Pharmacy & Therapeutics - December 2008 - (Page 722)

MEETING HIGHLIGHTS: Ophthalmic Summit and Onmark Forum demonstrated mixed results, although there is continued interest. Interest in intravitreal corticosteroids (e.g., triamcinolone acetonide [TA]), with their potent anti-inflammatory and anti-angiogenic effects, also continues. Their tendency to promote cataracts and glaucoma, however, limits the use of these agents. A fluocinolone acetonide intravitreal implant (Retisert, Bausch & Lomb), another steroid implant (Posurdex, Oculex/ Allergan), and a preservative-free and solvent-free emulsion (Nova-63035, Novagali Pharma) have all been tested with some success. The Diabetic Retinopathy Clinical Research Network (DRCR.net) trial of patients with DME tested two Allergan TA doses against laser in more than 800 eyes. Patients were treated at four-month intervals for two years. Measures of corneal thickness and visual acuity for the 4-mg dose were superior to laser at four months and were equivalent to laser at one year. Beyond 16 months, however, laser treatment was superior. Visual acuity was superior to laser with TA at eight months but not at a year or beyond. With TA, cataracts occurred in 51% of patients and intraocular pressure increased more than 10 mm Hg in 33%. Dr. Edelman said that TA was a very good drug in an optimized preservative-free formulation that failed to meet its primary endpoint of superiority to laser at two years; however, the many patients who were withdrawn from steroids because of adverse effects undoubtedly affected the analysis. Among intravitreal anti-angiogenesis and anti-vascular endothelial growth factor (VEGF) agents, Pfizer’s pegaptanib sodium injection (Macugen) has demonstrated some benefit on visual acuity measures, macular thickness, the need for focal laser therapy, and regression of neovascularization. Ranibizumab (Lucentis, Genentech) is being evaluated for DME, as is Genentech’s intravitreal bevacizumab (Avastin) in studies comparing it with laser and in combination with laser. Opko Health, Inc., has completed phase 2 trials of a small interfering RNA molecule bevasiranib sodium (Cand5) in DME. Pfizer’s gene-silencing, RNA-inter ference agent (siRNA), known as PF-04523655, a negative regulator of mTOR, is also being compared with laser in phase 2 testing. Macusight, Inc., is testing rapamycin, an immunosuppressant/mTOR pathway modulator. Dr. Edelman discussed oxidative stress as a postulated cause of diabetic retinopathy, citing studies showing an association between vitreous reactive oxygen species and proliferative severity.1 He noted, however, that although animal studies suggest a benefit of vitamin C in iris endothelial dysfunction, no convincing clinical evidence has shown that antioxidants improve outcomes in patients with diabetic retinopathy. He concluded with a caution to researchers: “Given the work in diabetic retinopathy by retinal specialists with multiple forms of laser and vitrectomy, it’s going to take a very good drug and a very safe drug to be successful in this area.” presents challenges in diagnosis and that its mechanisms are inadequately understood help make it difficult to choose clinical trial endpoints. Dry eye can be easily mistaken for seasonal allergic conjunctivitis or LASIK-associated dry eye, because perceived dryness and foreign-body presence, changes in the blink rate, ocular discharge or irritation, and burning or itching are symptoms common to both conditions. Furthermore, symptoms may occur at early stages of the disease before any clinical signs become evident, such as corneal and conjunctival redness, decreased tear production, non-uniform tear film, exposed ocular surface, and transient blurry vision. Many generally noninvasive clinical diagnostic tests for dry eye are available, but the sensitivity, reproducibility, and predictive power of these tests are generally poor. Dr. Rittenhouse singled out tear film osmolarity tests as promising but said that their predictive value was recently reported as only 73%. Furthermore, these tests are improving and becoming easier to apply, but the instrumentation is still in the testing stages and is not commercially available. Current therapeutic approaches include the use of tear substitutes, lubricants, or palliatives; tear-retention strategies; nutritional aids (e.g., flaxseed), anti-inflammatory drugs and immune modulators (cyclosporine, corticosteroids, tetracycline antibiotics); and secretagogues. Products under investigation for dry eye include Ista’s ecabet (formerly made by Tanabe/Senju), Duramycin (Moli1901, Lantibio, formerly made by Molichem), non-antimicrobial doxycycline (ALTY0501, Alacrity Biosciences), pimecrolimus (Novartis), rebamipide (Acucela/Otsuka), diquafosol (Prolacria, Allergan/Inspire), rimexolone (Vexol, Alcon), and cyclosporine A ophthalmic suspension (Restasis, Allergan). Other products are listed in ClinicalTrials.gov. Citing the FDA’s approval of Restasis (a calcineurin inhibitor) as an example of a problematic process, Dr. Rittenhouse stated that the choice of inclusion and exclusion criteria can make or break a program. Including patients who have no residual ability to make tears or whose disease is so mild that they respond well to artificial tears can confound results. With this latter group, therapeutic effects of the vehicle given as the control drug can reduce the efficacy signal of the tested drug. With Restasis, the vehicle was Endura, which itself has demonstrated some efficacy. The inaccuracy of diagnostic tests, inconsistencies in disease classification, and irregular correlation between signs, symptoms and disease stage added further to the uncertainties of the drug approval status for Restasis in treating dry eye. The FDA advisor y committee panel of experts recommended against approval of Restasis in July 1999, citing failure to meet the standard of replicating benefit in signs or symptoms in two well-controlled phase 3 clinical trials. After further data submission, even though New Drug Application (NDA) approvable letters were sent in August 1999, March 2000, and October 2000, NDA 21-023 approval did not occur until late December 2002. As for diquafosol, despite two approvable letters from the FDA in 2003 and 2005, with phase 3 trials meeting endpoints inconsistently, the regulatory hurdles for this drug remain high. Dr. Rittenhouse identified another important factor that confounds approvals for dry eye therapies: Dry Eye: Why Have So Many Trials Failed? • Kay Rittenhouse, PhD, Director and Head, Ophthalmology Translational Medicine, Pfizer Inc., and founder, Drug Development and Delivery Summit Dry eye is a widely heterogeneous disease. The fact that it 722 P&T® • December 2008 • Vol. 33 No. 12 http://www.DRCR.net http://www.ClinicalTrials.gov

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - December 2008

Pharmacy & Therapeutics - December 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Interpreting Estimates of Treatment Effects Chemotherapy Foundation Symposium XXVI: Innovative Cancer Therapy for Tomorrow Third Annual Onmark National Payor/Provider Forum Fourth Annual Ophthalmic Drug Development and Delivery Summit Classification and Pharmacological Management Of Obesity CE Test and Forms Season’s Greetings: Thanks to Our Readers and Reviewers

Pharmacy & Therapeutics - December 2008

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