Ilya Petrou, MD

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-Fenretinide may be effective in slowing and halting the disease progression of geographic atrophy (GA) in patients with age-related macular degeneration (AMD), according to the preliminary results of ongoing research presented at the Association for Research in Vision and Ophthalmology (ARVO) annual meeting. 

Dry macular degeneration accounts for approximately 90% of all AMD, and in many patients, the classic clinical lesion seen is GA. Research has shown that GA is related to the buildup of lipofuscin and A2E in the retinal pigment epithelium (RPE), leading to the death of the RPE and the overlying photoreceptors, ultimately resulting in severe central vision loss. 

The various therapies tried in the past have not shown any efficacy in slowing, stopping, or reversing the ongoing macular degeneration in patients suffering from this disease. Anecdotally, dietary supplements of xanthine and zinc, likely due to their antioxidant effect, were largely believed to be effective in preventing or reducing the incidence of macular degeneration related to cataracts; however, past trials also have shown this approach to be ineffective in stemming the progression of GA. In the preliminary analysis of an ongoing trial with fenretinide, however, a slowing in the progression of GA was observed, giving hope to patients who are otherwise faced with a bleak prognosis for their disease. 

In the ongoing 2-year, multiple-site, double-masked, placebo-controlled, dose-comparison study, 246 patients with GA due to AMD were randomly assigned to receive either fenretinide 100 or 300 mg or placebo soft-gel capsules once a day. Participants included in the study had a total atrophic area of 2.54 mm² to 20.32 mm² (more than 1 to less than 8 disc areas) in one or both eyes as assessed by fundus photography and fluorescein angiography. Baseline measurements included fundus autofluorescence, visual acuity (VA), reading rate, contrast sensitivity, microperimetry, night vision, serum retinol-binding protein (RBP) levels, and full labs. Patients were to be followed up at 1, 3, 6, 12, 18, and 24 months. The primary outcome was the growth rate of the aggregate GA lesion area. 

Results of the interim analysis undertaken when all subjects had completed at least 12 months showed that at baseline, the mean age of participants was 78 years. These patients had a mean GA lesion area of 9.72 (±5.19) mm

 . The mean serum RBP level was 5.94 (±1.58) mg/dl, and the mean VA was 67.69 (±10.73) letters. Fenretinide treatment was associated with a dose-related reduction in RBP. In patients who received 300 mg once a day and had been followed for at least 18 months, the rate of GA lesion progression appeared reduced, although statistical significance has not been reached in this subgroup analysis. 

The study reported that there was no tendency for lesion area to be correlated to serum RBP before the initiation of treatment. No correlation was found between the age of the patient and lesion size at baseline, nor was any correlation found between lesion area and VA. In an interim analysis of the progression of GA lesions above and below the median at baseline, the smaller lesions seemed to have responded better than the larger lesions. There was evidence of some response in the 100 mg treatment group and a very good response in the 300 mg treatment group in the smaller lesions.  

It appears that by initiating therapy in earlier stages of the disease, the disease is being treated before serious damage has been done, meaning before too much lipofuscin and A2E have been allowed to build up in the RPE. This finding may have an impact on when to start treatment as well as on prognosis. 

The potential advantage of fenretinide treatment for GA is that it is an oral therapy taken once a day, which is very different from periodic injections of growth hormone inhibitors and other painful as well as ineffective therapies that have been tried in AMD.  

Roger Vogel, MD, chief medical officer of Sirion Therapeutics, Tampa, FL, which is investigating fenretinide for GA associated with AMD, is a co-author on the poster presented at ARVO. He said that fenretinide binds with the RBP, resulting in a reduction in the retinol uptake by the RPE. In previous studies in animals, this process caused a reduction of lipofuscin and A2E (toxic end products of the visual cycle) products, which are increased in GA and thought to play an integral role in the etiology of the disease. 

"No other therapeutic approach as of yet has been shown to reduce the progression of GA lesions. The 1-year preliminary data are promising, and if these positive trends are maintained throughout the remainder of the study, this could be the first evidence of a significant advance in the treatment of this disease," Dr. Vogel said. 

In this study, fenretinide appeared to be relatively safe, and the study participants tolerated the drug well. Adverse events included night blindness or delay in dark adaptation, dry eye, anemia, rash, pruritus, diarrhea, and elevated liver enzyme levels. Because no other treatment exists, however, as well as because of the repercussions involved in this progressive blinding disease, patients were willing to continue their therapy because they determined that the potential benefits outweighed the side effects. 

According to Dr. Vogel, the final results will be available at the completion of the 2-year trial in the spring of 2010 and will show whether this oral therapy should be evaluated in phase III studies and might one day become a treatment for AMD.			

Articles

Oral fenretinide given once daily may slow the progression of geographic atrophy in patients with age-related macular degeneration, according to an interim analysis.

Oral fenretinide may slow, halt geographic atrophy in those with age-related macular degeneration

Because of their high efficacy and good tolerability, prostaglandin analogs such as latanoprost (Xalatan, Pfizer), bimatoprost (Lumigan, Allergan), and travoprost (Travatan, Alcon Laboratories) are often used as first-line therapies for the treatment of elevated IOP associated with open-angle glaucoma and ocular hypertension. They are considered by most ophthalmologists as the gold standard in topical glaucoma therapy. These drugs are associated with some side effects, however, including hyperemia, which may lead to cessation of treatment or a switch to other therapies. 

In the Glaucoma Adherence and Persistency Study (GAPS), hyperemia was the most commonly reported side effect, and was the factor most causative in switching therapy. The GAPS data were the foundation for the model presented at the annual meeting of the Association for Research in Vision and Ophthalmology. 

"Switching medications may help the patient find a more efficient and tolerable therapy, but this switch results in higher overall costs," said Dr. Schwartz, of Glaucoma Consultants, Greater Baltimore Medical Center, and Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore. 

Dr. Schwartz and colleagues conducted a recent study aimed at estimating and comparing the cost of changing therapy due to hyperemia in patients with glaucoma treated initially with latanoprost, bimatoprost, or travoprost monotherapy. 

Using the HealthCore Integrated Research database, 13,977 patients with glaucoma diagnosed who were newly treated with latanoprost, bimatoprost, or travoprost monotherapy were identified. From this patient cohort, 8,743 patients started treatment with prostaglandin analog monotherapy only (latanoprost, 5,726; bimatoprost, 1,633; travoprost, 1,384). 

The data showed that across all treatment groups, costs among hyperemia-free patients were $73.67 versus $140.02 for those who discontinued the initial prostaglandin analog due to hyperemia. Results also showed that the per patient costs were lowest in the group initially treated with latanoprost. Using latanoprost as the reference product, and only including cost of initial drug and an additional office visit, total per patient incremental costs due to each hyperemia-driven change in therapy were $5.92 and $5.43 for bimatoprost and travoprost, respectively. 

"Hyperemia is the most frequently reported prostaglandin-[analog]-associated adverse event and occurs less frequently among patients treated initially with latanoprost compared [with] bimatoprost or travoprost, confirming previously reported findings," said Sameer Kotak, BSPharm, MS, associate director of global outcomes research at Pfizer Inc., New York. 

According to Dr. Schwartz, all three prostaglandin analogs can achieve similar IOP reductions, however, latanoprost is less frequently associated with hyperemia. This is likely due to the lack of a double-bond on a benzene ring in its structure that is present in bimatoprost and travoprost and suspected to be the cause of hyperemia with these drugs. 

"All three drugs can achieve similar IOP reductions," Dr. Schwartz said. "Therefore, latanoprost may be the [most] cost-effective choice simply because it has a lower incidence of hyperemia and therefore a higher probability that patients [taking] latanoprost will not need to switch to another therapy as frequently." 

Incidences of hyperemia vary between drug agents and classes. Hyperemia occurs less frequently with other medications such as the beta-blockers, however, the prostaglandin analogs have a higher efficacy in lowering IOP, creating a tug-of-war among efficacy, side effects, and cost, according to S. 

"In clinical practice, we do not expect our patients to tolerate permanent hyperemia. From GAPS, we could see that the hyperemia did not subside over time," Dr. Schwartz said. "We start [treating] them [with] a prostaglandin analog and choose from this group of agents based on clinical judgment. If a patient has either a lack of efficacy or an adverse reaction to the drug, including the degree of hyperemia, then we consult . . . about alternative choices. We could switch within the prostaglandin [analog] class to an agent that has potentially less hyperemia, or switch outside of this class, or consider laser trabeculoplasty." 

Selective laser trabeculoplasty (SLT) has become a very common, efficient, and safe procedure in glaucoma care. Though SLT represents a good therapeutic option, the procedure is not equally effective in reaching the targeted IOP in all patients. The chance of laser therapy allowing patients to stop drop therapy essentially depends upon how far they are from their ideal pressure. 

"If patients [are] dissatisfied with the level of hyperemia, then they are more likely to discontinue the drug," Dr. Schwartz said. "Adherence to therapy has a significant financial impact, and in today's economy, where health-care dollars are being watched very closely, choosing a medication with a lower rate of hyperemia may be the wiser financial choice. 

"If a patient is not adherent, the chance of glaucomatous progression rises, creating higher costs for the patient, insurance company, and overall for society," Dr. Schwartz concluded. 

Hyperemia is one of the main reasons why patients with glaucoma do not adhere to or persist with their topical therapeutic regimen. Patients end up switching to another possibly more tolerable medication, and the changing of medications has significant financial implications. Latanoprost has the lowest incidence of hyperemia among the prostaglandin analogs. Patient adherence is crucial in a chronic progressive disease such as glaucoma, where non-adherence can lead to visual loss and decline in quality of life, creating societal health and economic burdens.

Glaucoma: Hyperemia a common cause for medication changes

"It is not uncommon that, over the course of 3 to 5 years, many [patients with glaucoma] will require more than one IOP-lowering agent to . . . manage and control their IOP [adequately]," said Ronald Fellman, MD, of Glaucoma Associates of Texas, Dallas. "The use of several different pressure-lowering agents can often lead to issues of compliance as well as an increased risk of ocular irritation. Fixed-combination drugs could potentially offer a solution to these problems." 

He reported the results of a study of one such drug, brimonidine tartrate 0.2%/timolol maleate 0.5% (Combigan, Allergan), that sought to evaluate in a clinical setting its efficacy, safety, and tolerability/comfort level in patients with glaucoma. 

In the 2-month, prospective, multicenter, open label, phase IV trial, 399 patients with primary open-angle glaucoma or ocular hypertension were treated twice a day with brimonidine/timolol as a fixed-combination monotherapy or as an adjunctive therapy to glaucoma treatment regimens that could not adequately achieve and control target IOP. Brimonidine/timolol may have been used in addition to or as a replacement for previous therapies as determined by the physician at baseline, he said. 

Participants were evaluated at baseline and at 1 month and 2 months. Eighty percent of patients completed the study. 

The primary outcome measure was mean IOP. Secondary outcome measures were change from baseline IOP, patient and physician satisfaction, and adverse events. IOP data were evaluated by measuring one eye from each patient. If the study medication was used in both of a patient's eyes, then the eye with the higher IOP at baseline was used; if IOP in both eyes was equal at baseline, then IOP in the right eye was measured on the subsequent visits. 

At the 1-month and 2-month study visits, all patients had a lower IOP compared with IOP at baseline. Significantly more patients (76%) reached their target IOP using brimonidine/timolol either as a single agent or adjunct therapy than did before beginning brimonidine/timolol therapy (40.5%). 

Also, 96.5% of patients reported a favorable acceptability and tolerability to brimonidine/timolol, and 55.3% rated brimonidine/timolol as better than medications they previously had used. 

Physicians reported that, compared with baseline, an improvement in both IOP-lowering efficacy and tolerability could be achieved with brimonidine/timolol, even in patients whose IOP previously was considered difficult to control. 

"Also, if the load of potential irritants and/or preservatives to the eye is decreased, the potential for ocular irritation is decreased as well, again leading to a better compliance and better IOP control results," he added. 

Adverse events each occurring in 2.5% or less of study patients included hyperemia, burning, oral dryness, and blurred vision, which, according to Dr. Fellman, is not uncommon with glaucoma medications. The study found that 25% fewer patients reported experiencing symptoms of stinging and burning with brimonidine/timolol compared with the glaucoma regimen they used before the study. Decreases also were found related to eye redness and blurred vision. Unlike controlled studies, this one was performed in a clinical setting, which may best mimic the real world, Dr. Fellman said. 

In this study, patient IOP was measured at various times during the day and throughout the study. This practice certainly mimics daily life in the glaucoma clinic, he added. 

The average reduction of IOP in study patients was approximately 20% (Figure 1). According to Dr. Fellman, this reduction is significant and respectable, particularly because most patients in the study already were taking a relatively powerful prostaglandin analog drop therapy that was not able to control IOP before the application of brimonidine/timolol. Topical prostaglandin analog drugs increase the outflow of aqueous, and brimonidine/timolol is designed to inhibit production and inflow of aqueous. 

"Having a patient [take] a drug that inhibits aqueous production along with a drug that enhances outflow can significantly help in reducing IOP and keeping it at a desired level," Dr. Fellman said. "This is probably why we saw many patients achieve their target pressure range." 

Another FDA-approved fixed-combination drug available for glaucoma in the United States is dorzolamide hydrochloride/timolol maleate ophthalmic solution (Cosopt, Merck), he said, which reportedly has an efficacy similar to brimonidine/timolol in reducing and stabilizing IOP. 

Dorzolamide/timolol also contains a beta blocker, but instead of being combined with an alpha-2 adrenergic receptor agonist (brimonidine), it is combined with a carbonic anhydrase inhibitor (dorzolamide), he said. 

Many physicians probably are underprescribing fixed-combination therapies, particularly for those patients in whom IOP is uncontrolled by their taking two or more medications, according to Dr. Fellman.  

Because such therapies increase patient adherence to therapy while they decrease ocular irritation, which can positively affect therapy adherence, prescribing such medications can simplify the lives of both the patient and physician, he concluded. 

Brimonidine 0.2%/timolol 0.5% fixed-combination ophthalmic solution effectively lowers and controls IOP and is likely to be associated with increased patient adherence to therapy and decreased unwanted side effects such as ocular irritation, according to one ophthalmologist.

Brimonidine/timolol controls IOP in clinical setting

-A recent study found a non-contact applanation tonometer (Ocular Response Analyzer [ORA], Reichert) to be more accurate in the assessment of IOP when compared with the Goldmann applanation tonometer (GAT), particularly when measuring for extremely low and negative IOP, according David A. Luce, PhD, speaking at the annual meeting of the Association for Research in Vision in Ophthalmology. 

"Corneal stiffness forces vary over a wide range, causing both over- and under-estimation of the true IOP," said Dr. Luce, chief scientist, Reichert. "The significant impact of the corneal biomechanical effect on the measurement of extremely low and negative IOP has become more apparent to ophthalmologists, and this realization has led to the dawn of other IOP assessment devices such as [this non-contact applanation tonometer], which can achieve more accurate IOP values by determining the negative Goldmann-equivalent IOP (IOPg) and more accurately compensate for corneal resistance." 

In a recent study, Dr. Luce and colleagues evaluated the effectiveness of the non-contact applanation tonometer in measuring extremely low IOP in eyes with "soft" corneas. Twelve eyes (nine with primary open-angle glaucoma, one with dry eye, and two normal eyes) with negative IOPg (defined as less than 1 mm Hg) were selected for analysis in order to determine the effect of corneal biomechanical compensation using this non-contact applanation tonometer's IOPg and corneal-compensated IOP (IOPcc) parameters. Also, the progression over time of the IOPg and IOPcc was evaluated for two of the participants. 

Results for the 12 eyes showed a mean IOPg of –1.40 mm Hg with a standard deviation of 1.29 mm Hg, ranging from –4.98 to –0.07 mm Hg. The mean IOPcc was +3.02 with a standard deviation 1.66 mm Hg, ranging from +0.2 to +6.3 mm Hg. The IOPcc was greater than zero in all of the eyes, and for the two patients who underwent multiple measurement sessions following glaucoma surgery, the IOPcc showed a regular increasing "recovery" IOP. 

The IOP measurements taken by ophthalmologists are generally accepted to be the true values; however, because very low and negative IOP values can occur when assessing IOP, why they occur is of particular interest. According to Dr. Luce, very low and even negative IOP readings are not at all uncommon following a trabeculectomy. Whatever the cause, the biomechanical properties of the cornea, such as tear film and corneal resistance, can significantly affect the true IOP value, and using a device that appropriately and accurately compensates for this is clearly the optimal IOP measurement technique. 

"Even though extremely low and negative IOP values are an unusual situation, the fact remains that they do occur and can be due to these properties of the cornea," Dr. Luce said. "After we understand why this happens, it would be advantageous to use a device that can accurately compensate for the corneal effect and subsequently produce a true IOP value." 

A non-contact applanation tonometer (Ocular Response Analyzer, Reichert) appears to be more effective than the Goldmann applanation tonometer (GAT) in assessing very low and negative IOP values using the non-contact applanation tonometer's corneal-compensated IOP (IOPcc) parameter. The GAT may be the long-accepted gold standard, but the more accurate assessment of IOP using the non-contact applanation tonometer challenges this gold standard and raises questions as to which of the two techniques is optimal in measuring IOP.

Ilya Petrou, MD

Articles

Glaucoma: Hyperemia a common cause for medication changes

Brimonidine/timolol controls IOP in clinical setting

Low IOP is measured with great accuracy using non-contact applanation tonometer

Oral fenretinide may slow, halt geographic atrophy in those with age-related macular degeneration