Intrastromal Ablation: A Technology Whose Time Has Come?

In an interview with Cataract & Refractive Surgery Today (October 2008 Issue), Frieder Loesel, General Manager of 20/10 Perfect Vision, following the announcement that his company had formed a joint venture with Bausch & Lomb focused solely on the laser refractive market, stated that the new company, Technolas Perfect Vision, would investigate laser-based treatments for presbyopia, including intrastromal ablation (ISA). That statement piqued my interest, since I have been involved with the concept of ISA since my earliest involvement with ophthalmic lasers beginning in the mid-1980s. I decided that the research being conducted by Technolas Perfect Vision might just lead, finally, to a successful conclusion to the search for the “home run” using this technique.

In this report, I would like to tell you about the technology of ISA, its history, and the results of the latest experiments being done by Dr. Luis Ruiz on behalf of 20/10 Perfect Vision (about to become Technolas Perfect Vision).

What is ISA?

Intrastromal ablation is the use of a focused laser beam to create a plasma in tissue which, when it expands, causes a shock wave, transforming into an acoustic transient, all resulting in a cavitation bubble which, upon collapse leaves behind a gas bubble containing carbon dioxide and other gases and a space. By using a tiny spot size and moving the laser focus within the cornea, an area of tissue can be accurately removed. Using this technique within the corneal stroma, and with the collapse of the upper layer of tissue above the gas bubble (with the absorption of the gases) onto the bottom layer, the shape of the cornea can be changed.

This technology is fully explained by the following figures taken from an article by Jay Pepose and Holger Lubatschowski, appearing in the October 2008 issue of Cataract & Refractive Surgery Today (1) . (Used with permission of the authors and the publisher.)

Figure 1. The course of a photodisruptive process is shown.

Due to multiphoton absorption in the focus of the laser beam, a plasma develops (A). Depending on the laser parameters, the diameter varies between 0.5 μm to several micrometers. The expanding plasma drives as a shock wave, which transforms after a few microns to an acoustic transient (B). In addition to the shock wave’s generation, the expanding plasma has pushed the surrounding medium away from its center, which results in a cavitation bubble (C). The maximum diameter of the cavitation bubble can reach 10 to 100 μm. Its lifetime is only a few microseconds. After the collapse of the cavitation bubble, a gas bubble (and space) is left behind, containing carbon dioxide and other gas molecules (D).


Figure 2. Tissue Removal

Higher pulse energy (A) allows the use of greater spacing between spots, because the cutting process is driven primarily by expanding cavitation and residual gas bubbles. Lower pulse energy (B) and smaller spot size and volume require substantially more spots with tighter spacing and greater overlap, as the cutting process here is driven primarily by the plasma itself. To deliver this many spots in a reasonable time frame requires a very-high-frequency engine.


The question remaining is: Can this tissue removal be done accurately and predictably enough to facilitate a pre-determined change in corneal shape?

In his latest paper (2) describing IntraCOR, the Intrastromal ablation for correcting presbyopia, Dr. Luis Ruiz says, “By means of the femtosecond laser, a customized pattern is applied into the cornea inducing a focal reorganization of the biomechanical fores. In dependence of the applied pattern, the corneal surface can be locally flattened or steepened”.

What Dr. Ruiz states may be so, but it still doesn’t answer the question posed above – can this technique result in a controllable, predictable result. We will just have to wait and see if the use of the femtosecond laser can do what others with other laser systems have tried and failed to do in the past.

The History of ISA

Automated Laser Systems

My involvement with ophthalmic lasers dates back to 1983, when I wrote a paper titled, “The Outlook for Lasers in Ophthalmology” for Decision Resources, a subsidiary of Arthur D. Little (ADL). This was shortly after the first lasers for use in ophthalmology were granted FDA approval.

In order to keep up with this emerging technology, I had begun to attend the annual meetings of the American Academy of Ophthalmology (AAO). At the 1985 AAO Meeting, I discovered a new, interesting company called Automated Laser Systems (ALS). This company had developed a finely focused, pulsed, excimer-pumped dye laser, the CALM 1000 (Computer Aided Laser Microsurgery), operating at 595 nm, that it claimed was capable of producing micro bursts of energy within the corneal stroma to ablate stromal tissue with an extremely small (5-10 microns) surrounding tissue damage zone. At the meeting, the company was demonstrating the laser by engraving clear, one-half inch diameter corneal-shaped acrylic discs with patterns within the center of the disc. I still have two of the patterned discs and have attempted to show the engraved patterns in the photographs below:















Photos taken of laser engraved acrylic discs using the ALS CALM 1000 laser, Fall 1985.



As I later learned, the ALS program ran out of funds and never completed its development program.

Phoenix Laser Systems

In August, 1989, I was retained by a new startup laser company, Phoenix Laser Systems, to produce a technology overview report of the ophthalmic laser workstation that they had developed, whose primary aim was to use intrastromal ablation for correcting vision. It turned out that the principals of Phoenix Laser, Steve Schiffer and Alfred Sklar, were also involved in starting up Automated Laser Systems, but they had severed their ties with ALS prior to forming Phoenix.

The Phoenix Laser Workstation was composed of a unique imaging and diagnostic system, along with a pulsed doubled YAG laser for performing intricate and precise laser tissue removal within the corneal stroma.

Over a period of several months, my colleague Ken Taylor and I visited the Phoenix laboratory facility, located near the Lawrence Livermore National Laboratories, and their corporate offices in San Francisco. We interviewed the principals and their staff of scientists and engineers, collected information about potential competitors, and assessed the market for their device. This culminated in a report, prepared in March 1990, titled, “Technology Overview: Phoenix Laser Systems”.

In September 1990, Ken Taylor and I, along with other colleagues from ADL, prepared an updated Technology Overview report. The updated report contained our assessment of the future potential for the Phoenix Ophthalmic Workstation, based on forecasted markets for specific applications. In addition, we reviewed and observed the initial animal and human clinical trials conducted with the Phoenix system.

I won’t go into detail about our forecasted market potential, but would like to briefly discuss the results of the first animal and human clinical trials observed by Dr. Taylor at the Barraquer Institute in Bogota, Columbia. The trials were supervised by Dr. Carmen Barraquer and Alfred Sklar, Director of R&D for Phoenix. (Interestingly, the Phoenix Laser system was set up in the former office space of Dr. Luis Ruiz, who had left the Barraquer Institute to start up his own ophthalmic institute in Bogota.)

The following passages are taken from our September 1990 report:

Animal Studies

Once optimal laser settings were established with the rabbit eyes, intrastromal ablations were performed and it was shown that the formed bubbles dissipated and were absorbed within 30 minutes. No trace of the lesions, except for a faint haze, could be seen within the following 24-48 hours, after which, even the trace haze was invisible to slit lamp investigation.

Intrastromal lesions placed in the anterior stroma caused significant flattening of the corneal surface above the lesions, which stabilized between 12-24 days postoperatively. No damage to descemet’s membrane or to endothelium cells was observed.

Human Eye Results

Just prior to Dr. Taylor’s arrival in Bogota, eight human non-sighted eyes were treated with intrastromal ablations. Dr. Taylor had the opportunity to review the case histories and evaluate two of the patients postoperatively. The patients reported no pain or foreign body sensations in their eyes and the corneas and all tissues in the region of the lesions remained clear. Neither the operating physician nor the observers were able to see the lesion edge two days postoperatively.

Flattening of the cornea was determined and the enucleated eyes were scheduled for histopathological examination at either Wilmer Eye Institute at Johns Hopkins or at the Barraquer Institute.


Over the following months, the Arthur D. Little team continued to be in touch with the principals at Phoenix Laser. However, I began asking searching questions about the clinical results, similar to what I have proposed in the beginning of this article, and soon was told my services were no longer needed.

Dr. Taylor continued to work for Phoenix for a few months more until, as with the predecessor company, ALS, funds were no longer available to support the company’s efforts.

It is my understanding that the company was never able to produce reliable and predictable results.

Intelligent Surgical Lasers (ISL)

At about the same time that the developmental work on ISA was underway at Phoenix Laser Systems in San Francisco, another California company was also conducting research in the use of a laser for ISA. This was Intelligent Surgical Lasers, located in San Diego and founded in December 1987 by Josef Bille, formerly of Heidelberg Engineering, and Dr. Stuart Brown of La Holla, CA.

I was impressed by the company’s initial showing at an AAO Meeting probably in 1989. At the meeting, it unveiled its model 2001 MPL picosecond, microjoule, diode-pumped YLF laser which it claimed could be operated at either 1053 nm, or doubled to 527 nm, thus allowing both photodisruption and photocoagulation.

In November 1989, and again in June 1990, I was asked by two investment firms to undertake a technical evaluation of ISL, similar to what had been done with Phoenix. However, the principal investment partner, H&Q Life Science Technology Fund, and its General Partner Robert Kunze refused to allow me to become involved with the company, and I was never provided access to any of the results obtained with its technology, other than from papers delivered at public ophthalmic meetings.

I can only assume that its picosecond laser was not successful in performing reliable and reproducible intrastromal ablations, as the company eventually lost its funding and merged with another company, Escalon Medical (see below).

Interestingly, Josef Bille went on to become a founder of another company pursuing the dream of intrastromal ablation, 20/10 Perfect Vision!

The Femtosecond Laser Companies and ISA

University of Michigan and IntraLase (now part of AMO)

In March 1994, I became involved with femtosecond lasers. I was hired by the University of Michigan to help them assess the commercial opportunities for their ultra-fast laser technology, developed by Ron Kurtz and his associates at the Ultra Fast Laser Center. After spending a day with representatives of the University Technology Management Office, the Ultrafast Optical Science division, and Dr. Kurtz from the W.K. Kellogg Eye Center, I prepared a several page report providing them my thoughts of what the ultra-fast lasers might be commercially capable of and for “hitting a home run” – which I said was refractive surgery via intrastromal ablation, if they could pull it off.

In July, 1997, the University of Michigan’s Technology Management Office announced the spin-off of Intralase Corporation, a startup company that would develop and commercialize novel ultra-fast laser technology, beginning in the ophthalmic field. The announcement mentioned an expected collaborative industrial relationship with an industry participant, which was in negotiation. That negotiation turned out to be with Escalon Medical, who had acquired the assets of Intelligent Surgical Laser, including its patent portfolio in a reverse buyout in February 1996.

As it turned out, Intralase concentrated its efforts with its femtosecond laser on creating flaps for LASIK surgery, and have been very successful in this effort, much to my surprise. I once wrote that I didn’t think many ophthalmologists would pay the high price of $350,000 for a laser microkeratome! Obviously, I was proven wrong.

During the late 1990s, I attended several presentations and wrote about doctors involved with IntraLase discussing their research on the use of the femtosecond laser for performing intrastromal ablation. Perhaps, the company is still conducting such research.


In addition to the IntraLase FS (the current version of the IntraLase laser) from Advanced Medical Optics (AMO), there are at least three other femtosecond lasers on the market – the Femtec from Technolas Perfect Vision; the VisuMax from Carl Zeiss Meditec; the Femto LDV from Ziemer Ophthalmic Systems Group; and at least one more in development from a startup group of former IntraLase scientists at a company called LensX in Aliso Viejo, CA.

For complete information about the four commercially available femtosecond lasers, please see the two articles in the October 2008 issue of Cataract & Refractive Surgery Today. The first, from Jay Pepose and Holger Lubatschowski titled: “Comparing Femtosecond Lasers”(1), while the second written by Perry Binder is titled: “Femtosecond Lasers: How do you select a system”(3).

IntraCOR Intrastromal Ablation for Correcting Presbyopia

As I mentioned up front, the reason this article was written is because I became aware of the work being done by Dr. Luis Ruiz of Bogota, Columbia on behalf of 20/10 Perfect Vision (soon to be Technolas Perfect Vision), on using intrastromal ablation for the correction of presbyopia in human eyes.

I would just like to comment briefly on Dr. Ruiz’s latest paper, taken from the 20/10 Perfect Vision website (2).

As reported by Dr. Ruiz, his paper summarizes the worldwide first, still preliminary clinical results of an ongoing pilot study concentrating on non-invasive, intrastromal correction of presbyopia, performed by means of a FEMTEC femtosecond laser system from 20/10 Perfect Vison of Heidelberg, Germany.

The general purpose of the study was to quantify the feasibility of non-invasive intrastromal corrections of ametropic eyes, with the first phase focused on the correction of presbyopia.

More than 200 presbyopic eyes underwent intrastromal refractive surgeries with the FEMTEC femtosecond laser, with all treatments performed at the Centro Oftalmologico Colombiano in Bogota, starting in October 2007.

Depending on the refractive properties, as well as on the individual biomechanical and geometrical properties of the cornea, a customized pattern for each eye was calculated, supported by Finite Element Modeling, and the intrastromal laser treatment was performed with treatment times between 18 and 30 seconds. The treatment was done in the mid-stroma, so as to not allow for an anterior or posterior surface incision, hence significantly reducing the risk of healing issues.

(The following figures and graphs are reproduced with permission of the author.)

The Finite Element Modeling using a spatial 3D grid adapted to the individual curvature of the cornea is illustrated in the following sketch:


Fig. 3: 3D Sketch of corneal Finite Element Modeling model used for the calculation of individual treatment patterns

While the customized intrastromal treatment pattern is shown below:

Fig. 4: Sketch of customized intrastromal treatment pattern

In general, the patients showed an increase in Near UCVA within minutes to a few hours of treatment. The induced increase was found to be stable within the observed follow-up time of up to 11 months, as shown in the graphs below:


Fig. 5: Efficacy and stability: Near UCVA change after intrastromal correction of presbyopia


Fig. 6: Refractive outcome distribution of Near UCVA according to Jaeger readings, pre-op and after the maximum observation period of at least 6 months


An important consideration is the factor of safety. Any approach to improving near vision is only viable if the Distance UCVA and Distance BSCVA are either unaffected or, at worst, only minimally affected.

The graphs below show the Cumulative Distribution of Distance UCVA and the distribution of Distance BSCVA following treatment:



Fig. 7: Cumulative distribution of Distance UCVA of patients undergoing intrastromal presbyopia correction

Fig. 8: Cumulative distribution of Distance BSCVA of patients undergoing intrastromal presbyopia correction

In summary, the preliminary results of the ongoing clinical study show an average gain of 6.2 +/- 2.8 Jaeger lines is achieved in Near UCVA after 3 months postop, by inducing only minor effects on the Distance UCVA.

As Dr. Ruiz concludes, “The promising initial results will need to be further supported by a larger number of procedures performed at several clinical sites in the near future. Parallel to the very successful investigation of intrastromal presbyopia correction, further treatment strategies for non-invasive correction of other forms of ametropia (myopia, hyperopia, astigmatism) are currently under investigation. The preliminary results of these treatments are equally promising for using the FEMTEC laser system for all kinds of such intrastromal corrections.”

So, it seems that perhaps the dream of intrastromal ablation may have found a solution. However, being the skeptic I am, I will await further proof before accepting the premise.


References:

1.“Comparing Femtosecond Lasers”, Pepose & Lubatschowski, Cataract & Refractive Surgery Today, October 2008, pgs 45-52.

2. “Preliminary clinical results with 11-months follow-up of intrastromal correction of presbyopia (IntraCOR) using the FEMTEC femtosecond laser system”, 20/10 Perfect Vision website, October 2008.

3. “Femtosecond Lasers: How do you select a system”, Binder, Cataract & Refractive Surgery Today, October 2008, pgs 53-56.

A copy of this article has been reproduced on Eye Doc News.

CATT Study Update 8: The Story Behind The CATT Study

As any of you who have read this Journal know, I began writing about Avastin on January 31, 2006, after starting this online Journal the month before. I had read the first reports about this new drug in a report from the Retina Society Meeting held in July 2005, and then the first reports out of that year’s AAO Meeting. You can read my comments in my writeup, Avastin: A New Hope for Treating AMD.

Since that time I have written about Avastin vs. Lucentis 24 additional times, and about the CATT Study a previous 7 times. When I inquired earlier this month about the status of the CATT Study, Maureen Maguire was kind enough to send me a copy of the article she and Drs. Martin and Fine had submitted to Retina Times for publication in its Fall 2008 issue. I requested permission from both the editor of Retina Times and the three authors to reprint their story in my Journal to allow for wider publication than just the membership of the American Society of Retina Specialists (ASRS). I thank all involved for their cooperation in this effort.

Re-printed with permission of the authors and the American Society of Retina Specialists (ASRS). This article appears in the Fall 2008 Issue of Retina Times, the official publication of the ASRS, and is accessible by members only. For information about the ASRS, please go to www.asrs.org.


Comparison of AMD Treatments Trials (CATT): Lucentis – Avastin Trial

Daniel F. Martin MD, Maureen G. Maguire PhD, and Stuart L Fine MD

Drs. Daniel Martin (Emory University) and Stuart Fine (University of Pennsylvania) are Co-Study Chairs for the CATT Study, while Dr. Maureen Maguire (Director of the Coordinating Center at University of Pennsylvania) is the CATT Study Director.

Published in the Fall 2008 issue of Retina Times

Just over 3 years ago, two major events dramatically transformed the treatment of choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). On July 17, 2005, the results of the MARINA trial comparing ranibizumab (Lucentis®) to placebo for the treatment of minimally classic and occult CNV were presented at the annual meeting of American Society of Retina Specialists meeting in Montreal. Patients assigned to ranibizumab were not only much more likely to maintain visual acuity (VA), but also had improvement in VA in unprecedented numbers. A few moments later, Philip Rosenfeld, MD, PhD presented a paper on the beneficial short-term effect of intravitreal injection of bevacizumab (Avastin®) in a single patient with neovascular AMD.

These events set off an explosion of controversy and debate on topics ranging from the penetration of molecules of different molecular weights through the retina to the ethics of off-label use of an untested agent when a well-studied, highly efficacious, and relatively safe drug was available, albeit at a very high price. By June 30, 2006 when the Food and Drug Administration approved ranibizumab for treatment of neovascular AMD, the data from additional Genentech randomized trials had provided strong evidence that ranibizumab’s efficacy and safety extended to a wide spectrum of neovascular lesions. In addition, substantial information on the pharmacokinetics, safety, and changes in vision after treatment with bevacizumab had accumulated, and the use of bevacizumab had become fully entrenched in many vitreoretinal practices.

The time was ripe for a head-to-head comparison to establish the relative efficacy and safety of these two drugs and to determine whether treating less than monthly with either drug could provide the same beneficial results on vision as the monthly injections. Led by investigators at Emory, University of Pennsylvania, and Duke, grant applications were submitted in January 2006 and received expedited peer review. In October 2006, the National Eye Institute approved funding for the Comparison of AMD Treatments Trials (CATT) – Lucentis-Avastin Trial.

Once funded, the major task that remained was to secure funding for the cost of ranibizumab and bevacizumab. The NEI grant covered the cost of purchasing, repackaging, and distributing Avastin. However, the $25 million drug cost for ranibizumab was not covered. This was anticipated and the CATT leadership had begun discussions with CMS early in the development of the trial design. The Centers for Medicare and Medicare Services (CMS) already were paying for ranibizumab for patients with neovascular AMD and the vast majority of affected patients were Medicare beneficiaries. The 2000 Clinton Initiative made it clear that routine care for patients in a clinical trial was covered by Medicare. Ranibizumab was already part of routine care and therefore it was logical to assume that it too would be covered. It was also expected that the potential cost savings to CMS from this study would serve as strong motivation for collaboration. This was acknowledged by CMS leaders early on, but the statutory authority of CMS to assist in the study was limited. The CATT leadership was told that to fully achieve the funding and masking that we requested would require “an act of Congress.” In addition, some concern was raised as to whether ranibizumab could indeed be covered in the trial by the existing Medicare Clinical Trial Policy.

Four months later (November 2006), the CATT leadership learned at an Institute of Medicine forum, where they had been asked to present these study related issues, that CMS lawyers had narrowly interpreted existing Medicare Clinical Trials Policy as forbidding the use of CMS funds for payment for ranibizumab within CATT. Despite alternative interpretations by officials in other branches of the National Institutes of Health and many Medicare carriers, the central CMS lawyers viewed the FDA-approved ranibizumab as investigational within CATT and not eligible for reimbursement. Over the next 14 months, the CATT leadership engaged in a steady stream of efforts to secure payment for ranibizumab for patients in the trial. Their efforts resulted in four important policy changes and clarifications that will be a lasting legacy of the CATT:

1) Drug Coverage: On July 9, 2007, the Revised Medicare Clinical Trial Policy was published. This policy change, driven in part by the CATT, and specifically stated that CMS could in fact pay for a drug (ranibizumab) in a clinical trial if that drug was otherwise available to Medicare beneficiaries outside of the study.

2) Masking: Over a six month period, CMS staff worked closely with the CATT to develop an AMD Demonstration Project that would have facilitated payment and masking of the study drugs. The project addressed many problems of billing for and maintaining masking of a drug when the injecting physician has no knowledge of the identity of the drug. In May, 2007 the AMD Demonstration Project was approved by CMS. However, it was not granted final approval by the Office of General Counsel (OGC). Although the Demonstration Project never became operational, it significantly stimulated discussion on these issues and contributed to the development of a National Public Forum on the Impact of Payment Policy on Clinical Trials hosted by CMS in September 2007 at which time issues raised by the CATT were presented. In addition, it is anticipated that the project may serve as a blueprint for payment of drug and patient care costs in a future NIH-sponsored trials.

3) Co-Pays: The issue of who can legally pay for a co-pay was clarified. The only entity that can legally pay a Medicare co-pay is another federal entity. As such, the NEI can pay a co-pay in the CATT and have committed funds to do so.

4) “Act of Congress”: The recent Medicare bill that rescinded the 10.6% fee cut also contained an amendment that granted to the Secretary of DHHS the authority to develop alternative payment mechanisms for items and services provided in an NIH sponsored trial if these mechanisms will enhance the scientific integrity (masking of drug) of the trial. This is the authority that the CATT needed from the very beginning. This amendment was proposed by the CATT leadership and introduced as part of a bill through the offices of Senator Herb Kohl (Democrat, Wisconsin). The bill passed on July 15, 2008.

By the end of this long process, the initial goal of providing study drug to CATT patients with no out-of-pocket expense was achieved. Lucentis is billed to CMS and 80% is covered as per the Revised Medicare Policy. Supplemental insurance policies will cover the remainder of the cost. In cases where the patient has no supplemental policy (estimated at 15% or less of patients), the NEI can legally pay the co-pay. While the Congressional amendment to the Medicare bill is too late to benefit the CATT directly, the leadership of the study was determined to prevent these delays from ever happening again and to clear the way for other comparative clinical trials that will follow.

In February, 2008, the first patients were enrolled in the CATT and by the end of July, more than 250 had enrolled. (Editor’s Note: As of October 10th, more than 400 patients are now enrolled.) Eligibility criteria for the trial are broad. Patients must have previously untreated CNV with the lesion or sequelae of the lesion (eg, blood, retinal pigment epithelium detachment, fluid) under the center of the fovea. While lesion composition (ie, classic or occult CNV) is assessed by the CATT Photograph Reading Center, there are no eligibility criteria related to lesion composition. Visual acuity must be between 20/25 and 20/320, inclusive.

Patients are assigned through randomization with equal probability to one of four groups for treatment during the first year (see below). The doses are 0.5 mg {0.05 ml} for ranibizumab and 1.25 mg {0.05 ml} for bevacizumab.

• Ranibizumab on a fixed schedule of every 4 weeks

• Bevacizumab on a fixed schedule of every 4 weeks

• Ranibizumab on variable schedule dosing; i.e., after initial treatment, monthly evaluation for treatment based on signs of lesion activity

• Bevacizumab on variable schedule dosing; i.e., after initial treatment, monthly evaluation for treatment based on signs of lesion activity
  

Formatech, Inc, an aseptic manufacturing and fill facility, repackages commercially available bevacizumab into smaller vials for use in CATT. Ranibizumab is supplied through the conventional supply mechanism for each clinic. Syringes are filled with study drug by the clinic coordinator or another person in the center and presented to the CATT ophthalmologist for injection. The CATT ophthalmologist and vision examiners are masked to the identity of the study drug.

Retreatment decisions in the two variable (as needed) dosing arms of the study are driven primarily by findings on the OCT. If any subretinal, intraretinal, or sub-RPE fluid is apparent on any of the 6 slow map scans, the eye is treated. If there is no fluid on OCT, but there are other signs of active CNV, the eye is treated. These signs include new subretinal or intraretinal hemorrhage, persistent subretinal or intraretinal hemorrhage, decreased visual acuity relative to the last visit without another explanation, increased lesion size on fluorescein angiography relative to the last angiogram, or leakage on fluorescein angiography. Fluorescein angiography is required at specific visits and may be used in deciding whether treatment is warranted. Fluorescein angiography may be obtained at other visits to aid in the decision on whether treatment should be applied.

The primary outcome measure is change in visual acuity. Secondary outcome measures include number of treatments, retinal thickness at the fovea, adverse events, and cost. At the 12-month visit, patients in the fixed schedule groups will be randomly assigned continue on the fixed schedule for a second year or to receive treatment according to the guidelines for variable schedule dosing. A total of 1200 patients will be enrolled and followed through two years.

The basic questions of the relative efficacy of ranibizumab and bevacizumab remain unanswered. All retinal specialists are eager to identify ways to decrease the frequency of injection. However, there is still no convincing data on whether any of the various approaches to decreasing treatment frequency provide the same level of visual acuity benefit as monthly dosing. The CATT will provide answers to these important questions, but the timing of those answers is entirely dependent on the rate of enrollment. More than 200 retina specialists are participating through more than 40 clinical centers (see http://www.nei.nih.gov/CATT or http://clinicaltrials.gov/ct2/show/NCT00593450 for a list of participating centers). The retina community and all patients with AMD will benefit from the results of CATT. There has never been a better time to consider referring a new neovascular AMD patient to a CATT clinical center for enrollment.

SOLX Titaniam-Sapphire Laser for Treating Glaucoma: A First Report

On September 18th, Solx Inc., a Boston-based spinout from Boston University's Photonics Center, now based in Waltham, MA, announced that it had received FDA 510(k) clearance for its SOLX 790 Titanium:Sapphire laser to perform laser trabeculoplasty (TLT).

The clearance was based on the results of a multicenter, international clinical trial that established equivalency of TLT to argon laser trabeculoplasty (ALT) in its ability to reduce IOP in patients who have primary open-angle glaucoma and have poorly controlled IOP on maximally tolerated medications, and/or who have prior failed trabeculoplasty.

The laser was previously approved for sale in Europe and Canada.

In the trial, which was conducted across the United States, Europe, Canada and Israel, more than 180 patients were randomized either for ALT or TLT. Results showed that patients at 12-month follow-up achieved a mean IOP reduction of 6.8 ± 4.7 mmHg (25.8 percent) for TLT vs. 5.7 ± 4.8 mmHg (22.2 percent) for ALT.

"Patients treated with the SOLX 790 laser achieved an immediate reduction in IOP which was maintained at clinically beneficial levels throughout the study," said Francisco Fantes, M.D., Bascom Palmer Eye Institute, Miami, Florida, and Medical Monitor for the trial. "TLT does so without causing significant thermal damage to the treated tissues which provides glaucoma specialists with an important new tool for managing this disease."

"This is a significant milestone for SOLX," said Doug Adams, President and founder of SOLX, "The SOLX 790 laser is the cornerstone of our glaucoma management system along with the SOLX Gold Shunt."

The SOLX 790 laser emits pulses of energy at a near-infrared 790 nm wavelength to loosen particles in the trabecular meshwork without causing significant thermal damage. The energy penetrates deeper into the tissue than other currently used trabeculoplasty lasers and may therefore lead to longer-lasting treatment benefits

The SOLX 790 Laser is a flashlamp-excited, solid-state laser that emits near-infrared light in pulses lasting five to 10 microseconds. The laser has been shown to provide deeper tissue penetration, about 200 microns, deeper, than the other lasers currently used in trabeculoplasty without causing damage to the trabecular meshwork.

The following graphics and illustrations were taken from the SOLX, Inc., 790 Laser website:


The SOLX 790 Laser
Technical Specifications


Approvals and Ongoing Trials


How it Works Compared to the Argon (ALT) and Doubled YAG (green) (SLT) Lasers

A Comparison of the Technical Specifications for the Three Laser Systems



The Thermal Effects Differences Between the Three Lasers



IOP Following SOLX 790 Laser TLT Treatment


Average Number of Medications Needed Following SOLX 790 TLT Treatment


Glaucoma

Glaucoma is a disease of the eye in which damage is caused by elevated pressure within the eye. This elevated pressure is caused by a backup of fluid (aqueous humor) in the space/chamber between the cornea (the front surface of the eye), and the lens within the eye. Over time this pressure buildup causes damage to the optic nerve. Normal pressure in the eye varies between 10-20 mmHg.

There are several different types of glaucoma which are generally grouped in to two large categories: open-angle glaucoma and closed angle glaucoma.

Open-angle glaucoma: Glaucoma in which the aqueous (fluid) that flows through the cornea into the anterior (front) chamber of the eye cannot get through a filtration system called the trabecular meshwork into the drainage canals, causing pressure to build up within the eye which can damage the optic nerve and impair vision. Open-angle glaucoma is the most common form of glaucoma, and can be treated with the above types of lasers.

Closed angle glaucoma, (also called acute glaucoma or angle closure glaucoma), accounts for about 9 percent of all glaucoma cases and occurs when the opening between the cornea and iris narrows, such that the fluid cannot get to the trabecular meshwork and normal drainage channels. This narrowing results in fluid build-up and intraocular pressure. The fluid build-up happens very quickly.


I have previously written on the surgical and laser treatments for glaucoma. An overview can be found in my “Advances in the Treatment of Glaucoma”, done as an Optistock Industry Overview in the Fall of 2001. In addition, I have written extensively about another laser treatment for glaucoma, Selective Laser Trabeculoplasty (SLT) – SLT: New Treatment for Glaucoma Becomes Available , both in Ocular Surgery News (May 15, 2001) and an update on this laser methodology – An Update on the Use of SLT for Treating Glaucoma – in this Journal.

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 3

During the 2008 Retina Society Meeting, held last weekend, NeoVista, Inc. provided eighteen-month data from its Phase II feasability study of the company’s novel beta radiation epi-retinal therapy for the treatment of the wet form of age-related macular degeneration (AMD). The long-term data from the study, which was initiated to test the safety and efficacy of their therapy when used in conjunction with Avastin (bevacizumab), showed a marked advancement in mean visual acuity results at month 18, while only a limited number of patients required additional injections of Avastin.

The data were presented at the Retina Society Meeting by Nelson R. Sabates, MD, Professor and Chairman, Department of Ophthalmology, University of Missouri-Kansas City (UMKC) School of Medicine and the lead investigator in NeoVista's ongoing Phase III study, CABERNET (CNV Secondary to AMD Treated with BEta RadiatioN Epiretinal Therapy).

"The data released demonstrate that NeoVista's concomitant approach has the potential to offer patients a less frequent treatment option that is just as effective, if not more effective, than the current standard of care," said Dr. Sabates. "It's highly encouraging to continually see patient outcomes improving as the study progresses."

"We're very delighted with the latest data from our Phase II study, as not only did the visual acuity improve in our patients over the long-term, but very few patients received additional injections as well," said John N. Hendrick, President and CEO of NeoVista. "The ultimate pledge of this therapy continues to be demonstrated as the long-term data hold promise in minimizing the treatment burden both for patients and physicians, not to mention the overall financial burden for the healthcare system."

NeoVista's revolutionary therapy applies a targeted dose of beta radiation to the leaking blood vessels that affect central vision; concomitantly, two injections of an anti-vascular endothelial growth factor (anti-VEGF) agent are delivered to maximize the acute therapeutic response. Preliminary data show that NeoVista's targeted radiation therapy can be safe for both the patient and the physician, and may be able to restore the patient's vision. The current standard of care for wet AMD requires persistent injections of anti-VEGF drugs for an indefinite period.

The ongoing multicenter feasibility study enrolled 34 trial participants (with a mean age of 72 years) from June 2006 to April 2007 at two centers in Brazil and one in Mexico. These patients, with predominantly classic, minimally classic, or occult (with no classic) choroidal neovascularization (CNV), received a single 24 Gy treatment of NeoVista's epiretinal brachytherapy in combination with two intravitreal injections of Avastin, one dose prior to or at the time of radiation delivery and another one month later, depending on which arm of the trial the patient was enrolled in. Additional therapy was delivered based upon the investigator's evaluation of disease activity.

Analysis of 18-month follow-up on the first 25 trial participants to reach that milestone, as shown in Graph 1 below, shows a mean improvement in visual acuity of 10.7 letters using the Early Treatment Diabetic Retinopathy Study (ETDRS) test; 96 percent of patients lost 15 letters or fewer, 76 percent gained some letters, 44 percent gained 15 or more letters, and 8 percent gained 30 or more letters. Of particular interest, 68 percent of the patients in the study did not require additional injections of Avastin throughout the 18-month period and the average number of additional injections within this subset was only 2.4 injections by month 18.


Graph 1

The visual acuity data after 18 months compares favorably with the results reported after 12 months, as shown in Graph 2 below. (This graph compares the Epi-Rad treatment without Avastin (purple color), with Epi-Rad plus Avastin (blue color) and the Marina (green) and Anchor (red) studies, which both used Lucentis.)

Graph 2

For more information on the NeoVista Epi-Retinal treatment, and for further information on the Marina and Anchor Studies, see my three earlier reports on NeoVista, posted November 19, 2007; July 11, 2007; and February 14, 2007.

Most of the limited number of adverse events were related to the vitrectomy procedure (retinal tear, retinal detachment, subretinal hemorrhage, and vitreous hemorrhage), rather than the epiretinal brachytherapy. To date, no instances of radiation toxicity have been reported by the Doheny reading center.

In contrast to other forms of radiation therapy for wet AMD, NeoVista's approach delivers the peak dose of energy directly to the lesion without damaging the normal retinal vasculature. Utilizing strontium 90, the focused energy is delivered to a target area up to 3 mm in depth and up to 5.4 mm in diameter. Importantly for patients, the systemic exposure to radiation is minimal, as the effective dose to the entire body from NeoVista's epiretinal device is less than that from a typical chest x-ray.

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.