Kerentech

- GSK has right to license and commercialize compounds at clinical proof-of-concept

- Isis gives GSK access to expertise in discovery and development of anti-RNA therapeutics

GlaxoSmithKline (NYSE: GSK) and Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) announced today a new strategic alliance that will apply the Isis antisense drug discovery platform to seek out and develop new therapeutics against targets for rare and serious disease, including infectious diseases and some conditions causing blindness.

Under the terms of the agreement, which covers up to six programs, Isis will receive an upfront $35 million payment from GSK and is eligible to receive on average up to $20 million in milestones per program up to Phase 2 proof-of-concept (PoC). GSK will have the option to license compounds at PoC, and will be responsible for all further development and commercialization.  Isis will be eligible to receive license fees and milestone payments, totaling nearly $1.5 billion, in the event all six programs are successfully developed for one or more indications and commercialized through to pre-agreed sales targets. In addition, Isis will receive up to double-digit royalties on sales from any product that is successfully commercialized.

“As a platform, the Isis antisense approach offers us an exciting opportunity to target certain severe diseases in a way that has not previously been possible,” said Dr. Patrick Vallance, Senior Vice-President and Head of Drug Discovery at GSK.  ”Isis Pharmaceuticals is a leader in antisense technology, and this new alliance will enhance our discovery platform in this promising research area.”

Antisense therapies target the proteins involved in disease processes through the RNA that is involved in building these proteins. The Isis discovery platform develops specific therapies that bind to messenger RNA (mRNA) and inhibit the production of disease-causing proteins. Isis recently announced data from a Phase 3 trial in heterozygous familial hypercholesterolemia patients that demonstrated the therapeutic effect of this approach.

This alliance provides GSK with access to Isis’ expertise in drug discovery and development of RNA-targeted therapeutics, with Isis retaining responsibility for the discovery and development of compounds to the alliance targets from inception to PoC.

“We are excited to be working with GSK to apply antisense technology to these new therapeutic areas.  We are particularly excited to work on the novel targets GSK brought to the alliance,” said Dr. Stanley T. Crooke, Chairman and Chief Executive Officer of Isis Pharmaceuticals.  ”This alliance is exactly the type of deal we want to do.  We retain control of the discovery and early development of our drugs while working together with a very high-quality partner to maximize the value of the drugs in late-stage development and commercialization.”

Isis will hold a conference call and live audio webcast today, March 31, 2010 at 8:00 a.m. ET to provide detailed information on its new strategic alliance with GSK.  Interested parties may listen to the call by dialing 866-783-2137 and refer to passcode “ISIS 2010,” or access the webcast at www.isispharm.com.

About RNA-targeted therapeutics

RNA-targeted therapeutics, or antisense therapies such as oligonucleotides, represent an opportunity for a new drug class.  Where most other medicines are small molecules or biologics that target a specific protein in a disease process, antisense therapies prevent protein synthesis by eliminating the mRNA – the template or pattern that guides the production of the protein.

Photoreceptors created from induced pluripotent stem cells.

By Janelle Weaver

Photoreceptors from skin: A photoreceptor cell (green) derived from human skin cells incorporates itself into a mouse retina (red). Credit: Thomas Reh

Think twice the next time you wipe a few flecks of dandruff from your shoulder. You might be shedding cells that may someday restore human vision.

Thomas Reh and colleagues at the University of Washington, in Seattle, have generated light-sensing retinal cells, called photoreceptors, from adult human skin cells. They then transplanted the cells into a mouse retina, showing that the photoreceptors integrated normally into the surrounding tissue. This technological feat raises hopes for the development of treatments for retinal diseases, such as retinitis pigmentosa and macular degeneration, which cause visual impairment or blindness in millions of people in the U.S.

Researchers used induced pluripotent stem (iPS) cell technology, activating a handful of genes in skin cells in order to revert them to a flexible embryonic state. They then used previously developed methods to differentiate the cells into photoreceptors. While Reh’s team has done similar experiments using embryonic stem cells, iPS cells are a preferable source for cell replacement therapies because they can be derived from the patient. Skin cells are a ready source of cells that are tissue-matched to the recipient, bypassing problems associated with immune rejection of stem-cell transplants.

The cells also provide a new way to study retinal degeneration diseases and to identify drug targets. Retinitis pigmentosa, for example, is an inherited disorder in which the photoreceptors begin to die. Retinal cells derived from a patient with the disease harbor all the genetic mutations that contributed to the patient’s disease, so scientists can try to determine the molecular mechanisms that lead to cell death. They can then use the cells to screen for molecules that can slow or stop the damage.

“There are no good drugs to slow photoreceptor degeneration,” said Reh, a neurobiologist at the University of Washington. “One reason we don’t have more molecules we can test is that we don’t have good animal models for many human retinal diseases.”

Scientists will still need to overcome some serious hurdles before using the cells for transplantation therapies. The genetic flaws that led to the disease would need to be fixed before implanting the cells into the eye. And researchers need to figure out how to get large volumes of cells to integrate effectively into the retina. In the current experiments, published last month in the journal PLoS ONE, the number of cells that took root in the mouse eye was too low to restore visual sensitivity. “We need about 10,000 cells to integrate into the retina for them to restore function,” Reh said.

Future research will have to explore how well the transplanted photoreceptors connect with other cell types in the retina and function as an integrated circuit. “The work still ahead is huge,” said Robert Lanza, chief scientific officer at Advanced Cell Technology. “But this is a very important first step.”

Copyright Technology Review 2010.

Quark founder and CEO Dr. Daniel Zurr said, “Over the next 15 months, at least one of our programs should enter a Phase III trial.”

Gali Wienreb

RNA interference (RNAi)-based drug development company Quark Pharmaceuticals Ltd. has reported that it has completed recruitment for its Phase II clinical trial of RTP-801i, its treatment for diabetes macular edema. Quark is developing the drug with Pfizer Inc. (NYSE: PFE; LSE: PFZ), which has the marketing license to the drug.

Pfizer is conducting its own Phase II clinical trial of RTP-801i for age-related macular degeneration (AMD). It purchased the rights for the drug for this purpose from Quark as part of the same licensing agreement.

Quark has also completed patient recruitment for two studies that it is conducting independently. One study is a Phase I clinical trial of its drug for the prevention of acute kidney injury following heart surgery. The second study is a Phase I/II trial of drug candidate QPI-1002 for the prevention of damage to kidney transplants,when the functioning of the new organ is delayed.

Quark hopes that, during the first quarter of 2010, it will begin recruiting patients for an independent study of drug candidate QPI-1007 for protecting nerve cells in the eye from degenerative diseases, such as glaucoma.

Quark founder and CEO Dr. Daniel Zurr said, “Over the next 15 months, at least one of our programs should enter a Phase III trial. We are currently undertaking four trials under US Food and Drug Administration (FDA) Investigational New Drug (IND) guidelines, and a fifth trial is slated to begin shortly.”

Quark’s drugs are based on new mechanisms for drug discovery. The company has developed a technique for investigating the effects of various genes on a range of illnesses by selectively silencing the genes. Both AKLi-5 and RTP-801i are silencing RNA (siRNA) drugs that temporarily inhibit the expression of human p53. The company currently only has Phase I trial results for RTP-801i for AMD, and the treatment was found to be safe.

In 2006, Quark raised tens of millions of dollars in a round led by Japanese funds. It signed the strategic agreement with Pfizer in the same year, under which the company transferred to Pfizer several molecules under development. Pfizer invested tens of millions of dollars in Quark at the time of the agreement, and Quark’s income from the agreement could reach hundreds of millions of dollars in the long term if the drugs reach market.

In early 2007, Quark planned to hold an IPO on Nasdaq on the basis of the Pfizer agreement. The company planned to raise $75 million at a company value of $250-300 million, but withdrew the offering when the market rejected the valuation.

The present announcement may be a feeler aimed at testing a new Nasdaq IPO, now that Quark has several products in the pipeline.

Published by Globes [online], Israel business news – www.globes-online.com – on December 2, 2009

© Copyright of Globes Publisher Itonut (1983) Ltd. 2009

Paris, France – October 1, 2009 – Sanofi-aventis (EURONEXT: SAN and NYSE: SNY) announced today that it has signed a binding agreement for the acquisition of Fovea Pharmaceuticals SA. (“Fovea”) a privately held French research and development biopharmaceutical company, focused on ocular diseases.

Eye cross section ( from Fovea website)

Created in 2005 in Paris, Fovea has a portfolio of three clinical compounds, a unique technology platform and several discovery programs dedicated to back of the eye diseases.

Fovea’s three products in clinical development are : FOV 1101, an eye drop, fixed dose combination of prednisolone and cyclosporine, currently in phase II for the treatment of persistent allergic conjunctivitis, FOV 2302, an intravitreal formulation of a plasma kallikrein inhibitor, in phase I for the treatment of Retinal Vein Occlusion induced macular edema and FOV 2304, a potent antagonist of bradykinin B1 receptors, active by eye drop, scheduled to enter in phase I by November 2009 for the treatment of diabetic macular oedema.

“The acquisition of Fovea, one of the pioneer French biopharmaceutical ophthalmology company, is a further step in our company’s goal to focus on new approaches to strengthen our R&D portfolio” , declared Christopher A. Viehbacher, Chief Executive Officer of sanofi-aventis.  “Fovea and its unique technology platform represent a major opportunity for sanofi-aventis in the very promising and dynamically growing ophthalmic area, driven by unmet medical needs and aging population. I am extremely excited to welcome Fovea in the sanofi-aventis family and to work with highly motivated teams to bring innovative solutions to patients for the treatment of ocular diseases”.

In addition, Fovea has scientific capabilities designed around an innovative proprietary discovery Platform, dedicated  to  ophthalmology  and  especially  retinal  diseases  and  several  ongoing  research  and development programs in glaucoma, retinitis pigmentosa and age-related macular degeneration.

Fovea is built upon close relationship with the Vision Institute, created and chaired by Professor José A. Sahel, at the National Eye Hospital in Paris, which gathers several research teams from University Pierre and Marie Curie, INSERM, CNRS, a Centre for Clinical Investigation fully dedicated to ophthalmology and the National Reference Center for Genetic Retinal Disease.

“We are extremely pleased to join sanofi-aventis as it will provide Fovea with the necessary resources and expertise needed to continue to aggressively grow our franchise and demonstrate the efficacy of our products through regulatory clinical development » said Bernard Gilly, President and Chief Executive Officer of Fovea Pharmaceuticals. « With the continued support of our founder, Professor José A. Sahel, our team is highly motivated and we are confident that we will successfully contribute to bringing innovative treatments to patients at risk of loosing sight. »

Under the terms of the agreement, sanofi-aventis has agreed to purchase Fovea for a total enterprise value of up to Euros 370 millions, including an immediate upfront payment and subsequent milestone payments related to the three clinical compounds.

NIH to Conduct Clinical Trial with Optiquel™

NEW YORK–(BUSINESS WIRE)–Sep 21, 2009 – Enzo Biochem, Inc. (NYSE: ENZ), announced today that it had entered into a Cooperative Research and Development Agreement (CRADA) with the National Eye Institute, part of the National Institute of Health, to conduct a human clinical trial of Optiquel™, Enzo’s oral, proprietary therapeutic for chronic autoimmune uveitis.

Under the terms of the CRADA, Enzo will supply its proprietary compound, Optiquel™, and will fund a portion of the studies. The clinical trial will be conducted to assess the safety and efficacy of Optiquel™ in a proof-of-concept clinical trial designed as a randomized, double-masked, placebo-controlled study with a long-term follow-up. The agreement additionally includes non clinical research focusing on the use of various compounds that may serve to enhance the immune mediated oral tolerance response to specific antigens. Such research may be applicable across the entire spectrum of the Company’s immune regulation platform, including Alequel™, and EGS21™, its therapeutic candidates for the treatment of Crohn’s Disease and NASH, respectively.

Robert Nussenblatt, MD, Chief of NEI’s Laboratory of Immunology, will serve as the Principal Investigator on this project. Dr Nussenblatt, a world-renowned ocular immunologist and expert in clinical research design and conduct, has authored or co-authored over 400 publications and a number of books, including a standard text on uveitis.

An autoimmune disorder is a malfunction of the immune system which causes it to attack itself. In autoimmune uveitis, the body’s own immune system attacks the uvea of the eye, the portion of the eye that lies between the outermost and innermost layers of the eye. Uveitis occurs most frequently in people ages 20 to 50. A recent study estimated that more than 280,000 people in the United States are affected by uveitis each year, and the disease is associated with 30,000 cases of blindness annually.

Patients with chronic autoimmune uveitis are currently treated with general immunosuppressive agents such as steroids. The aim of immunosuppression is to control inflammation and to preserve visual acuity. However, immunosuppression therapy is frequently associated with significant adverse effects, including ocular toxicity (glaucoma and cataract), that limit the duration and intensity of treatment. Therefore, there exists an urgent need for new, non-general and specific therapeutic approaches with less material side effects.

Optiquel™ has been designed as such a therapeutic approach as it specifically targets the HLA proteins. A Phase I study of Optiquel ™ showed no treatment related side effects. Optiquel™ therapy is based on oral tolerance, an immunologic mechanism that down-regulates immune responses in an antigen-specific manner, rather than a non-specific immunosuppressive approach. A Phase I study of Optiquel™ demonstrated a therapeutic effect with no treatment-related side effects. Optiquel™ has been awarded orphan drug status in the European Union and it is anticipated that a similar designation will be applied for in the US. Enzo has exclusive rights to both US and international patents claiming the use of this compound for the treatment of uveitis.

Enzo will sponsor an investigational new drug (IND) application and submit it to the FDA. Additionally, Enzo has completed all of the bulk manufacturing, stability studies, pharmacokinetics evaluations, and formulation in capsules, as well as prepared the necessary documentation to treat patients. Toxicity studies have all proven negative.

About NEI and NIH

The National Eye Institute (NEI) is part of the National Institutes of Health (NIH) and is the Federal government’s lead agency for vision research that leads to sight-saving treatments and plays a key role in reducing visual impairment and blindness. For more information, visit the NEI Website at www.nei.nih.gov.

The National Institutes of Health (NIH) – The Nation’s Medical Research Agency – includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

About Enzo

Enzo Biochem is engaged in the research, development, manufacture and licensing of innovative health care products and technologies based on molecular biology and genetic engineering techniques, and in providing diagnostic services to the medical community. Enzo’s Life Sciences division develops, produces and markets proprietary labeling and detection products for gene sequencing, genetic analysis and immunological research among others. Its catalog of over 30,000 products serves the molecular biology, drug discovery and pathology research markets. The Company’s therapeutic division is in various stages of clinical evaluation of its proprietary immune regulation medicines for uveitis and Crohn’s disease and conducts pre-clinical research on several candidate compounds aimed at producing new mineral and organic bone, including technology that could provide therapy for osteoporosis and fractures, among other applications. Enzo’s Clinical Labs division provides routine and esoteric reference laboratory services for physicians in the New York Metropolitan and New Jersey areas. Underpinning the Company’s technology and operations is an extensive intellectual property estate in which Enzo owns or licenses over 240 patents worldwide, and has pending applications for over 200 more. For more information visit our website www.enzo.com.

Ophthalmic Imaging Systems will merge with Israel’s MediVision Medical Imaging as part of the deal.

Gali Weinreb

Investment fund Accelmed has invested $6 million in California-based Ophthalmic Imaging Systems Inc. (Bulletin Board: OISI) (OIS). Accelmed chairman Dr. Uri Geiger and chairman of the investment committee Moshe (Mori) Arkin founded the Israeli investment firm.

Besides developing it own products, OIS owns a subsidiary that markets ophthalmic industry computer systems. As part of the deal with Accelmed, OIS will acquire the activities of Israeli ophthalmic products maker MediVision Medical Imaging Ltd. (EuroNM:MEDV), which is OIS’s controlling shareholder. The two companies have been working closely for a long time, and planned to merge a year ago, but did not go through with it. As a result of the present deal, MediVision will basically become a holding company, whose main asset will be about a third of OIS’s shares. OIS will forego a $4.7 million loan to MediVIsion and will also assume a $1 million loan to MediVision from Mizrahi Tefahot Bank (TASE:MZTF).

Accelmed’s investment in OIS is in two parts: $4 million was transferred in late June, and $2 million will be paid in April 2010, subject to OIS meeting certain conditions.

OIS’s board appointed Arkin and Geiger as directors, effective last month.

Geiger told “Globes”, “Accelmed intends to add to OIS a range of additional ophthalmic products.”

OIS was founded 20 years ago, and in addition to its ophthalmic business, it provides informatics solutions for managing patients’ medical reports.

Published by Globes [online], Israel business news – www.globes-online.com – on July 2, 2009

© Copyright of Globes Publisher Itonut (1983) Ltd. 2009

via Israeli fund Accelmed invests in US co OIS.

MENLO PARK, Calif., June 22 /PRNewswire/ — Transcend Medical, Inc., an ophthalmic device company dedicated to delivering breakthrough advances in the treatment of glaucoma, announced today that it has closed a $35 million Series B round and is continuing the rapid development of its Transcend CyPass(TM) System, a novel proprietary system for the minimally-invasive treatment of glaucoma.

Lead investor HLM Venture Partners, along with other new investors Canaan Partners, Technology Partners and Latterell Venture Partners made significant contributions to this round of financing, which was also strongly supported by current investors Morgenthaler Ventures and Split Rock Partners.

 ”Completing this round is a testament to the progress of our technology and a strong validation of its potential to impact the future of glaucoma treatment,” said Brian Walsh, President and Chief Executive Officer of Transcend Medical. “We are now well-capitalized to accomplish all initial clinical and commercial milestones for the company.”

 The Transcend CyPass System is being developed to both replace current glaucoma therapies, which either lack effectiveness or are very invasive, and to expand treatment to a much larger patient population. Transcend Medical is focused on a less invasive procedure using a novel, proprietary system that reduces intraocular pressure (IOP).

 ”There is a significant need to improve how we treat glaucoma,” commented Eugene de Juan, Jr., M.D., Jean Kelly Stock Distinguished Professor of Ophthalmology at UCSF and Founder of Transcend Medical. “Today’s treatment options for glaucoma are highly limited and only feasible in a limited portion of those affected by the disease worldwide.”

 ”We are encouraged by the CyPass System’s minimally invasive delivery which is of significant benefit to patients, provides important ease of use features for physicians, and could result in earlier intervention in the glaucoma disease process,” added Ike Ahmed, M.D., Assistant Professor, University of Toronto who is a world renowned glaucoma specialist and a clinical investigator of the CyPass System. “The CyPass System has shown promising initial results in a challenging population, with a very straight-forward procedure. We have been quite impressed with our experience to date in this growing patient group.”

 About Transcend Medical, Inc.

 Transcend Medical (www.transcendmedical.com) is focused on the research and development of medical devices for the treatment of glaucoma, the leading cause of adult irreversible blindness. It is estimated that nearly four million people in the U.S. and 70 million worldwide are afflicted with the disease today and the numbers are expected to grow to nearly six million in the U.S. and to over 80 million worldwide by the year 2013. Based in Menlo Park, Calif., Transcend Medical was the first company to be spun out of ForSight Labs (www.forsightlabs.com), an incubator solely focused on ophthalmic innovations.

 SOURCE Transcend Medical, Inc.

GEN News Highlights  

More than half U.S. population has been afflicted by visual impairment due to a disease of the eye. While there are a number of drugs currently in clinical trials for many ocular diseases, in general their development and FDA approval has progressed slowly. This article provides a background on three major ocular diseases and an update on the development of therapeutics for dry eye syndrome (DES), uveitis, and age-related macular degeneration (AMD).

There are currently five million people in the U.S. diagnosed with DES. The majority of these patients have either remained untreated or have turned to artificial tear therapy such as Restasis (Allergan and Inspire Pharmaceuticals), which is utilized in the most severe cases. Current thinking regarding the treatment of DES is moving away from the idea of increasing tears and moving toward the idea of correcting ocular damage.

In the U.S., uveitis affects approximately 400,000 people and may be responsible for up to 10% of blindness cases. Uveitis may affect different sections of the eye, and both the pattern of disease and the approach to treatment will vary substantially by location.

AMD affects eight million people in the U.S., and due to the aging population, its prevalence is expected to increase to about 12 million by 2020. While there are approved treatments for the more advanced, or wet form of AMD, these treatments are moderately effective. In addition, there are currently no approved therapies for the more common dry form of AMD.

DES Pathophysiology
Originally thought to be purely a lack of tear production, DES is now understood to be a multifactorial disease involving inflammation, autoimmunity, and damage to the surface of the eye. Dry eye results from either a tear deficiency (aqueous-deficient DES) or from excessively dry physiological conditions (evaporative DES). Aqueous deficient DES is caused by Sjögren’s syndrome, an autoimmune condition affecting the lacrimal and salivary glands, or non-Sjögren’s syndrome abnormalities (NSDE). NSDE includes gland-duct obstruction and is a side effect of laser surgery. Evaporative DES is either intrinsic or extrinsic.

It has become apparent that symptoms of DES do not necessarily reflect the severity of the disease. Studies also show that inflammatory changes characteristic of severe DES may cause a decrease in ocular nerve sensitivity, which may explain the lack of symptoms in other patients.

New Approaches to Treating DES
Product sales in the U.S. totaled approximately $700 million with Restasis accounting for $500 million and artificial tear products accounting for the balance, according to industry experts. The advancement of our understanding of the mechanisms underlying DES has lead to a number of novel agents for DES, including 20 that have been tested in clinical trials.

The major impediment to the development of new agents for DES has been the limited ability of clinical trials to produce results that meet the FDA’s criteria for efficacy. Primary endpoints usually focus on the improvement of at least one sign and one symptom with both being shown to be statistically and clinically significant. Signs and symptoms may not correlate with disease severity in DES though. The complexity of the approval process is highlighted by the approval of Restasis, which was not based on the primary endpoint of the pivotal clinical trial but rather on the secondary endpoint (improvement in the Schirmer test results and a correlation of symptom improvement in a subset of patients).

Additionally, clinical trials in DES are confounded by the effect of placebo on tear production. A recent report by the International Dry Eye Workshop suggested that no treatment would provide a better comparator arm in future clinical trials and that the use of surrogate markers as trial endpoints should be further explored.

In general, approaches to the development of drugs for dry eye focus on either anti-inflammatory approaches or the secretagogue approaches. Anti-inflammatory drugs in late-stage clinical trials rely on either the use of cyclosporine derivatives (Phase III ST603 from Sirion Therapeutics and Phase III Nova22007 from Novagali) or novel anti-inflammatory approaches such as doxycycline-induced protease inhibition (Phase III ALTY-0501 from Alacrity Bioscience).

Novel DES therapies that follow the secretagogue route aim to promote tear production directly. These include mucin secretion stimulants (Phase II Escabet sodium from ISTA Pharmaceuticals and Phase III OPC12759 from Acucela and Otsuka), adenosine receptor agonists (Phase III Prolacria from Inspire Pharmaceuticals and Allergan), and chloride channel stimulators (Phase II Moli1901 from Apotex and Lantibio).

MEDACorp consultants are optimistic about the prospects of targeting DES with these newer approaches, either singly or in combination. Can-Fite BioPharma’s CF-101, is an adenosine A3 receptor agonist in Phase II development, and SARcode’s LFA-1 antagonist, SAR1118, is in a Phase I study.

Uveitis Pathophysiology
Uveitis, or inflammation of the uveal tract of the eye, was originally thought to be a single disease, but is now understood to represent a collection of common symptoms reflecting a number of diseases with different etiologies. The two most common ways to classify uveitis are by the etiology of the disease (infectious, noninfectious, and masquerade syndromes) and by the portion of the eye involved (anterior, intermediate, posterior, and pan uveitis). For most ongoing clinical trials, the anatomical strategy of classifying the disease is most commonly employed.

Anterior uveitis (AU) is the most common type of disease, accounting for 90% of all cases of uveitis seen in the community setting. Most cases of AU have no clear cause, occur in healthy people, and are believed to result from trauma to the eye. AU does not usually cause visual impairment but can be quite painful.

Intermediate uveitis (IU) involves inflammation of the structures between the retina and the anterior chamber. IU is not usually a painful disease, and most commonly patients complain of blurry vision and/or floaters as their main reason for seeking medical evaluation.

Penetration of topical drugs is very poor in the intermediate and posterior of the eye, so systemic steroids are often prescribed. Because IU is most commonly associated with an infection, primary therapeutic options also include anti-infectives. The majority of noninfectious IU cases are idiopathic without systemic disease, and treatment may be more complicated. IU is well known as the type of uveitis with the longest duration. Interestingly, IU has been linked to sarcoidosis, multiple sclerosis (MS), and Lyme disease.

Posterior uveitis (PU) describes inflammation of the choroid and retina. Like IU, there is little pain or redness, and symptoms are mostly limited to floaters, blurry vision, or loss of visual field. The most common cause of PU is toxoplasmosis. As in IU, the structures involved are not readily accessible to topical steroids, and treatment often employs systemic glucocorticoids.

Current and Developing Therapies
Although the use of steroids as part of treatment is based more on clinical experience than clinical trial data, it is the preferred first-line therapy. The preferred mode for steroid administration in AU is by the topical route and logically, treating any underlying infection in infectious uveitis is also important.

In 2005 the FDA approved an intraocular glucocorticoid (fluocinilone) implant (Retisert, BOL) for the treatment of refractory PU. Retisert 2008 sales in the U.S. totaled about $10 million, but placement has some surgical risk, and drug development predominantly focuses on noninvasive means to treat PU. In the past few years there has been a surge of reports on the use of biologics in intermediate and posterior uveitis. Three main strategies have been explored: anti-TNFalpha, anti-interleukin, and prointerferon.

Remicade (infliximab, Johnson and Johnson) has dominated the anti-TNF category with activity in AU and PU. Data show an 80–100% initial response rate, but the effect seems to be temporary, and patients often require repeated infusions for sustained activity. The main drawbacks of Remicade include infusion reactions with continued administration and risk of cancer.

Humira (adalimumab, Abbott Laboratories), another TNF-directed biologic has been pursued for uveitis. This drug requires only a subcutaneous injection, but efficacy does not appear to be on par with the response rates seen with Remicade. In spite of Humira’s lower efficacy, its low incidence of adverse events and convenience of dosing make it an attractive treatment. Lastly, in the anti-TNF category, Enbrel (etanercept, Amgen and Wyeth) has also been tested, but its efficacy pales in comparison to Remicade and Humira, and it is not widely used.

Anti-interleukin therapy has focused on two main drugs, Zenapax (daclizumab, Roche) and Kineret (anakinra, Biovitrum). Zenapax, an interleukin 2 (IL-2) receptor antagonist, has been tested in an IV infusion and subcutaneous setting; efficacy was seen with both routes of administration. Less data is available on Kineret, a recombinant version of a naturally occurring interleukin 1 (IL-1) antagonist. Small studies indicate this drug may have activity in TNF-refractory uveitis.

The prointerferon (IFN) strategies have focused on the use of recombinant IFNá. Recombinant IFNalpha-2a (Roferon, Roche; Pegasys, Roche) and IFNalpha-2a (PegIntron, Schering-Plough) have been shown to be effective in steroid refractory patients, but side effects are a significant hindrance.

Novel treatments in clinical development for uveitis include a Phase III drug delivery system for transport of glucocorticoids in the posterior eye chamber (Posurdex, Allergan), a Phase II mAb to the IL-2 receptor (Simulect, Cerimon/ Novartis), and a Phase II protein kinase C inhibitor (AEB071, Novartis). These strategies include interesting twists on existing therapies (moving steroid into the previously inaccessible posterior eye chamber) and completely new approaches (recombinant alpha-fetoprotein, PKC antagonist).

MEDACorp consultants are particularly excited about the prospect of steroid delivery into the posterior chamber of the eye and eagerly await data on longer acting implants and novel delivery devices. Other compounds in development are Phase III Durezol (Senju Pharmaceutical and Sirion Therapeutics), a phospholipase A2 inhibitor; Phase III Luveniq (Lux Biosciences), a calcineurin inhibitor; Phase II EGP437 (EyeGate Pharmaceuticals), an iontophoretic delivery of a GR agonist; and a Phase II AEB071 (Merrimack Pharmaceuticals), an alpha-fetoprotein receptor agonist.

AMD Pathophysiology
AMD has four main classifications: early AMD, intermediate AMD, advanced non-neovascular AMD (dry AMD), and advanced neovascular AMD (wet AMD). The hallmark of early, intermediate, and advanced dry AMD are drusen—focal depositions of debris in the retina. In early AMD, a few small drusen may result in mild visual disruption. Upon progression to intermediate AMD, one large drusen and many small drusen may result in a loss of vision in the center of the visual field. In advanced dry AMD, there is drusen and large-scale retinal damage.

Wet AMD is quite different from dry AMD; overproduction of VEGF and other cytokines play a critical role in disease progression. Individuals with dry AMD typically experience a gradual reduction in central vision as a result of retinal and retinal pigment epithelium atrophy. Patients with wet AMD often suffer a more abrupt and profound loss of vision secondary to the development of choroidal neovascularization.

Current and Developing AMD Treatments
The recent introduction of a new class of drugs, vascular endothelial growth factor (VEGF) inhibitors, has revolutionized the management of wet AMD in dramatic fashion. In May 2006, Dr. Judah Folkman, widely regarded as the father of angiogenesis, received the Helen Keller Prize for Vision Research for his groundbreaking work on the angiogenic mechanisms that are central molecular mediators of choroidal neovascularization. The current first-line treatment for wet AMD is based on anti-angiogenic mAbs against VEGF first developed to treat cancer.

Three anti-VEGF therapies—Macugen (pegaptanib, OSI Pharmaceuticals), Lucentis (ranibizumab, Genentech), and Avastin (bevacizumab, Genentech)—are currently available and widely used to treat wet AMD. Lucentis and Avastin are currently the most commonly used therapy for wet AMD. Lucentis is designed for intravitreal injection, while Avastin was designed for systemic use.

The Table shows a sampling of drugs in clinical development. Due to the high cost of Lucentis, trials are now studying the effect of intravitreal injections of Avastin. Additional approaches include the use of combination therapies of steroids, novel drugs targeting angiogenic molecules, and anti-VEGF drugs are also under way.

Dry AMD has had little clinical advancement for decades. The large market and barren drug landscape makes this area particularly appealling, and companies are investigating some interesting and novel targets in an effort to find a drug that is effective in treating dry AMD. MEDACorp consultants are optimistic about several novel therapeutics including strategies targeting ciliary neutrophic growth factor  alphaVbeta1 and alphaVbeta3 integrins.