Gene Therapy in Ophthalmology Update 2: Foundation Fighting Blindness Funds Six New Gene Therapy Projects

In a news release that I found on the net, I learned that the FFB was going to put $8.25 million into six gene therapy projects, either already underway or about to start. The release contains good information about several projects that I knew about, and others that I did not.

Here, for your edification is their news release:


Foundation Fighting Blindness Invests $8.25 Million in 6 New Gene Therapy Research Projects
Foundation Fighting Blindness, 10/25/11

The Foundation Fighting Blindness, a national nonprofit dedicated to advancing sight-saving research, announces an $8.25 million investment in six new gene therapy research projects that are targeted to have treatments ready for clinical trials within three years. The grants focus on treating a broad range of retinal degenerative diseases and will be allocated through the Foundation's Translational Research Acceleration Program, which funds research efforts with strong, near-term clinical potential.

"The Foundation Fighting Blindness recognizes the great potential of gene therapy for saving and restoring vision, and we're eager to build on the clinical development of retinal gene therapies that has been accelerating at an incredible rate over the past few years," said Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. "It was just three years ago that we reported groundbreaking results from our first gene therapy clinical trials that restored vision in children and young adults who were virtually blind from Leber congenital amaurosis (LCA). The success of those studies set the stage for this rapid expansion in gene therapy development."

As part of the new $8.25 million investment, one innovative project involves the use of gene therapy to resurrect and reactivate cone cells that are compromised by disease. In many inherited retinal conditions, including retinitis pigmentosa, cones stop working before they completely degenerate. The Institut de la Vision in Paris and the Friedrich Miescher Institute in Basel, Switzerland, are developing a gene therapy that revives degenerating cones, enabling them to regain their ability to respond to light and provide vision. The treatment also improves the health of cones and extends their lifespan significantly. This therapeutic approach holds the potential to benefit people affected by a range of conditions, because it works independently of the underlying disease-causing genetic defect. Resurrecting cones can improve an affected individual's well being, because these cells provide central, daytime and detailed vision that is critical for independent living.

The Foundation is also funding the Oklahoma University Health Sciences Center, which in collaboration with Copernicus Therapeutics, is developing a nanoparticle gene therapy system.
Nanoparticles are tiny manmade particles, 1/12,000th the diameter of a human hair, which can readily penetrate retinal cells, making them effective for delivery of therapeutic genes. They may provide advantages in certain cases over viral gene delivery technologies currently used in retinal disease therapies. Perhaps most beneficial is their ability to deliver large genes - genes that exceed the capacity of viral delivery systems - for treating some diseases.

Through a Foundation grant to Applied Genetic Technologies Corp. (AGTC), a clinical stage biotechnology company, funds will support researchers at Oregon Health & Science University's Casey Eye Institute and the University of Florida in their pre-clinical work to evaluate a gene therapy treatment for X-linked retinoschisis, a blinding disease that affects over 35,000 patients in the United States and Europe.

Portions of the Foundation's $8.25 million investment will also go toward research happening at the Massachusetts Eye and Ear Infirmary and the University of Florida for projects investigating gene therapy for two different LCA-causing genes. The final grant supports work at the University of Pennsylvania for choroideremia gene therapy led by Dr. Jean Bennett, who is also one of the lead investigators on the landmark LCA gene therapy clinical trial that has restored vision in more than 40 patients.

There are now human studies of gene therapy underway for Leber congenital amaurosis, wet age-related macular degeneration, and Stargardt disease, with clinical trials for Usher syndrome (the leading cause of deaf-blindness) type 1B and autosomal recessive retinitis pigmentosa scheduled to begin in late 2011 or early 2012. Currently supporting 30 other gene therapy efforts, including RDH12 and other genetic forms of LCA and RP, which are at various stages of development, the Foundation allocates funding toward basic research and investigation into a gene's role in disease, as well as projects poised for clinical trials.

Editor's Note: I have put together a matrix, that at the moment contains eight companies involved in Gene Therapy in Ophthalmology projects. Anyone wishing to obtain a copy of the matrix, please email me.

Stem Cells in Ophthalmology Update 11: Catheter Delivered Stem Cells to Treat Geographic Atrophy in Dry AMD

Selected Reviews of AAO 2011 Retina SubSpecialty Day Presentations

From afar (my home), I reviewed the program for the Retina SubSpecialty Program and decided to write about several of the presentations on the program. I was able to obtain a copy of the program abstracts (from a friend in attendance) and got in touch with each of the presenters of interest and requested an electronic copy of their presentations. The presentations of interest included the following:

The Genetics of Retinitis Pigmentosa by Stephen Tsang, MD;
Attacking Leber Congenital Amaurosi by Albert Maguire, MD;
Gene Testing and AMD: Are We Ready to Start? by Ivana Kim, MD;
Dry AMD Treatment: How Will We Define Sucess? by Phil Rosenfeld, MD;
Drug Delivery Implants for Geographic Atrophy by Baruch Kupperman, MD;
A Complement-Based Gene Therapy for AMD by Elias Reichel, MD; and,
The Promise of Stem Cells for AMD and Retinal Degenerations by Marco Zarbin, PhD.

In addition, in following the reporting by various sources of the meeting, I discovered that a paper by Dr. Michael Samuel about the delivery of stem cells to the macula via a specialized catheter was also presented (apparently in an update session). I was not familiar with either this approach or the program (even after writing A Primer on the Use of Stem Cells in Ophthalmology in September, last year), so I got in touch with Dr. Samuel (and his sponsor, iScience Interventional, the supplier of the special delivery catheter) and asked their permission to obtain an electronic copy of the presentation. After some back and forth, I learned that the actual sponsor of the clinical study that Dr. Samuel was reporting on, was the Centecor Division of Johnson & Johnson, from whom I would also need permission.

I attempted to get in touch with the appropriate people at Centecor/J&J and am still waiting to hear back from them.

In the meantime, after a little due diligence online, I discovered a couple of things. First, J&J’s Centecor was the sponsor of two ophthalmic clinical trials using its CNTO2476 stem cells, one for the treatment of retinitis pigmentosa (now terminated for business reasons – but no further explanation given) and the second for treating geographic atrophy in dry AMD.

I also came across a review article by Dr. Allen Ho on the GA program in the current (October) issue of Retina Today. Finally, I also discovered that EyeTube.net had a video online of Dr. Samuel presenting the results of the initial GA trial on the first set of twelve patients, apparently summarizing his presentation from the Retina SubSpecialty Day session.

So, armed with all of this new found information, I believe I can now tell the story of Centecor/J&J’s program to deliver stem cells to the macular in the hopes of treating geographic atrophy.

The other stories selected from the Retina SubSpecialty Day Program will be presented in other entries on this blog.

Novel Technique for Stem Cell Therapy to the Subretinal Space
Dr. Michael Samuel, and

Human Adult Umbilical Stem Cells: Potential Treatment for Atrophic AMD
Dr. Allen Ho


The Program

Treating Geographic Atrophy

As described by Dr. Ho, “Geographic atrophy (GA) is a slowly progressive pathology in nonexudative ("dry") age-related macular degeneration (AMD), for which there is currently no safe and effective treatment. Investigational strategies for treatment of atrophic AMD include oral nutraceutical formulations, vitamin A visual cycle modulators, and injectable molecular interventions with molecular targets such as complement system modulators to retard the progression of GA. The goals of these investigational interventions include preventing photoreceptor and retinal pigment epithelial (RPE) cell loss, reducing the load of toxic metabolites in these cells, and suppressing or modulating inflammation.

Another approach under investigation in relation to preventing photoreceptor and RPE cell loss in GA is cell-based therapy – the harvesting and transfer of stem cells to support or replace diseased cells. Traditional pharmaceutical agents work on a molecular level; cell-based therapies work on a cellular level to restore or preserve cellular function.

The main sources for the cells used in cell-based therapies include embryonic stem cells, which have been controversial, and adult stem cells. Sources for adult stem cells include bone, blood, umbilical cord, and, in the eye, the corneal limbus.”

The Approach

Again, as Dr. Ho has written, “Two approaches are used in stem-cell therapies: regenerative and trophic (Figure 1). In the regenerative approach, embryonic or adult stem cells are isolated, expanded (grown to larger number of cells), and differentiated into the stem-cell therapy product. That is, they are progressed to become another cell type: for example, corneal stem cells (or retinal pigment epithelial [RPE] cells). These functional cells are intended to replace lost or injured native cells to restore organ function. In the trophic approach, the stem cells are themselves the product. The adult cells are isolated, characterized, and expanded, but they remain differentiated, not progressed to become another cell type. In this approach, the role of the cells is to support or repair injured native tissue and preserve function by altering the microenvironment of the injured tissue, for example through cytokines or cell-to-cell interactions.

Figure 1. Regenerative (A) and trophic (B) stem-cell therapy. In the regenerative approach, embryonic or adult stem cells are isolated, expanded (grown to larger number of cells), and differentiated into the stem-cell therapy product. In the trophic approach, the stem cells are themselves the product.

In the regenerative approach, the stem cells are the precursor to the product. An example of regenerative stem-cell-based therapy is corneal limbal stem cell transplantation, in which autologous allogeneic adult corneal limbal stem cells from the palisades of Vogt are transplanted to help the corneal epithelium regenerate. The corneal limbal stem cells are transplanted onto the surface of the eye, repopulating the damaged cornea.

One example of trophic cell-based therapy is the NT-501 (Neurotech), an intraocular device that delivers ciliary neurotrophic factor (CNTF), a protein that has been investigated for the treatment of motor neuron disease, to the posterior segment. The implant contains human RPE cells that have been genetically modified to secrete CNTF. In a phase 2 clinical trial, NT-501 slowed the loss of vision in patients with GA due to dry AMD. Implanted in an OR-based procedure, the technology was superior to sham injection in stabilizing best corrected visual acuity (BCVA) at 12 months. No serious adverse events were reported, and the implant was well tolerated. Further study of this technology is ongoing.

Another example with a putative trophic mode of action is human adult umbilical stem cell rescue of photoreceptor cells. In the Royal College of Surgeons rat, in which most of the photoreceptors degrade before 100 days of age because of a defect in the RPE, both structure and function of the retina were preserved after transplantation of human umbilical-derived cells. Of 4 cell types evaluated, the umbilical-tissue derived cells demonstrated the best photoreceptor rescue.”

Editor’s Note: It must be noted that other companies besides Centecor/J&J are pursuing stem cells – and even gene therapy – approaches to treating the dry state of AMD. Advanced Cell Technology has an ongoing clinical study, using human embryonic stem cell derived RPE in treating dry AMD (as well as Stargardt’s disease). Retrosense – among others – using gene therapy, plans to study dry AMD after it gets its retinitis pigmentosa (RP) program underway, and Oxford BioMedica has just begun a clinical study to treat a form of RP associated with Usher’s Syndrome (type 1B) with gene therapy. (I have written about all three of these companies programs in this space.)

The Clinical Trial

As noted above, and also reported by Dr. Ho, Centecor/J&J has initiated a clinical study using their CNTO 2746 therapy in patients with geographic atrophy associated with the dry form of AMD. This clinical trial was initiated in October 2010. As stated in the clinical trial information sheet, the main purpose of the study is to assess the effects (good and bad) of the CNTO 2476  therapy for patients with age related macular degeneration. Patients will have CNTO 2476 injected by the surgeon into the subretinal space of the macula of one of their eyes. The patients will then be assessed over a period of at least one year by their surgeon.

CNTO 2476 is composed of human umbilical tissue-derived stem cells (hUTC) from Centocor, Inc.

Twelve patients were enrolled in the Phase I dose escalation and safety study at sites in Philadelphia and Los Angeles. In the Phase II study, an additional 56 patients will be enrolled at the two current and four additional study centers, and will be randomized to 1 of 2 optimal doses identified during Phase I.

Surgical Delivery

Again, as described by Dr. Ho, “CNTO 2476 is delivered to the subretinal space with the iTrack 275 microcatheter (iScience, Menlo Park, CA). The microcatheter is combined with a fiberoptic illuminator and a microcalibrated pump, which ensures rate-controlled delivery of the stem cell product.

The microcatheter is inserted through a sclerotomy and choroidal fistula. A wire-tipped cannula is used to inject sodium hyaluronate viscoelastic (Healon, Abbott Medical Optics) to create a peripheral retinal bleb; the retinal elevation allows subretinal cannulation of the probe. Ultrasound is used to visualize the creation of the bleb, and it can be directly visualized with an intraocular endoscope. The illuminated beacon tip of the microcatheter then can be visualized through the pupil to verify its position in the posterior pole, and CNTO 2476 is delivered to the subretinal space near the macular GA (Figure 2). The surgical procedure is challenging and continues to evolve.”

Figure 2. The iTrack is guided from the choroidotomy through the subretinal space to the macula.

Results to Date

(This is where I had hoped to report on Dr. Samuel’s presentation, given at the SubSpecialty session. But, since I have yet to receive it, I will relate what he said in his video on EyeTube, along with what has been reported by others who were at the meeting.)

From the OSNSupersite report:

Three serious adverse events were reported in a phase 1b study of 12 patients with advanced geographic atrophy undergoing a surgical technique that delivers mesenchymal stem cells via catheter to the macula.

"First and foremost, this was a safety study," Michael A. Samuel, MD, said, while delivering the "broad strokes" of the study's interim results at Retina Subspecialty Day preceding the annual meeting of the American Academy of Ophthalmology.

"The surgical procedure is difficult, and it's not something we're used to," he said, "...but we've learned many things, and we've refined the surgery."

The surgical technique employs a lighted catheter (iScience) that passes through a choroidotomy and delivers stem cells to the targeted area.

There was a clinical response in that half the patients in the study had "very substantial improvement in vision," he said.

Additional information derived from the EyeTube video:

The iTrack 275 catheter enabled delivery into the subretinal space below the macula.
In the last patient treated (at Wills Hospital in Philadelphia), visualization was done through an endoscope that enabled a much better look at where the catheter was delivering the stem cells and was considered a “quantum leap” forward in visualization.

Of the 12 patients treated, six had improved vision; four gained +4 lines, while 2 gained +6 lines. Of the remaining patients, 2 had retinal detachments and 1 lost vision because of macular pucker/loss of traction.

The Phase II study is expected to get underway in the next couple of months (see notes above in the Clinical Trial section).

Gene Therapy Update 1: First Clinical Trial for a Form of Retinitis Pigmentosa (RP) Approved to Begin

In an announcement today, Oxford BioMedica said that it had gained approval from the FDA to begin a Phase I/IIa Clinical Trial for a form of Usher’s Syndrome, Type 1B, which leads to progressive retinitis pigmentosa combined with a congenital hearing defect.

Usher syndrome is the most common form of deaf-blindness which affects approximately 30,000-50,000 patients in the U.S. and Europe. One of the most common subtypes is Usher syndrome type 1B. The disease is caused by a mutation of the gene encoding myosin VIIA (MY07A).

The open label, dose escalation Phase I/IIa study will enrol up to 18 patients with Usher syndrome type 1B at the Oregon Health and Science University's Casey Eye Institute, Portland, Oregon. The study, led by Professor Richard Weleber, will evaluate three dose levels for safety, tolerability and aspects of biological activity and is expected to be initiated by the end of 2011.

Here is the complete news release from Oxford BioMedica:

Oxford BioMedica Announces US IND Approval for Novel Ocular Product in Usher Syndrome Type 1B

Third ocular product partnered with Sanofi approved to enter clinical development

Oxford BioMedica plc announced that the US Food and Drug Administration (FDA) has approved its Investigational New Drug (IND) application for the Phase I/IIa clinical development of UshStat, a novel gene-based treatment for Usher syndrome type 1B. UshStat was designed and developed by Oxford BioMedica using the company’s proprietary LentiVector platform technology and is the third program to enter clinical development under the Phase I/II ocular collaboration agreement signed with Sanofi in April 2009.
                   
The approval of the IND follows the decision by the US Recombinant DNA Advisory Committee (RAC) to approve the UshStat Phase I/IIa protocol in May 2011. The open label, dose escalation Phase I/IIa study will enrol up to 18 patients with Usher syndrome type 1B at the Oregon Health and Science University's Casey Eye Institute, Portland, Oregon. The study, led by Professor Richard Weleber, will evaluate three dose levels for safety, tolerability and aspects of biological activity and is expected to be initiated by the end of 2011.

Usher syndrome is the most common form of deaf-blindness which affects approximately 30,000-50,000 patients in the US and Europe. One of the most common subtypes is Usher syndrome type 1B.  The disease is caused by a mutation of the gene encoding myosin VIIA (MY07A), which leads to progressive retinitis pigmentosa combined with a congenital hearing defect. UshStat uses the company’s LentiVector platform technology to deliver a corrected version of the MYO7A gene to address the vision loss associated with the disease. On the basis of pre-clinical data, it is anticipated that a single application of UshStat to the retina could provide long-term or potentially permanent stabilization of vision. There are currently no approved treatments available for Usher syndrome type 1B. UshStat has received European and US Orphan Drug Designation which brings development, regulatory and commercial benefits.

John Dawson, Chief Executive Officer of Oxford BioMedica, said: "This is the third ocular IND approval that Oxford BioMedica has received from the US regulatory agencies over the last 12 months which represents an exceptional achievement for our R&D and regulatory teams. The continued progress of our ocular program partnered with Sanofi will further support the development path for other LentiVector platform products. With no approved treatment available for patients, we look forward to bringing UshStat into Phase I/IIa clinical development later this year."

Professor Richard Weleber, Principal Investigator at the Casey Eye Institute, commented: "We are delighted to be partnering with Oxford BioMedica in the design and conduct of this; the first trial of gene replacement for retinitis pigmentosa associated with myosin 7A-deficient type I Usher syndrome. As such, this trial represents a major milestone in the history of Usher syndrome. We conclude that the gene replacement therapy that will be evaluated in this trial has the potential to provide a substantial, durable benefit for the vision of these patients."

Dr Stephen Rose, Chief Research Officer of the Foundation Fighting Blindness, an early funding collaborator of Oxford BioMedica's pre-clinical ocular program, added: "The IND approval for UshStat is great news for people affected by a particularly devastating condition. UshStat will be the first vision treatment for any type of Usher syndrome to move into a human study and, as a corrective gene therapy, it holds potential to halt the disease in its tracks."


Editor’s Note: The other two programs involving gene therapy for ophthalmic applications that Oxford BioMedica is involved with, with Sanofi, are RetinoStat for treating the wet form of age-related macular degeneration, a Phase I study; and the treatment of Stargardt’s disease, using StarGen, a Phase I/II study.

If you have Usher Syndrome, Type 1B, or know someone who does, and would like more information about the study, please contact Maureen Toomey, Study Coordinator for the UshStat trial, at the Casey Eye Institute at toomeym@ohsu.edu.

Also, for additional background information on the use of gene therapy in the treatment of RP and dry AMD, please see my article: “The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD”.

Avastin/Lucentis Update 51: And, the Dam Breaks!

After reporting on the news out of England earlier this week (Update 50), I have been waiting for the “other shoe” to drop – and it just has, as reported by InPharm this morning (as tweeted by RetinaToday). Here is the story found on the InPharm website:


Novartis cuts Lucentis price amid growing pressure

Published on 10/07/11 at 10:15am
InPharm

Novartis has been forced to cut the Swiss price of its eye drug Lucentis by 30% after sharp negotiations with the government. The deal was negotiated by Switzerland's Health Minister Didier Burkhalter and could save the country hundreds of millions of francs over the next five years, according to local newspaper La Matin.

Lucentis (ranibizumab) is licensed in Europe to treat the eye disease wet age-related macular oedema, a leading cause of blindness in the over fifties. But ophthalmologists have been opting to treat patients with Roche's cancer drug Avastin (bevacizumab), which - though not licensed for wet AMD - is chemically similar to Lucentis and around 20 times cheaper.

Roche co-markets Lucentis with Novartis in the US, and has no plans to seek a new licence for Avastin for the eye disease because it would be undercutting its own drug. According to La Matin Burkhalter knew this, but still pressured Roche to conduct new trials for Avastin in wet AMD in order to persuade Novartis - whose head office is in Switzerland - to negotiate over the price of Lucentis.

The price cut could go even deeper. A ministry spokesman for the health ministry told La Matin: "We have been successful on this last point with a drop of 30%," but added that if nationwide sales of the drug exceed 108 million francs, then the price will have to drop again. This could have repercussions across other countries as Switzerland acts as a reference for many other markets, although many countries are already investigating using Avastin off-label without Roche's consent.

This is happening in the US where nationally-funded trials are ongoing to see if Avastin is as safe and effective as Lucentis in treating wet AMD. The main impetus is cost as analysts are projecting that switching treatments could save the US $1 billion over the next two years.

Both Roche and Novartis have fought against the use of Avastin in wet AMD, saying that patients are at risk of infections and other side effects from using Avastin off-label because it has not been studied for safety in wet AMD patients. But the Swiss price cut represents a realization that Lucentis must still compete with Avastin, even if it doesn't want to. This is especially true now that austerity measures start to take aim at healthcare budgets, with drugs like Lucentis representing an easy target for swift savings.

Ben Adams

Avastin/Lucentis Update 50: A Possible Break in the Dam?

News has just come out of England that Novartis may discount the price of Lucentis to off-set the gains made by Avastin in the treatment of wet AMD. As Nick Smith of APM Health Europe wrote yesterday, Novartis is considering cutting the price of Lucentis because of the gains being made by doctors using Avastin to treat AMD.

Here is Nick’s story...and as we hear more, we will bring you the news:

Novartis UK may cut Lucentis price to compete with off-label Avastin in AMD
by Nick Smith, APM Health Europe

LONDON, Oct 4 (APM) - Novartis on Tuesday indicated it may discount Lucentis (ranibizumab) in age-related macular degeneration (AMD) to curb the off-label use of Roche's Avastin (bevacizumab) in the UK.

In a statement to APM following earlier press reports that Novartis may take such a step, the company said: "We recognize the cost pressure within the National Health Service" adding it was "working with the Department of Health and NICE ... exploring all options, to help make Lucentis available for as many as possible of the patients who could benefit from this treatment."

Novartis gave no further indication of what steps it might be prepared to take to boost sales volume but did highlight that NICE had found the drug cost-effective in AMD.

PATIENT ACCESS SCHEME

It did not mention the patient access scheme, then known as a 'risk-sharing' scheme, which was used to discount the drug to gain approval.

The company agreed to pay the cost of the drug beyond 14 injections in August 2008, (APMHE 12490) but this did not stop the UK government undermining the agreement by asking NICE if it could examine Avastin for cost-effectiveness in the indication, despite the fact it is not licensed for the use.

Early take up of Lucentis seemed slow, leading to some sales figures coming below analysts' expectations.

However, an ever-wider global market, ageing population and innovative pricing schemes has helped the company turn this around and second quarter sales reached the equivalent of 310 million euros.

ns/ra