Retina research homes in on underlying disease pathology

Early trials suggest new drug therapies derived from genetic research may offer a viable approach to treating retinal vascular disease.

Anti-complement drugs and integrin peptide therapy represent a complex, novel method of treating diseases such as age-related macular degeneration, one centered on underlying disease pathology.

“Developing drug therapies from genetic discoveries is a tricky business, especially in chronic diseases. This is not the typical Mendelian form of mutations where we need to replace an enzyme or protein and, voila, we have a treatment or cure,” Michael Tolentino, MD, said in an email interview with OSN Retina.

The difficulty of modulating complement, for instance, can be explained by viewing the system’s cascading activation process as analogous to the detonation of a bomb, according to Dr. Tolentino.

“The complement system consists of 30 proteins in our blood that are waiting to be triggered, much like gunpowder, which sits inert until detonated,” he said. “Once detonated, a chain reaction of events occurs that results in the formation of the membrane attack complex, which acts like shrapnel and penetrates membranes. Unfortunately, these ‘shrapnel’ are not targeted, and if they explode on a retinal pigment epithelial cell or a photoreceptor, the explosion will have the same destructive properties.”

Likewise, integrin peptide therapy is complicated in its multiple-factor approach. According to Hugo Quiroz-Mercado, MD, it disrupts VEGF production, down-regulates receptors and interrupts tyrosine kinase enzymes associated with such receptors. Additionally, it interferes with cell-to-cell adhesion and produces high levels of posterior vitreous detachment and vitreous liquefaction, allowing VEGF to filter out of the eye.

“Unlike anti-VEGF approaches that bind up already produced VEGF, integrin peptide therapy approaches the angiogenic cascade earlier in the process and at multiple steps simultaneously,” Dr. Quiroz-Mercado said.

Anti-complement therapy

The complement system is a biochemical pathway that serves as immunological defense against pathogens. To control this system and prevent immunopathology, the body initiates a series of regulatory proteins during activation. However, in certain circumstances, control is insufficient or does not occur due to genetic abnormalities.

“The complement system has factors that serve as the bomb squad. A major one is factor H. This factor is meant to protect our cells from these bombs by defusing the complement chain reaction that results in formation of the membrane attack complex,” Dr. Tolentino said. “Imagine if, instead of having a crackerjack bomb squad, you have a bunch of high school students as your squad. Then you will have a lot of collateral damage.”

Activation of the complement cascade and its regulation represent two areas of interest for researchers focused on AMD treatment. Some are working on anti-complement drugs to block C3, the key modulator at the top of the cascade, while others are investigating therapies to block C5, which is lower and may theoretically be safer. Still others are investigating fusion proteins to restore factor H, which could be mutated in patients with AMD.

In a review on anti-complement therapy published in Clinical and Experimental Ophthalmology, researchers noted that evidence implicating the system’s involvement in AMD began to surface over 15 years ago.

“Histological and biochemical studies of drusen discovered that various components of the complement system were identifiable as molecular constituents of the characteristic extracellular deposits found in early AMD. In addition, eyes obtained from human donors diagnosed with a complement-related renal disorder … demonstrate drusen-like deposits in the fundus that were clinically and compositionally analogous to drusen in AMD,” the study authors wrote.

Subsequent validation occurred in 2005, they said, when studies showed a link between allelic variants in the factor H gene and AMD. Additionally, increased risk of AMD alongside mutations in other complement-encoding genes has since been reported.

“As we get older, we develop chronic inflammation, and eye cells become bombarded with stray complement destruction. … Over time, we develop debris that builds up and rusts (oxidizes), which results in production of drusen. The oxidation of these drusen incites VEGF upregulation that causes wet AMD, and the rusting inflammatory debris activates macrophages, which may result in the ‘eating up’ of tissue, leading to geographic atrophy,” Dr. Tolentino said.

Ongoing research

The biggest question facing anti-complement researchers is whether the complications of AMD can be stopped once initiated, Dr. Tolentino said.

“We are studying geographic atrophy patients with inhibitors of the complement cascade to see if this will stop the macrophages from eating the retina and possibly decrease upregulation of VEGF by eliminating the stimulus of anaphylatoxins,” he said, noting inflammatory anaphylatoxins amplify the damage of the complement cascade by propagating a feed-forward loop.

Another question is whether the factor H polymorphism is a predisposing gene that sets the stage for AMD complications or the central factor contributing to their propagation.

Dr. Tolentino believes all tactics to inhibit “detonation” are worthwhile. However, blocking complement at a higher level could inactivate opsonization, a process by which bacteria are coated with factors that ease phagocytosis and therefore risk infection, he said. Conversely, blocking too low may result in ineffective treatment.

“Theoretically, defusing the explosion is a better tactic, unless you have a molecule that can be potent and quick enough to catch all the shrapnel the instant it explodes,” he said.

In a presentation at the 2011 American Academy of Ophthalmology meeting, Peter K. Kaiser, MD, OSN Retina Board Member, mentioned Alcon’s synthetic cyclic peptide AL-78898A as a potential blocker of C3, as well as FDA-approved Soliris (eculizumab, Alexion) and ARC-1905 (Ophthotech) as potential blockers of C5. A Fab fragment known as FCFD4514S (Genentech/Roche), which blocks factor D-mediated cleavage of factor B, was also discussed.

Other anti-complement drugs under investigation include POT-4 (compstatin, Potentia) to inhibit C3, TA106 (Taligen Therapeutics) to target complement factor B and recombinant factor H (Taligen/Optherion) as supplementation, among others.

“Pharmacologically, therapies optimized to specific components of the pathway will differ in their mechanism of action, facilitating inhabitation, replacement or modulation of their target,” the study authors wrote.

While Dr. Tolentino is optimistic about anti-complement drugs for AMD, he believes that research should also focus on visual cycle modulation and macrophage biology, common pathways in the development of end-stage macular degeneration.

Integrin peptide therapy

Another option is integrin peptide therapy, an emerging treatment class for vascular eye diseases such as wet AMD and diabetic macular edema.

“Molecules that interfere with integrins have been described for more than 15 years. … Interestingly, while this area has been understood for many years, there are very few molecules that can actually bind to the target integrin receptors in the desired fashion,” Dr. Quiroz-Mercado, MD, told OSN Retina.

One such molecule, the oligopeptide ALG-1001, binds to multiple receptor sites and affects multiple pathways, according to a December 2011 press release from Allegro Ophthalmics. It was discovered by Allegro in collaboration with CalTech and is currently undergoing a phase 1b/2a study including 30 participants with diabetic macular edema. The trial has a dose-ranging design, with participants receiving three monthly injections followed by 4 months of evaluation. The primary endpoint is safety, and the secondary endpoint is efficacy.

Study performed by Peter Campochiaro, MD, at Wilmer Eye Institute at Johns Hopkins University in a well-established laser-induced mouse model for choroidal neovascularization showed a 43% reduction in the area of neovascularization with ALG-1001 (n = 10) vs. vehicle (n = 9) with statistical significance (P = .018).

Source: Quiroz-Mercado H, Allegro Ophthalmics

ALG-1001’s prior phase 1 study, which had an open-label, single-dose design, included participants with advanced-stage diabetic macular edema with vision of 20/100 or worse with or without proliferative diabetic retinopathy. More than 50% showed best corrected visual acuity improvement of three to five lines after 90 days, the release said, as well as improvement in central macula thickness seen by optical coherence tomography.

Moreover, those without improvement did not show disease progression or deterioration in visual or central macular thickness outcomes over the 150-day trial period.

“Our human and animal testing thus far has demonstrated integrin peptide therapy to be extremely safe. In hundreds of animals, in multiple species and with multiple doses, no safety concerns have arisen. Furthermore, in our initial human phase 1 study, there were no reported significant adverse effects or significant adverse events,” Dr. Quiroz-Mercado said, noting that integrins targeted by the drug are upregulated and present only in cells involved with neovascularization.

Study performed by Peter Campochiaro, MD, at Wilmer Eye Institute at Johns Hopkins University in an ischemic retinopathy treated mouse model for pre-retinal neovascularization showed ALG-1001 caused significant inhibition of neovascularization, with three doses exhibiting statistical significance.

“Cells throughout the body not actively involved in neovascularization will not produce these integrin receptors, and thus our drug will have no other binding sites,” he said.

According to Allegro’s release, the ALG-1001 molecule has a unique mechanism of action that shuts off VEGF production at its source, potentially making it more potent and longer-lasting than anti-VEGF therapy.

“While anti-VEGF treatments are an extremely valuable part of the treatment armamentarium, there is a tremendous untapped need by physicians and patients for new, potent alternatives. Integrin peptide therapy has the potential to meet this need, and consequently, we eagerly await further human and animal data being generated in coming months,” Dr. Quiroz-Mercado said. – by Michelle Pagnani

Reference:

Lorem Troutbeck R, Al-Qureshi S, Guymer RH. Therapeutic targeting of the complement system in age-related macular degeneration: a review. Clin Exp Ophthalmol. 2012;40(1):18-26.

For more information:

Hugo Quiroz-Mercado, MD, can be reached at Medica Sur, Pente de Piedra 150-514, México DF 14050, México, or the University of Colorado Denver Health Medical Center, 777 Bannock St., Denver, CO 80204; 720-425-0230; email: hugoquiroz@yahoo.com.
Michael Tolentino, MD, can be reached at the Center for Retina and Macular Diseases, 250 Avenue K SW, Winter Haven, FL 33803; 863-297-5400; email: miket@crmd.net.
Disclosures: Dr. Quiroz-Mercado is a consultant for Allegro Ophthalmics. Dr. Tolentino receives research grants from Novartis, Genentech, Ophthotech and Pfizer. He is also a consultant for Catalyst Biosciences, Promedior, Bausch + Lomb, Bayer, Ophtherion, Sequenom and Artic Dx.