Why it’s taken drug companies so long to appreciate the huge unmet medical need for new therapies to treat back-of-the-eye diseases is somewhat of a mystery, since age-related macular degeneration alone is the leading cause of functional blindness in the industrialized world, affecting some 15 million Americans. This number could double by 2010, as baby boomers enter their sixties. As well, 75 percent of all individuals with diabetes -- itself a massive and growing patient base -- will eventually develop diabetic retinopathy. Fortunately, pharma and biotech firms now recognize the stunning opportunity available to them, and dozens of drug candidates are in the clinic. We’ll examine four of them, each of which takes a different approach – including gene therapy and gene silencing.
In preparing for the upcoming Christmas holiday, Brian’s days were filled with the usual hustle and bustle associated with that joyous season. But his miscellaneous chores seemed more tedious than usual, and it was hard for him to concentrate. He also had to wear his reading glasses more often that normal and he had trouble seeing little things. But he didn’t give much thought to these events at the time.
After New Year’s, he went for a long overdue physical, and noticed much to his chagrin that the examining room was two different colors at the same time: His left eye saw the room as grey; his right eye saw it as peach. The room was peach, all right, but the doctor attributed this quirk to holiday-induced anxiety.
Four days later, Brian knew something was not normal in his left eye, for now there was a grey blank area in the center of it. He had to wait another four days for an appointment with his ophthalmologist and he was a nervous wreck. That doctor’s comments – “interesting” and “I haven’t seen this for a couple of years” – only served to heighten his anxiety, and he lost his appetite, became depressed and had trouble sleeping.
Credit: National Eye Institute, National Institutes of Health.
The ophthalmologist sent Brian to a retina specialist, who performed a number of tests, including a flourescein angiogram – which three weeks later confirmed that he had multifocal inner choroiditis (an inflammatory retinal disease) with secondary subfoveal choroidal neovascularization (CNV; the formation of new blood vessels in the tissue that lies beneath the retina).
Brian was relieved to find out that he didn’t have cancer or an aneurism, nor did he have age-related macular degeneration (AMD) -- but he did have CNV, and the results are the same (since CNV is always associated with the wet form of AMD). The damage to his left eye cannot be repaired and stays at 20/400 with some peripheral vision. The normal right eye may degenerate, too: Brian has already noticed that the “fuzzy blobs” he sees with that eye are slowly growing.
Credit: National Eye Institute, National Institutes of Health.
Think this won’t happen to you? Think again. You may not come down with multifocal inner choroiditis, but if you live long enough, you will definitely get age-related macular degeneration (which affects the central area on the retina that allows us to see fine details). If you are “lucky,” you’ll contract dry AMD, which involves fatty deposits (drusen) beneath the light-sensitive cells in the retina – and your vision will gradually deteriorate over the course of many years. You may even retain some central vision.
But if you have the wet form of the disease, which occurs when abnormal blood vessels leak fluid beneath the macula -- which causes scarring -- you will lose your central vision rapidly and become functionally, even legally, blind. You won’t be able to read, walk or drive.
There’s still no cure for AMD or CNV. Or, for that matter, other back-of-the-eye diseases such as diabetic retinopathy and diabetic macular edema. Sadly, the treatment options today are quite limited: There are two methods available for treating wet AMD – laser photocoagulation and photodynamic therapy – but each is effective in only a small subset of affected individuals and recurrences after photocoagulation are common. Photocoagulation is also used to treat advanced cases of diabetic retinopathy. There are no therapies for dry AMD.
But all that’s about to change: Pharmaceutical and biotechnology companies have suddenly seized the opportunity to develop therapies for these very common and exceedingly devastating diseases – and the first new drug could be on the market by 2005.
Why it’s taken so long for drug companies to appreciate the huge unmet medical need presented by back-of-the-eye diseases is somewhat of a mystery, since AMD alone is the leading cause of functional blindness in the industrialized world, affecting some 25-30 million people. In fact, it’s more common than cataracts and glaucoma combined.
AMD affects about 15 million Americans over the age of 50, and another 1.7 million new patients are being diagnosed annually. As baby boomers enter their sixties, 30 million more individuals are expected to contract AMD by the year 2010.
Most individuals with AMD contract the dry form of the disease. But dry AMD can progress to wet AMD, which accounts for 10-15 percent of all cases – about 200,000 new cases every year and a total patient population of about 1.6 million in the U.S. alone.
Like wet AMD, diabetic retinopathy (DR) is characterized by the growth of abnormal blood vessels in the back of the eye, which then leak blood into the center of the eye, causing severe retinal damage. There are about 18 million people in the U.S. with diabetes, and after 10 years of disease duration, 75 percent of them will develop some form of diabetic retinopathy.
Fluid can also leak into the center of the macula, which causes it to swell and thicken. This condition, diabetic macular edema (DME), is the leading cause of vision loss in individuals with diabetes. It affects about 500,000 individuals in the U.S. and accounts for 75,000 new cases annually – and with the alarming rise in the prevalence of diabetes in the States, this patient population is growing quickly.
Obviously, the market for new therapies to treat these diseases is enormous – billions of dollars for AMD alone – and drug companies are finally in hot pursuit of this virtually untapped opportunity to create more blockbuster drugs. In fact, at least two dozen firms – both biotech and big pharma – now have experimental compounds in the clinic for age-related macular degeneration, diabetic retinopathy and diabetic macular edema. (Selected compounds are profiled in the tables scattered throughout this article.)
And while Eyetech Pharmaceuticals Inc. is only one company in what’s becoming a crowded playing field, it’s also arguably the firm that finally opened everyone’s eyes to the potential market opportunity for ophthalmic therapies. First, it signed a blockbuster $745 million deal with mega-pharma Pfizer Inc. to jointly develop and commercialize Macugen, its experimental drug for treating wet AMD and DME. (For details of this alliance, and the previous ones formed around Macugen, see the Signals article, “The Licensing-Go-Round.”) Then, Eyetech pulled off the first – and most spectacular – biotech-related IPO of 2004, raising $157 million in the process. The stock jumped 54 percent its first day out and hasn’t looked back since – proving that investors are now keenly aware of the market potential for eye-disease drugs.
But it wasn’t always that way. According to Eyetech co-founder and CEO David Guyer, when he first started talking to pharmaceutical companies in the late 1990s about developing new therapies for AMD, they just weren’t interested. “There were a lot of interesting drugs” that could have been tested in clinical studies, “but pharma companies did not see the size of the market. They chose not to run trials.” It was frustrating – especially to Guyer, an ophthalmologist who is an authority on macular diseases.
“The back-of-the-eye disease market was unrecognized at the time,” he explained. And two of Eyetech’s board members – one of whom has AMD and was also frustrated because so few seemed to recognize the huge unmet medical need for new therapies – suggested that Guyer and CSO Tony Adamis, who trained at Harvard under Judah Folkman, the “father” of angiogenesis, start a company. Which they did – and they pinned their hopes on Macugen, which they had in-licensed from Gilead Sciences Inc.
Amsler grid. Left: As it appears to someone with normal vision.
Right: As it might appear to someone with age-related macular degeneration,
Credit: National Eye Institute, National Institutes of Health.
“When we started the company, we were already in clinical trials,” he said. And, because he had met resistance when he first approached pharmaceutical companies about new AMD therapies, Guyer decided to finish patient recruitment for the pivotal trials before setting out to search for a partner that could develop and market Macugen overseas. “We wanted a partner that knew how to commercialize break-through products,” he said. This time around, he had no trouble attracting interest: “By 2002, everybody saw how big the market is. It was easy to get companies interested and we got term sheets from all six potential partners.” But Pfizer won out.
Eyetech’s Macugen – a PEGylated aptamer that blocks vascular endothelial growth factor (VEGF) – is only one of several VEGF antagonists currently in the clinic, but it will probably be the first to win marketing approval.
VEGF is responsible for the growth of new blood vessels by stimulating the endothelial cells that form the walls of the vessels. Neovascularization plays a restorative role in many parts of the body, but wreaks havoc in others. It’s now well-known that VEGF is responsible for the formation of new blood vessels by tumors – and Genentech Inc.’s recently approved anti-VEGF antibody Avastin has demonstrated once and for all in a clinical setting that it’s possible to halt neovascularization by blocking VEGF from binding to its receptor.
If it works in tumors, it should work in those eye diseases characterized by neovascularization, as well. And the results of Eyetech’s two pivotal Phase II/III clinical trials on Macugen in wet AMD indicate that it does: The product, which is delivered by intravitreal injection, is able to slow the progression of the disease in a very broad patient population, irrespective of lesion size, lesion subtype (predominantly classic, minimally classic and occult) or initial visual acuity. In fact, Eyetech and Pfizer are so confident of the one-year results from these trials (which were statistically significant for the primary endpoint of change in visual acuity) that they intend to submit an NDA in the third quarter of 2004.
As well, the partners are testing Macugen in patients with DME: Results from a Phase II trail, reported in early May, were also statistically significant for visual and anatomical outcomes.
If the FDA approves Macugen for wet AMD, it will be the first product available to patients who suffer from any subtype of the disease. To date, the only other therapy on the market is QLT Inc.’s Visudyne, a photodynamic therapy that works by converting cell-based oxygen into a highly energized form (singlet oxygen) that destroys new blood vessels by disrupting normal functions.
Visudyne is currently approved in the U.S. only for treating predominantly classic AMD, which occurs in about 25 percent of all patients with wet AMD. However, that situation is now changing: In January 2004, the Centers for Medicare and Medicaid Services decided to reimburse Visudyne therapy in minimally classic and occult cases where the lesions have shown signs of progression. As well, QLT is conducting advanced-stage clinical trials in both subtypes, so Visudyne could eventually garner the FDA’s blessing for use in all AMD patients.
Since it’s possible to halt blood vessel development by preventing VEGF from binding to its receptor, then perhaps other anti-VEGF approaches might work, too – including shutting down production of VEGF entirely by destroying its messenger RNA (mRNA). Acuity Pharmaceuticals is betting on it.
The privately held company has licensed patent applications from the University of Pennsylvania that cover the broad therapeutic use of mammalian RNA interference (RNAi) technology and for the use of short interfering RNA (siRNA) to treat specific disease targets. Gene silencing – in which double stranded RNA is used to knock out gene expression by chewing up the target’s mRNA -- is one of the hottest technologies around, and Acuity Pharmaceuticals stands a good chance of being the first company to start clinical trials with an siRNA therapeutic drug candidate. (For details of this technology, see the Signals article, “Shoot The Messenger.”)
Acuity’s first product Cand5, which targets VEGF mRNA, is intended to treat both wet AMD and DR. And because a single RNAi drug molecule is able to stop the production of hundreds or even thousands of VEGF protein molecules, the company believes that it will prove to be significantly more potent that other therapies under development.
Selected Products In Development For Back-Of-The-Eye Diseases*
|
Company; Partner
|
Product
|
Description
|
Effect
|
Indication
|
Development Stage
|
|
Acuity Pharmaceuticals
|
Cand5
|
siRNA; blocks production of VEGF by destroying its mRNA
|
Inhibits growth of new blood vessels and vascular leakage
|
Wet AMD and DR
|
Preclinical
(5/04)
|
|
Alcon
|
Retaane
|
Anecortave acetate (depot suspension); angiostatic cortisene (steroid
derivative)
|
Slows or stops growth of new blood vessels
|
1) Wet AMD
2) To slow the progression of advanced dry AMD to wet AMD
|
1) Phase III
(8/03)
2) Phase III
(1/04)
|
|
Eyetech Pharmaceuticals; Pfizer
|
Macugen
|
Aptamer (single stranded nucleic acid) that prevents VEGF from binding
to its receptor
|
Stops growth of new blood vessels
|
1) Wet AMD (all subtypes)
2) DME
|
1) Phase II/III
(8/01; 10/01)
2) Phase II
(10/02)
|
|
Genaera
|
Squalamine
|
Synthetic aminosterol derived from dogfish shark tissue
|
Inhibits blood vessel formation and causes partial regression of formed
vessels
|
Wet AMD
|
Phase II
(5/04)
|
* AMD = age-related macular degeneration; CNV = choroidal neovascularization; DME = diabetic macular edema; DR = diabetic retinopathy; PEDF = pigment epithelium-derived factor; VEGF = vascular endothelial growth factor
Acuity has already tested its product “in mouse and primate models [laser-induced choroid neovascularization] for wet AMD,” explained president and CEO Dale Pfost. In results presented at the Association for Research in Vision and Ophthalmology (ARVO) meeting last year, company scientists reported that “in the mouse model, there was a substantial decrease in neovascularization,” he said. “More recently, we’ve found a substantial decrease in leakage and a decrease in the area of choroid neovascularization in the primate model,” the results of which were published in the February 2004 issue of Retina, the Journal of Retinal and Vitreous Diseases.
These were both clinically relevant endpoints, and the demonstration of siRNA efficacy in a non-human primate using intravitreal injection (which is also clinically relevant) is, to the company’s knowledge, a first. Moreover, Pfost said, “the effect has a duration of several weeks,” which means the drug could be administered less frequently than other experimental compounds. Armed with those data, Acuity is poised to file an IND in wet AMD by the end of this year.
And the eye is the perfect place to test an siRNA-based drug: “The circumstances are really lined up for a favorable outcome,” Pfost said. “The retinal epithelial pigment cells are post-mitotic,” which means that the effect of siRNA won’t be diluted. As well, the eye contains phagocytic cells, “so the delivery issue is pre-solved by the natural physiology of the eye.” And because delivery is localized, the probability of systemic toxicity is “essentially zero,” he added.
Not all companies involved in developing new therapies for AMD and DR are targeting VEGF, however. GenVec Inc., for instance, is using gene delivery to produce pigment epithelium-derived factor (PEDF) protein directly in the eye. This factor, licensed from Northwestern University and the NIH, inhibits abnormal blood vessel formation. It is considered one of the key natural regulators of vascularity in the eye and an extremely potent anti-angiogenic factor.
GenVec decided to develop gene therapies for AMD and DR because at the time “it was clearly an unmet medical need,” explained Lisa Wei, GenVec’s director of preclinical sciences and PEDF team leader. “After talking to specialists, we learned that there were very few treatments available. Other companies recognized that as well,” she added. Moreover, “Macugen caught a lot of attention, as did Eyetech’s agreement with Pfizer,” essentially validating ophthalmics as an important therapeutic area.
“It was unexpected that PEDF is also a potent anti-angiogenic factor,” Wei said. “For 10 years it had been investigated for its roles as a neurotropic factor and a neuronal survival factor.” The first paper describing PEDF’s anti-angiogenic properties was published in 1999 (Dawson et al. Science. July 9, 1999: 245-248). “It’s more potent than Endostatin and Angiostatin,” she added.
Selected Products In Development For Back-Of-The-Eye Diseases*
|
Company; Partner
|
Product
|
Description
|
Effect
|
Indication
|
Development Stage
|
|
Genentech; Novartis Ophthalmics
|
Lucentis
|
Humanized MAb fragment to VEGF
|
Inhibits blood vessel formation and leakiness
|
1) Wet AMD (minimally classic and occult)
2) Wet AMD (predominantly classic)
|
1) Phase III
(3/03)
2) Phase III
(6/03)
|
|
GenVec
|
AdPEDF
|
Gene therapy; PEDF delivered via adenoviral vector
|
Inhibits blood vessel formation and causes regression of formed vessels
|
Wet AMD
|
Phase I
(11/02)
|
|
Miravant Medical Technologies
|
SnET2-PDT
|
Photodynamic therapy; tin ethyl etiopurpurin
|
Selectively destroys new blood vessels
|
Wet AMD (all subtypes)
|
NDA submitted
(3/04)
|
|
OXiGENE
|
Combretastatin A4 Prodrug
|
Vascular targeting agent; synthetic compound derived from the bark
of the African Bush Willow tree
|
Affects microtubules that form the cytoskeleton of the endothelial
cells lining blood vessels, thus shutting down blood flow and destroying
the vessels; also induces vessel regression
|
Wet AMD
|
Phase I/II
(7/03)
|
* AMD = age-related macular degeneration; CNV = choroidal neovascularization; DME = diabetic macular edema; DR = diabetic retinopathy; PEDF = pigment epithelium-derived factor; VEGF = vascular endothelial growth factor
GenVec is already in the clinic with AdPEDF in patients with severe wet AMD, and it intends to demonstrate that this product can not only halt disease progression but also cause the regression of abnormal blood vessels. In late April, the company reported interim results of its Phase I trial at the ARVO meeting in Ft. Lauderdale. A single intravitreal injection proved safe and, though early, investigators observed positive changes in visual acuity and retinal appearance at the higher dose levels tested.
Importantly, “PEDF was the first molecule with published data that demonstrate it causes abnormal vessels in the eye to regress,” Wei said. “The reason patients go to see their doctors is because they already have abnormal blood vessels. [The ability to induce] regression is clinically more relevant than prevention of abnormal blood vessel formation.”
OXiGENE Inc. has chosen another way to attack already-formed blood vessels – through the use of a vascular targeting agent called Combretastatin A4 Prodrug (CA4P). This product, a synthetic compound that was originally derived from the bark of the African bush willow tree, affects the microtubules that form the cytoskeleton of the endothelial cells that line newly formed blood vessels.
CA4P, which the company licensed from Arizona State University, is already in Phase I/II trials in patients with wet AMD, where it is administered systemically. The beauty of CA4P, explained Dai Chaplin, OXiGENE’s CSO and head of R&D, is not only that its target tubulin is ubiquitous, but also that “it binds reversibly to the target. After several hours it comes off and disappears.”
Selected Products In Development For Back-Of-The-Eye Diseases*
|
Company; Partner
|
Product
|
Description
|
Effect
|
Indication
|
Development Stage
|
|
Peregrine Pharmaceuticals
|
------
|
Vascular targeting agent; monoclonal antibody and/or other agent
|
Binds to endothelial cells lining blood vessels and then initiates
thrombosis
|
Ocular diseases, including AMD and DR
|
Preclinical
(4/04)
|
|
QLT; Novartis Ophthalmics
|
Visudyne
|
Photodynamic therapy; verteporfin (benzoporphyrin derivative)
|
Selectively destroys new blood vessels
|
1) Wet AMD (predominantly classic CNV)
2) Occult with no classic CNV in AMD
3) Minimally classic CNV in AMD
|
1) FDA approval
(4/00)
2) Phase III (enrollment completed 9/03)
3) Phase III
(9/03)
|
|
Regeneron Pharmaceuticals; Aventis
|
VEGF Trap
|
Fusion protein that contains portions of the extracellular domains
of two different VEGF receptors
|
Inhibits growth of new blood vessels
|
Wet AMD
|
Phase I
(3/04)
|
* AMD = age-related macular degeneration; CNV = choroidal neovascularization; DME = diabetic macular edema; DR = diabetic retinopathy; PEDF = pigment epithelium-derived factor; VEGF = vascular endothelial growth factor
“These endothelial cells have to lie flat, and that shape is determined by tubulin in immature cells,” Chaplin said. When tubulin is disrupted, these cells round up, “blocking the vessel and shutting off blood flow,” he continued. “This is the Achilles heel, because blood flow will also be blocked to more mature areas of the vessel.”
Once that happens, the cells are cut off from oxygen and nutrients and they die. “Several independent investigators have shown that CA4P also induces the regression of newly formed blood vessels,” he added.
All these experimental therapies, as well as others listed in the tables, target the neovascularization that underlies devastating back-of-the-eye diseases such as wet age-related macular degeneration and diabetic retinopathy – but each represents a unique approach for tackling the problem. Several compounds target vascular endothelial growth factor, the protein responsible for promoting the growth of new blood vessels. Eyetech’s Macugen prevents the binding of VEGF to its receptor; Genentech’s Lucentis binds to VEGF itself; Regeneron Pharmaceuticals Inc.’s VEGF Trap literally traps VEGF molecules so they can’t get to their receptors; and Acuity Pharmaceuticals’ Cand5 stops the production of VEGF protein dead in its tracks by destroying the messenger.
Other compounds, such as GenVec’s AdPEDF and Genaera Corp.’s Squalamine, are anti-angiogenic agents that cause the regression of newly formed abnormal blood vessels. And drugs such as QLT’s Visudyne and OXiGENE’s CA4P act by destroying those vessels – either through photodynamic therapy or the use of vascular targeting agents.
All approaches have merit – and several of them will no doubt receive regulatory approval in the not-too-distant future. Then, finally, the millions upon millions of individuals who now seemed destined to go blind will have access to medications that will preserve their sight instead.
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