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Intacs may provide therapeutic treatment for keratoconus, keratectasia
In the 21st century, the clinical investigators and new owners of Intacs inserts hope to expand the application of the technology to include therapeutic applications.
PITTSBURGH — Intacs prescription inserts are being used in the treatment of keratoconus in U.S. phase 1 clinical trials. Therapeutic applications of Intacs inserts, a refractive device approved in the United States and several international markets for low myopia, have shown promise for patients with progressive keratectasia.
The therapeutic applications may also show promise for the technology’s new owners — Addition Technology. The recently formed specialty refractive surgery company acquired the Intacs technology from KeraVision after that company filed for bankruptcy last year.
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“Intacs are an exciting new option for the treatment of keratoconus. The goal is to reduce the amount of irregular astigmatism so that patients can see better with glasses or contact lenses,” Deepinder K. Dhaliwal, MD, said here at the University of Pittsburgh Medical Center. She performed the first U.S. implantation of Intacs for keratoconus as part of the phase 1 clinical trials here.
Keratoconus is a degenerative disease that causes ectasia and severe corneal thinning. The condition often starts in the late teen years and progresses throughout adulthood. In the United States there are nearly 300,000 people with the condition.
Management of the disease typically begins with glasses or contact lenses. However, if vision continues to deteriorate, lamellar or penetrating keratoplasty is required.
A transplant can provide good results, but of necessity it is a last resort option. Visual rehabilitation is slow, and complications can be vision-threatening. Even after transplant, sometimes keratoconus recurs years later in the host tissue.
“There is also fear of graft rejection, infection and excessive hemorrhage,” Dr. Dhaliwal said, “Intacs implantation is a measure we can hopefully use to delay — or possibly prevent — a keratoplasty procedure.”
According to Dr. Dhaliwal, Intacs are believed to reinforce and flatten the weak cornea so that it becomes more spherical. Her surgery here was the first implantation of 20 that will be done in U.S. phase 1 trials at four centers nationwide.
The surgery Dr. Dhaliwal performed was a standard implantation of the Intacs segments. Two 0.35-mm ring segments were inserted into the cornea of a patient who was in a moderate stage of keratoconus. Segments were placed through radial incisions into circumferential corneal tunnels using forceps. They were positioned nasally and temporally with a Sinskey hook so that the superior ends were 3 mm apart. The segments were inserted at 70% depth in the stroma.
Initial postop results were successful, and Dr. Dhaliwal is optimistic about this potential therapeutic application for the Intacs inserts.
Postop results and anticipation
“I am extremely pleased with initial results,” she said. “The segments were securely placed and we have had no complications.”
In patients with keratoconus there is a risk of extrusion or perforation of Intacs segments because of the thin keratoconic cornea. These complications may result if the channels are created imperfectly and the segments are placed into the stroma either too deeply or too superficially. If these complications arise, the segments must be removed immediately, Dr. Dhaliwal said.
“The beauty of this technology is that it is removable. Patients like this concept because it’s not permanent, and doctors like it because it if a complication begins to occur, the segment can be removed,” she said.
“If any complications arise, Intacs can be removed and [patients] go back to their original correction. I’ve also done power adjustments by removing certain segments after the primary procedure,” said Brian S. Boxer Wachler, MD, director of refractive surgery at the Jules Stein Eye Institute of the University of California, Los Angeles and is also participating in the U.S. phase 1 clinical trial. More than two years ago Dr. Boxer Wachler performed the first case of Intacs for keratoconus in the United States and has performed more than 150 such cases since.
European results
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The idea of using this refractive device on keratoconic eyes was conceived by Joseph Colin, MD, of Bordeaux, France, in the mid-1990s.
“I was involved in the trials of Intacs for low myopia and I saw how well we were able to flatten the myopic cornea with Intacs. So I got the idea of using Intacs to flatten a keratoconic cornea,” Dr. Colin said.
Dr. Colin performed his first Intacs procedure for keratoconus in June 1997. In the past 5 years, he has performed 200 cases, including 40 cases performed in the European trials. The CE mark for the therapeutic application is expected to be obtained sometime in 2002, he said.
“In most cases, results have been very positive,” Dr. Colin said, “but in some cases we do not get the improvement that we are expecting.”
Dr. Colin said that in 80% of cases there has been a significant improvement in patients’ vision. After surgery there has been “very good” stabilization of the topography of the cornea.
Unfortunately, 20% of cases have showed no significant improvement, and these disappointing results have not been predictable.
“So far, we have not found any factors that can predict the possibility of a positive or negative outcome,” Dr. Colin said.
According to Dr. Colin, there are many variables involved in the outcome of surgery. The outcome may depend on the stage of the disease, the rigidity and location of the cone, the placement and thickness of segments and the age of the patient.
“We are trying to find out which are the parameters that could help us predict the outcome, so that we can accurately treat keratoconus,” he said.
Dr. Dhaliwal agreed. “There are many unknowns,” she said, “but I am very excited about offering patients something other than a corneal transplant. It provides them a less invasive option to improve their vision.”
Treating keratectasia
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In the future, the service may be offered not only to patients with keratoconus, but also to those with similar disorders of the cornea.
“There appears to be a very large interest in the therapeutic applications of the Intacs inserts technology,” said Thomas A. Silvestrini, executive vice president and chief scientific officer of Addition Technology. Mr. Silvestrini is a co-inventor of the Intacs technology.
In the past year, several presentations have been made by surgeons who have been using Intacs inserts off-label in the treatment of keratectasia, he said. Keratectasia is a pathological condition similar to keratoconus but less severe. The disease may occur after LASIK or in cases of congenital glaucoma. The cornea becomes abnormally thin and bulges forward.
“Sometimes there is a protrusion of the cornea after LASIK, due to the extreme thinning that LASIK causes. In these cases we have been able to implant Intacs to flatten the cornea and decrease the ectasia,” Dr. Colin said, “We have done six cases and all have been successful. Patients could see better after surgery.”
In the United States, David J. Schanzlin, MD, of San Diego, has used Intacs inserts in several cases of corneal ectasia following LASIK. In Europe both Dr. Colin and Carlo F. Lovisolo, MD, of Milan, Italy, have had positive results with Intacs for this therapeutic application. Other researchers including Ioannis G. Pallikaris, MD, PhD, and Charalambos Siganos, MD, have published preliminary results using Intacs inserts to treat LASIK-induced corneal ectasia.
“I have found the results for keratectasia to be pretty much on par with keratoconus,” said Dr. Boxer Wachler.
“These reports make us think there is a market for therapeutic applications in the future,” Mr. Silvestrini said.
Historical resistance
Currently, clinical trials throughout Europe are still focusing on the refractive applications of Intacs inserts for astigmatism, myopia with astigmatism and hyperopia. The Intacs technology was approved in the United States for use in the treatment of 1 D to 3 D of myopia with an astigmatic component of +1 D or less. Intacs inserts were approved for myopia of up to –5 D in Europe and Canada. These approvals came after almost 20 years of development of the device.
“There is an interesting phenomenon called the ‘innovator’s dilemma’ coined by Clayton Christensen, a Harvard professor of business,” Mr. Silvestrini said. “When something new enters the marketplace, the marketplace is sometimes not ready for the product, and time is needed for customers to determine where it will fit in. This appears to have happened with Intacs inserts.”
According to Mr. Silvestrini, in the beginning, KeraVision’s technology looked to the ophthalmic profession like a device that was not destined to succeed.
“We encountered a lot of resistance in the 1980s, because two large companies had experimented with putting lenticules into the cornea, and they had failed. These initial failures convinced many people that corneal implants would not be successful,” he said.
The original concept was envisioned in the late 1970s by technology pioneer A.E. “Gene” Reynolds and was realized with the help of John Petricciani and Joseph Krezanoski, PhD. In 1991, Mr. Silvestrini began working for KeraVision.
Extensive development
Mr. Silvestrini established a tissue laboratory, expanded the company’s scientific and medical advisory board and began working on animal and eye bank eyes. At this point, the Intacs design was not yet in segments.
“It was called the intrastromal corneal ring (ICR) and was a 360° PMMA ring that was designed to be expanded or contracted to make refractive corrections,” he said.
However, Mr. Silvestrini and his colleagues found that the expansive ring was difficult to control, so they decided to vary the thickness of the device instead. “The thickness became the major adjusting mechanism,” he said.
From 1990 to 1996, KeraVision undertook extensive reconfiguring and development on the ICR.
Members of the advisory board, in particular Dr. Schanzlin, Terry Burris, MD, Profs. Bernie McCary of Emory University and Peter Pinsky of Stanford University, and consultant Phil Baker were instrumental in helping the development effort succeed.
“With the help of this high-powered team, we developed sophisticated techniques to measure the optical wavefront of the corneal surface and to predict the mechanical and nutritional response to the implant in the cornea,” Mr. Silvestrini said.
Using high-tech optical metrology developed by Baker Consulting and a sophisticated finite element method developed by Mr. Pinsky, the researchers were able to determine how the device could work safely and predictably within the cornea.
From there, development progressed into varying the sizes of the corneal rings for the intended uses of astigmatism, hyperopia and myopia. Later, the 360° ring was modified into two separate semicircular segments of 150° each. These segments were renamed intrastromal corneal ring segments (ICRS). The ICRS were renamed Intacs prescription inserts, the same product design that is now marketed by Addition Technology.
Bad timing for approval
In 1996 in Europe and 1999 in the United States, regulatory approval was granted for the technology for correction of low myopia. In the United States, unfortunately, approval from the Food and Drug Administration came at a bad time — just as LASIK was taking the refractive market by storm.
“The timing was very unfortunate for Intacs inserts, because LASIK really took off about a year before we obtained FDA approval,” Mr. Silvestrini said.
The penetration of LASIK into the public consciousness made it difficult for Intacs inserts to capture a significant part of the suddenly expanding refractive market, Mr. Silvestrini said.
Additionally, Intacs inserts could treat myopia only from –1 D to –3 D, while LASIK was able to handle a wider range of myopia and eventually hyperopia. Also, the refractive market in the 1990s predominantly attracted patients with the need for higher myopic corrections, patients who were more appropriate candidates for LASIK, Mr. Silvestrini said.
So, amidst the LASIK boom, the commercial introduction of Intacs inserts was largely overlooked by the profession.
March 2001 brought another unfortunate event — KeraVision filed for bankruptcy after being unable to raise additional funding. Since 1986, more than $100 million had been invested into the Intacs technology, but poor financial foresight had finally led the company into Chapter 11.
A new beginning
Not long after KeraVision filed for bankruptcy, in June 2001, the company’s assets were acquired by a private investment firm, Vision Management Associates LLC. With some former KeraVision personnel and executives from Wesley Jessen Corp., Vision Management formed Addition Technology. Like KeraVision, the new company’s sole financial interest was the marketing and manufacturing of Intacs inserts.
“Upon acquiring the assets of KeraVision, we went through an internal process of streamlining the company,” said William M. Flynn, president and chief executive officer of Addition Technology. “We’ve now begun to rebuild the sales force, market extensively on a practice level and invest in new approvals applications.”
Trying to build both the refractive and therapeutic applications of the technology, the company is marketing Intacs inserts as an additive option among refractive surgical procedures.
“It’s addition technology, as opposed to subtraction technology like LASIK and other surgical procedures that remove part of the cornea,” Mr. Silvestrini said.
“I believe Intacs will do well for therapeutic applications because it doesn’t involve weakening the cornea like laser procedures can do in these specific cases. With Intacs, we’re not removing tissue, we’re almost reinforcing the cornea,” said Dr. Boxer Wachler.
He said surgeons have published and presented early off-label uses of Intacs inserts to repair eyes that were damaged by tissue removal surgeries. Initial work on this has been done by Michael Kritzinger, MD, and other surgeons.
“If they can actually repair eyes that are unstable optically or physically from too much tissue removal, it could be a therapeutic application of the technology,” he said. By adding the Intacs segments to an ectatic cornea, surgeons may be able to reinforce the tissue for an improved physical and optical effect, Mr. Silvestrini said.
With the variety of applications for the technology, company officials believe Intacs inserts fall into a different category from LASIK.
“We don’t think that Intacs inserts should be looked upon as a competitor to LASIK,” Mr. Silvestrini said. “We think a synergy between Intacs and other refractive surgery methods may exist.”
“The technology has been proven to work in preliminary clinical applications,” Mr. Flynn said, “Now it’s just a matter of allowing Intacs’ differentiating features to be recognized through the smoke of competition.”
“It’s true,” Mr. Silvestrini said. “In the meantime, all we can do is keep marching forward.”
“Intacs have a definite place in the role of vision correction,” said Dr. Boxer Wachler. “In the future, I’m looking forward to using different size myopic segments perhaps with hyperopic segments and evaluating that for specific subtypes of keratoconus.”
For Your Information:
- Deepinder K. Dhaliwal, MD can be reached at the Eye and Ear Institute, University of Pittsburgh Medical Center, 203 Lothrop St., Pittsburgh, PA 15213; (412) 647-2200; fax: (412) 647-5119; e-mail: dhaliwal@vision.eei.upmc.edu. Dr. Dhaliwal has no direct financial interest in the products mentioned in this article, nor is she a paid consultant for any companies mentioned.
- Brian S. Boxer Wachler, MD, can be reached at the Jules Stein Eye Institute, 100 Stein Plaza, Los Angeles, CA 90095-7000; (310) 206-7692; fax: (310) 267-1921; e-mail: BBW@jsei.ucla.edu. Dr. Boxer Wachler has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
- Joseph Colin, MD, can be reached at Service d’Ophthalmologie, CHU Pellegrin, Place Amelie Raba-Leon, 33000 Bordeaux, France; (33) 556 795 608; fax: (33) 556 795 909; e-mail: joseph.colin@chu-bordeaux.fr. Dr. Colin has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
- Thomas Silvestrini can be reached at 48630 Milmont Drive, Fremont, CA 94538; (510) 353-3000; fax: (510) 353-3030; e-mail: taf@keravision.com. Mr. Silvestrini is executive vice president and chief scientific officer of Addition Technology.
- William M. Flynn can be reached at 950 Lee St., Suite 210, Des Plaines, IL 60016; (847) 297-8419; fax: (847) 297-8678. Mr. Flynn is president and chief executive officer of Addition Technology.
Reference:
- Addition Technology, manufacturer of Intacs prescription inserts, can be reached at 48630 Milmont Drive, Fremont, CA 94538; (510) 353-3000; fax: (510) 353-3030.
- Siganos CS, Kymionis GD, Astyrakakis N, Pallikaris IG. Management of corneal ectasia after laser in situ keratomileusis with Intacs. J Refract Surg. 2002;18:43-46.