An MD&DI January 1997 Column

R&D HORIZONS

Medical device and pharmaceutical firms are joining forces to advance the uses of light-activated drugs, opening up new applications for lasers and fiber optics.

The synergy of drugs and devices represents an enormous and largely untapped potential for both clinical progress and corporate profit. That potential is only beginning to be seen as drug and device companies team up to offer systems for conducting photodynamic therapy (PDT), whereby drugs injectedinto patients are activated by light.

Transurethral catheter (codeveloped by PDT, Inc., and Boston ScientificCorp.) used in the treatment of benign prostatic hyperplasia. Photo courtesy ofPDT, Inc.

The opportunity for device companies is extraordinary. In orderfor these drugs to work, they must be accompanied by devices—a high-qualitylight source, such as lasers; light-delivery systems, including not only fiberoptics but catheters or endoscopes; and dosimeters for measuring the lightirradiating the target. "The field is really emerging dramatically,"says Alan Voss, director of regulatory assurance at Coherent, Inc. (Palo Alto, CA), one of two companies with lasers approved by FDA for this marketplace. Particularly appealing is the freedom from cost concerns that plague most other sectors of the device industry. "If you can do something that helps eradicate cancer, frankly, practitioners and patients don't give a damn what it costs," explains Robert Quillinan, vice president and CFO of Coherent.

Most drug developers vying for a niche in this marketplace depend on device companies to provide the necessary hardware. Only one—PDT, Inc. (Santa Barbara, CA)—has the ability to make the peripheral devices in-house. PDT originally focused entirely on devices in house, but expanded its repertoire to fully realize the potential of this young market. "We decided that if we're going to be in the business, we have to be able to control everything," says Daniel Doiron, president of PDT Systems, Inc., the subsidiary focused on developing medical devices. Doiron and members of his staff work closely with the other half of PDT, called PDT Pharmaceuticals, which specializes in the development of drugs. "From an operational point of view, the two subsidiaries are fully integrated," he notes.

PDT had been a supplier of devices to the medical community and to pharmaceutical companies. "But because of the demand from our own clinical base, we have turned inward," Doiron says. "Selling into the research market or to other companies was diluting our efforts to get our own package to the market."

PDT's decision to exit the supply side has opened the door wider for other device companies interested in this new marketplace. Among them are two laser vendors, Coherent and Laserscope (San Jose). Earlier this year, the two companies became the first medical device vendors to offer products for use in photodynamic therapy as part of a package offered by QLT PhotoTherapeutics, Inc. (Vancouver). In December 1995, QLT obtained FDA approval of three premarket approval (PMA) applications and a new drug application (NDA) to market a treatment for patients with tumors partially or totally obstructing the esophagus who cannot otherwise be effectively treated. The PMAs cover two lasers and a fiber-optic system.

Both Coherent and Laserscope adapted existing technologies for use in this therapy. The key was to generate laser light at 632 nm--the wavelength that activates QLT's drug, called Photofrin. "These drugs are activated by a very specific bandwidth and you've got to be within 2 or 3 nm, otherwise you don't get activity of the drug," says Voss.

Coherent had a leg up on the process in that the company was able to adapt an existing red-dye laser. The adaptation led to the Coherent Lambda Plus PDL1and PDL2, which can be tuned to emit light at wavelengths between 630 and 690 nm.

Photofrin is the core of QLT's treatment system—a drug administered intravenously that accumulates in tumors while over a period of several daysclearing from most other tissues. Photofrin has no apparent effect on tumorsuntil activated by nonthermal light, which produces an active form of oxygen that destroys the cancer.

The patient population for this application is relatively small. According to the American Cancer Society,about 11,000 persons die from esophageal cancer each year in the United Statesand 12,000 new cases are reported in the nation annually. But this indicationis just the first of possibly many others. QLT plans to file an NDA later thisyear to use Photofrin against both early- and late-stage lung cancer, accordingto Thomas Dougherty, MD, who discovered the drug. Dougherty, a professor ofmedicine, and his colleagues at RoswellPark Cancer Institute (Buffalo, NY), are now clinically testing othercompounds that show potential for PDT.

BROADENING APPLICATIONS

The wide clinical range of this type of therapy is one reason this marketplace holds such promise for medical device companies. "Photodynamic therapy has been used in so many different ways that if physicians wonder about its applicability, they can go to the literature and find out for themselves," Dougherty says.

A portable, semiconductor diode light source, light delivery catheter,and photoreactive drug (tin ethyl etiopurpurin) used in phtodynamic therapy.Photo courtesy of PDT, Inc.

Studies have documented the effects of PDT when treating cancers of the brain, head and neck, skin, colon, and bladder. Preclinical data indicate that the therapy may also be effective against atherosclerosis and inflammatory conditions, such as arthritis. "We are very excited about the gynecological applications of PDT, both for cervical cancer, potentially for ovarian cancer, and even for endometrial cancer, as well as for the treatment of noncancerous endometrial problems," says Michael W. Berns, PhD, director and CEO of theBeckman Laser Institute and Medical Clinicat the University of California, Irvine. "But you talk to 10 differentpeople and they're probably going to tell you the area they think is going tobe best."

Analysts and company executives estimate that the annual market in the United States for photodynamic therapy of cancer alone will exceed $350 million.That figure effectively doubles when other world markets are included. Photofrin has already been approved for sale in France, Japan, and Canada for varioustypes of cancer. And cancer may be only the first of many indications.

Photoactivated drugs could eventually be tailored to battle a wide range of diseases, with liposomes and monoclonal antibodies being used to deliverphotoactivated toxins to pathogens including viruses, such as HIV, and bacteria.When these pathogens are associated with a localized problem, as in the case ofHelicobacter pylori, a major cause of stomach ulcers, the light might bedelivered to a site inside the patient. When pathogens are systemic, bloodcontaining these pathogens might be removed from the body, exposed to PDT, and returned so as to create an immune response against the disease-causing agents. PDT might even be used to ensure the quality of blood stockpiled fortransfusion.

Some of that potential could be realized in the next year or 18 months. QLT has a second-generation drug, a bezoporphyrin derivative (BPD), in Phase IIIclinical studies for the treatment of age-related macular degeneration, whichcauses blindness. PDT has a tin-based, synthetic chlorophyll in Phase IIIclinical trials and expects to file for FDA approval in 1997. Primaryapplications are cutaneous cancers, such as metastatic breast cancer, skincancer, and cutaneous cancers related to AIDS. Other indications, such as the treatment of benign prostatic hyperplasia, do not involve cancer.Pharmacyclics (Sunnyvale, CA) has a productcalled Lu-Tex (lutetium texaphrin) in Phase I trials, which may be effectiveagainst a variety of cancers, including breast cancer, and also may be usefulin treating patients with atherosclerosis. Also encouraging is the low incidenceof side effects. Pharmacyclics executives believe the progress being made inclinical studies now and the fast-track reviews that cancer drugs are receivingat FDA could allow the company to be on the market with a product by 1999.

FDA took less than two years to review QLT's therapy system, approving anNDA for Photofrin and three PMAs for its related devices. "We don't makedevices and we're not going to make devices," says Richard Miller, MD,president and CEO of Pharmacyclics. "If our drug is good, people are going to be there with the devices."

LASER ADVANCES

The key to tapping the device market for these and other therapy systems is having the right technology, says Coherent's Voss. But that is not easy, "becausethe market is still evolving," he says. His colleague, Bob Quillinan, notesthat "the device technology tends to trail the drug technology by a little,because no one wants to spend money developing a device when they're not surethere will be a market. If the drug doesn't go, neither does the device."

For the time being, only high-powered lasers costing $100,000 or more are approved by FDA for use in PDT. But that may change in the near future. Coherent is developing a type of diode laser for use with QLT's second-generation drug, BPD. Diode lasers, which produce coherent beams of light using semiconductors, promise cost advantages through mass production—an efficiency that could bringdown the cost of a laser to a few thousand dollars or less. Diode lasers arealso more durable, are easier to use, and require much less maintenance, sincethere are no gas tanks to replace or mirrors to keep aligned.

Gas lasers, which are often the size of refrigerators, create a portability problem that is solved by diode lasers that, even with a power source attached, are about the size of a fist. Diode lasers are also more efficient than conventional gas lasers, requiring only 5 W, rather than the conventional lasers' 5000 W, to generate a 1-W beam. "They're also very user-friendly," says Julia Levy, MD, president and cofounder, CEO, and chief scientific officerof QLT. "They just plug into the wall. Compared to the argon laser used for Photofrin, this is a huge leap forward in terms of ease of use."

Levy would like to have a diode laser for Photofrin, but "it's harder to get these lasers to generate wavelengths around 630 nm," she says. "The higher the wavelength, the easier it is for the diode laser to generate." BPD, she notes, is activated by light with a wavelength of about 690 nm, which makes it a target for diode lasers.

And diode lasers also have inherent power limitations that restrict their use. "Traditionally with higher power, you lose the ability to focus a semiconductor laser on its target," says John Marciante, a graduate researcher at the University of Rochester (Rochester, NY). "Rather than a single strong beam, you get three to five weaker beams, greatly diminishing the laser's power and performance."

But Marciante and his mentor, professor of optics Govind Agrawal, believe they may have found a way to clean up the beams produced by semiconductor lasersso they can generate a sharply focused beam with two to four times the power ofcurrent diode lasers, up to 6 to 12 W of power. A prototype of the laser has yetto be built, but the laser design has performed well in computer simulations.

LIGHT OPTIONS

Diode lasers are just one alternative. Light-emitting diodes (LEDs) comprise another. Arrays of LEDs can be constructed to emit red light with wavelengths of about 700 nm or more. Pharmacyclics' Lu-Tex, which is activated by light at 732 nm, can be activated by LEDs. In an upcoming Phase II trial of Lu-Tex, Pharmacyclics plans to use a postcard-size array of LEDs applied to the chest wall of breast cancer patients who have undergone mastectomy. Cancers recur in 20 to 30% of these patients, according to Miller. "Compared to the laser we've used in the Phase I trials, the LEDs put out twice as much light, cost one-tenth as much, require no water supply for cooling, can plug into any wall socket—and you can carry them around the hospital, basically put them in your briefcase," he says. Other possible applications for LEDs include cancer of the skin and dermatological conditions.

And there is another possibility for a light technology. Noncoherent light sources have been shown to generate light ranging from 200–1200 nm up to several watts. Light from these sources is generated by a base unit and can then be filtered, focused, and either aimed by an application unit to cover a wide external area or pumped through a fiber-optic system to an internal site. Not only could such a technology provide a range of outputs but it could be engineered with a simple set of controls so that training of clinical personnel and maintenance would be minimal. Like LEDs, noncoherent light sources can be designed as compact units, allowing easy portability among treatment rooms.

Light source technology constitutes one of several opportunities for device companies. Critical to the success of photodynamic therapy is getting the light to the target. QLT met that challenge through the development of its Optiguide fiber-optic diffuser. Physicists at the company developed the diffuser device and now hold a patent on its design—but the device itself is being built by an outside contractor. "We don't do devices in our company," Levy says. "We're strictly a drug company. For all our devices we rely on partnerships with companies that do what they do well."

How the light is delivered depends on the location of the target. Esophageal and lung tumors may be illuminated by light transmitted through fiber optics threaded the length of endoscopes. Atherosclerotic plaque, which mightbe the target of Lu-Tex, may be attacked via intravascular catheters. Advancesagainst these varied pathologies present opportunities for the makers of both endoscopes and catheters, as well as for the manufacturers of optics.

Another type of technology involved in photodynamic therapy is the dosimeter. This type of device is essential in conducting research in order to determine the amount of light necessary to activate the drug effectively. "During clinical trials we have to define what is the right amount of drug and how much light to give," Dougherty says. "It's not the same for every site."

Dosimetry may also play an important role in mainstream therapeutic devices. PDT Systems has designed a dosimeter into its light-delivery system, one that measures the light at the tissue interface and controls the system on the basis of those measurements, adjusting for differences in the optical properties of the tissue. "This gives you better accuracy—better control—and makes the system easier to use," Doiron says. "Nobody's doing any calculations. The system does it all for the user."

REGULATORY FRUSTRATIONS

The technical challenges of photodynamic therapy are just one of the hurdles to getting to market, however. Another, and arguably one of the biggestfor device manufacturers, is getting through the regulatory process. In orderfor any medical device to be used as an integral part of a PDT system, it must be approved for that indication by FDA. Coherent and Laserscope products haveeach been approved for this use--but neither company holds the PMA. The drug developer, QLT, does.

The reason for this is the dependence of the device on the drug and theneed for a single company to take responsibility for obtaining regulatoryapproval. Doiron of PDT Systems describes the regulatory process as one of the biggest sources of frustration in the development of photodynamic therapy. "FDA reviewers are not experienced in dealing with a procedure-based technology," he explains. "They look at the therapy as a drug, and some of thequestions that they come back with wouldn't even be considered questions in thedevice center."

Device companies might like to cut out their reliance on drugs entirely for photodynamic therapy. And some visionaries have proposed that differenttissues, and particularly cancers, bacteria, and viruses, might selectivelyabsorb certain wavelengths, raising the possibility of destroying just thedisease agent while having no effect on collateral tissue—even without the useof drugs. But that is not likely to happen, at least not in the case of cancer."There really is not a lot of difference between cancer cells and normalcells," says Beckman Laser Institute director Berns, who is also aprofessor of developmental and cell biology. "Cancer cells divide morerapidly and they've got a little bit more DNA, but the light-absorbingproperties of DNA are the same."

As a result, device companies will have to depend on drug companies to blaze trails for their products if they are to sell into the PDT marketplace. "But if this particular therapy is growing like we think it is, we want to beinvolved in it," says Coherent's Voss. "We want to be very active—andwe plan to do whatever it takes."

Copyright © 1997 Medical Device & Diagnostic Industry