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AMD Update 14: Neurotech Pharmaceuticals NT-501 Implant Shown to Slow Vision Loss in Patients with Geographical Atrophy Associat

Posted Apr 08 2011 6:43pm
Back in December 2009, I reproduced Dr. Philip Rosenfeld’s excellent article that presented an overview of the drugs in development to treat dry AMD. At the time, and still today, there was no drug or treatment approved for the treatment of the dry stage of AMD, that represents about 90% of AMD sufferers.

Here is what I presented (from Dr. Rosenfeld’s article ) about drugs to promote the survival of photoreceptors and retinal pigment epithelium (RPE) for the treatment of dry AMD
“No matter what the underlying cause of AMD, drugs that can preserve viable photoreceptors and maintain the RPE should preserve vision. One strategy to promote survival of photoreceptors and the RPE is to protect cells against ischemia and improve the choroidal circulation in patients with dry AMD. Two studies are currently using this strategy. In Europe, an ongoing multicenter, randomized, placebo-controlled study is investigating the use of an offlabel, generic drug known as trimetazidine (Vastarel MR, 35 mg tablet), a drug currently used for the treatment of angina pectoris. Trimetazidine improves myocardial glucose utilization by stopping fatty acid metabolism, and it is considered to have cytoprotective effects in ischemic conditions. Other uses for this drug include the treatment of vertigo, tinnitus, and vision loss and visual field loss due to vascular causes. The primary goal of this study is to slow the conversion of dry AMD to wet AMD.”

“Another drug being investigated for its vasodilatory effect is Alprostadil, also known as prostaglandin E1 (PGE1). The presumed rationale is based on the belief that improved circulation would slow the progression of AMD. This multicenter, randomized, placebo-controlled study is ongoing in Europe.”

“Another strategy to preserve the macular function is to prevent apoptosis by using neuroprotective agents. Ciliary neurotrophic factor (CNTF), a potent neuroprotective agent, has been shown to inhibit photoreceptor apoptosis in an animal model of retinal degeneration  and is being investigated as a treatment for dry AMD. Using encapsulated cell technology that permits CNTF-producing transfected cells to be implanted into the vitreous cavity, Neurotech Pharmaceuticals (Lincoln, RI) has developed a sustained-release platform that produces CNTF for a year or longer. The phase 2 study is completed and data analysis is currently under way. Other neuroprotective agents currently under investigation for dry AMD include a brimonidine tartrate intravitreal implant (Allergan, Irvine, CA) and topical tandospirone (Alcon, Fort Worth, TX).”

Well, this week, Neurotech Pharmaceuticals, Inc., announced that a report in the Proceedings of the National Academy of Sciences (PNAS) (published online March 28, 2011) showed that its product candidate NT-501, slowed progression of vision loss in patients with geographic atrophy (GA) associated with dry age-related macular degeneration (AMD) in a Phase 2 study.

The report, “ Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration ”,  is the first to show the benefits of a therapy to slow the progression of vision loss from this disease. The results highlight the benefit of the use of a neotrophic factor to treat geographic atrophy and provides hope to the nearly one million sufferers of this vision loss disease.

NT-501 is an intraocular implant that consists of human cells genetically modified to secrete ciliary neurotrophic factor (CNTF) - a nerve growth factor capable of rescuing and protecting dying photoreceptors. GA is a condition that destroys sharp central vision, often resulting in serious vision loss to one or both eyes, for which there is no available treatment.

The Phase 2 study was a multi-center, double-masked, sham-controlled, dose-ranging study in 51 subjects with GA. Subjects were randomly assigned to receive either a high- or low-dose NT-501 implant or sham surgery. The primary study endpoint was change in best corrected visual acuity (BCVA) at 12 months. The study results demonstrated a dose-dependent increase in retinal thickness suggesting increased photoreceptor metabolic activity. This increase was followed by visual acuity stabilization (loss of fewer than three lines of vision, or 15 letters) of 96.3% in the high-dose group compared to 83.3% in the low-dose group and 75.0% in the sham group. In a sub-group analysis of subjects with better vision at base line (20/63 or better), 100% of the high-dose group (n = 10) maintained visual acuity stabilization compared to 55.6% (p = 0.033) in the combined low- and sham-treated groups (n = 9). In this sub-group analysis, there was a 0.8 mean letter gain in the high-dose group compared to a 9.7 mean letter loss in the combined low- and sham-treated groups. Overall, there were no serious adverse events reported and the surgical procedures were well tolerated. The proof of concept study results were originally reported by the company in March 2009.

Quoting from an earlier safety study , published in PNAS in March 2006, the authors then noted: “This trial indicates the safety and promising utility of encapsulated cell delivery as a mode of administration of protein therapeutics to the eye. The results raise the intriguing possibility that CNTF may improve visual acuity in some eyes with advanced RP and atrophic macular degeneration. At the end of the 6-month implantation duration, all explanted capsules contained viable cells that secreted CNTF at expected levels that were therapeutic in the rcd1 dog study. Because pharmacokinetic data on preclinical studies showed continued CNTF production out to 1 year and beyond, encapsulated cell implants may provide a longer-term therapeutic release that will facilitate efficacy studies in retinal and macular neurodegenerative diseases. These results, coupled with robust implant performance, provide the basis for considering the next stages of human trials of CNTF delivered by encapsulated cell implants.”

(Editors note: Whereas the earlier safety study indicated that NT-501 might improve visual acuity in some eyes with advanced RP and GA, the Phase 2 study results, the focus of this article, indicated that the device might slow vision loss.)

The current study's lead author and one of its clinical investigators was Dr. Kang Zhang, Professor of Ophthalmology & Human Genetics, Shiley Eye Center and Director of the Institute for Genomic Medicine, University of California, San Diego. He noted, "The study findings are very promising since both structural and functional improvements were demonstrated in a disease that is currently untreatable. These results support the initiation of larger confirmatory studies of NT-501 in patients with GA."

Paul Sieving, MD, PhD, Director of the National Eye Institute and Principal Investigator of Neurotech's Phase 1 study of NT-501 in retinitis pigmentosa, commented that, "The results of this Phase 2 study suggest that CNTF delivered by the ECT platform may be a useful approach to slow the progression of vision loss in GA patients, and warrant further study in a larger trial of patients exhibiting early onset of this condition."

Ted Danse, Chief Executive Officer of Neurotech stated, "These results in GA demonstrate the significant opportunity of NT-501 to fill a much needed treatment void for sight-robbing retinal degenerative diseases. The data also provide further validation of our proprietary ECT technology and strongly support the introduction of additional product candidates from the platform."

About Dry AMD/ Geographic Atrophy (GA)


Age-related macular degeneration (AMD) is a chronic progressive disease of the macula that results in the loss of central vision. It is the leading cause of blindness in elderly people in the developed world. There are two forms of AMD - dry and wet. Dry AMD is the most common form of AMD representing approximately 90% of all AMD cases. In its advanced stages dry AMD can lead to the degeneration of photoreceptors, those cells of the retina responsible for fine central and color vision, and retinal pigment epithelial cells, those cells responsible for nourishing photoreceptors, resulting in a chronic condition called geographic atrophy (GA). There are currently no approved GA therapies for the nearly 1 million individuals affected in the United States.

About NT-501

NT-501 is one of Neurotech's lead product candidates under development and consists of encapsulated human cells genetically modified to secrete ciliary neurotrophic factor (CNTF). CNTF is a nerve growth factor capable of rescuing dying photoreceptors and protecting them from degeneration. NT-501 is designed to continually deliver a therapeutic dose of CNTF into the back of the eye in a controlled, continuous basis for up to twelve months, by means of the company's proprietary Encapsulated Cell Therapy (ECT) platform. Delivery via ECT bypasses the blood-retinal barrier and overcomes a major obstacle in the long-term treatment of retinal disease.

About Encapsulated Cell Therapy

Neurotech's core technology platform is Encapsulated Cell Therapy (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 human cells that have been genetically modified to produce a specific therapeutic protein and encapsulated in a semi-permeable hollow fiber membrane. The diffusive characteristics of the hollow fiber membrane are designed to promote long-term cell survival by allowing the 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 enables the controlled, continuous delivery of therapeutic factors directly to the retina, thereby bypassing the blood-retina barrier.

The ECT Implant

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 implant has a suture loop at one end to anchor it to the sclera in the vitreo-retinal body inside the eye. The current product is 6 mm in length, roughly the size of a grain of rice.



ECT Device
ECT Placement

In contrast to gene therapy, ECT does not modify the host genome. The implant is surgically placed in the vitreous body of the eye as an out-patient procedure in about 15 to 20 minutes. The implant is sutured in a manner that allows for its retrieval when desired, providing an added level of safety as well as the ability to reverse or adjust therapy, if needed.

Placement in the eye
How it Delivers its Drug

The diffusive characteristics of the ECT hollow fiber membrane are designed to promote long-term cell survival by allowing the influx of oxygen and nutrients while simultaneously preventing direct contact of the encapsulated cells with the cellular and molecular elements of the immune system.

Delivery Action

ECT Applications

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, stabilize or halt disease processes in the eye. ECT represents a unique platform for the safe and effective delivery of many of these factors for the treatment of various chronic ophthalmic diseases as follows
    * Neurotrophic factors for the treatment of retinal degeneration in geographic atrophy (a serious condition associated with the atrophic (dry) form of age-related macular degeneration), retinitis pigmentosa, glaucoma and others.

   * Anti-angiogenic factors for the treatment of the wet form of age-related macular degeneration, retinal vein occlusion, vascular proliferation in diabetic retinopathy and for the treatment of abnormal vascular permeability for various forms of macular edema.
 
  * Anti-inflammatory factors for the treatment of ocular inflammations such as uveitis.

The graphic below shows the status of several of the company’s programs involving its encapsulated cell technology devices.


Neurotech Device Pipeline

About Neurotech Pharmaceuticals, Inc.

Neurotech is developing sight-saving therapeutics for the treatment of chronic retinal diseases. NT-501, one of the company's lead product candidates, is currently in late-stage clinical development for retinitis pigmentosa (RP) and advanced dry age-related macular degeneration (dry AMD). The company's portfolio of product candidates also includes treatments for wet AMD, including NT-503 that delivers a VEGF antagonist. All of Neurotech's development programs are based on the company's proprietary Encapsulated Cell Therapy (ECT). ECT uniquely enables the controlled, continuous delivery of biologics directly to the back of the eye, thereby overcoming a major obstacle in the treatment of retinal disease. To learn more, please visit our web site at www.neurotechusa.com .

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