Pharmacotechnology: Novel Methods to Deliver Ocular Drugs to Improve Efficacy and Durability

SEENU M. HARIPRASAD, MD

Pharmacotechnology, a term coined to capture the contribution of pumps, implants, inserts, and other innovations designed to improve delivery of therapeutic agents, offers great promise in the treatment of retinal diseases. In deep ocular tissues, such obstacles as the blood-retinal barrier or poorly vascularized spaces inhibit effective delivery of active agents by either systemic or topical routes. Intravitreal injection, an approach proved effective for placing active therapies into the retina, is impractical for treatment requiring frequent or sustained dosing. The potential for pharmacotechnology is underscored by the fact that the most significant hurdle to effective treatment for many retinal diseases is not the availability of an active drug but an effective method of delivering drugs to their site of action.

This review will evaluate selected technologies at late stages of development or that appear to have promise for supplanting current ophthalmic therapies. Clinicians should familiarize themselves with emerging concepts in pharmacotechnology due to their significant potential to advance management of retinal diseases. Moreover, novel methods of drug delivery are likely to become more rather than less important, with a growing emphasis on biologic treatments directed at modifying specific molecular events. These drug delivery technologies, discussed in order of likely approval offer the promise of improved therapeutic effect, as well as a more favorable ratio of efficacy to safety inherent to drugs with focused activity. The diversity of academic and commercial research into pharmacotechnology makes drug delivery an extremely dynamic area. No summary can be considered comprehensive.

INTRAVITREAL DEVICES

Of new pharmacotechnologies in late stages of development, devices capable of intravitreal drug delivery are perhaps the most promising. The pioneer in intravitreal implants is Vitrasert (Bausch & Lomb, Rochester, NY), which delivers ganciclovir to control cytomegaloviral retinitis and has been available for more than 10 years. Retisert (Bausch & Lomb), which was more recently approved by the Food and Drug Administration (FDA), delivers fluocinolone acetonide (FA) to control noninfectious posterior uveitis. Subsequent innovations are expected to facilitate drug delivery and extend applications. The main advantage of newer products relative to Vitrasert or Retisert is non-surgical insertion. Many products using slightly different approaches are in development.

Iluvien, previously known as Medidur FA (Alimera Sciences, Alpharetta, GA), a nonerodable insert (Figure 1), is in phase 3 trials for extended delivery of FA in patients with diabetic macular edema (DME). Because of the urgent need for more effective DME treatments, Iluvien will be submitted under Fast Track designation to the FDA. Alternatives for treatment of DME, including laser photocoagulation, vitrectomy, off-label use of corticosteroids, and inhibitors of vascular endothelial growth factor (VEGF), have important disadvantages, including limited efficacy and a substantial risk of complications.

Figure 1. The Iluvien insert, shown on a human finger to indicate size.

Iluvien is 3.5 mm long and 0.37 mm in diameter. A 25-g insertion system facilitates intravitreal delivery of the Iluvien insert in an office-based setting (Figure 2). Once in the retina, the insert has an initial daily release rate of either 0.23 or 0.45 μg of FA, the lowest doses of any drugs currently being studied for sustained delivery. (Two doses are being evaluated in the phase 3 trial) and its therapeutic effect is expected to last up to 36 months (Figure 3). When active drug is depleted, the inert Iluvien insert is not retrieved but remains in the eye. Two phase 3 registration trials for Iluvien in a study program called FAME (Fluocinolone Acetonide in Diabetic Macular Edema) completed enrollment of 956 patients in October 2007. The studies include DME patients from North America, Europe, and Asia. The efficacy analysis will be completed in late 2009 after follow-up of 24 months, with a final analysis planned at the end of 36 months. Reassurance about the viability of Iluvien was provided when an interim analysis conducted by the FAME Data and Safety Monitoring Committee earlier this year recommended continuation of the trial without changes to the protocol.¹

Figure 2. Inner view of pars plana with needle of device releasing Iluvien (Medidur FA) into the vitreous cavity.

Figure 3. Schematic of Iluvien (Medidur) releasing FA near surface of retina into the vitreous cavity.

Iluvien is not expected to be limited to the treatment of DME with FA. A pilot safety study has already been announced to evaluate it in combination with ranibizumab (Lucentis, Genentech) injections in patients with exudative (ie, "wet") age-related macular degeneration (AMD). Ranibizumab, an antibody that binds to VEGF, has previously demonstrated activity against wet AMD in single injections.² Constant and prolonged treatment with FA in addition to ranibizumab may improve outcomes and/or decrease treatment frequency.

There are also plans to evaluate Medidur for the treatment of nonexudative (ie, "dry") AMD by delivering reactive oxygen species inhibitors. In an agreement already reached with Emory University, Alimera Sciences is pursuing its potential for the delivery of nicotinamide adenine dinucleotide phosphate NADPH oxidase inhibitors.³

Another implantable device, called Posurdex (Allergan, Irvine, CA), has also reached a phase 3 evaluation for the treatment of DME and retinal vein occlusion (RVO). Posurdex is a polymer pellet that releases drug as it biodegrades. The pellet completely dissolves in about 37 days, although initial studies suggest that the effect of the drug may persist for 2 or more months after dissolution. Although Posurdex was surgically implanted initially, the phase 3 studies evaluating delivery of dexamethasone in patients with DME are being conducted with a 22-g applicator that permits treatment as an office procedure.

In a phase 2 dexamethasone study with Posurdex, 306 patients were randomized to receive a 350-μg implant, a 700-μg implant, or observation.⁴ Although the majority of patients in this study had DME, 102 had RVO, 25 had Irvine-Glass syndrome, and 14 had uveitis. When evaluated at 6 months, 36% of those randomized to 700-μg group and 27% of those randomized to 350-μg group vs only 19% of the observation patients had at least a 2-line improvement in best-corrected visual acuity (VA). A 3-line or better improvement was achieved in 19% of those on the highest dose of dexamethasone vs 8% of the observation group. The most common adverse event was an increase in intraocular pressure. A 10 mm Hg or greater pressure increase was observed in 17% of the 700-μg group, 12% of the 350-μg group, and 3% of the observation group.

Like Iluvien, the Posurdex platform has the potential for a variety of applications outside of the current initiative to deliver steroids for the treatment of DME and RVO. For example, studies have already been initiated to evaluate this system along with combination therapy with ranibizumab to treat exudative AMD. Other therapies, including other targeted therapies that have the potential for improved activity when placed in the vitreous, will be candidates for Posurdex delivery if the phase 3 DME and RVO trials demonstrates efficacy.

A third drug delivery platform, I-Vation (Surmodics, Eden Prairie, MN), has been evaluated in a 30-patient phase 1 study, testing the delivery of triamcinolone acetonide in patients with DME.⁵ Although phase 1 studies are primarily safety evaluations, favorable changes in VA were reported along with acceptable tolerability. I-Vation, which can be matched with a variety of polymer matrix formations, is expected to be compatible with a broad array of active agents, including biologics. Unlike Iluvien and Posurdex, I-Vation requires surgical implantation is fixed at the pars plana. The device is designed for implantation under the conjunctival membrane, facilitating retrieval if necessary. Relative to Iluvien or Posurdex, the compatibility of the I-Vation platform with different polymers may increase its versatility for developing dosing characteristics specific to different types of retinal therapies. Unfortunately, the phase 2 clinical trial investigating the use of I-Vation for the treatment of DME was suspended.

Other injectable intravitreal devices are in development. Although the majority of clinical studies have so far been concentrated in the treatment of DME, uveitis, and retinitis, the potential advantages for controlling diseases associated with neovascular disruption of the retina, particularly AMD, are at least as great. Single intravitreal injections of such agents as pegaptanib sodium (Macugen, OSI/Pfizer) have been associated with significant clinical benefits, including improvement in VA,⁶ but sustained VEGF inhibition may increase the proportion of responders. It is unclear whether any of the concepts currently in development has the potential to eventually dominate for most indications for sustained intravitreal drug delivery or if differences in the design and characteristics may produce relative advantages of a given device for different indications.

EYEDROPS AS A DELIVERY SYSTEM TO THE POSTERIOR REGION

While eyedrops have been used for topical and anterior-segment disorders for decades, only recently have drops been considered for the treatment of retinal disease. There are several AMD trials either currently under way or in follow-up that have employed eyedrops as the delivery method. OT-551, developed by Othera Pharmaceuticals (Exton, PA), was developed for the treatment of geographic atrophy in patients with dry AMD. A phase 2 trial is currently in follow-up. For exudative AMD, the anti-VEGF agent pazopanib, developed by GlaxoSmithKline (Philadelphia), has already been through 2 phase 1 safety/efficacy trials, one of which evaluated the drug in combination with Allergan's Refresh eyedrops. Pazopanib is currently being evaluated in 2 phase 2 trials, one an extension study of the original phase 1 trial.

CoMentis, Inc. (South San Francisco, CA), has been pursuing trials on ATG003 (mecamylamine), a nicotinic antagonist that has been on the market for years as an antihypertensive and as a smoking-cessation drug. One Phase 1 wet AMD trial and another DME trial have already been completed and a phase 2 AMD trial is currently enrolling patients. The apparent use of mecamylamine as a drop is as an adjunct to anti-VEGF treatment, such as ranibizumab. Another drug that has been put through both AMD and DR trials is TargeGen's TG100801 (tetrahydrozoline hydrochloride), which passed phase 1 safety/efficacy studies for both AMD and diabetic retinopathy and is now currently in follow-up for a phase 2 trial to test for the efficacy of tetrahydrozoline in the treatment of CNV due to AMD.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are another class that have been developed as eyedrops and are being subjected to retina clinical trials. Bromfenac (Xibrom, ISTA) and nepafenac (Nevanac, Alcon) are currently being evaluated for use in various disease states such as DME, AMD, and cystoid macular edema. The prodrug formulation of the new generation NSAID nepafenac theoretically allows for better ocular penetration and greater efficacy for posterior pole disease compared to older generation NSAID.

Finally, sirolimus (Rapamune, Wyeth) is currently in a phase 1 study to test its safety in DME patients. Originally designed to prevent organ rejection in transplantation procedures, sirolimus is also being tested as a part of combination therapy for the treatment of both AMD and DME.

NOVEL CONCEPTS IN DRUG FORMULATIONS: THERMOGELS AND NANOTECHNOLOGY

The effort to deliver drugs by routes other than pill or injection is not new, but the specific features of the eye provide novel strategies with particular promise. While inhalants for respiratory diseases are an example of an organ-specific approach to drug delivery, many tissues, including the lung, are readily accessible by drugs circulated in the blood. Even monoclonal antibodies delivering biologic therapies targeted at specific cells can often be effectively delivered by the oral route. In the retina, new drug delivery strategies offer the potential to dramatically alter our ability to reach pathological processes. Even for new strategies not necessarily developed for ocular diseases, approaches that improve penetration or resident time in poorly vascularized spaces may completely change current paradigms for disease management.

Thermogels are one of the new strategies for drug transportation not initially envisioned for ophthalmic use. Liquid at room temperature, these biocompatible products enter a gel state at body temperature. They can be applied topically or injected and have the advantage of prolonged dwell time, increasing exposure to the active drug. The initial studies have been conducted in healing of bones and chronic wounds. New initiatives have begun in cancer. One of the potential advantages for use in the eye is that degradation time has been controllable in experimental studies, ranging from hours to days or months.

Nanotechnology has a variety of potential attributes for drug delivery and is being aggressively pursued in oncology and other fields. In ophthalmology, this strategy has been labeled nano-ophthalmology, and there is a growing literature exploring this concept. The projected applications include improvements in drug delivery to the anterior or posterior segment, tissue repair, and strategies to facilitate surgery. The National Eye Institute is among funding sources for initiatives that include nanotechnology to address eye diseases.^7,8

CONCLUSION

Due to the unique challenges of treating ocular tissues, novel therapeutic strategies are not new to ophthalmology. Many devices, including Vitrasert and Retisert, were met with initial skepticism but have been highly effective in patient populations for whom other options were exhausted. Visudyne (verteporfin, QLT/Novartis), which is a photodynamic therapy activated by a cold laser, was first commercially available in 2000, using a technology unprecedented in clinical medicine to destroy the leaky blood vessels that characterize wet AMD. Not yet fully replaced by other options for wet AMD, Visudyne continues to be a viable and effective option in selected patients. It is emblematic of the potential for approaches beyond pills or injected drugs to offer options for a fragile organ.

Clinical medicine is profiting from 2 related sets of scientific progress. While advances in understanding the molecular steps in pathology are permitting advances in chemistry and genetics to conceive of new therapies, technological advances are guiding novel delivery systems that may build on these pharmacologic advances. Advances in the material sciences are allowing new treatments to be delivered to the disease site more efficiently, precisely, and safely. Although recently created, the term pharmacotechnology captures the effort to improve the precision of drug delivery, an attribute that has particular relevance to the control of ophthalmic disorders. RP

REFERENCES

1. Alimera Sciences press release. http://www.alimerasciences.com/news-pressrel-03-24-08.asp. Accessed June 23, 2008.
2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
3. Alimera Sciences press release. http://www.domainvc.com/%5CPDF%5CAlimera%20Sciences%20Closes%20Series%20C%20-%20031808.pdf. Accessed June 23, 2008.
4. Kuppermann BD, Blumenkranz MS, Haller JA, et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007;125:309-317.
5. Dugel PU, Cantrill HL, Eliott D, et al. Clinical safety and preliminary efficacy of an intravitreal triamcinolone implant (I-vation TA) in DME. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology, May 6-10, 2007; Fort Lauderdale, FL.
6. Cunningham ET, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an antivascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747-1757.
7. Jain KK. Nanomedicine: application of nanobiotechnology in medical practice. Med Princ Pract. 2008;17:89-101.
8. Olsen TW. Drug delivery to the retina using intravitreal aerosolized nanoparticles. Retinal Physician. 2008;5(5):26-32.