We have effective drugs for most of the ophthalmic conditions we encounter, but there are downsides to many. Based on a webinar by Dr. Jeffrey Jamison, PhD, Director of the Ocular Laboratory at MPI Research, here is a look at the current treatments we use, areas of void and potential, and how we have started to restructure certain drugs to better fit our needs.
- Wet AMD: There are effective treatments but poor delivery. For instance, intravitreal injections are needed several times per year for life. Here is an opportunity for a better drug delivery platform.
- Dry AMD: There is currently no approved therapy other than vitamins, but there are several compounds in some phase of clinical development that we can look forward to.
- Diabetic Retinopathy: The current state of the art treatment is laser cauterization. Since diabetic retinopathy is both a vascular and neural disease, there is crossover with wet AMD and potential for new drugs and delivery systems.
- Dry Eye: There is currently only one prescription medication and OTC drops provide limited relief. This is an area with a huge need for new treatments.
Repurpose Existing Drugs
- We have used oncology drugs as angiostatics for wet AMD and diabetic macular edema.
- Treatment for Alzheimer’s disease : anti-ABETA RN6G from Rinat can be used for the treatment of dry AMD.
- Serotonin agonists for CNS disorders (anti-anxiety drugs) – Alcon AL-8309 are in phase 3 trials for progression of geographic atrophy.
- Stroke treatment and neuroprotectants are used for ganglion cells and can be applied to glaucoma, retinal degeneration, and dry AMD.
- Systemic allergy and inflammation drugs have been reformulated for topical delivery so you get a more concentrated dose to the area of interest. These can be used for ocular allergy and post op pain management.
- Gastrointestinal (mucin secretagogues ) are used in dry eye patients to increase the quality of the tear film
The Future of Ophthalmic Drugs
Although we have been creative, there are still problems that need to be addressed. The treatment of uveitis with corticosteroids is one example of a constant challenge. There are topical, injections (periocular and intraocular) and systemic delivery methods. Some may poorly cross the blood-retinal barrier. Topicals do not penetrate well into the posterior segment. Injections can deliver high doses of drug to the eye with few or no systemic side effects but are associated with significant complications and must often be repeated. To overcome these limitations, an increasing number of sustained-release drug delivery devices have been developed to treat uveitis.
Solid Implants
Retisert, FDA approved in 2005 as an orphan drug for the treatment of chronic noninfectious uveitis affecting the posterior segment. Each Retisert consists of a tablet containing 0.59 mg of fluocinolone acetonide and other inactive ingredients including alcohol in which it is soluble. The drug release rate is 0.6ug/day initially, which decreases over the first month to a steady state between 0.3 and 0.4 ug/day up to about 30 months. Side effects include cataracts, increased IOP or hypotony, and endophthalmitis
Iluvien from Alimera Sciences are tiny, extended release intravitreal, non-erodible inserts the size of a grain of rice. They provide a method to deliver fluocinolone acetonide corticosteroid to the retina for up the 3 years for the treatment of diabetic macular edema. The inserts are 3.5mm in length and 0.37mm in diameter and contain 180ug of fluocinolone acetonide (FA). Iluvien provides a low daily dose of FA (0.23 ug/day) or high dose (0.45 ug/day). It is inserted with a proprietary inserter using a 25g needle (Medidur delivery platform) that creates a self sealing wound. Iluvien is inserted into the vitreous and natural fluid dynamics distribute FA to the retina. This device is currently under review by the US FDA and is being investigated in 2 global phase 3 pivotal clinical trials involving 956 patients.
Surodex from Allergan, Inc. is a rod-shaped biodegradable matrix implant. It is 1.0 x 0.5mm in size and consists of dexamethasone and poly lactide-co-glycolide acid with hydroxypropyl methylcellulose, which provides sustained drug release at a constant rate of 60 ug over 7 to 10 days. The implant is designed for post cataract inflammation. It is inserted into the anterior chamber following cataract surgery, does not require suture fixation and is well tolerated.
Ozurdex is a preservative-free intravitreal implant containing 0.7 mg dexamethasone in a NOVADUR solid polymer drug delivery system. The implant also contains PLGA matrix that slowly degrades to lactic acid and glycolic acid so that when the active agent is consumed, degradation products are water and CO2, leaving no residue in the eye. Ozurdex is a single use injectable rod-shaped implant that is inserted directly into the vitreous cavity via a 22-gauge applicator. It can deliver dexamethasone for up to 6 months with a relatively mild side effect profile. This implant was approved for the treatment of macular edema following BRVO or CRVO in 2009 and is currently in trials for the treatment of ocular inflammation in the setting of posterior and intermediate uveitis.
Vitrasert, marketed by Bausch & Lomb, is the first implantable ganciclovir delivery device approved by the FDA in 1996 for the treatment of CMV retinitis. This is a large device that requires a 4-5mm sclerotomy at the pars plana for implantation and releases the drug for 5 to 8 months. It is non-biodegradable so needs to be removed during a second procedure. Currently the same type of implant containing dexamethasone, fluocinolone acetonide or cyclosporine is being tested for treatment of severe uveitis.
Cyclosporine Devices
Cyclosporine devices are useful in patients who can not tolerate steroids (steroid-induced glaucoma or those refractory to steroid therapy). Cyclosporine is an immunosuppressive agent that suppresses T-cell activation. It penetrates the eye poorly when applied topically so this method of delivery is not generally given for control of intraocular inflammation. Moderate intraocular cyclosporine levels are achieved with oral and systemic administration, but the potential side effects are grim (oral ulceration, hypertrichosis, malaise, muscle cramps, GI disturbance, etc.). Direct intraocular injection of cyclosporine has been shown to control intraocular inflammation in an animal model of uveitis, but the half-life is short which limits its effectiveness. Gilger and coworkers described a discoid intravitreal device developed for the sustained release of cyclosporine in horses.
Injectable Systems
Icon Biosciences Inc (Sunnyvale, CA) is developing a drug delivery technology called Verisome. This system is designed to release a broad range of pharmaceutical agents. The basic technology is versatile and can be formulated into a biodegradable solid, gel, or liquid substance that provide drug release in a controlled manner over weeks to a year, depending on the volume injected, for ocular, systemic or topical applications. Verisome-based products can be injected into the vitreous as a liquid via a standard 30-gauge needle. When the drug is injected into the vitreous, it coalesces into a single spherule that settles inferiorly. The Verisome spherule shrinks over time as it simultaneously degrades and releases active agents. In the phase 1 study, Verisome was well-tolerated and showed efficacy in patients with CME secondary to RVO. No injection-related adverse events or safety concerns were noted during the trial.
The Cortiject implant by Novagali Pharma is a preservative and solvent-free injectable emulsion that contains a tissue-activated corticosteroid prodrug. The prodrug is converted into the active agent by enzymes in the target tissues. A single intravitreal injection of the emulsion provides sustained release of corticosteroid over a 6 to 9 month period. Cortiject is currently being studied in a phase 1 dose-escalation study in patients with DME.
Particulates (microparticles and nanoparticles) containing different drugs are currently being studied for inhibition of intraocular inflammation in animals with success. Dexamethasone in microspheres proved to deliver a sustained dose over 45 days in vitro, a large improvement considering the intravitreal half-life of dexamethasone administered via direct intravitreal injection is less than 4 hours.
Over the last few years, liposomes have become a popular subject of research when it comes to delivery systems. Liposomes are small vesicles, typically ranging from 0.01 to 10mm that are used for controlled and targeted drug therapy. One study used vasoactive intestinal peptide (VIP) for the treatment of intravitreal inflammation with promising results. The prospect of an ocular anti-inflammatory medication that is not only effective but also lacks the conventional side effects of steroids is encouraging.
Transscleral Iontophoresis
Iontophoresis is a method of drug delivery using a small electrical current to enhance diffusion of drug molecules across an intact sclera. This is a non-invasive and well-tolerated method that may replace the need for repeated intravitreal injections. Eyegate (Optis Group, Paris) and OcuPhor (IOMED, Salt Lake City) are two main ophthalmic iontophoresis systems under investigation. Studies show that a significant proportion of patients with uveitis treated with this method experienced more rapid recovery and/or increased comfort.
In conclusion, not only are there creative ways to use existing drugs in the eye, but also there are many novel drug delivery systems that are coming down the pipeline, targeted to overcome the drawbacks with our current delivery systems. Keep your eyes peeled!