Research in Retinal Disease The Foundation Fighting Blindness Invests 2 1 Million in Seven New Research Efforts

As I continually search the web for interesting news about new technologies for treating retinal diseases, I came across this news from the Foundation Fighting Blindness’ website  yesterday afternoon. It relates to some of the annual grants to researchers that the FFB will be funding this year. It includes better ways of looking at retinal cells (via use of the adaptive optics laser scanning ophthalmoscope) and several projects involving gene therapy, along with a couple looking at ways of, hopefully, stopping the progression of dry AMD.

The following write up is reprinted with permission of the FFB.

The Foundation Invests $2.1 Million in Seven New Research Efforts

The Foundation Fighting Blindness

August 15, 2013

The Foundation's Scientific Advisory Board (SAB) recently completed its annual grants review process, leading to the allocation of $2.1 million in funding for seven new research projects, including those for identifying new disease-causing gene mutations, developing cross-cutting gene therapies and advancing potential treatments for dry age-related macular degeneration. The three-year grants were awarded after the SAB reviewed 117 proposals submitted to the Foundation last October.

"Grants review is a rigorous, multi-step process that takes most of the year to complete," says Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. "Due to revenue limitations, we can only fund a fraction of the high-quality projects we'd like to fund. That makes the selection process even more challenging. We had to leave several excellent proposals on the table."

Here are brief descriptions of the new research projects:

AOSLO: Detecting Retinal Degeneration Before Vision is Lost

The adaptive optics laser scanning ophthalmoscope (AOSLO) is like a powerful microscope that enables retinal researchers to see structural changes in the retina well before vision is lost from a retinal disease. That power can enable researchers to more quickly determine if a treatment is working in a clinical trial. Austin Roorda, Ph.D., of the University of California, Berkeley, is performing studies of AOSLO to correlate changes in the retina (e.g., loss of photoreceptors) with changes in vision.

Enhancing AOSLO for Expanded Clinical Use

Like Dr. Roorda, Stephen Burns, Ph.D., of the University of Indiana, is working with AOSLO to study the correlation between retinal and vision changes. He is also making AOSLO more affordable by using newer camera technology. In addition, he's employing state-of-the-art computing technologies derived from video games to decrease image-processing times and costs. The new technology will make the imaging process more comfortable for the patient by tolerating more head and eye movement.

Figuring Out Why Severity of Vision Loss Varies for People with XLRP

Researchers have reported for many years that the severity of vision loss for people with X-linked retinitis pigmentosa (XLRP) can vary greatly, even for people within the same family. Stephen Daiger, Ph.D., of the University of Texas Health Science Center at Houston, will be looking at the role of a various biological, genetic and environmental factors in vision-loss variability for those with XLRP. The identification of a significant factor that modulates vision-loss severity - perhaps a protective protein - could lead to a potential treatment.

Finding New Genes Linked to ADRP

Researchers have identified almost two dozen genes linked to autosomal dominant retinitis pigmentosa (adRP), but many are yet to be found. Rui Chen, Ph.D., of Baylor College of Medicine, is on the hunt for those remaining adRP genes. With DNA from 118 adRP families, including 18 families with at least nine affected members, Dr. Chen is well positioned to identify additional genes linked to adRP. Finding the new genes will provide researchers with targets for treatments and cures.

Developing Neuroprotective Gene Therapies to Preserve Vision

John Ash, Ph.D., is developing gene therapies that have the potential to preserve vision in people affected by a broad range of retinal diseases. Unlike corrective gene therapies, which work only for conditions caused by a specific gene, Dr. Ash's proposed treatments are designed to keep the retina healthy independent of the underlying disease-causing gene. He also believes the proteins delivered by his treatments - PIM-1 and STAT3 - will be less likely to cause damaging inflammatory side effects than some previously investigated neuroprotective proteins.

Targeting Inflammation to Halt AMD

Thanks to previous Foundation-funded genetic studies, researchers have strong evidence that the progression of age-related macular degeneration is associated with an over-active immune system. This ultimately leads to inflammation and cell death in the retinal pigment epithelium (RPE), a layer of cells that provides critical waste and nutritional support to photoreceptors. Loss of the RPE subsequently leads to loss of photoreceptors and vision. Jayakrishna Ambati, M.D., of the University of Kentucky, is developing a gene therapy that preserves the RPE by preventing the harmful sequence of immune-system events.

Boosting Cells' Energy Supplies to Save Vision in AMD

Based on prior research, Deborah Ferrington, M.D., of the University of Minnesota, believes that mitochondrial dysfunction in the RPE plays a significant role in the development of AMD. Mitochondria are like miniature organs (organelles) within all cells that provide energy. When not working properly in retinal cells, they can lead to cell death and vision loss. Dr. Ferrington is evaluating compounds that help protect mitochondrial function in the RPE.

NeoVista Epi Retinal Strontium 90 Treatment for AMD Update 4

NeoVista just released an update, discussing the first commercial utilization of its Epimacular Brachytherapy device in Germany. The Epi-Rad device, now renamed as the VIDION ANV (Anti Neo Vascular Therapy System) has been commercialized in Europe since November 2009. The first patients treated were in Pisa, Italy, quickly followed by patients treated in London, UK, also in November of 2009, and now in Hamburg, Germany this month.

To bring you up-to-date, I began following NeoVista in February 2007, writing an initial piece describing the procedure and initial clinical results. I also asked a series of questions of management and printed their responses. That first piece was:
NeoVista Epi-Retinal Strontium 90 Treatment for Wet AMD

In July 2007, the company announced the initiation of the CABERNET clinical study, and I posted an update, including more questions about the study to management. This piece was:
NeoVista Epi-Retinal Strontium 90 Treatment for AMD Update

In November 2007, during the annual AAO Meeting, NeoVista provided new data from its one-year feasibility study, and I published this data in a second update:
NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 2

And, the final update (until now) was written following the 2008 Retina Society Meeting in September 2008. This included 18-month data from the Phase II feasibility study, and concluded with the statement: “With the continued promise of these Phase II trial results, NeoVista continues to enroll patients in the company's pivotal trial, CABERNET. CABERNET is a multicenter, randomized, controlled study that will enroll 450 subjects at 45 sites worldwide, evaluating the safety and efficacy of NeoVista's epiretinal brachytherapy delivered concomitantly with the FDA-approved anti-VEGF therapy Lucentis (ranibizumab) versus Lucentis alone.”
NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 3

This new update (Update 4) will attempt to bring you up-to-date on both the clinical trials underway, as well as provide a few quotes from the press releases announcing the patient treatments upon commercialization of the device in Europe.

Commercialization in Italy

From the press release about the  first patients treated in Pisa, Italy, announced November 12, 2009:

The first VIDION patients were treated by Dr. Stanislao Rizzo, from the S. Chiara Hospital,Azienda Ospedaliera Universitaria Pisana, Pisa, Italy, who said, “We are very excited to be the first hospital to perform this innovative one time treatment procedure, which can help to treat a devastating disease that otherwise requires chronic treatment for an indefinite period of time. NeoVista’s targeted epimacular brachytherapy treatment may provide us the ability to improve vision by offering a distinct mechanism of action that affects multiple disease pathways unlike the conventional anti-VEGF therapy, and may dramatically change the patient’s quality of life by eliminating frequent eye injections. This promising treatment is a cost-effective alternative to treat neovascular AMD,” continued Dr. Rizzo. “Monthly injections can become quite expensive for our health care system, whereas a single procedure will potentially allow our specialists to treat more patients and bring down the costs associated with ongoing treatments.”

Commercialization in the United Kingdom

From the press release about the first patient treatments in London, UK, announced November 16, 2009:

The new device is initially being introduced in 15 hospitals across the UK as part of a large clinical trial called MERLOT, where it will be used in patients whose current standard of care treatment involves regular injections of a drug into the eye to control their condition (up to one injection every month, indefinitely). Although the treatment is initially only available at select hospitals, it is anticipated that the number of sites using the device will increase quickly, to provide nationwide availability.

The MERLOT trial has been recently awarded portfolio status by The National Institute for Health Research (NIHR) Comprehensive Clinical Research Network (CCRN). The CCRN was created as part of the government’s research and development strategy, “Best Research for Best Health” to provide a world-class infrastructure for clinical trials in all areas of disease and clinical need within the NHS in UK.

Mr Tim Jackson, a Consultant Eye Surgeon at King’s College Hospital, who is the lead investigator for MERLOT said: “This is a relatively straightforward operation and the published results are very impressive. My experience in our own trials of this device has also been encouraging and it is a big step forward to be able to offer patients this new treatment throughout the UK, within a large randomized controlled clinical trial.”

(For more on MERLOT, see the clinical trial section below.)

Commercialization in Germany

And, from the press release describing the first commercialization of the VIDION ANV in Germany, January 19, 2011:

NeoVista, Inc. announced today the first commercial utilization of Epimacular Brachytherapy in Germany. Epimacular Brachytherapy is performed using the VIDION ANV Therapy system and is being offered as an adjunct therapy to anti-VEGF injections for the treatment of neovascular age-related macular degeneration.

John N. Hendrick, President and CEO of NeoVista commented, "Today is an extraordinary day for NeoVista, our local business partner, OctreoPharm Vertriebs GmbH, and the multitude of patients who suffer from this debilitating and life-altering disease. The burden of wet AMD to those afflicted with the disease, and their caregivers, is enormous."

Professor Gisbert Richard, Professor and Head of the Ophthalmology Department in the University Medical Center of Hamburg-Eppendorf, stated, "Our highly qualified medical staff is quite pleased to now be able to offer another therapeutic option to patients suffering from wet AMD - especially those patients who require frequent anti-VEGF injections." Multiple studies have demonstrated that injections alone are not able to effectively treat this disease in a large portion of the population." 

 
Mr. Hendrick added, "The German health care system presents a welcome opportunity for NeoVista to demonstrate the effectiveness of this emerging technology. I believe the use of Epimacular Brachytherapy in the treatment of wet AMD will continue to gain momentum in Germany, and in many other countries, as the rising cost of health care, on a global basis, encourages more and more patients to continue seeking out additional or alternate therapies."

The NeoVista approach to treating wet AMD delivers a focused dose of strontium 90 beta radiation directly to the back of the eye, without damaging the adjacent healthy retinal vasculature. Importantly for patients, the systemic exposure to radiation is minimal and highly controlled to a local area. The effective dose to the entire body from NeoVista's device is less than that from a typical chest x-ray.

Clinical Trial Studies

Finally, I would like to remind you of the clinical studies that have been undertaken and are continuing in the effort to better understand how epimacular brachytherapy can be utilized in possibly reducing the number of intravitreal injections needed in alleviating/stopping wet AMD.

Pilot Studies:

NVI-068

The NVI-068 trial was a study of subjects treated with a single dose of 15 or 24 Gy epimacular brachytherapy. Safety parameters evaluated included incidence and severity of ocular adverse events identified by slit lamp and indirect ophthalmoscopic examination, fluorescein angiography, and optical coherence tomography. Patients will be followed in this trial for 3 years to evaluate safety. (24 month data has been presented.)

NVI-111

The NVI-111 trial was a study of subjects treated with a single dose of 24 Gy epimacular brachytherapy and two injections of bevacizumab (1.25 mg). Subjects received one injection prior to surgery (10±4 days) or at the time of surgery and the second injection at Month 1. Subjects were re-treated with bevacizumab per the investigator’s discretion at follow-up visits. Safety parameters evaluated included incidence and severity of ocular adverse events identified by slit lamp and indirect ophthalmoscopic examination, fluorescein angiography, and optical coherence tomography. Patients are being followed in this trial for 3 years to evaluate safety. (36 month data has been presented and submitted for Peer Publication)


Feasibility Study:

MERITAGE I

MERITAGE I is a multi center international feasibility study designed to decrease the burden of treatment, it is fully enrolled (n=53) and is ongoing. The study is designed to evaluate the safety and efficacy of epimacular beta radiation therapy in patients that require persistent frequent anti-VEGF therapy to treat Wet AMD. It is planned for two sites, one in the US and one in the UK. (12 month data has been presented and a manuscript is being prepared for Peer Publication)


Pivotal Studies:

CABERNET

With the continued promise from the above two Phase II trial results (NV-068 and NV-111), NeoVista has finished enrollment in the company’s pivotal trial, CABERNET. CABERNET is a multicenter, randomized, controlled study that has enrolled 492 subjects at 45 sites worldwide, evaluating the safety and efficacy of NeoVista’s epiretinal brachytherapy delivered concomitantly with the FDA-approved anti-VEGF therapy Lucentis® (ranibizumab) versus Lucentis alone. (Initial results will be reported in Q4, 2011)

Meritage II

A pivotal study for FDA approval treating chronic wet AMD patients. (This study idea has been abandoned)


Special Population/Reimbursement Studies:

Pinot

A feasibility study treating a specific vascular tumor. Begun in Q3 2009, and still underway..

Merlot

An investigator-sponsored study in the UK;  It is a head-to-head comparison of NeoVista epimacular beta radiation therapy and standard-of-care treatment with Lucentis®, begun in Q4 2009 and >40% enrolled.

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ELLEX 2RT Retinal Regeneration Laser An Update – First Clinical Results

In November 2007, just prior to that year’s AAO meeting, I learned about a new laser that had the potential to alleviate the early stages of age-related macular degeneration and other retinal diseases including diabetic maculopathy, caused by compromised Bruch’s membrane. The laser-based therapy was called ELLEX’s 2RT (Retinal Regeneration Therapy).

The theory behind the therapy was based on research conducted by Professor John Marshall at St. Thomas’ Hospital of London, and his colleague Dr. Ali Hussain. They found, after experimentation, that a specially-built Q-switched doubled YAG laser (532 nm) operating at 3 ns pulses, could be used subthermally to trigger a renewal process of the retinal pigment epithelial (RPE) cells, a sort of biostimulation, without damaging the overlying retina, including photoreceptors. This caused the RPE to migrate and release matrix metalloproteinases, enzymes, which act to clean up Bruchs membrane. The scientists were able to demonstrate and measure Bruch’s ability to transport water and chemicals and thus rejuvenate the retina.

      

For the rest of the story, please see my complete initial report of November 2007. (Link at the end of this post.)

First Clinical Results

In November 2008, Ellex released the six-month clinical study results of the first trial. In this clinical study, conducted at St. Thomas’ Hospital in London by Professor John Marshall, 23 patients (38 eyes) with newly-diagnosed diabetic maculopathy and/or macular edema were recruited and treated with Ellex 2RT. Seventeen patients (28 eyes) completed the six-month follow-up examination.

Patients are being followed for one year. Postoperative testing includes optical coherence tomography and microperimetry.

At the six-month follow-up, for the17 patients (28 eyes), the LogMar visual acuity had improved by two or more lines in 43% of eyes and between one and two lines in 28%. It remained unchanged in 15% of eyes, and deteriorated by two or more lines in 14%. Central macular thickness decreased by more than 5% from baseline in 46% of patients, remained stable in 39%, and had an increase of more than 5% in 15% of patients. The number of hard exudates decreased in 41% of eyes, stayed stable in 43%, and increased in 16%. Vascular leakage decreased in 55% of eyes, was unchanged in 31%, and increased in 14%. Slit-lamp ophthalmoscope microperimetry confirmed that photoreceptor function was not affected by the laser treatment. No adverse effects occurred during the study period.

The six-month results show that Ellex 2RT is clinically safe and effective in the treatment of macular edema secondary to diabetic retinopathy.

An example of the minimal damage to retinal cells is shown in the following illustration of 2RT treated Porcine RPE:

Research Program Update (April 2010)

Since the release of preliminary clinical results in 2007 and of the six-month results in 2008, Ellex has initiated a series of pilot clinical studies aimed at evaluating the clinical efficacy of Ellex 2RT for a number of indications, the most important of which is age-related macular degeneration (AMD). The studies are making good progress, with eight prototype systems currently in use throughout Australia and the United Kingdom in these studies. Patient recruitment is nearing completion in two of the key pilot studies, with follow-up planned over a 12-month period.

Studies focused on diabetic macula edema (DME) and proliferative diabetic retinopathy (PDR) are being undertaken in collaboration with the Royal Adelaide Hospital at three study sites. A major benefit of these studies is that they include control groups, allowing Ellex to more accurately benchmark the effect of Ellex 2RT treatment against conventional laser treatment.

A third study, focused on early AMD treatment, is being undertaken in collaboration with the Royal Victorian Eye and Ear Hospital, a major Australian teaching institution, under Professor R. Guymer.

Ellex will present preliminary results from these studies at the 2010 ARVO meeting in May. Once the results from this round of pilot studies have been fully analyzed, the company will evaluate the opportunity to undertake a multi-center randomized study, and look to expand their study sites beyond Australia and the UK.

In addition, as announced earlier this month, Ellex has sublicensed the SRT (selective retinal therapy) patent, U.S. 5,549, 596, from Massachusetts General Hospital, and can now enter the U.S. market with this technology.

(For more information on this development, please see my report: AMD Update 8: Breaking News – Ellex Sublicenses SRT Patent, linked at the end of this report.)

References:

Press Release: Ellex Announces Six-Month Results on Retina Regeneration Therapy, November 2008

Can Early Laser Therapy Delay Disease Progression?, John Marshall, Retinal Physician, September, 2009.

Links:

Ellex 2RT Retina Regeneration Therapy: A First Report (November 2007)

AMD Update 8: Breaking News -- Ellex Medical Sublicenses SRT Patent

(April 2010)