Aiming to Change the Face of Refractive Surgery—Again

As founder, chairman of the board, and chief executive officer of Summit Technology in the 1980s and 1990s, David Muller, PhD, shepherded the first excimer laser refractive surgery system in ophthalmology through the US Food and Drug Administration (FDA) approval process. Currently, he is President and Chief Executive Officer of another start-up company, Avedro, Inc., (Waltham, Massachusetts). Avedro is developing Keraflex (see Thermo-Biomechanics for Treating Keratoconus and Refractive Errors, CRST Europe, March 2010, pages 16-18), a procedure in which microwave energy is used to reshape the cornea. This year, the company also became a sponsor of the US clinical trials of corneal collagen crosslinking (CXL) for the treatment of keratoconus and post- LASIK ectasia. The company has begun clinical trials in Europe combining the two technologies in a procedure called Keraflex KXL. CRST Europe spoke to Dr. Muller to get his perspective as a physicist and a businessman on the past, present, and future of refractive surgery.

CRST Europe: You were involved in the start-up of Summit Technology in the 1980s, and now, a quarter century later, you are involved in the start-up of Avedro. How would you compare the two experiences?

David Muller, PhD: I was more than involved in the startup of Summit; I founded the company and guided it from start-up in 1985 to the first FDA approval of an excimer laser for ophthalmology in 1995. In 2003, I became interested in a microwave technology being developed at Dartmouth College as another possible modality for refractive vision correction. After consulting with my friend and colleague John Marshall, PhD, FMedSCI, FRCPath, FRCOphth(Hon), in London, and performing some proof-of-principle work, I founded Avedro to bring that technology to market.

One of the biggest differences between these two experiences is that, when we started Summit in 1985, there was no general acceptance of refractive surgery as a field of ophthalmology. The only refractive surgical procedure that existed was radial keratotomy (RK), which was on the fringes of ophthalmology, performed by only a few hundred people, if that. At that time, we were coming on to a much different scene than we face today.

Technologically, excimer lasers had existed for about 10 years when we started applying them to the cornea, and the technology itself was raw and difficult to harness.

But in addition to the lack of a market and the technological challenges, there was also a huge emotional challenge in introducing excimer lasers. When we were experimenting with ablation on the front surface of the cornea, at a time when the only refractive surgery was RK, the dogma was, “Never touch the optical zone of the cornea.” With our concept of central surface ablation, we were heretics. In those days, when potential investors would present the business plan to ophthalmologists, they often would get booted out of the office. The feeling was, “You cannot do this; this is just wrong.” It was something that people did not want to accept. It is interesting how things change; some of the same ophthalmologists who originally fought tooth-and-nail against what we were doing are now leaders in the field of excimer laser surgery.

Bringing a completely new technology to market in 2010 has its challenges, and they are in some ways parallel but also different. Today, unlike in the 1980s, there is an accepted paradigm for refractive surgery because a refractive surgery marketplace exists. However, it is for the most part excimerlaser— based, so it is interesting to watch the resistance of people to the idea that there could be another paradigm.

Before the introduction of the excimer laser, several other types of lasers had been tried in refractive surgery, including dye laser systems and CO₂ laser systems, and they had all failed. When the excimer laser came along, it was tarred with the same brush. But it turned out that it was a different kind of laser, and it was successful.

I see an analogy today with using microwaves to reshape the cornea. It is true that hot pokers did not work for thermokeratoplasty, lasers did not work, and radio frequency did not work well. That does not mean that a new modality might not work for thermokeratoplasty. Before it is out of the gate, this technology is tainted by experiences with earlier technologies. So, in addition to technical challenges, we face an emotional challenge similar to the one we faced in 1986. There is also another form of resistance. People want to know why we need a new technology to treat myopia when we already have the excimer laser. This refractive surgery modality has treated perhaps only a few percent of the eligible population, a small market penetration compared with what was originally envisioned. Maybe we might want to try something else.

As for the process of creating the two companies, in building Avedro, I understand ophthalmology and ophthalmologists better than I did 20 years ago, and also I know the road to regulatory approval that the technology has to travel. With the excimer laser, it took 4 years before we treated our first patient. With this microwave technology, it took about 18 months. In that respect, the previous experience helped us become more efficient.

CRST Europe: The introduction of the excimer laser changed the face of refractive surgery. Can you envision repeating that experience with the Keraflex procedure?

Muller: The excimer laser actually built the refractive surgery market of today. RK never gained wide acceptance like laser refractive surgery. Today, the exhibit hall at the European Society of Cataract and Refractive Surgeons (ESCRS) meeting is the hall that excimer lasers built. It looks nothing like the exhibit halls of 20 years ago. Can we envision repeating that with what we are doing now? My answer is yes—but in a broader sense.

The concern with any kind of thermokeratoplasty technology is durability. Just like any previous form of thermokeratoplasty, on its own our microwave procedure has limited durability. But from the beginning we have envisioned combining it with CXL, a relatively new technology that is widely accepted in Europe. We think the combination will make a big difference in durability.

Our plan is to combine these two interesting tools, the microwave technology and CXL. We anticipate that our biggest market will be refractive surgery, but my sense is that this combination tool of heating and locking will have much broader applicability than refractive surgery. It is not limited to treating native myopes. There are potential applications in other cases such as post-cataract patients, post- LASIK patients, and patients with keratoconus. This heatingand- locking tool will allow ophthalmologists to manipulate the cornea so that its behavior is predictable.

Having said that, we recognize that refractive surgery is potentially the biggest market in ophthalmology. One of the reasons we think Keraflex will be successful for refractive surgery is that it does not have to be permanent. Excimer laser refractive surgery has been successful, but a limited number of patients have had bad results, which feeds the fear factor that keeps larger numbers of patients from coming to the technology. We believe that, with Keraflex, we will offer a procedure that patients can hypothetically take for a test drive. Patients could be treated with the Keraflex knowing that the effect will go away in a few months if they do not like it. But if they like it, after about 1 month or so when the proper effect has been achieved, the surgeon can use CXL to lock it in. This is a different paradigm potentially for a different patient population.

Our clinical trials show that, with the thermokeratoplasty treatment alone, most of the correction is gone within 3 or 4 months. But we have also shown that if we crosslink those lesions, the reshaping is persistent. We have only limited data to date; we do not know how long it persists. We are preparing to start a multicenter trial outside the United States within the next few months to determine the appropriate dose of CXL and other parameters.

CRST Europe: Do you see this technology as competing with the excimer or complementing it?

Muller: We do not see Keraflex competing directly with excimer laser; we see it as adjunctive. I cannot foresee a day when the role of excimer lasers in refractive surgery will be extinguished. But currently those lasers are treating only a small percentage of the potential patient population. There is a huge patient population that has not been touched.

There may be some overlap, but we see this technology as additive. I hope ophthalmologists acknowledge that we are not trying to disrupt what already exists, but rather opening up a market space that heretofore did not exist.

CRST Europe: Previous corneal heating procedures have resulted in corneal steepening. Yours results in corneal flattening. What is the explanation for that difference?

Muller: Flattening or steepening depends on where the heat is applied. With the current radiofrequency technology, for example, the energy is applied in spots in a circular pattern at a diameter outside the patient's optical zone. The tissue shrinkage acts like a belt, tightening and steepening the cornea. But those heated spots leave permanent scars in the cornea. The same technology applied in the center of the cornea would flatten it, but it would leave a scar in the middle of the optical zone. Our procedure is performed at about a 4-mm diameter zone. The cornea remains prolate, and there is no scar, so we do not disrupt the visual quality in the optical zone. If we applied our microwave energy at an 8- mm diameter zone, we could steepen the cornea. It is where you put the lesions that determines the corneal shape.

CRST Europe: Are you developing other technologies?

Muller: In March, we took over as sponsors of what had been the Peschke Meditrade GmbH (Huenenberg, Switzerland) clinical trials of CXL for progressive keratoconus and ectasia.^1,2We see CXL as an adjunct to what we are doing with microwaves. It is the combined microwave- CXL procedure that we believe over time will develop a range of applications. We also see CXL as a potentially large market, a standalone entity for treatment of post-LASIK ectasia, keratoconus, and forme fruste keratoconus—indications for which there are no commonly used treatments available. In taking over sponsorship of those trials, we hope to get the CXL technology through the FDA approval process first. We expect that to be our lead product in the United States and then follow with the microwave product.

We are coming into a new era in ophthalmology. As I mentioned, at ophthalmology meetings today, you see the exhibit hall that excimer lasers built. That market has been building for a couple of decades, but eventually something new comes along. This powerful combination tool, which we have dubbed thermobiomechanics, will offer ophthalmology a new treatment modality. I hope 20 years from now to see the exhibit hall that thermobiomechanics built.

David Muller, PhD, is President and Chief Executive Officer of Avedro, Inc. He may be reached at tel: +1 781 768 3400; e-mail david@avedro.com.

1. Corneal Collagen Crosslinking for Progressive Keratoconus (CXL). http://clinicaltrials.gov/ct2/show/NCT00647699. Accessed April 16, 2010.
2. Corneal Collagen Crosslinking for Ectasia (CXL). http://clinicaltrials.gov/ct2/show/NCT00674661. Accessed April 16, 2010.