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Insight & Intelligence™ : Jun 10, 2009

Into the Looking Glass—The Future of Ocular Therapeutics

An overview of disease types, current therapies, and drug candidates.
  • Jessica Barnes

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.

Table. Select Drugs in Clinical Development for AMD

Product

Company

Status

Mechanism of Action

Photrex

Miravant Medical Technologies

postapproval

Photosensitizer

Zinthionein

 

Adeona Pharmaceuticals

III

Zinc-monocysteine complex

Visudyne with Triamcinolone

QLT

III

VEGF-A

Bevasiranib with ranibizumab

Opko Health

 

III

VEGF

VEGF Trap-Eye

Bayer and Regeneron

III

VEGF

AGN745

Allergan and Merck & Co.

II

VEGFR1

Visudyne with Lucentis, Dexamethasone

QLT

II

VEGF-A

Medidur FA with Lucentis

pSivida

 

II

VEGF-A

Lucentis with Visudyne

Genentech

II

VEGF-A

TG100801

Targeted Genetics

II

VEGF

ST602

Sirion Therapeutics

II

PDGFR-b

Neurosolve

Vitreoretinal Technologies

II

Retinal Stimulant

OT551

Othera Pharmaceuticals

II

Nuclear Factor-Kappa B (NF-kB) Inhibitor

RTP801i

Quark Pharmaceuticals and Silence Therapeutics

II

DNA-Damage-Inducible Transcript 4 (DDIT4) Inhibitor

Armala

GlaxoSmithKline

II

C-Kit Receptor Tyrosine Kinase (CD117) Inhibitor; PDGFR; VEGFR

NT501

Neurotech

II

Ciliary Neutrophic Growth Factor (CNTF) Receptor Agonist

ATG003

CoMentis

II

Alpha7 Non-Neuronal Nicotinic Receptor Antagonist

Iluvien

Alimera

I

Slow-release corticosteroid; being studied in dry AMD

Isonep

Lpath

I

Sphingosine-1-Phosphate (S1P) Receptor Antagonist

PG11047

Progen Pharmaceuticals

I

Polyamine Analogue

E10030 with Lucentis

Ophthotech

I

PDGFR-b

AdPEDF

GenVec

I

Pigment Epithelial derived GF delivery via adeno vector

ACU4429

Otsuka Pharmaceutical/
Acucela

I

Non-retinoid visual cycle modulator

Sirolimus

MacuSight

I

mTOR Inhibitor

POT4

Potentia Pharmaceuticals

I

Complement Factor C3 Inhibitor

ARC1905 with Lucentis

Ophthotech

I

C5 Complement Inhibitor; VEGF-A Inhibitor

GS101

Gene Signal

I

Antisense insulin receptor Substrate 1 (IRS-1)

SB267268

GlaxoSmithKline

I

AlphaVBeta3 Integrin Receptor Antagonist

Volociximab

Biogen Idec and PDL BioPharma

I

AlphaVBeta1 Integrin Receptor Antagonist

JSM6427

Jerini/PR Pharmaceuticals

I

Alpha5Beta1 Integrin Receptor Antagonist