectively without damaging the retina. Human microplasmin is a 29 kD protein containing 1 protease active site of plasmin.

A phase 2, randomized, sham-injection controlled, double-masked, ascending-dose, dose-range-finding trial (MIVI-II) is currently recruiting participants. This is a multicenter study to compare multiple doses of intravitreal microplasmin for nonsurgical PVD induction for treatment of patients with DME.³⁸

COMBINATION

Combination therapy can attack more than 1 pathophysiological factor responsible for DME simultaneously.

Laser-Ranibizumab-Triamcinolone for Diabetic Macular Edema (LRT for DME) Trial

This is a NEI/DRCRnet sponsored phase 3 randomized, double-masked, parallel-assignment efficacy study. The purpose of the study is to find out which is a better treatment for DME: laser alone, laser combined with an intravitreal injection of triamcinolone, laser combined with an intravitreal injection of ranibizumab, or intravitreal injection of ranibizumab alone. At the current time, it is not known whether intravitreal steroid or anti-VEGF injections, with or without laser treatment, are better than laser alone. It is possible that 1 or both of the types of injections, with or without laser treatment, will improve vision more often than will laser without injections. However, even if better vision outcomes are seen with injections, side effects may be more of a problem with the injections than with laser. Therefore, this study is being conducted to find out whether the benefits of the injections will outweigh the risks.

This study is currently recruiting participants. Enrollment is estimated at 701 patients and completion is estimated to be March 2011.³⁹

PROTEIN KINASE BETA INHIBITOR

Diabetes-induced activation of PKC ß appears to mediate increases in retinal vascular permeability and neovascularization in animal models and changes in retinal blood flow in diabetic patients. Protein kinase C inhibitor ameliorates the adverse effects of high glucose on microvasculature.

Ruboxistaurin (Eli Lilly and Company)

Ruboxistaurin works by limiting the overactivation of PKC β, a naturally occurring enzyme that has been linked to the development of diabetic retinopathy. Last year, the research team presented results of 2 phase 3 trials, which included 813 patients with moderate to severe nonproliferative diabetic retinopathy, who were randomly assigned to 32 mg daily ruboxistaurin or placebo. Results showed a 41% relative reduction in the risk of further vision loss over 3 years, the investigators maintained.

A nonrandomized, open-label, phase 3 study to evaluate the effect of additional ruboxistaurin treatment on vision loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy and any severity of DME is ongoing but not recruiting participants at this point.⁴⁰

CONCLUSION

DME management in the past few years has changed dramatically. This is an exciting and ever-changing field. We are currently witnessing the emergence of some of the most promising treatments. However, we hope that with these new emerging drug-delivery technologies and new drugs, the best is yet to come. RP

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