Avastin/Lucentis Update 47: Should the UK’s NICE Consider Adding Avastin to It’s Approved Drugs?

In a blog, appearing on the BMJ (British Medical Journal) Group Blogs, James Raftery, a health economist with several decades' experience with the National Health Service (NHS) and a professor of health technology assessment at Southampton University, regularly writes about NICE  (the UK’s National Institute for Health and Clinical Excellence). He is a keen "NICE-watcher," and has provided economic input to technical assessment reports for NICE.

In this blog entry, he discusses the case to be made for including Avastin in the approved drug registry for treating AMD and DMO (or DME, as we know it).

Avastin, Lucentis, and NICE
By: James Raftery

28 Jun, 11 | BMJ Group Blogs

A useful update was provided at a meeting this week sponsored by the Royal National Institute for the Blind (RNIB) and Patients Involved in NICE (the National Institute for Health and Clinical Excellence). As the proceedings are to be written up and published, I focus here on the key points that emerged for me.

The stakes in the Avastin/Lucentis (bevacizumab/ranibizumab) contest have been raised as the target condition has enlarged from macular degeneration to include diabetic macular oedema (DMO). This matters hugely because NICE is currently appraising Lucentis for this condition and has had to rule out consideration of Avastin because it is unlicensed. The potential patient population for DMO is put at 3% of people with diabetes, or around 100,000 patients each year. By contrast the estimates for wet age-related macular degeneration (AMD) are 20,000-25,000. NICE's appraisal consultation does not recommend use of Lucentis for DMO. Avastin, it notes, is already being used off label to treat DMO in the NHS. This draft guidance, if it remains unchanged, will increase this use. By not recommending Lucentis for DMO, off-label Avastin will be the only option available. The draft guidance seems unlikely to change since the appraisal committee considered that "a model that relied on a combined set of plausible assumptions would be certain to produce ICERs [incremental cost-effectiveness ratios] that substantially exceed the range it could consider to represent an effective use of NHS resources" (para 4.26).

The meeting heard that Avastin is being widely used in the private sector to treat AMD. Some primary care trusts (PCTs) have offered patients the choice of immediate treatment in private clinics using Avastin or waiting for NHS treatment with Lucentis.

The reasons private clinics are using Avastin are unknown but plausibly relate to its price (£85 pre VAT per injection supplied by Moorfields pharmacy compared with £740 for Lucentis). Extraordinarily, it seems that some ophthalmologists may be using Avastin in private practice but, depending on the local PCT, they may be required to use Lucentis in their NHS practice. The extent to which NHS use is split between Avastin and Lucentis for AMD is unknown. However, a recent US study showed that 64% of all AMD Medicare patients received Avastin.

What is clear is that UK ophthalmologists are using Avastin off-label to treat AMD and DMO and that this use is likely to increase, particularly in DMO. Legally it was suggested that ophthalmologists are covered by their host NHS trusts via the NHS Litigation Authority. GPs, it was suggested, might not be so likely to do so, but GP commissioning groups might well be happy to contract for off-label use of Avastin by their providers.

In any legal challenge to off-label Avastin prescribing the guidance to doctors from the General Medical Council (GMC) would be hugely important. The meeting received an update on the GMC consultation on changing its 2008 guidance Good Practice in Prescribing Medicines. The consultation proposed to change the requirement that off-label prescribing be "better" to "as good as." The 2008 guidance specified that the prescriber had to "be satisfied that it would better serve the patient's needs than an appropriately licensed alternative." The 2011 update proposed off-label prescribing if: "There was no appropriately licensed alternative available or you are satisfied on the basis of authoritative clinical guidance that is as safe and effective as an appropriately licensed alternative."

The GMC, it appears, has been lobbied particularly by ophthalmologists on this issue and the consultation, the results of which are being analysed, seems likely to support change. Acceptance of the proposed change would require clarification of "authoritative clinical guidance". Authoritative clinical guidance cited elsewhere by the GMC included that from NICE, royal colleges, the US Food and Drugs Agency (FDA), British National Formulary (BNF), or local prescribing committees. The meeting considered the possibility that a guideline, particularly if issued by a competent authority such as NICE, might also count.

Could a NICE guideline include off-label use of Avastin? Someone from NICE explained that although NICE cannot consider unlicensed drugs (or off-label use of licensed drugs) within the remit for technology appraisals, it can and has included such uses in its clinical guidelines. Almost all guidelines to do with children have to include off label use of licensed drugs. Which sparks the thought of what would happen if a NICE clinical guideline for either AMD or DMO included Avastin.

Could off-label Avastin be referred by the secretary of state for health to the Medicines and Healthcare products Regulatory Agency (MHRA) for "market approval"? Yes, is the answer, based on the precedent of such referrals of blood products and vaccines, which were noted at the meeting. NICE was asked if it could assess Avastin for AMD. The unsurprising answer was yes. "The next step is for the Department of Health to decide whether or not to refer bevacizumab (Avastin) to NICE for consideration as part of its technology appraisal process." That was NICE's view in December 2010.

I came away from the meeting thinking that the ophthalmologists are voting with their syringes and that some of the NHS is finding ways to follow their lead.

A Potential Breakthrough in the Treatment of Glaucoma

Three related news items caught my attention last week. They had to do with the medical treatment of glaucoma.

The first item noted that patients don’t properly use their prescription eyedrops in treating elevated intraocular pressure (IOP). Dr. Ari Weitzer, writing in his Eye Doc News Blog, noted that a retrospective hospital study in a recent issue of the Archives of Ophthalmology said that after 1 year, only 22% of patients were adhering to their glaucoma treatment regimen and putting drops in their eyes – and this dropped to 11% after 3 years. It turned out that this was a study done in Singapore on an Asian population, but similar studies done in the U.S. show similar patterns.

So, compliance with putting drops in the eye is a major ongoing concern. In an editorial, also in the Archives of Ophthalmology, Drs. Kelly Muir and Paul Lee noted that many patients (only 31%) were able to correctly install a single eyedrop. Approximately 20% of patients depend on another person to install their eyedrops.

The second item that caught my attention was that the cost of glaucoma treatment drugs has gone up strongly over the past six years, with spending on glaucoma medications increasing 25% over the period 2001 to 2006. Part of this is due to a change to newer, more expensive medications such as the prostaglandin analogs, which are now the most prescribed and popular drugs in use, compared to older types like the beta blockers. Also, the prevalence of glaucoma is rising as the U.S. population ages (and people live longer). By 2020, it is estimated that 3.4 million people are expected to be affected. Currently, some 2.2 million Americans aged 40 or older have primary open angle glaucoma and the annual direct medical cost is estimated to be $2.8 billion.

But, the third item that caught my eye may be the saving grace. In a news release on June 14th, pSivida announced the commencement of a Phase I/II clinical trial to study a new bioerodible drug delivery implant for the treatment of glaucoma and hypertension. The implant is designed to provide long-term sustained release of latanoprost, one of the new class of prostaglandin analogs. The drug delivery implant, based on the company’s Durasert technology system, will be injected into the subconjunctival space in the eye (between the sclera and the lower lid), be bioerodible and is expected to deliver its drug for a period of months.

If successful, this implant would solve the problems of non-compliance, the inability to administer the drops and, depending on its price, perhaps address the increasing cost issues.

The new dose-escalating study is designed to assess the safety and efficacy of the implant in patients with elevated intraocular pressure and with hypertension. If successful, pSivida plans to advance the product into a multicenter Phase II study.

A Little Background Information

The Treatment of Glaucoma

I first wrote about glaucoma in the fall of 2001. At that time I prepared a comprehensive overview of what glaucoma is, how it is diagnosed/detected, and both the medical and surgical treatment options available or under development at that time. I even included some information on the U.S. market sizes for both treatment and equipment. To read this report, Advances in the Treatment of Glaucoma, published by OptiStock, please follow this link.

Sustained Release Drug Delivery Systems

I have also, more recently, written an extensive overview of ophthalmic drug delivery systems in my article titled, Iluvien and the Future of Ophthalmic Drug Delivery Systems. This report describes the development of Alimera Science’s Iluvien which delivers a corticosteroid (fluocinolone acetonide – FA) to the retina for treating macular edema for up to three years. It is based on a drug delivery system developed by pSivida and licensed to Alimera for this application.

The report also discusses both FDA-approved sustained delivery drug systems as well as those still in development. One of the systems mentioned as under development was a latanoprost coated punctal plug to treat open-angle glaucoma, that was being developed by QLT Therapeutics. It was supposed to stay implanted and deliver its drug for up to three months. Apparently, the plug did not stay in place well and did not demonstrate efficacy and, to my knowledge, is no longer being evaluated.

The pSivida Latanoprost Implant

Some Background Information

In their press release, pSivida stated that this was a joint development with Pfizer Inc. Pfizer and pSivida have been working together on drug delivery technology since 2007, with Pfizer investing in the company and helping to fund research and development.

According to the press release, the insert is being developed under the recently amended Research and Collaboration Agreement with Pfizer Inc. Under the revised agreement, Pfizer will make an initial payment of $2.3 million. pSivida will, with technical assistance from Pfizer, have the right to develop the glaucoma product candidate through Phase II clinical trials. At that point, Pfizer may exercise its option for an exclusive, worldwide license to develop and commercialize the product candidate in return for a $20 million payment, double-digit royalty payments on any sales of the product and additional development, regulatory and sales performance milestone payments of up to $146.5 million. If Pfizer does not exercise its option, pSivida will retain the right to develop and commercialize the glaucoma product on its own or with a partner. As part of the amended agreement, pSivida regains all rights to its intellectual property in ophthalmic applications previously included in the original Research and Collaboration Agreement other than that required for the latanoprost implant.

Latanoprost, which was approved for use in the eye in 1996,  is now off-patent and low-cost generic forms of the drug are available.

Officials from both companies commented on both the new agreement and on the proposed new application of the implant to treat glaucoma and hypertension:

"Pfizer is an excellent partner, and we are pleased to be entering into this new stage of our relationship involving development of a potentially enhanced glaucoma product," said Dr. Paul Ashton, President and CEO of pSivida. "The $2.3 million payment from Pfizer comes on top of the approximately $7.0 million in R&D support we have already received from Pfizer since we first started our partnership in 2007. We believe that regaining rights to intellectual property in the ophthalmic arena outside the scope of the amended agreement is a key step for our company."

Yvonne Greenstreet, Senior Vice President and Head of the Medicines Development Group for Pfizer's Specialty Care Business Unit, added, "Latanoprost is the most commonly prescribed drug for reduction of intraocular pressure in the treatment of ocular hypertension and glaucoma. If successfully developed and approved by regulatory authorities, using pSivida's unique drug-delivery technology to deliver latanoprost could play a significant role in addressing compliance issues associated with a daily eye drop regimen for the treatment of glaucoma."

The Technology: How the Implant Will Work

The Durasert latanoprost implant (see Figure 1), is a tiny translucent cylindrical polymer tube, between 3 to 4 mm in length and about 0.4 mm in diameter, that contains a small amount of latanoprost (supplied by Pfizer). It is about the size of a grain of rice, and is designed to provide a low daily dose of latanoprost, which has a good history of treating open-angle glaucoma and hypertension.

Figure 1. The pSivida Durasert latanaprost implant.      

The implant will be injected into the subconjunctival space of a patient's eye (between the sclera and the lower lid – see Figure 2) using a proprietary insertion device. The implant is bioerodible and is expected to deliver an appropriate dosage of latanoprost for about three months and, depending on the results of the Phase I/II dosing study, might last as long as six months. Since the implant is bioerodible, it will be absorbed by the eye and will not have to be surgically removed.

Figure 2. Illustration showing conjunctival space where implant will be placed.

Latanoprost, now off-patent and available in generic form, is one of the class of prostaglandin analogs which  reduce pressure in the eye by increasing the outward flow of fluid from the eye. They generally work by relaxing muscles in the eye’s interior structure to allow better outflow of fluids, thus reducing buildup of eye pressure. According to glaucoma specialists, the prostaglandins have taken the lead in recent years as a first-line therapy for treating open-angle glaucoma.

Side effects may include eye redness or irritation, a change in eye color (mostly in hazel or green eyes), increase in thickness and number or eyelashes, and joint aches or flu-like symptoms.

The Phase I/II dose-escalating study is currently underway at the University of Kentucky.

Stem Cells in Ophthalmology Update 8: ...and So It Begins

Advanced Cell Technology announced today that it had enrolled the first patients in its two Phase I/II clinical trials, using retinal pigment epithelial (RPE) cells derived from embryonic stem cells (hESCs) for treating Stargardt’s Macular Dystropyy (SMD) and for the treatment of the dry form of age-related macular degeneration (Dry AMD). The first of twelve patients in each trial were enrolled at the Jules Stein Eye Institute at the University of California, Los Angeles (UCLA).

The two patients will be treated with immunosupressants  for about a week before the RPE cells will be implanted.

Here is the full announcement:


ACT Announces First Patients Enrolled in Two Clinical Trials Using Embryonic Stem Cells to Treat Stargardt's Disease and Dry Age-Related Macular Degeneration

Patients for Phase 1/2 Trials Enrolled at UCLA

MARLBOROUGH, Mass. - June 16, 2011 - Advanced Cell Technology, Inc. ("ACT"; OTCBB: ACTC), a leader in the field of regenerative medicine, announced today the enrollment of the first patients in its two Phase 1/2 clinical trials for Stargardt's Macular Dystrophy (SMD) and Dry Age-Related Macular Degeneration (Dry AMD) using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs). The patients were enrolled at the Jules Stein Eye Institute at the University of California, Los Angeles (UCLA).

The Phase 1/2 trials are prospective, open-label studies primarily designed to determine the safety and tolerability of the RPE cells following sub-retinal transplantation into patients with SMD and Dry AMD. Each study will enroll 12 patients with cohorts of three patients in an ascending dosage format. The primary endpoint of both studies is to determine the safety and tolerability of hESC-derived RPE cells at 12 months.

"The enrollment of the first patients in our two clinical trials marks an important step forward for the field of regenerative medicine," said Gary Rabin, interim chairman and CEO of ACT. "We are very pleased with the progress that has been made toward bringing this ground-breaking technology to the patients who need it most. If these therapies work as we hope they will, particularly with small volumes of cells, then we should be in an excellent position to take advantage of our patented techniques for manufacturing large numbers of doses of RPE cells that can be conveniently stored and shipped to clinicians following the basic manufacturing and distribution systems already familiar to pharmaceutical and biotech companies."

Principal investigator Steven Schwartz, M.D., Ahmanson Professor of Ophthalmology at the David Geffen School of Medicine at UCLA and retina division chief at the Jules Stein Eye Institute at UCLA, said, "These trials mark a significant step toward addressing what is one of the largest unmet medical needs of our time -- treatments for otherwise untreatable and common forms of legal blindness, Dry AMD, SMD and other forms of atrophic macular degeneration. Dry AMD is the most common form of macular degeneration. It is the leading cause of blindness in the developed world, and is the leading cause of blindness in people over the age of 55. The incidence of Dry AMD is expected to double over the next 20 years as the population ages. This trial will begin the process of understanding whether stem cell-derived RPE cells have the potential to be a safe and effective treatment for these debilitating diseases. We are looking forward to evaluating the safety and tolerability data of these Phase 1/2 trials, and hope that these early trials will also produce key information relating to engraftment and function of the transplanted RPE cells."

The progress of disease in both SMD and Dry AMD includes atrophy or thinning of the layer of RPE cells in the patient's macula at the center of the retina, the region specialized for high acuity vision. With the loss of RPE cells in the macula comes the eventual loss of photoreceptors. Over time, the progressive loss of RPE cells and concomitant loss of photoreceptors can cause severe central visual deterioration and even blindness as the macula becomes less functional and central vision is gradually lost. ACT's SMD and Dry AMD therapeutic programs utilize transplanted RPE cells to treat these conditions by replacing RPE cells in the patient's eyes before all RPE function is lost.

"Initiating these two clinical trials represents an important milestone for embryonic stem cell research," said Robert Lanza, M.D., chief scientific officer of ACT. "After a decade of extensive research and preclinical studies, it is very satisfying to finally be moving into the clinic. We hope that these cells will, in the future, provide a treatment not only for these two untreatable diseases ‘Stargardt's disease and macular degeneration’ but for patients suffering from a range other debilitating eye diseases."

In addition to the Jules Stein Eye Institute at UCLA, the Casey Eye Institute (CEI) at Oregon Health & Science University (OHSU) in Portland, OR, is also open for enrollment of patients with SMD. As additional sites are ready to enroll patients with SMD and dry AMD, they will be listed on the Clinical Trials page on ACT's Web site and on www.clinicaltrials.gov.

Further information about patient eligibility for the SMD and the Dry AMD studies are also available on www.clinicaltrials.gov.

AMD Update 15: Visualization of Living Rods and Cones

Back in February 2009, I first wrote about David Williams and his research group at the Institute of Optics at the University of Rochester, and their announcement that they had used adaptive optics to image RPE cells in vivo. That report, AMD Update 4: Does Visualizing RPE Cells Hold the Key to Understanding AMD? gave us a first look at how adaptive optics could image some of the retinal cells in the back of the eye in helping to understand how the effect of new drugs and treatments could be visualized in the living eye, providing a diagnostic mechanism to see changes in RPE cells, possibly when applying some of the new retinal treatment techniques.

Well, another group of researchers at  the same Institute of Optics at the University of Rochester, along with colleagues from several other research institutions have done it again. This time using their knowledge of applying adaptive optics to visualizing the much smaller photoreceptor rod cells present in the living eye.

This innovation, described in two papers in the Optical Society's (OSA) open access journal Biomedical Optics Express, will help doctors diagnose degenerative retinal eye disorders sooner, leading to quicker intervention and more effective treatments.

Here is the complete press release from the OSA, describing the two papers recently published:

Historic First Images Of Rod Photoreceptors In The Living Human Eye

Adaptive optics technology likely to spur sight-saving interventions, usher in new era of eye disease research, diagnosis and treatment

08 Jun 2011 

Scientists today reported that the tiny light-sensing cells known as rods have been clearly and directly imaged in the living eye for the first time. Using adaptive optics (AO), the same technology astronomers use to study distant stars and galaxies, scientists can see through the murky distortion of the outer eye, revealing the eye's cellular structure with unprecedented detail. This innovation, described in two papers in the Optical Society's (OSA) open access journal Biomedical Optics Express, will help doctors diagnose degenerative eye disorders sooner, leading to quicker intervention and more effective treatments.

"While therapies are only emerging, the ability to see the cells you are trying to rescue represents a critical first step in the process of restoring sight," says researcher Alfredo Dubra of the University of Rochester in New York, who led the team of researchers from Rochester, Marquette University, and the Medical College of Wisconsin (MCW), Milwaukee. "It's impossible to overemphasize how important early detection is to eye disease."

"One of the major hurdles in detecting retinal disease is that by the time it can be perceived by the patient or detected with clinical tools, significant cellular damage has often already occurred," adds team member Joseph Carroll of MCW.

The breakthrough that is ushering in a new era of eye disease research, diagnosis, and treatment is an improved design of a non-invasive adaptive optics imaging system. Dubra and his colleagues were able to push the device's resolution to its optical limits of nearly 2 microns (a micron is 1/1,000 of a millimeter), or the approximate diameter of a single rod in the human eye.

Rods are much more numerous than cones and are vastly more sensitive to light. With the optical design method successfully demonstrated by Dubra's team, even the smallest cone cells at the center of the retina, known as the foveal center, can be seen very clearly. Rods can be seen clearly in a less central retinal location.

"This is a really exciting breakthrough," says Steve Burns, a professor in the School of Optometry at Indiana University, who is not involved in the Biomedical Optics Express research. "Imaging contiguous rod mosaics will allow us to study the impact of a whole new class of blinding disorders on the retina. Since many of the eye diseases most amenable to intervention affect the rods, this should become a major tool for determining what treatments work best for those disorders."

De-twinkling Stars, Visualizing Rods

In astronomy, adaptive optics is able to correct for the blurring effect of Earth's atmosphere, effectively removing the "twinkling" from starlight and rendering cosmic objects as very sharp points of light. To achieve this correction, the AO system requires a reference point-either a bright, nearby star or an artificial "guide star" produced in the upper atmosphere by lasers mounted on a telescope. By monitoring that reference point, AO systems use a deformable mirror to create the exact but opposite distortion that is happening in the atmosphere. The result is a clearer image with much greater resolution.

Just as light passing through the atmosphere becomes bent and distorted, so too does light passing through the front part of the eye. This distortion is inconsequential on the scale of human vision, but poses a significant barrier in the microscopic realm of medical imaging.

In 1997, David Williams of the University of Rochester led the group that first demonstrated using AO technology to study the interior of the human eye. In this system, called an adaptive optics ophthalmoscope, a laser creates a reference point that is used to correct the blurring of the image obtained with a fundus camera. Today the fundus camera is commonly replaced by a second laser for imaging, which is known as an adaptive optics scanning laser ophthalmoscope. By moving the laser point across the retina and correcting the distortion along the way, line-by-line an accurate image emerges, in much the same way that a CRT monitor renders an image.

Though earlier AO systems could effectively image cones and have become a mainstay of high-resolution retinal imaging research, the smaller rods, which outnumber cones 20 to 1 in the retina, have eluded clear and contiguous observation in the living eye.

Breakthrough Design

The breakthrough in the design of the AO instrument that led to clearly visualizing rods was, according to Dubra, "embarrassingly simple, and relied on well-known equations and concepts." By simply folding the spherical mirrors that act as lenses in the instrument into a three-dimensional structure, the image quality of the retina was improved sufficiently to clearly resolve the contiguous rod mosaic, as well as the entire cone mosaic at the foveal center.

"By combining careful optical engineering, excellent adaptive optics control, and knowledge of the visual system the authors have made a major advancement in both biomedical imaging and vision science," says Burns.

Improving Patient Care

According to the researchers, their next step is to develop a clinical model that could be widely available. A related task is simplifying and teaching the art of interpreting AO images to guide clinical decisions about diagnosis and treatment.

When that occurs, hopefully in the next 5 to 10 years, doctors will likely be able to routinely peer into a living human eye with such precision and clarity that they will be able to see and evaluate individual rods-and do three things never before possible: accurately describe the physical presentation of specific rod disorders-the "phenotype" of a disease, intervene with early treatment at the first sign of disease, and even determine how individual cells are responding to a specific treatment.

"That's what's really exciting about this imaging device: it can really make a difference in a patient's life," says Carroll. "The ability to now resolve these cells opens up new possibilities for improving care that researchers have been anticipating for a long time-such as using the information in these retinal images to aid in targeting, delivering, and evaluating therapies."


Paper: "Non-invasive imaging of the human rod photoreceptor mosaic using a confocal adaptive optics scanning ophthalmoscope" Biomedical Optics Express, Volume 2, Issue 7, pp. 1864-1876.

Abstract:

The rod photoreceptors are implicated in a number of devastating retinal diseases. However, routine imaging of these cells has remained elusive, even with the advent of adaptive optics imaging. Here, we present the first in vivo images of the contiguous rod photoreceptor mosaic in nine healthy human subjects. The images were collected with three different confocal adaptive optics scanning ophthalmoscopes at two different institutions, using 680 and 775 nm superluminescent diodes for illumination. Estimates of photoreceptor density and rod:cone ratios in the 5°-15° retinal eccentricity range are consistent with histological findings, confirming our ability to resolve the rod mosaic by averaging multiple registered images, without the need for additional image processing. In one subject, we were able to identify the emergence of the first rods at approximately 190 μm from the foveal center, in agreement with previous histological studies. The rod and cone photoreceptor mosaics appear in focus at different retinal depths, with the rod mosaic best focus (i.e., brightest and sharpest) being at least 10 μm shallower than the cones at retinal eccentricities larger than 8°. This study represents an important step in bringing high-resolution imaging to bear on the study of rod disorders.


Paper: "Reflective afocal broadband adaptive optics scanning ophthalmoscope" Biomedical Optics Express, Volume 2, Issue 6, pp. 1757-1768.

Abstract:

A broadband adaptive optics scanning ophthalmoscope (BAOSO) consisting of four afocal telescopes, formed by pairs of off-axis spherical mirrors in a non-planar arrangement, is presented. The non-planar folding of the telescopes is used to simultaneously reduce pupil and image plane astigmatism. The former improves the adaptive optics performance by reducing the root-mean-square (RMS) of the wavefront and the beam wandering due to optical scanning. The latter provides diffraction limited performance over a 3 diopter (D) vergence range. This vergence range allows for the use of any broadband light source(s) in the 450-850 nm wavelength range to simultaneously image any combination of retinal layers. Imaging modalities that could benefit from such a large vergence range are optical coherence tomography (OCT), multi- and hyper-spectral imaging, single- and multi-photon fluorescence. The benefits of the non-planar telescopes in the BAOSO are illustrated by resolving the human foveal photoreceptor mosaic in reflectance using two different superluminescent diodes with 680 and 796 nm peak wavelengths, reaching the eye with a vergence of 0.76 D relative to each other.

The papers appear as part of a special feature issue of Biomedical Optics Express on "Cellular Imaging of the Retina."

Menu 19: Updates for March 2011 - May 2011

A lot of interesting news was made over the past few months that I posted online. This update covers the period from March through May of 2011, including extensive coverage of developments from the recent ARVO Meeting held the beginning of May, and several other items.

I would like to start with my coverage of developments announced either just prior to or during the ARVO Meeting.

ARVO Highlights – Synopses and Links:

I have posted several items to my online Journal, based on what I learned was presented at ARVO 2011. Here are a few short briefs of what I’ve put online, along with the links to each posting.

CATT Study Updates

CATT Study Update 13: A First Peek (April 27, 2011)

The day prior to the release of the NEJM writeup about the CATT Study results, Andrew Pollack of the NY Times broke the story after speaking with two of the researchers involved in the study (and who presumably had access to the study results), Pollack basically said that the study will be interpreted in many ways, as some complicating factors may indicate that Lucentis is safer to use than Avastin, but essentially the two drugs showed equivalent results.

CATT Study Update 14: One-Year Study Results Show Equivalency Between Avastin and Lucentis (April 28, 2011)

Probably the biggest news from this year’s ARVO Meeting was the presentation of results of the one-year results of the CATT Study, along with its publication in the NEJM.

In this posting I summarized the results from the NEJM that showed equivalency of Avastin and Lucentis, but with the latter having a 40x larger price tag.

CATT Update 15: Preliminary Two-Year Safety Data Presented at ARVO (May 3, 2011)

During the presentation at ARVO, the study co-authors presented on some of the preliminary safety data that they had collected, but not yet published. This was, perhaps, to refute the charges made by Genentech later in the week that a retrospective study that they had had conducted by a researcher from Johns Hopkins showed that Lucentis was apparently safer than Avastin (surprise!). In the data presented by Drs. Martin and McGovern, there were no major differences in safety.


Other Updates Announced During ARVO:

Iluvien Sustained Release for Treating Diabetic Macula Edema

Iluvien Update 2: New Safety and Efficacy Data Presented at ARVO (May 6, 2011)

Alimera presented on a subset of their FAME Study using Iluvien to treat DME. In this study, the subset data showed that 34% of patients treated with the low dosage of Iluvien that had had DME for three or more years before treatment, gained three lines of vision after therapy.

This subset of data will be provided to the FDA in response to the CRL letter issued by the FDA in December 2010, in response to the New Drug Application filed last summer.


New Results on 2RT for Treating Dry AMD
 

Ellex 2RT Updated Clinical Results: ARVO 2011 (May 7, 2011)

I have been closely following the exciting news about the Ellex 2RT laser treatment for stopping the progression of dry AMD. Based on the 12-month data presented at ARVO, it appears that we may have a non-invasive treatment that might be able to stop dry AMD in its tracks and prevent the progression into the vision-losing forms of this disease.


And, the Rest of the Recent Postings:

The Development of Femtosecond Lasers for Cataract Surgery (March 27, 2011)

Several years ago, I wrote about my history with intrastromal lasers. That became “Intrastromal Ablation: A Technology Whose Time Has Come?” In that article, I wrote about Automated Laser Systems; its successor, Phoenix Laser Systems; another company working on ISA at the time, Intelligent Surgical Lasers; and, finally, the followup of ISL’s work with picosecond lasers that became the laser development work done at the University of Michigan’s Ultrafast Laser Center, that spawned IntraLase, and its femtosecond (FS) laser.

That is where my history of the development of femtosecond lasers stopped – although I did mention the FS lasers were being developed by Technolas Perfect Vision. Carl Zeiss Meditec, and Ziemer Ophthalmic Systems, and the then startup LenSx, begun by former Intralase founders. In addition, I also wrote about the work being done by Dr. Luis Ruiz, using the Technolas FS laser in treating presbyopia.

Then, recently, Stephen Daily, news editor for CRST, wrote about what happened to the FS laser companies in the several years after my story. His story, “The Origins of Laser Cataract Surgery: Three companies' pathways from development to commercialization” picks up where my story ended.

A Golden Retriever Named Trevor and Retinitis Pigmentosa (April 6, 2011)

Katie McCormick recently learned about a genetic defect in her dog that has its counterpart in humans. The dog defect,  photo receptor cone disease (prcd), associated with progressive retinal atrophy (PRA) is genetically similar to retinitis pigmentosa (RP) in humans. There is extensive research being done on RP, but little on PRA in dogs.

To read about Trevor, a golden retriever diagnosed with PRA as a puppy, and its owners search for a cure, perhaps due to RP research, please see my writeup about Trevor.


Drug Eluting Device Slows Vision Loss in Geographic Atrophy Brought on by Dry AMD

AMD Update 14: Neurotech Pharmaceuticals NT-501 Implant Shown to Slow Vision Loss in Patients with Geographical Atrophy Associated with Dry AMD (April 8, 2011)

A new study, recently published in the Proceedings of the National Academy of Sciences (PNAS) shows that a potential treatment for the advanced stage of dry AMD, geographic atrophy (GA), can be used to slow vision loss in this blinding condition that affects more than a million people.

Neurotech Pharmaceuticals’ NT-501 drug eluting device can be placed in the vitreous of those suffering from GA and will deliver a neuroprotective agent, ciliary neurotrophic factor (CNTF), for up to a year and should result in preservation of vision. NT-501 is not yet FDA approved, as further testing will be required before marketing can occur.


Some Further Updates:
Iluvien Update 3: Alimera Files Resubmission for Approval of Iluvien (May 13, 2011)

Alimera Sciences Inc. filed a resubmission of its New Drug Application (NDA) for the use of Iluvien in treating diabetic macular edema (DME). This resubmission addresses the questions raised in the Complete Response Letter (CRL) received in December 2010. (See Iluvien Update: FDA Marketing Approval Delayed)


Stem Cells in Ophthalmology Update 7: Research Studies with Induced Pluripotent Stem Cells Suggest Opposite Results (May 15, 2011)

Two research studies were recently published about the use of induced pluripotent stem cells (iPSCs) in treating retinal problems, but with opposing results.

In one study, published in Nature, Dr.Yang Xu and his colleagues at the University of California, San Diego, found that iPSCs made from mouse skin cells were rejected by genetically identical mice. (Similar studies with iPSCs, also published in Nature earlier this year, also showed problems, including genetic and epigenectic abnormalities. See Stem Cells in Ophthalmology Update 5: Gene Defects Common in Induced Stem Cells.)

In the second study, Dr. Budd Tucker and his colleagues at the Schepens Eye Research Institute used iPSCs derived from skin to regenerate large areas of damaged retinas and improve visual function in specially  grown degenerative mice. This study was just published in PloS ONE.


Avedro Update: Company Completes U.S. Phase III Study of Microwave Treatment for Progressive  Keratoconus and Ectasia after Refractive Surgery (May 18, 2011)

I have been following the progress of Avedro since I first learned about the formation of the company back in May 2009 (The Rebirth of Thermal Keratoplasty). I then wrote about the company a second time in February 2010 (Avedro Keraflex: Microwaves for Reshaping the Cornea).

Now the company has announced completion of the one-year follow up visits of patients enrolled in its two multi-center Phase III clinical studies, although, not releasing the data as yet, which is undergoing timely analysis.
Oraya IRay Update: Company Completes Enrollment in European Clinical Trial (May 25, 2011)

Since first writing about this company in November 2009 (Oraya IRay In-office Stereotactic X-ray Treatment for AMD: A First Report), I have been following its progress. As I wrote back then, its Phase III Clinical Trial, which planned to enroll approximately 450 patients at 15-20 sites in both the U.S. and Europe, was expected to initiate in mid-2010.

In January, 2010, I learned that the groundbreaking clinical trial, being conducted at seven European sites, and to include a minimum of 150 patients, with approximately one third of those receiving a sham exposure and the remainder receiving radiation dosing of either 16 or 24 Gray (GY), had been initiated.

Now the company has announced that it has completed enrollment in the European arm of the study, as reported in this update. I also asked company officials about the U.S. study arm and the company has responded with some information.


And, Finally, the Completion of my Trilogy About the Discovery of Avastin:

Avastin/Lucentis Update 46: Avastin — The Rest of the Story (April 18, 2011)

Early in April, I came across an important missing piece in the story behind the decision to try Avastin in the treatment of wet AMD. I learned of a story that had been written in November 2006 about how and why Dr. Phil Rosenfeld decided to try Avastin on his patients. I have posted this tidbit as, Avastin/Lucentis Update 46: Avastin — The Rest of the Story. I hope you enjoy this piece of history that might have changed the way that wet AMD is treated forever.