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Advances in Photodynamic Therapy Lure Device Innovators

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 injected
into patients are activated by light.


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


The opportunity for device companies is extraordinary. In order
for these drugs to work, they must be accompanied by devices—a high-quality
light source, such as lasers; light-delivery systems, including not only fiber
optics but catheters or endoscopes; and dosimeters for measuring the light
irradiating 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 PDL1
and 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 days
clearing from most other tissues. Photofrin has no apparent effect on tumors
until 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 States
and 12,000 new cases are reported in the nation annually. But this indication
is just the first of possibly many others. QLT plans to file an NDA later this
year to use Photofrin against both early- and late-stage lung cancer, according
to Thomas Dougherty, MD, who discovered the drug. Dougherty, a professor of
medicine, and his colleagues at Roswell
Park Cancer Institute
(Buffalo, NY), are now clinically testing other
compounds 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 the
Beckman Laser Institute and Medical Clinic
at the University of California, Irvine. "But you talk to 10 different
people and they're probably going to tell you the area they think is going to
be 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 various
types 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 deliver
photoactivated toxins to pathogens including viruses, such as HIV, and bacteria.
When these pathogens are associated with a localized problem, as in the case of
Helicobacter pylori, a major cause of stomach ulcers, the light might be
delivered to a site inside the patient. When pathogens are systemic, blood
containing 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 for
transfusion.

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 III
clinical studies for the treatment of age-related macular degeneration, which
causes blindness. PDT has a tin-based, synthetic chlorophyll in Phase III
clinical trials and expects to file for FDA approval in 1997. Primary
applications are cutaneous cancers, such as metastatic breast cancer, skin
cancer, 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 product
called Lu-Tex (lutetium texaphrin) in Phase I trials, which may be effective
against a variety of cancers, including breast cancer, and also may be useful
in treating patients with atherosclerosis. Also encouraging is the low incidence
of side effects. Pharmacyclics executives believe the progress being made in
clinical studies now and the fast-track reviews that cancer drugs are receiving
at 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 an
NDA for Photofrin and three PMAs for its related devices. "We don't make
devices 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, "because
the market is still evolving," he says. His colleague, Bob Quillinan, notes
that "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 sure
there 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 bring
down the cost of a laser to a few thousand dollars or less. Diode lasers are
also more durable, are easier to use, and require much less maintenance, since
there 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 officer
of 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 lasers
so they can generate a sharply focused beam with two to four times the power of
current diode lasers, up to 6 to 12 W of power. A prototype of the laser has yet
to 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 might
be the target of Lu-Tex, may be attacked via intravascular catheters. Advances
against 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 biggest
for device manufacturers, is getting through the regulatory process. In order
for 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 have
each 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 the
need for a single company to take responsibility for obtaining regulatory
approval. 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 the
questions that they come back with wouldn't even be considered questions in the
device center."

Device companies might like to cut out their reliance on drugs entirely for
photodynamic therapy. And some visionaries have proposed that different
tissues, and particularly cancers, bacteria, and viruses, might selectively
absorb certain wavelengths, raising the possibility of destroying just the
disease agent while having no effect on collateral tissue—even without the use
of 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 normal
cells," says Beckman Laser Institute director Berns, who is also a
professor of developmental and cell biology. "Cancer cells divide more
rapidly and they've got a little bit more DNA, but the light-absorbing
properties 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 be
involved in it," says Coherent's Voss. "We want to be very active—and
we plan to do whatever it takes."


Copyright © 1997 Medical Device & Diagnostic Industry

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