Iluvien and the Future of Ophthalmic Drug Delivery Systems

I was recently sent a news release from Alimera Sciences, who have filed an NDA requesting priority review for its Iluvien sustained release drug delivery system for treating diabetic macula edema, which if granted could result in an action letter granting approval for marketing before the end of this year.

This got me thinking that I hadn’t written about ophthalmic drugs (except for Avastin and Lucentis) since I wrote about “Site Specific” Ophthalmic Drugs in June 1990, for the old Ophthalmology Management magazine. I followed that up with a series of three articles titled, On the Pharmaceutical Front – parts 1&2 appearing in the March and April 1991 issues of that same magazine, and the 3rd (and final) part began my ten-year plus run of writing a regular column (Technology Update) for Ocular Surgery News in December 1991.

Back in 1990, the key words were “site specific”, i.e., drugs that were activated at the site where they were needed, under development by Xenon Vision, based on the drug delivery patents of Dr. Nicholas Bodor of the University of Florida. Then in 1991, I wrote about Alza and its Ocusert sustained delivery system. It was a drug-filled rod inserted under the lower lid to dispense drugs. Also, Escalon Ophthalmics obtained rights to a rod-shaped sustained drug release device from the Institute of Ophthalmology in London, that apparently was inserted into the conjunctiva. And, at the time, Chiron Ophthalmics and Bausch & Lomb were investigating the release of drugs from collagen shields and contact lenses.

At that time, I was not aware of anyone developing drug delivery systems that could be inserted into the vitreous to deliver drugs to the retina, and I stopped writing about drugs and delivery systems until my new interest in drugs and devices for treating AMD upon my retirement in December 2005.

I have recently written about a new drug delivery system, the On Demand Therapeutics device, from the Dr. Robert Langer labs at MIT, that supposedly can hold several cells of drugs in a reservoir and have each cell activated to release its contents via a laser beam. (AMD Update 11: Potential Breakthrough Drug Delivery System for AMD) But, this development is in a very early stage and may or may not ever reach commercial development.

So, I began some research into current thinking and developments in ophthalmic sustained release drug delivery systems and I quickly learned that I’ve missed a lot, and as my friend Jerry Helzner wrote in a recent issue of (the new) Ophthalmology Management, “I have seen the future of medical ophthalmology and its name is sustained-release drug delivery.”

What I would like to relate in this opus is what Iluvien is all about, how it was developed, and a little about what others are doing in this field.

The Iluvien Story

Iluvien is a tiny, extended release intravitreal insert, that is being developed by Alimera Sciences as a way to deliver fluocinolone acetonide (FA), a corticosteroid, to the retina for up to three years of treatment for diabetic macular edema (DME).

The Iluvien intravitreal insert (see picture 1), is a tiny cylindrical polyimide tube, 3.5mm in length and 0.37mm in diameter, that contains 180 μg of fluocinolone acetonide (FA). It is about the size of a grain of rice, and is designed to provide a low daily dose of FA, a non-proprietary corticosteroid with a history of treating ocular disease. Iluvien is inserted into the patient's eye using a proprietary inserter with a 25 gauge needle, which allows for a self-sealing wound. Iluvien is placed in the back of the eye, in the vitreous (see picture 2), to take advantage of the eye's natural fluid dynamics to deliver FA to the retina. A single Iluvien insert is designed to provide sustained therapy for 24 to 36 months. By combining FA and a delivery device that provides for a unique long term, low dose delivery of FA to the back of the eye, it is believed that Iluvien has the potential to improve vision of those suffering from diabetic macular edema, while reducing common side effects of corticosteroids.

Picture 1 Comparison to grain of rice

Picture 2 Insertion into the vitreous

The Iluvien insert uses the Medidur delivery platform, licensed from pSivida in 2005. (For more on the Medidiur technology and pSivida’s role in the development of the sustained release delivery system, see The Back Story below.)

Addressing Diabetic Eye Disease

Diabetic retinopathy is the most common eye disease affecting people diagnosed with diabetes mellitus and is a leading cause of blindness in adults. The term "diabetic retinopathy" refers to a variety of disorders characterized by changes in the eye's retina that can occur in people diagnosed with diabetes. Diabetic eye diseases cause damage to the retina through swelling, fluid leaks, or abnormal growth of blood vessels, resulting in severe vision loss or blindness. Usually affecting both eyes, diabetic retinopathy may not be noticeable for some time, developing so gradually that serious retinal damage may take place before any changes in vision are noticed.

A Progressive Condition

Retinopathy progresses through four stages:

1. Mild Non-proliferative Retinopathy - This is the stage in which small areas of balloon-like swelling occur in tiny blood vessels in the retina.

2. Moderate Non-proliferative Retinopathy - At this stage, blood vessels that supply nutrients to the eye become closed off and blocked.

3. Severe Non-proliferative Retinopathy - More and more blood vessels cease to function, cutting off blood supply to the retina. The retina signals the body to grow new blood vessels.

No treatment is required for mild Non-proliferative Retinopathy, other than through control of levels of blood sugar, blood pressure, and serum cholesterol to retard early disease progression. (Diabetic Macular Edema can occur between moderate and severe non-proliferative, all the way through proliferative, and it is treated by lasers, see below.)

4. Proliferative Retinopathy - New blood vessels appear, but they are abnormal and weak. They grow along the clear gel that fills the eye (the vitreous). When the thin, fragile walls of the blood vessels begin to leak blood, severe vision loss or blindness can occur.

Treatment options for Proliferative Retinopathy include forms of laser surgery called scatter photocoagulation and focal photocoagulation. In photocoagulation, tiny burns are placed on the retina with a special laser. These burns seal the blood vessels and stop them from growing and leaking. In scatter photocoagulation, abnormal blood vessels are shrunk by a retinal specialist who applies as many as 2,000 laser burns in a polka dot pattern in areas of the retina away from the macula. While some loss of side vision may occur, scatter photocoagulation can save the rest of a person's sight. However, it is only effective before bleeding or detachment has progressed very far. In focal photocoagulation, specific leaking blood vessels in a small area of the retina, usually near the macula, are addressed. The retinal specialist identifies individual blood vessels for treatment and makes a limited number of laser burns to seal them.

Eye disorders attributable to diabetic retinopathy include: diabetic macular edema, cataracts, and glaucoma

Diabetic Macular Edema

Macular edema occurs when blood vessels in the retina begin to leak into the macula, the part of the eye responsible for detailed central vision. When this occurs in a patient with diabetes, it is referred to as diabetic macular edema or DME and is the major cause of vision loss in people with diabetic retinopathy. The lifetime risk for diabetics to develop DME is about 10%.

These leaks cause the macula to thicken and swell, progressively distorting acute vision. While the swelling may not lead to blindness, the effect can cause a severe loss in central vision. DME is classified into two types; focal and diffuse. Focal macular edema is caused by vascular abnormalities, primarily microaneurysms, which tend to leak fluid whereas diffuse macular edema is caused by dilated capillaries in the retina. This condition, at the moment, is treated with local focal coagulation as there is presently no FDA approved drug treatment.

Disease Prevalence

Diabetic retinopathy and vision loss Diabetic retinopathy is the leading cause of vision loss among working age adults in developed countries. For people with diabetes, the risk of blindness is more than 3 in 100,000 people. The disease affects nearly half of all Americans diagnosed with diabetes, and is the leading cause of new cases of blindness among adults between the ages of 20 to 74. Over 12,000 to 24,000 new cases of blindness occurring each year are attributed to diabetic retinopathy.

When the blood vessel leakage of diabetic retinopathy causes swelling in the macula, the part of the eye responsible for central vision, the condition is called DME. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that over a ten-year period approximately 19% of diabetics studied were diagnosed with DME. Based on this study and the current U.S. diabetic population, Alimera estimates there to be a prevalence of close to one million people and an incidence of approximately 300,000 new cases of DME annually in the United States. As detection of diabetes increases, the company expects its current estimates of the annual incidence of diagnosed DME to also increase.

Results to Date

Alimera is currently conducting two Phase 3 pivotal clinical trials (collectively known as the FAME Study) for Iluvien, involving 956 patients in sites across the United States, Canada, Europe and India, to assess the efficacy and safety of Iluvien with two doses, a high (an approximate initial 0.45 micrograms (µg) per day) dose and low (an approximate initial 0.23 micrograms (µg) per day) dose, in the treatment of DME.

In December 2009, the 24-month clinical readout from the FAME Study was completed and announced. The primary efficacy endpoint for the FAME Study is the difference in the percentage of patients whose best corrected visual acuity (BCVA) improved by 15 or more letters from baseline on the ETDRS eye chart at month 24 between the treatment and control groups. The study will conclude later this year with the final patient visits at the three-year data point.

The 24-month analysis demonstrated statistical significance with 26.8% to 30.6% of the low dose patients having an improvement in BCVA of 15 letters or greater over baseline and 26.0% to 31.2% of the high dose patients having an improvement in BCVA of 15 letters or greater from baseline. In addition, both the low and high dose Iluvien showed greater numerical efficacy at month 24 than at month 18, a requirement for NDA submission with 24 month data in the United States.

Safety was assessed for all patients treated in the study. Intraocular pressure (IOP) increases of 30 millimeters of mercury (mmHg) or greater at any time point, a key adverse event studied in the trial, were seen in 16.3% of the low dose patients and 21.6% of the high dose patients. Over the 24 month period, 2.1% of patients receiving the low dose and 5.1% of the patients receiving the high dose had undergone a trabeculectomy (filtration procedure) to reduce their eye pressure.

A 30-month analysis of the FAME date was presented at the Citi Investment Research Global Health Care Conference on May 27th, 2010. The analysis focused on the primary efficacy variable of the number of patients who improved by 15 letters or more, based on observed cases. At month 24, 31% of the low dose patients had improved vision of 15 letters or more and at month 30, with a sample size of 123 patients, an improvement in visual acuity of 15 letters or more was seen in 40% of the patients. (See Graph 1). Statistical significance versus control was seen by three weeks among the observed cases, and this significance was maintained through month 30. The complete 36-month dataset will be presented at the fall AAO Meeting after the trial concludes in October 2010.

Graph 1. Percent of patients achieving greater than or equal to15 letters of visual acuity improvement using the observed cases method.

Based on these and other data, Alimera, on June 29, 2010, filed a New Drug Application (NDA) to the FDA for the low dose of Iluvien for the treatment of DME. In the submission, Alimera requested priority review, which, if granted, could result in an action letter from the FDA in the fourth quarter of 2010.

On July 8, 2010, the company also submitted a Marketing Authorization Application (MAA) to the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom (UK). The MAA is being submitted through the Decentralized Procedure with the UK MHRA as the Reference Member State (RMS). Applications have also been submitted to the following other Concerned Member States (CMS) in the European Union: Austria, France, Germany, Italy, Portugal and Spain..

Alimera's Future Focus On Diabetic Eye Disease

Alimera Sciences Inc. is a public biopharmaceutical company that specializes in the research, development and commercialization of ophthalmic pharmaceuticals. The company is currently in the process of completing two 36 month Phase 3 pivotal clinical trials with Iluvien for diabetic macular edema (DME). Combined enrollment of 956 patients was completed in October 2007 and a preliminary 24 month readout of the studies occurred at the end of 2009. As incidences of diabetes and diabetic retinopathy escalate, Alimera Sciences is in the forefront of research and development to meet the increasing need for reliable, effective treatments.

While dedicating much of its early resource allocation to the study of DME, the company looks forward to applying its efforts with the Medidur delivery platform (used with Iluvien), for super-antioxidants, and other therapies under investigation for the management and control of other retinal diseases.

As shown in the Pipeline graphic below, Alimera is developing Iluvien devices for the treatment of wet (as an adjunct to Lucentis) and dry (for geographic atrophy) AMD and retinal vein occlusion. In addition, the company is in the pre-clinical stages of development of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase inhibitor, also for treating geographic atrophy in dry AMD.

The Back Story

As I have related in the introduction, there have been many attempts at using sustained release in treating various eye diseases, including gels, rods, loaded contact lenses, and impregnated devices placed in the conjunctiva.

However, it wasn’t until the ganciclovir implant was developed by co-inventors Paul Ashton, Andrew Pearson, Thomas Smith and David Blandford at the University of Kentucky in 1989, in response to the AIDs crisis of the 1980s and 1990s, that a long-acting implantable device became available. That device, now known as Vitrasert, became available after Paul Ashton left Kentucky to start a small drug delivery development company in the Boston area called Control Delivery Systems, and partnering with Chiron, now Bausch & Lomb, got Vitrasert approved for marketing by the FDA in 1996 to treat cytomegalovirus (CMV) retinitis, a condition associated with late-stage AIDS that often leads to blindness.Vitasert releases ganciclovir (Cytovene) directly to the diseased area of the eye over a period of six to eight months and has been a successful treatment for thousands of patients over the past 14 years.

In 1989, Pearson, Smith, Blandford and Ashton were all at the University of Kentucky working on a device to deliver drugs for glaucoma filtering surgery. (Smith was the principal investigator and a glaucoma surgeon; Ashton had just completed post doctorate work, – his Ph.D. is in drug delivery, and Pearson and Blandford were doing their residencies in ophthalmology). According to Ashton, Pearson had the idea to adapt the drug delivery system for the back of the eye and put ganciclovir in it in order to help treat AIDS patients who were then going blind due to CMV Retitis. The first person to be implanted was an AIDS patient from Texas who received the implant in 1990. Smith went into private practice around 1992 as did Blandford, when he qualified as an ophthalmologist. Ashton moved to Boston  to take a position with New England Eye Center. Pearson, however, remained at the University of Kentucky and is now chairman of the Department of Ophthalmology.

Control Delivery Systems was acquired by the Australian company pSivida Ltd. in 2005 and was re-named pSivida Corp. in 2008 when the company reincorporated as a Delaware company. It is headquartered in Boston and Ashton is CEO. CDS also developed, and pSivida now owns, the technology used for the Retisert fluocinolone acetonide (FA) intravitreal implant, marketed by Bausch & Lomb and currently approved for the treatment of chronic noninfectious uveitis affecting the posterior segment, and the Medidur implant technology, licensed to Alimera Sciences and used in the Iluvien FA intravitreal insert. pSivida has also licensed the underlying Medidur technology for all ophthalmic indications not licensed to Bausch & Lomb or Alimera, to Pfizer for all other ophthalmic indications.

pSivida, as shown in Graph 2 below, has several other products in its pipeline in addition to Vitrasert, Retisert and Iluvien. For more information about pSivida and its products and technology, please visit the company’s website: http://www.psivida.com/products.html.

Graph 2 pSivida Pipeline of New Implantable Drugs

In addition, an article by Glenn J. Jaffe, MD, “Sustained Drug-delivery for Retinal Disease: Current technologies include implanted and injected devices”, in the June 2010 issue of Retina Today (2) explains more about the development of Vitrasert, Retisert, and Iluvien by CDS and pSivida and its licensee, Alimera Sciences.

Other Sustained Release Ophthalmic Drugs

As stated by Dr. Robert Avery in his editorial comments introducing the June 2010 issue of Retina Today, “As evidenced by the number of abstracts and posters on drug delivery that were presented at the 2010 ARVO meeting, the science of delivery of pharmaceuticals to the back of the eye is clearly a burgeoning field in the subspecialty of retina. Goals in drug delivery research include targeting therapy for maximum or minimal effect on collateral tissue, creating a depot system that would offer sustained therapy with single administration, reducing the physical burden on patients and physicians (eg, frequent intravitreal injections), and reducing associated costs.”

Dr. Avery further stated, that as of the date of his preparing the editorial commentary, “...there are three FDA-approved therapies that provide sustained posterior- segment drug delivery. The first is the ganciclovir implant (Vitrasert, Baush & Lomb), approved for cytomegalovirus retinitis; the second is approved for uveitis (intravitreal fluocinolone acetonide 0.59 mg implant (Retisert, Bausch & Lomb) and the third is intravitreal dexamethasone 0.7 mg, approved for the treatment of retinal vein occlusion (Ozurdex, Allergan, Inc.). Additionally, several modes of delivery are being evaluated in the preclinical and clinical trial setting to determine safety and efficacy. “

In the same issue of Retina Today, Dr. Szilard Kiss stated, “Retina practices are becoming overwhelmed with the ever-increasing burdens of repeated intravitreal injections for the treatment of age-related macular degeneration (AMD) and macular edema associated with retinal vein occlusion (RVO) and diabetic retinopathy. The need for frequent intraocular injections and the potential side effects associated with those injections has focused attention on the development of alternative systems for the delivery of ophthalmic medications. A variety of methods have been proposed that achieve longer duration of pharmacologic effect with lower administration frequency and minimal side effects.”

I would like to briefly describe some of the sustained release ophthalmic drug systems that 1) have been approved for marketing, and 2) are being developed for use in treating retinal and other ocular diseases.

FDA-Approved Systems

Vitasert (B&L, pSivida) – is a ganciclovir implant tht provides an antiviral release into the eyes of patients with AIDS for the treatment of cytomegalovirus retinitis. It is an ethylene viny acetate and polyvinyl alcohol polymer, sutured into the eye wall to deliver the drug over a 5-8 month period.

Retisert (B&L, pSivida) – is a flucinolone acetonide (FA) implant for release of this corotocosteroid into the eye to treat uveitis. It uses a silicone-polyvinyl alcohol combination polymer, and like Vitasert, is sutured into the back of the eye, for delivery of the drug for up to 30 months.

Ozurdex (Allergan) – is a dexamethasone biodegradable implant for treating macula edema following branch or central retinal vein occlusion. The Novadur system is composed of a poly D,LSustained lactide-co-glycolide (PLGA) polymer matrix that slowly degrades to lactic acid and glycolic acid, enabling extended release of dexamethasone over thirty days, with the expectation that patients can go six months without the need for additional treatment.

Sustained Delivery Systems Under Development

Alimera/pSivida – Iluvien – wet AMD (adjunct to Lucentis)

– Iluvien – dry AMD/geographic atrophy

– Iluvien – retinal vein occlusion

Alimera/Emory Univ. – NADPH – dry AMD/geographic atrophy

Allergan – brimonidine implant. A selective alpha 2 adrenergic agonist as an IVT implant for GA in dry AMD

Genentech/Surmodics – Lucentis for 6-8 month treatment of wet AMD

Glaukos – drug eluting stent

Icon Biosciences – Verisome (IBI-20089) – sustained release drug delivery system that injects a liquid into the vitreous that coalesces into a single spherule. It delivers a titrable drug for up to 1 year for the treatment of edema associated with retinal vein occlusion

Jerini Ophthalmics/PR Pharmaceutical – JSM 6427 –integrin anatagonist injectable sustained release technologies

Lux Biosciences – Lumiject (LX201) – an episcleral implant for delivery of cyclosporine A for prevention of corneal transplant rejections.

MacuCLEAR/Mystic Pharmaceuticals – Versidoser (MC1101) – delivers an anti-hypertension drug to prevent dry AMD from progressing to the wet stage, by preventing the rupture of Bruch’s membrane.

Macusight/Sirolimus – Perceiva – subconjunctival injectable immunosuppressant that uses the sclera for sustained release

Merck/Surmodics – I-Vation – triamcinolone acetonide helical implant for delivery of TA for up to 2 years for DME. The trial has been suspended, data supported focal/grid photocoagulation over the drug delivery. Further, Merck has pulled out of its licensing deal with Surmodics.

Neurotech – NT-501 – encapsulated cell technology (ECT) to deliver ciliary neurotrophic factor (CNTF). For treatment up to 12 months in treating progressive loss of photoreceptors in retinitis pigmentosa, AMD, and related retinopathies, including geographic atrophy in dry AMD

Novagali Pharmaceutical – Cortiject (NOVA63035) – injectable emulsion containing a proprietary tissue-activated corticosteroid, acting for 6-9 months in treating DME

On Demand Therapeutics/InterWest Partners – a unique drug delivery reservoir that can hold multiple cells of a drug and have each cell release its contents by puncturing the cell with a laser beam, for example, Lucentis or Avastin could be placed in the reservoir and released “on demand” using an ophthalmic laser.

Potentia/Alcon – POT-4 – depot forming properties of the cyclic peptide compstatin that functions as a complement factor C3 inhibitor that forms gel-like IVT deposits for slow release in treating wet AMD

QLT – latanoprost coated punctal plug to treat open angle glaucoma for up to 3 months

Regeneron – VEGF Trap-Eye – protein blocks of VEGF-A, VEGF-B and Pl GF (placental growth factor) for wet AMD, CRVO and DME

References:

1. Sustained-Release Drugs: Heralds of the Future, Jerry Helzner, Ophthalmology Management, March 2010.

2. Sustained Drug-delivery for Retinal Disease: Current technologies include implanted and injected devices, Glenn Jaffe, MD, Retina Today, June 2010.

3.Sustained- release Corticosteroid Delivery Systems, Szilard Kiss, MD, Retina Today, June 2010.