Advances in Drug Delivery for AMD

Intravitreal injection is currently the most common route of administration for AMD treatments, and most existing drugs as well as drugs in development are injected intravitreally. Unfortunately, this mode of drug delivery carries several important disadvantages, including risk of intraocular infection and the inconvenience and cost of frequent office visits.

Many attempts are ongoing to develop new drug-delivery systems to overcome some of the disadvantages of intravitreal injection. This article describes some of the more promising treatment approaches that are in the pipeline for the treatment of AMD.

Subconjunctival Administration

Subconjunctival injection
Subconjunctival injection

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. Using a hypodermic needle, the drug is injected under the conjunctiva, the outer membrane that covers the eye. 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 (Rapamycin)

Sirolimus is a relatively new immunosuppressant drug approved by the US Food and Drug Administration (FDA) for systemic use in renal transplantation. It inhibits the mammalian target of rapamycin (mTOR). According to its developers, this drug acts by immunosuppressive, anti-angiogenic, antimigratory, antiproliferative, antifibrotic, and antipermeability mechanisms.

For the eye, sirolimus is injected either subconjunctivally or intravitreally, and lasts up to 3 months when given subconjunctivally. After positive data in phase 1 trials, National Eye Institute (NEI)-sponsored phase 2 trials have been initiated. The study is currently recruiting participants.

Posterior Juxtascleral Administration

The posterior juxtascleral depot method of drug delivery involves using a hypodermic needle to deposit the drug onto the surface of the eyeball in the region of the macula. This method of drug delivery avoids the risk of intraocular damage and endophthalmitis posed by an intravitreal injection. Much like subconjunctival injections, there is an increased risk of systemic drug exposure due to drug contact with orbital tissue when compared with intravitreal injections, though there is much less systemic exposure than occurs with either topical or systemic therapy.

Anecortave Acetate

Anecortave acetate is a steroid that has been chemically modified to eliminate the likelihood of steroid-related ocular side effects, such as glaucoma and cataract. Anecortave inhibits vascular proliferation by decreasing extracellular protease expression and inhibiting endothelial cell migration. It is administered as a depot injection every 6 months.

AART is a phase 3, randomized, double-blind, placebo-control, single group assignment designed to study the safety and efficacy of anecortave. The study is ongoing but not currently recruiting patients. Approximate enrollment is 2500 patients and the study is estimated to be completed in February 2010.

Implants

Advances in technology and surgical technique have led to the development of drug-delivery implants, which can overcome many of the limitations of other therapeutic approaches. Implants are associated with significantly less systemic exposure than either topical or systemic administration. Additionally, intravitreal implants typically provide better control of disease with significantly less drug than with any other form of therapy.

Fluocinolone Acetonide

Retisert (Bausch & Lomb), the only FDA-approved steroid implant, contains a small amount of fluocinolone acetonide within a small reservoir, which delivers chronic sustained low levels of the drug into the vitreous for up to 3 years. It is approved for uveitis. However, despite showing significant efficacy in patients with uveitis, chronic administration of even this low level of steroid was associated with high levels of cataract and glaucoma. As a result, further development of Retisert for diabetic macular edema and AMD has been reconsidered.

Medimur intravitreal implant
Medimur intravitreal implant

The Medidur implant (Alimera Sciences) is a similar but smaller fluocinolone-based implant. The MAP study is a phase 2 single-masked, randomized comparison of the safety and efficacy of Medidur in patients with wet AMD who have received ranibizumab. This study is not yet open for participant recruitment.

Ciliary Neurotrophic Factor

Ciliary neurotrophic factor (CNTF) is a member of the interleukin-6 (IL-6) family of cytokines. Animal models of retinal degeneration have demonstrated a slow-down in photoreceptor degeneration after the use of CNTF. CNTF can protect photoreceptors in AMD also.

Encapsulated cell technology /NT-501 contains genetically engineered retinal pigment epithelial cells that produce CNTF protected by a semipermeable membrane. An NEI-sponsored phase 2 trial has completed enrollment of 36 patients with geographic atrophy (GA) and evaluation is ongoing.

Brimonidine

Brimonidine is an alpha2-adrenergic agonist currently used in the treatment of glaucoma. The neuroprotective effect of brimonidine was evaluated recently and the results suggest the drug may enhance the survival of retinal cells.

A brimonidine intravitreal implant for patients with GA due to AMD is in development. The phase 2 study, which is not yet open for participants, will be carried out in 2 stages. Stage 1 is a patient-masked, dose-escalation, safety evaluation of brimonidine intravitreal implant. Patients will receive the implant in 1 eye and "sham" treatment in the fellow eye. Stage 2, which will begin after the safety of stage 1 has been evaluated over a 1-month period, is a randomized, double-masked, dose-response, sham-controlled evaluation of the safety and efficacy of brimonidine intravitreal implants in patients with GA from AMD. Follow-up is for a period of 2 years. Enrollment is estimated to be 95 patients and will start in May 2008, with an estimated completion date of December 2011.

Topical Drops

Eye drop instillation
Eye drop instillation

Topical instillation of ophthalmic drops is the most common method used to administer treatments for ocular disease. The most significant challenge for effective topical therapy is finding molecules that are small, potent, and have charge characteristics suitable for enhanced ocular penetrance. Additionally, topical therapy results in significant systemic exposure through tear drainage.

OT-551 (Othera)

The OT-551 is a free radical scavenger that might prevent retinal damage due to oxidative stress. The OMEGA (OT-551 Multicenter Evaluation of Geographic Atrophy) study is a randomized, double-masked, dose-ranging, multicenter, phase 2 study comparing the safety and efficacy of OT-551 with placebo to treat GA associated with AMD. Enrollment is estimated at 198 patients and completion is estimated to be February 2010.

ATG-3 (CoMentis)

ATG-3 inhibits endothelial nicotinic acetylcholine receptors and decreases angiogenesis and vascular permeability. The phase 2 study plans to randomize 333 patients receiving maintenance therapy with an anti-VEGF agent to 1 of 3 treatment groups: 2 different doses of ATG-3 administered twice daily, or placebo. All patients will be treated for up to 48 weeks, during which time they will be monitored to assess the drug's safety, tolerability, and efficacy.

TG100801 (TargeGen)

TG100801 is a selective multi-target kinase inhibitor that acts to inhibit vascular permeability, angiogenesis and inflammation simultaneously. The phase 1 trial was completed in February 2007. Following these positive results, a phase 2 open-label, randomized, pilot study of safety and preliminary efficacy of TG100801 in patients with choroidal neovascularization due to AMD was begun. This study is ongoing, but not currently recruiting participants.

OC-10X (Ocucure)

OC-10X is a nontoxic vascular targeting agent with selective tubulin inhibition. The agent is lipid soluble and crosses the human cornea; it achieves therapeutic concentrations at the retina-choroid. The drug achieved a corneal level of 100%, a lens/vitreous level of 11%, and a retina-choroid-sclera level of 83% in rats when given once every hour for 4 hours.

Other Drugs

A number of other topical therapies are also being investigated. Some that have shown positive results in initial studies include AdGVPEDF (phase 1), fenretinide (phase 2), glatiramer acetate (phase 2 and 3), pazopanib eye drop (phase 2), REDD14NP (phase 1), JSM6427 (phase 1), POT-4 (phase 1), AGN211745 (previously known as Sirna-027; phase 2), and E10030 (phase 1).

Source

Sharma A, Kuppermann BD. The Future of Drug Delivery in Age-Related Macular Degeneration. Medscape Ophthalmology. 9 June 2008. Available online