Enzymatic Options For the Vitreous

June and July saw the completed patient enrollment of Ista Pharmaceuticals’ (Irvine, Calif.) Phase III clinical trials for Vitrase, which received “fast track” designation from the U.S. Food and Drug Administration for the treatment of vitreous hemorrhage. The ability to clear a hemorrhage via a pharmaceutical agent would spare patients from undergoing a vitrectomy and being exposed to its associated risks.

Vitrase makes use of the enzyme hyaluronidase to liquefy the vitreous.

“By doing this, it really allows blood cells to settle into the lower part of the eye so that the pathology [if present] can be seen up above and it can be treated,” says Los Angeles surgeon Edgar Thomas, lead investigator for the Phase II trial and co-lead for Phase III.

A pharmaceutical agent that clears a vitreous hemorrhage would spare patients a vitrectomy and its associated risks.

One of the prospective, double-masked, randomized, placebo-controlled trials includes 680 patients at investigational sites in the United States, Mexico and Canada, while the other is comprised of 510 subjects at sites in Europe, Brazil, Australia and South Africa. A key component of the trials is a placebo control. One wasn’t included in the Phase II studies, which instead used a low dose of 7.5 International Units of Vitrase, says Dr. Thomas.

So far, the results have been promising. According to Ista, Vitrase effectively cleared the vitreous hemorrhages of 56-63 percent of the patients who received the highest dose in the 378-patient Phase II studies. The drug appears to be safe so far, with side effects limited to mild ocular inflammation that cleared spontaneously within a few days, according to Dr. Thomas, who adds that they have observed no clinically significant inflammation or cataract formation.

According to Baruch Kuppermann, MD, PhD, of Irvine, Calif., a clinical investigator for the drug, the primary benefit of Vitrase is its potential to eliminate the waiting period that vitreous hemorrhages now entail.

“… Doing injections in the office is very straightforward,” he says. “It doesn’t take a lot of time or effort, and, if it doubles the likelihood that a patient’s going to clear more rapidly, such that we can give him the laser [treatment] he needs, then I think that [the drug] is going to be embraced by the vitreoretinal specialist.”

Fellow investigator Sam Mansour, MD, of San Jose, Calif., concurs.

“One of the most frustrating things in managing these patients is the common scenario whereby a vitreous hemorrhage has developed in an eye that has had either no ... or incomplete laser treatment,” he says. “We know that such individuals are at a very high risk for developing long-term complications from the vitreous hemorrhage, which often cause them to become legally blind. The development of scar tissue in the vitreous, tractional bands that cause retinal detachments and so forth is much higher in a patient who has untreated diabetic retinopathy and sustains a vitreous hemorrhage than a patient who has received a full and adequate PRP treatment and then subsequently gets a vitreous hemorrhage.”

Another area of strong interest lies in the drug’s potential ability to induce a posterior vitreous detachment, a capability currently under investigation in the company’s 60-patient, prospective, randomized, placebo-controlled Phase IIa study in Mexico City. Interim results presented at the 2000 annual meeting of the American Academy of Ophthalmology reported PVDs in 60 percent of eyes treated with a single dose of Vitrase vs. 6 percent of control patients, 53 percent of those treated with sulfur-hexafluoride, and 50 percent of those treated with a combination of Vitrase and SF6 gas. The theory behind inducing a PVD is that it will reduce a patient’s risk for developing neovascularization and a vitreous hemorrhage.

“The emerging use of biologic adjuvants in the vitreous to create a PVD is a very exciting development,” comments Dr. Mansour. “If you can intervene early on in the course of the disease, then you can not only minimize the need for complicated vitreous surgery, but potentially minimize the number of high-risk, proliferative diabetic retinopathy patients reaching threshold for laser treatment.”

It’s in the enzymatic creation of a PVD that San Antonio surgeon J. Michael Jumper is most interested, but, while he believes that Vitrase may form a part of the vitreoretinal specialist’s pharmacological armamentarium, he thinks greater hope lies with agents like plasmin, dispase and chondroitinase.

“[Vitrase] would be helpful for cases such as non-clearing vitreous hemorrhage, in which you hope to eliminate the need for a surgical procedure, while these other enzymes may be useful in the operating room for cases such as pediatric retinal detachment when you need to create a PVD on the order of minutes,” explains Dr. Jumper.

He expresses the hope that the enzymatic removal of the vitreous will prove useful in surgery for many retinal diseases, including diabetic retinopathy, retinopathy of prematurity and vitreomacular traction syndrome.

The Vitrase trials appear to be a harbinger of an exciting trend in the vitreoretinal subspecialty: the advent of a host of new pharmacological agents for use in lieu of or as adjuncts to surgery and of new drug delivery systems. Dr. Mansour, who was involved with the early sustained release devices for cytomegalovirus retinitis in HIV patients, marvels at the advances in this technology. He characterizes the old implants as bulky and likens them to “a pill on a stick” that lasted 8 months at most. He notes that there are implants in development that last 3 years and have a smaller profile, so they’re easier to place in the eye.

“In some instances, you can actually inject the implants safely into the anterior portion of the vitreous space, where they remain fairly secure and unobtrusive,” he says.
To Dr. Jumper, concurrent advances in drug and delivery-system development bode well for surgeons.

“I think it will not only make conventional surgery as we know it more efficient and effective, but it’s also going to allow us to do less invasive forms of surgery on a subset of patients,” he says.

Drs. Kuppermann and Mansour estimate that short-term, Phase III data on Vitrase should be assembled by this December.

Popular Media Pounds LASIK

Though complications after LASIK are rare, popular newspapers and television news magazines have recently given a voice to an outspoken minority of patients who don’t like what LASIK did to them. On Dateline NBC, for instance, audiences watched as a Chicago surgeon almost operated on a nightmarish LASIK prospect—a patient with huge pupils and super-thin corneas. In a September article in the Denver Post, a LASIK patient with a bad outcome was quoted as saying, “I would give anything just to have my old eyes back.”

Even if it results in a decrease in the number of LASIK patients, however, surgeons say this negative coverage may be a blessing in disguise, making for more informed patients.

Stephen Kilmer, spokesman for TLC Laser Eye Centers, says that many of the companies in the eye center industry saw business go down by over 10 percent in the quarter ending on May 31 compared to the previous quarter. “This wasn’t seasonal,” he says. “It was because of the coverage.” He believes the big laser centers may have contributed to some of the frenzy by “rallying around patients left by the bankrupt centers. The media were surprised to hear that LASIK wasn’t a slam dunk,” he says.
Overland Park, Kan., surgeon Dan Durrie thinks the focus on complications in the media may be part of a progression for the procedure. “In general, this is a natural cycle,” he says. “Three or four years ago, the press was hyping LASIK as a miracle. It got blown out of proportion.”

He thinks that a negative reaction may help focus efforts on improving the procedure. “I think patients’ perception of LASIK has had a positive effect,” he says. “I support patients’ being vocal about their problems, because they’ve challenged the surgeons and engineers to improve even more.”

Even if this is a cycle LASIK has to go through, it’s created an atmosphere in which patients may be more likely to sue.

“We’re seeing an upkick in the number of claims for LASIK,” says Paul Weber, risk manager for the Ophthalmic Mutual Insurance Company. “There are a million procedures being done, though. We’re probably seeing a frequency of claims in relation to the number of procedures.” He says that the number of LASIK-related suits represented 10 percent of all open OMIC claims in 1999. This year, as of August, they accounted for almost 20 percent. The LASIK malpractice cases currently being handled by OMIC appear in the boxed text at right.

The growing raw number of complications has attracted the attention of the American Trial Lawyers Association, which has commissioned a special group to focus on laser eye surgery. The group is headed by Aaron Levine, a Washington, D.C., attorney. He claims laser eye surgery came to the group’s attention because “informed consent is inadequate. Surgeons don’t tell their prospective clients the true risks.”

OMIC’s Mr. Weber, however, says it’s unclear how juries will react to LASIK suits. “Will the jury say the patient knew it was a risk?” he wonders, “or will they say the doctor exaggerated his results and misled the patient?”

The one “wild card,” according to Mr. Weber, is a surgeon’s advertising. “If he advertised heavily and his ads claimed LASIK was ‘safe and effective,’ then a jury could get angry,” he says. He explains that advertising “puts the doctor in the role of salesman, and takes away from the persona of someone who’s there to help and take care of people.”

If a surgeon does advertise, Mr. Weber recommends that the advertising have something in it to put the idea in the readers’ minds that LASIK is, after all, a surgical procedure. “Not something frightening,” he says, “but just cast the ad in a different way.” He also says to read any patient literature your laser center gives you to promote the procedure, because, as soon as you hand it out, you may liable for the claims it makes.

If advertising does quiet down, and patients take a more realistic view of LASIK, surgeons who want to grow their refractive surgery practice may be allowed to focus on what some doctors feel got lost in the fervor of LASIK promotion: the quality of the surgeon.

“I think there will be a change toward emphasizing quality, long-term care and knowing who your surgeon is,” says Dr. Durrie. “The important questions will be: ‘What laser is he using?’; ‘Is he going to be there for my postop care?’; and ‘Whom am I trusting my eye to?’”