Wet and Dry Age-Related Macular Degeneration (AMD)

The present Competitive Intelligence Report about Wet and Dry Age-Related Macular Degeneration (AMD) provides a competitor evaluation in the field of R&D projects for treatment of AMD as of February 2009.

Macular degeneration in the elderly (“age-related macular degeneration”, AMD) is a major cause of blindness. Its prevalence increases to 30% in patients 75 to 85 years of age. AMD occurs in two forms: dry and wet AMD. Central geographic atrophy, the “dry” form of advanced AMD, results from atrophy to the retinal pigment epithelial layer below the retina, which causes vision loss through loss of photoreceptors (rods and cones) in the central part of the eye. While no treatment is available for this condition, vitamin supplements appear to slow the progression of dry macular degeneration and, in some patients, improve visual acuity. Neovascular or exudative AMD, the “wet” form of advanced AMD, causes vision loss due to abnormal blood vessel growth in the choriocapillaries, ultimately leading to blood and protein leakage below the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated.

It is only recently that new drugs have been approved for wet AMD which halt progression of the visual loss or even lead to improvement. The humanized antibody fragment ranibizumab (Lucentis) directed against vascular endothelial growth factor (VEGF) was developed by Genentech and Novartis has been approved in more than 70 countries worldwide since 2006 and posted record sales of US$ 1.76 bln in 2008.

The proven effectiveness and commercial success of the anti-VEGF treatment of wet AMD has encouraged many companies to develop new treatments of wet AMD based on the proven target VEGF as well as on other experimental approaches (anti-angiogenic, anti-proliferative, anti-inflammatory). More than 20 different approaches are in clinical development and more than 20 preclinical stage projecs are under evaluation for wet AMD. Among the projects are many biologics (antibodies, peptides, proteins, antisense, DNA, cells) facilitated by the topical (intravitreal administration). Small molecule approaches may confer the convenience of oral administration but efficacy still has to be demonstrated. Fewer projects are in clinical development for dry AMD, but the most prominent ones have reached advanced clinical testing, but definitive results are still lacking.

Time course of morphologic effects on different retinal compartments after ranibizumab therapy in age-related macular degeneration.

Ophthalmology. 2008 Aug;115(8):e39-46.


Ahlers C, Golbaz I, Stock G, Fous A, Kolar S, Pruente C, Schmidt-Erfurth U.

Medical University of Vienna, Vienna, Austria.

PURPOSE: To analyze the effect of ranibizumab therapy on retinal and subretinal compartments in age-related macular degeneration and to compare the time course of compartment specific effects to visual function.

DESIGN: Prospective noncomparative case series.

PARTICIPANTS: Fourteen patients with changes in 3 major compartments owing to neovascular age-related macular degeneration.

METHODS: Standard treatment with 3 monthly doses of intravitreal ranibizumab was performed. Eyes were examined at baseline and weeks 1, 4, and 12 using a standardized protocol. Manual segmentation was applied to all 128 B-scans contained in a macular raster scan (MRS).

MAIN OUTCOME MEASURES: Morphology and time course of different retinal and subretinal compartments.

RESULTS: High-definition optical coherence tomography and manual segmentation allowed for precise identification of volumes within individual compartments. All morphologic parameters responded positively to therapy, but demonstrated a specific time course. Subretinal fluid was identified as the most relevant factor for visual function, whereas changes in retinal and subpigment epithelial volumes did not correlate with the time course of functional rehabilitation.

CONCLUSION: Analysis of MRS identified a characteristic impact of therapy on retinal and subretinal morphology.

PMID: 18675694 [PubMed - indexed for MEDLINE]

Serum Cystatin C Level, Kidney Disease Markers, and Incidence of Age-Related Macular Degeneration

The Beaver Dam Eye Study

Ronald Klein, MD, MPH; Michael D. Knudtson, MS; Kristine E. Lee, MS; Barbara E. K. Klein, MD, MPH

Arch Ophthalmol. 2009;127(2):193-199.

Objective
To examine the associations of the serum cystatin C level and chronic kidney disease with the incidence of age-related macular degeneration (AMD) over 15 years.

Methods
In this population-based cohort study of 4926 individuals aged 43 to 86 years at baseline, 3779 participated in 1 or more follow-up examinations. Age-related macular degeneration was determined by grading photographs of the macula. Individuals were defined as having mild or moderate to severe chronic kidney disease based on a value of more than 45 mL/min/1.73 m2 to 60 mL/min/1.73 m2 or less and 45 mL/min/1.73 m2 or less, respectively, according to the Modification of Diet in Renal Disease Study equation.

Results
While controlling for age and other risk factors, the level of serum cystatin C at baseline was associated with the incidence of early AMD (odds ratio per log standard deviation [95% confidence interval], 1.16 [1.01-1.35]) and exudative AMD (1.42 [1.03-1.96]) but not geographic atrophy (0.89 [0.56-1.41]) or progression of AMD (1.02 [0.88-1.18]). Mild chronic kidney disease was associated with the 15-year cumulative incidence of early AMD (odds ratio per log standard deviation, 1.36 [95% confidence interval, 1.00-1.86]) but not the incidence of other AMD end points.

Conclusion
There is a relationship between the level of serum cystatin C and chronic kidney disease with the incidence of AMD. The underlying biological processes remain to be determined.

Author Affiliations: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison.

Age-Related Eye Disease Study (AREDS) Examines Macular Degeneration Risk Related to Cataract Surgery

Age-related macular degeneration (AMD) and cataract are leading causes of visual impairment in the United States. Both are related to aging, and they share other risk factors, but it has been unclear whether a direct causal link might be involved. Several large epidemiological studies had raised concern that cataract surgery might accelerate AMD progress and threaten vision. To address this concern, Emily Y. Chew, MD, of the National Eye Institute, and colleagues analyzed data for a cohort of participants in the Age-Related Eye Disease Study (AREDS). This cohort is the only large prospective study in which the severity of AMD was documented before and after cataract surgery and which included more than five years of in-depth participant follow-up.

AMD causes changes in the retina, the light-sensitive tissue that focuses images at the back of the eye, and severe AMD leads to loss of central vision. Cataract is cloudiness or opacity in the eye's lens that interferes with the clear focus of images on the retina.

AREDS researchers concluded there was little evidence that cataract surgery had a negative effect on progression to advanced AMD. ?These data may provide some reassurance to patients with AMD who are considering cataract surgery,? Dr. Chew said.

The primary purpose of the AREDS multicenter controlled randomized clinical trial was to assess whether antioxidant and mineral supplements affect progress to advanced AMD and development of cataracts. The cohort study included 4,577 participants (8,050 eyes) aged 55 through 81 at enrollment; it compared the risk of advanced AMD in patients who had cataracts removed versus the risk for those who did not have the surgery. All participants took either antioxidant/mineral supplements or placebos. Study eyes were examined every six months over five or more years. One analysis compared AMD progression in matched pairs of eyes, where one eye had cataract surgery after baseline but before developing advanced AMD, and the paired eye did not have cataract surgery. Matched pairs were determined based on similar risk factors for AMD, assigned antioxidant or placebo treatment, baseline AMD category, person?s age, and other factors. Results of the matched pair analysis and of two other standard analytical models revealed no consistent pattern of accelerated AMD progression after cataract surgery.

Several factors may explain the divergent conclusions reached by AREDS and the earlier studies. The most likely cause would be that earlier studies had unintended biases or confounding variables. Also, techniques of cataract surgery and lens replacement have changed over time, and AREDS participant surgeries were performed more recently than those tracked in the combined-population studies. A significant number of subjects in earlier studies did not have lens replacement after cataract extraction, while AREDS participants were likely to have had ultraviolet-B light blocking lenses inserted, which may have protected their maculae and decreased AMD risk.

Neurotech's ECT Technology Wants to Rid the World of Intraocular Problems

Neurotech Pharmaceuticals, Inc., a Lincoln, Rhode Island based firm, has announced that the FDA has granted Fast Track designations for the firm's lead product candidate, the NT-501, for treatment of visual loss in two indications: retinitis pigmentosa (RP) and dry form of age-related macular degeneration (dry AMD). Such designations should allow the company to accelerate clinical development of its continuous, long-term release formulation of the therapeutic protein Ciliary Neurotrophic Factor (CNTF), designed to be released into the vitreous body from a proprietary Encapsulated Cell Technology (ECT) device.


More about Neurotech's technology platform and the NT-501:

Neurotech's core technology platform is Encapsulated Cell Technology (ECT), a unique technology that allows for the long term, sustained delivery of therapeutic factors to the back of the eye.

ECT implants consist of cells that have been genetically modified to produce a desired therapeutic factor that are encapsulated in a section of semi-permeable hollow fiber membrane. The diffusive characteristics of the hollow fiber membrane are designed to promote long-term cell survival by allowing influx of oxygen and nutrients while simultaneously preventing direct contact of the encapsulated cells with the cellular and molecular elements of the immune system. The cells continuously produce the therapeutic protein which diffuses out of the implant at the target site. ECT therefore enables the controlled, continuous delivery of therapeutic factors directly to the retina, bypassing the blood-retina barrier. Long-term protein delivery (18 months) in the vitreous cavity of the eye has consistently been achieved when ECT devices containing human cells genetically engineered to secrete CNTF have been implanted in a highly disparate mammalian species (rabbits). In addition, the implants can be retrieved, providing an added level of safety as well as the ability to reverse or adjust therapy, if needed.

ECT based products can be tailored to address the three main clinical manifestations of retinal diseases: degeneration of photoreceptors and/or ganglion cells in the neural retina, vascular proliferation and inflammation. A number of proteins have been discovered in the field of ophthalmology that possess powerful neurotrophic, anti-angiogenic and anti-inflammatory properties. These proteins have the potential to significantly slow or halt disease processes in the eye. ECT represents a unique platform for the safe and effective delivery of various factors for the treatment of these chronic ophthalmic diseases as follows:

# neurotrophic factors for the treatment of retinal degeneration in Retinitis Pigmentosa (RP), Geographic Atrophy (serious condition associated with the Dry form of Age-related Macular Degeneration), Glaucoma, Retinal Vein Occlusion and others.

# anti-angiogenic factors for the treatment of vascular proliferation in Diabetic Retinopathy and the Wet form of AMD, and for the treatment of abnormal vascular permeability for various forms of Macular Edema.

# anti-inflammatory factors for the treatment of Ocular Inflammations (Uveitis)

The current product is 6 mm in length and consists of genetically-modified human cells packaged in a semi-permeable hollow fiber membrane with a suture loop at one end to anchor the implant to the sclera. In contrast to gene therapy, ECT does not modify the host genome. The implant is surgically placed in the vitreous body. The implant is sutured in a manner that allows for its retrieval when desired. The surgical procedure is performed as an out-patient procedure in about 20 minutes...

... NT-501, consists of encapsulated human cells genetically modified to secrete ciliary neurotrophic factor (CNTF). NT-501 is designed to continually deliver a low, safe and therapeutic dose of CNTF, a well-established neurotrophic factor, into the back of the eye. The Company believes that CNTF activates dying retinal photoreceptors and protects them from degeneration.

FDA OKs First Human Trials of Embryonic Stem Cells

By Alexis Madrigal
January 23, 2009 | 4:10:36 PM

The Federal Drug Administration has approved the first human trials of embryonic stem cells — a sign of a new, liberal attitude toward stem cell research, which was hamstrung by the Bush administration.

Starting this summer, the biotech firm Geron will treat a small group of spinal-cord injury patients using neurons derived from stem cells, marking the first time embryonic stem cells will be tested in humans.

The trial is designed to test the safety of the treatment, not how well it works. Nonetheless, it's a huge first step for the field.

"It signals to me that we have the primary regulatory authorities on board for embryonic stem cells," said Alan Trounson, president of the California Institute of Regenerative Medicine, a $3 billion state initiative to support stem cell research. "That really is a tremendous piece of news."

Under the Bush administration, stem cell research was slowed by an executive order, signed in August 2001, that (severely) restricted the types of stem cells and stem cell research that could be conducted. President Barack Obama is widely expected to lift Bush’s executive order, perhaps as soon as next week.

Working in a handful of medical centers around the country, Geron will treat eight to 10 recent paraplegics, who can use their arms but not their legs. The patients will receive an injection of neurons to the site of the damage, followed by a short treatment of anti-rejection drugs.

Previous animal studies suggest the new neurons will repair damaged neurons and secrete substances to help nerves function and grow.

Amy Rick, president of Coalition for the Advancement of Medical Research, a group of dozens of research institutions that support stem cell research, said the Geron trial is a milestone.

"It's hugely significant in the sense that it's the first approval of a human embryonic stem cell trial," she said. "In this week of hope and change, it feels even better."

While Geron scientists waited months for FDA approval of the stem cell treatment, they are reluctant to link the go-ahead directly to the inauguration of Obama.

A Geron spokeswoman said that the company had no evidence of political influence aiding their application.

“It’s just coincidental timing,” the spokeswoman said.

Karen Riley, an FDA spokeswoman, echoed that the timing was coincidental. "We make science-based decisions and politics is not a factor," she said.

But the new president surely didn't hurt matters. The chairman of Trounson's organization told the New York Times, "I think this approval is directly tied to the change in administration."

The approval is expected to the first of several trials involving embryonic stem cells. A recent CAMR report found that nine companies, including Geron, were in the process of developing human embryonic stem cell treatments.

Embryonic stem cells are like blank slates that can be transformed into different types of tissue. They've been hailed as the next big thing in medicine ever since University of Wisconsin scientist James Thomson showed their ability to regenerate in 1998. Since then, stem cells have been like a high school star turned NBA draft pick — talented and expensive but undisciplined and perhaps not quite ready for the glare of the big game. Like many biotechnology techniques, the lag between scientific discovery and clinical treatment can be decades.

Still, the Regenerative Medicine Institute’s Trounson, who was a stem cell scientist in Australia before heading the California institute, said that experimental treatments are outpacing his expectations.

"We're running an agency funding this work and I'm astounded at what's happening in this space,” he said.

Trounson said there’s evidence in animal trials that stem cells are effective in treating ailments as varied as diabetes, Alzheimers, multiple scleorsis and macular degeneration.

“It’s just fantastic,” Trounson said. "And I would expect some of these to enter clinical trials sooner, rather than later."

His agency expects to fund up to a dozen scientists who think they can submit their stem cell work to the FDA for clinical trial approval within four years.

From there, those so-called investigational new drugs will have to follow the path that Geron's treatment did. The company submitted its application early in 2008. It was then put on hold in May 2008 and kicked back to the company for further review. Seven months later, the company resubmitted the application and received approval Wednesday, the day after the inauguration.

That said, Obama's political influence is likely to invigorate a field that — despite impressive state-level and private efforts — has been ham-strung by Federal regulation and the specter of increased government regulation.

"With President Obama there, there will be a big change not only in government administration and the public sector, but I think it will encourage the pharmaceutical companies to be involved as well," Trounson said.

International Stem Cell Begins Pre-Clinical Testing of Its Parthenogenetic Stem Cells for Treatment of Retinal Disease First Company To Grow Human Cor

OCEANSIDE, Calif., Jan 13, 2009 (BUSINESS WIRE) -- International Stem Cell Corporation has created layered human tissue from its unique parthenogenetic stem cells and transplanted this tissue into animals in pre-clinical trials to establish a potential new treatment for human retinal diseases, such as macular degeneration or retinitis pigmentosa.

"Intact layers of retinal progenitor cells have been shown to restore lost visual responses in several retinal degeneration rodent models," said Dr. Hans Keirstead, Co-Director of the Sue and Bill Gross Stem Cell Research Center at the University of California, Irvine. "Thus, we are developing intact retinal layers derived from International Stem Cell's human parthenogenetic stem cells which could become a sustainable, FDA-approved therapeutic supply for patients with retinal degenerative diseases."

ISCO's human parthenogenetic stem cells have the potential to treat human disease yet possess key medical and ethical advantages over other kinds of stem cell products. They can be matched to common immune types and thus reduce the chance of transplant rejection among large segments of the population. Because they are created from unfertilized human eggs, they do not require the destruction of human embryos.

"We are aggressively pushing forward safe treatments for human diseases using parthenogenetic stem cells," said Jeffrey Janus, President of International Stem Cell. "If we are successful in this work, our next step is to manufacture this layered human tissue for further tests, including human trials. This illustrates the strengths of combining scientific collaborations with outside researchers such as Dr. Keirstead with ISCO's science and cell manufacturing expertise."

For more information, visit the ISCO website at: www.internationalstemcell.com.