OCT 2012

EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.

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84 EW CORNEA October 2012 Why are there no imminent breakthroughs in ocular drug delivery? by Tony Realini, M.D. replacement. Finally, he said, they must have a long period of ac- tivity before drug depletion or they will not be practical to implant. When might a new I n many ways, the eye is an ideal organ for medical ther- apy. Unlike internal organs, the eye is partially externalized and easily accessible. Also, the ocular surface is relatively absorptive so that topically applied medications can easily gain access to the anterior segment and, to a lesser extent, the posterior segment. These characteris- tics greatly facilitate the administra- tion of topical medical therapy for ocular diseases and conditions. Eye drops have their limitations, however. According to Gary Novack, Ph.D., PharmaLogic Development Inc., San Rafael, Calif., "Eye drops are relatively inefficient given their large volume relative to the pre- corneal space. Also, they require the patient to correctly deliver treatment to the affected eye or eyes at least once daily for pulsatile treatment." The need for new ocular drug delivery systems is about more than efficiency or convenience. Consider that glaucoma is a chronic disease requiring daily therapy. Adherence to glaucoma medications is notori- ously poor. A system that provided continuous IOP-lowering therapy for weeks or months without patient effort would be desirable. Consider also the new standard of care for neovascular age-related macular de- generation, which involves monthly intravitreal injections of anti-VEGF agents. A system that provided con- tinuous or pulsed delivery of these agents for months to years at a time would be highly advantageous in re- ducing the cumulative risks of ongo- ing monthly intravitreal injections. Ideally, a drug delivery system could be developed that would work with a large variety of different drugs, provide sustained release of the drug to achieve steady state drug levels, and require infrequent replacement or refill, said Dr. Novack. Solutions employed to date have included the use of prodrugs to enhance penetration (such as dipive- frin as the prodrug to epinephrine, and all of the prostaglandin ana- logues), more viscous vehicles to increase resident time on the ocular surface to maximize absorption, and controlled release inserts (posterior segment devices containing fluoci- nolone acetonide [Retisert, Bausch + Lomb, Rochester, N.Y.] and dexamethasone [Ozurdex, Allergan, Irvine, Calif.]). Novel delivery systems in clinical development A number of innovative ophthalmic drug delivery systems are presently in various stages of clinical develop- ment. Among these are ketotifen impregnated into a contact lens to be used to treat allergic conjunctivi- tis and punctal plugs manufactured with latanoprost for glaucoma and with moxifloxacin for ocular infections, said Dr. Novack. Another interesting drug is the steroid derivative anecortave acetate that was initially developed as a drug for age-related macular degen- eration but was found to lower IOP. This drug was meant to be injected into the sub-Tenon's space periodi- cally for sustained IOP reduction. Because Phase II testing showed lim- ited efficacy in many patients, its de- velopment was abandoned by Alcon (Fort Worth, Texas), Dr. Novack said. Replenish Inc. (Pasadena, Calif.) has developed what they describe on their website as "a small, refillable, implantable ocular drug pump." The device resembles a typical tube shunt device and is meant to be implanted in the sub-Tenon's space. Unlike a tube shunt device, Replenish pumps drug from its sub- Tenon's reservoir through the tubing into the anterior segment of the eye. "The tiny MicroPump can be 're- plenished' using a disposable, pro- prietary 31-gauge needle tubing kit," according to the company's website. What are the obstacles to developing alternatives to eye drop delivery of ophthalmic medications? "Novel delivery systems add the complexity of putting days to weeks of treatment into a confined space that must be stable at 37 degrees C," Dr. Novack explained. Further, "the delivery system must deliver the drug at the intended rate, which is often the ideal of zero-order kinetics, or flat over time. The components of the delivery system may be erodible or non-erodible," he said, noting that the latter requires either removal of the empty shell upon depletion or the accumulation of multiple shells with repetitive system be available? How far away is a new ocular drug delivery system? "Phase III trials typ- ically involve 12 months of patient treatment, not including the time required to enroll subjects and ana- lyze the data afterward," said Dr. Novack. "Given that drug approval takes a minimum of 6-10 months in the U.S., the soonest a new treat- ment could get approval would be 3-4 years. Since I am not aware of any ocular drug delivery systems in Phase III testing at present, it seems that we are at least 4 years from any new system." This assumes that the delivery system utilizes an already approved drug; if not, the delay could be even longer, he pointed out. Malvina Eydelman, M.D., director, Division of Ophthalmic, Neurologic and ENT Devices, Center for Devices and Radiological Health (CDRH), FDA, said, "My team and I are excited to bring novel drug delivery devices to market." But when asked if any were im- minent, she replied, "All investiga- tions in the U.S. are conducted under Investigation Device Exemp- tions (IDE) or Investigational New Drug (IND) applications. The con- tents of IDEs and INDs are confiden- tial." Stand-alone drug delivery services are regulated by CDRH and stand-alone drugs are regulated by the Center for Drug Evaluations and Research (CDER). When a drug is chemically or physically combined with the delivery device (e.g., con- tact lens impregnated with a drug), or co-packaged with the device, it constitutes a combination product. Drug delivery device combination products with the drug providing the most important therapeutic benefit are regulated by CDER. EW Editors' note: Drs. Eydelman and Novack have no financial interests related to this article. Contact information Eydelman: Malvina.Eydelman@FDA.HHS.GOV Novak: gary_novack@pharmalogic.com

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