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.

CATT Study Update 12: Status of WorldWide Studies

With the anticipated arrival of the one-year results of the CATT Study this Spring, I thought it would be appropriate to update where the other worldwide studies stand.

During the Retina Subspecialty Day sessions, held prior to the recent 2010 AAO Meeting in Chicago, Daniel Martin, MD provided an update on the various comparative studies underway around the world between Avastin and Lucentis. Here are Dr. Martin’s comments, as reported by the Market Scope team in the November issue of Ophthalmic Market Perspectives.


Daniel Martin, MD, updated comparative studies of Lucentis and Avastin, describing the ongoing clinical trials and noting that results will begin to become available soon. One-year results of the much-awaited CATT study will be available in the spring of 2011.

IVAN, the trial sponsored by the National Health Service in the UK, is similar to CATT but smaller and its recruitment is now complete.

The German study VIBERA is examining a higher dose of Avastin and will be fully enrolled sometime in 2011.

MANTA in Austria began in mid-2008 and is likely to complete enrollment by the end of 2010.

LUCAS, the Norwegian study, uses a treat and extend strategy and is more than halfway enrolled, and France's GEFAL study began in the fall of 2009 and is halfway to its enrollment goal.

For more on full coverage of the 2010 AAO Meeting, please contact Market Scope, for complete subscription information to their monthly Ophthalmic Market Perspectives newsletter.

Iluvien Update: FDA Marketing Approval Delayed

Last July, I wrote a comprehensive report about Iluvien and the status and promise of other sustained release drug delivery systems (Iluvien and the Future of Ophthalmic Drug Delivery Systems). At that time, Alimera Sciences, the company developing Iluvien (under license from pSivida) had filed a new drug application (NDA) to treat diabetic macula edema (DME). The company obtained priority review status for the NDA at the end of August, raising the expectation that an approvable letter might be obtained by the end of 2010.

However, instead of an approvable letter, Alimera Sciences received a “complete response letter” (CRL) from the FDA, communicating to the company that its NDA application “cannot be approved in its present form”.

The good news is that the FDA did not request any additional clinical trials, only that it wanted additional data and analysis from the company’s two clinical trials (the FAME study) conducted with Iluvien. The company had submitted 24 month data from the studies in its NDA and the FDA wanted an additional 12 months worth of data, out to month 36. The 36 month FAME study was completed in October, and the company is currently in the process of compiling the data requested by the FDA.

In addition, the FDA requested information concerning controls and specifications related to the manufacturing, packaging, and sterilization of Iluvien. (A hopeful sign.) The FDA also identified shortcomings in good manufacturing practices during inspections of two third-party manufacturing facilities conducted in August and September. According to the company, the third-party manufacturers are working diligently to correct the deficiencies.

Alimera has requested an expedited meeting with the FDA, expected to occur in February, and expects to be prepared to file the requested additional information by the end of the first quarter of 2011.

Based on the data we have seen for results for Iluvien through 30 months, we do not anticipate any problems with the 36 month data requested by the FDA. (See the Graph below.)

From: A presentation on the FAME Study results, by Andrew Pearson MD, Professor Ophthalmology, University of Kentucky, given at the ASRS Meeting, Vancouver, Canada, August 2010.

According to two investment reports that we have seen (from Citigroup and Oppenhiemer – both of which follow the company), the analysts believe that the company will be able to fulfill the FDA’s requests and both expect that the company will obtain marketing approval either in the 4th quarter of 2011, or 1st quarter of 2012, with product launch by early 2012.

About the FAME Study

Alimera conducted two Phase 3 pivotal clinical trials (collectively known as the FAME Study) for Iluvien involving 956 patients in sites across the United States, Canada, Europe and India to assess the efficacy and safety of Iluvien with two doses, a high and low dose, for the treatment of DME. The primary efficacy endpoint for the FAME Study was the difference in the percentage of patients whose best corrected visual acuity improved by 15 or more letters from baseline on the ETDRS eye chart at month 24 between the treatment and control groups. The study concluded in October 2010 with the final patient visit at the three-year data point.

Stem Cells in Ophthalmology Update 4: ACT Receives FDA Approval to Use hESCs to Treat Dry AMD

Advanced Cell Technology Inc., announced today that it  had received approval from the FDA to commence its clinical trial using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs) to treat the dry form of age-related macular degeneration. ACT is now permitted to initiate a Phase I/II multicenter clinical trial to treat patients with dry AMD, the most common form of macular degeneration in the world. There are currently no approved treatments available for this prevalent disease of an aging global population. Dry AMD, representing a substantial global market opportunity and afflicts between 10-15 million Americans, and a further 10 million Europeans.

Age-Related Macular Degeneration has two predominant forms, wet and dry. Dry AMD is the most common form, accounting for almost 90% of all cases. The progress of dry AMD includes a breakdown or thinning of the layer of RPE cells in the patient's macula, the region at the center of the retina responsible for high acuity vision. Over time, the progressive loss of RPE cells and accompanying loss of photoreceptors can cause severe vision loss and even blindness.

"ACT is now the first company to receive FDA clearance for two hESC trials, and is now a true translational leader in the field of regenerative medicine," said Gary Rabin, Interim Chairman and CEO of ACT. "It marks a major step forward, not just within the stem cell sector, but, potentially for modern healthcare techniques. We plan to proceed into the clinic with both of our hESC-based programs as quickly as possible." (For both dry AMD and for treating Stargardt’s Disease, approval for which was obtained in November 2010.)

The Phase I/II trial will be a prospective, open-label study that is designed to determine the safety and tolerability of the RPE cells following sub-retinal transplantation into patients with dry AMD. Twelve patients will be enrolled in the study at multiple clinical sites. Sites currently under consideration are the Jules Stein Eye Institute at UCLA, and the Ophthalmology Department at Stanford University School of Medicine. Additional sites may be considered.

"Dry AMD is the leading cause of blindness in individuals over the age of 55," stated Robert Lanza, MD, ACT's Chief Scientific Officer. "As the population ages, the incidence of AMD is expected to double over the next 20 years, further exacerbating this unmet medical need. Using our clinical-grade hESC lines, we are able to generate a virtually unlimited and reproducible supply of healthy RPE cells. Because only a small number of cells (50-200K) are needed to treat each patient, manufacturing and distribution of the therapeutic product is scalable with many similarities to the drug businesses that pharmaceutical companies understand well. Based on our animal model studies, we are very excited about the opportunity to treat patients. In a rat model of macular degeneration, we have seen a remarkable improvement in visual performance over untreated animals, without any adverse effects. We have also maintained near-normal function in a mouse model of Stargardt's Disease, a form of juvenile macular degeneration. In addition to this trial, we plan to concurrently use our RPE cells in our Phase I/II Clinical Trial for Stargardt's Disease, which received the green light from the FDA in November. We hope to see a similar benefit in both Stargardt's Disease and Dry AMD patients."

ACT's dry AMD therapeutic program uses RPE cells derived from hESCs to replace the lost RPE cells in the patient's eyes. ACT's proprietary RPE cell manufacturing process is protected by a number of broad patents, as is the use of hESC-derived RPE cells for treating macular degeneration. While the initial portion of the clinical trial will focus on safety, in subsequent clinical trials the company hopes to demonstrate that the RPE cells injected into the retinal space will be capable of slowing or halting progression of the disease, and potentially even restoring some visual acuity to patients.

"It is estimated that over ten million Europeans suffer from Age-Related Macular Degeneration, representing a vast unmet need and a significant market opportunity," commented Edmund Mickunas, ACT's Vice President of Regulatory Affairs. "We are moving ahead aggressively to seek regulatory clearance from the European Medicines Agency to conduct clinical trials in Europe."