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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

Originally it was inferred that the light was generated by endogenous


porphyrins. More recent development work demonstrated that tumors in
animals injected with hematoporphyrin fluoresced red-orange when
exposed to near ultraviolet light. Eventually a hematoporphyrin
derivative was used for fluorescent detection of tumors in humans and
this lead directly to the treatment of patients with cancers.
Modern PhotoDynamic therapy works by injecting the photosensitizing
drug intravenously into the human patient. Allowing time for the drug to
be absorbed by all the cells, the drug rapidly leaves most normal cells
but remains in cancer cells for longer periods of time. The cancer cells
targeted for treatment are then exposed to light from a laser. This light
The December 1995 FDA activates the photosensitizing drug that absorbs the light, producing an
approval of the application of active form of oxygen that destroys the surrounding cancer cells. Light
Photofrin for the treatment of exposure timing is critical; to be therapeutically effective it must occur
esophageal cancer was the first after most of the photosensitizing drug has left the normal cells but is
ever approval for a drug-light still present in the cancerous cells. While timing is critical, there is a
device combination and ushered broad window within which to effect a positive application. That is
in the modern era of possible because of scale. The photosensitizer drug is expunged or
PhotoDynamic Therapy.
expelled by normal cells in a very short order leaving more than half of
January 1999 witnessed the full- the remaining time in which to effect the treatment on the targeted cells
scale medical market launch of only.
Photofrin in the U.S. Laser generation of light and fiber-optic technology facilitate the delivery
of the light and allows for precise management of the exposure
4Q99-1Q00 is the expected FDA
approval milestone for the
sequence. Fiber-optic technology also permits treatment of skin cancers
treatment of Age-related Macular and cancers immediately below the surface of the skin. And allows light
Degeneration (AMD) by to be directed through a bronchoscope into the lungs, through an
PhotoDynamic Therapy. endoscope into the esophagus and intestinal tract or through a
cytoscope into the bladder.
The main advantage of PDT is the non-invasive nature of the treatment;
healthy tissue is virtually unaffected. A primary limitation (evident by
virtue of the physical property of laser light) is that it cannot pass
through more than about three centimeters of tissue (light emitted at
wavelengths employed currently in PDT); thereby limiting treatment to
areas accessible by direct delivery of the light such as tumors on or
immediately under the skin or in the lining of internal organs or
passageways. Work is currently underway exploring methods and
approaches which extend the penetration of light beyond current
limitations and with alternative methods of amplification so as to,
metaphorically, relay the light further along into the density of the
targeted tumors.
The main side effect of PDT remains skin sensitivity, making patients
Side effects of noninvasive very prone to sunburn. The skin may remain sensitive to light for six
PhotoDynamic Therapy are weeks or more after treatment. Sunscreens are not completely effective
minimal insofar as they may
in protecting the skin from the sun, so patients are advised to avoid
demand the patient wear light
direct sunlight for at least this six-week period. Other temporary side
screening clothing for a short
period post-treatment. The effects include nausea, vomiting and eye sensitivity to light. Current
current class of photosensitizers advances in the PhotoDynamic drug family, in the case of QLT
is proving to be efficacious and PhotoTherapeutics, Inc., have reduced post-treatment light sensitivity to
are producing NO harmful a 24-hour period, making it an extremely viable and utilitarian
outcomes in patients treated. application. Additionally, most photosensitizers currently in the pipeline
are ‘designer drugs’, the properties of which are continually being
modified to address the post-treatment light sensitivity concerns,
concurrent with other sought attributes.

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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

The December 1995 threshold event had the U.S. Food and Drug
Administration (FDA) approve porfimer sodium (PHOTOFRIN™) a
photosensitizing drug developed and patented by QLT PhotoTherapeutics
Inc. This application was designed to relieve symptoms of esophageal
cancer that is causing an obstruction and for esophageal cancer that
cannot be satisfactorily treated with lasers alone.
In January 1998, the FDA approved porfimer sodium for treatment of
early non-small cell lung cancers in patients for whom surgery and
radiotherapy are not options. The National Cancer Institute and other
institutions are supporting ongoing clinical trials to further evaluate the
use of PhotoDynamic therapy for other cancers. As well, research is
ongoing to find different laser types and new photosensitizers that might
increase the effectiveness of PDT against cancers located below the skin
or internal to an organ.

Epidemiological data and PDT target markets

Esophageal Cancer
Estimated Annual Market @ US$30 Million

Esophageal cancer is the ninth most common cancer in the


world. It is a disease of the mid-to-late adulthood, roughly 60-70 years.
The probability of surviving esophageal cancer is low; only 8% of
patients survive five years or more and the median survival is nine
months. There are no differences in survival rates according to sex,
racial background and/or histologic type. These statistics are based on
National Cancer Center data collected between 1973 and 1989. In more
recent reports these figures above may prove to be slightly better.
There is, however, a marked variation in the incidence of this cancer,
more than for any other tumor, according to sex, geographical area,
racial, and economic background. The annual age-adjusted incidence
rate varies from less than five cases per 100,000 population among
whites in the United States to 18.7-26.5 per 100,000 population in some
regions of France, reaching a pronounced incidence of up to 100 cases
per 100,000 in Linxian, China or the Caspian region of Iran. In most
countries esophageal cancer is two to three times more frequent in men
than in women.

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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

In Iran and China, however, this cancer is as frequent in women as men.


Esophageal squamous cell carcinoma occurs five times more often
amongst African-Americans than whites, with this excess being greater
at younger ages. Esophageal cancers are one of the most common
Statistical data referred herein malignancies amongst black men under the age of 55. In China, the
has been gleaned from a number country with the highest mortality rate due to this disease, incidence has
of sources including:
been decreasing since the 1970s, likely due to dietary changes where
American Cancer Society
there has been an increase in content of food rich in proteins, carotene,
Chemistry in Britain vitamins C and E and riboflavin. At the same time, more cases of
Center for Disease Control squamous cell carcinoma are due to an increase in consumption of
National Cancer Institute tobacco and alcohol, reflecting the economic changes in the area. An
Medical Informatics at Louisville, increased incidence is also observed in regions where the disease was
Kentucky once rare, such as Germany, Denmark and countries of the ex-Soviet
The University of Wisconsin block where there is a high rate of alcohol consumption. The patterns of
Cancer Center incidence of histologic subtype are changing, with rates of squamous cell
Washington University STL
carcinomas decreasing and adenocarcinoma increasing rapidly (five to
University of Pennsylvania
The Wall Street Journal
six fold) in several countries. In the United States, squamous cell
The Globe and Mail carcinoma (predominant type) occurs more often in African-Americans
Oregon Medical Laser than in whites (five fold). Adenocarcinoma occurs more often among
American Medical Assess. white men, where by 1990 it accounted for nearly half of all esophageal
The Economist cancers.
Ocular Surgery News
Journal of the National Cancer Its incidence has been increasing for the past 20 years in excess of any
Institute other neoplasm in the order of 5% to 10% per year throughout the
American Society of Clinical 1980s. Overall mortality rates parallel the incidence of esophageal
Oncology cancer and are relatively stable in most countries. Significant (more than
50%) decreases in mortality rates have been observed in Finland and
Switzerland since the 1950s, but a modest increase is reported in other
European countries.

Barrett’s esophagus
Estimated Annual Market @ US$40 Million

This condition is a pre-cancerous condition which occurs when the lining


of the esophagus coverts to a stomach-type tissue as a response to
chronic acid reflux. Some 2 million people suffer from this
condition in North America alone. This condition increases the risk
Chronic acid reflux affects some 2 of developing esophageal cancer 30 to 40 fold. As a result, removal of
million North Americans annually. the esophagus is recommended in the 5% of patients with severe
disease called high-grade dysplasia.
Although symptoms of acid reflux can be controlled, no treatment exists
to eliminate Barrett’s esophagus and decrease the risk of developing
cancer. In clinical trials using porfimer sodium, high-grade dysplasia was
eliminated in 75% of cases; in patients where the condition had
progressed to superficial cancer, treatment resulted in the complete
elimination of carcinoma.
Phase III trials are currently being conducted using a range of porfimer
polymers throughout Europe and North America. In addition, second
and third generation drugs are being employed in treatment protocols
for earlier stages of Barrett’s esophagus.

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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

Melanoma - Skin Cancer


Estimated Annual Market @ US$150Million
Each year approximately one million new cases of highly curable basal
cell or squamous cell cancers are reported. Incidence rates are about 20
times higher among whites than among African-Americans. The current
annual rate of melanoma in the United States is about 41,600
people for 1998. Since 1973, the rate of melanoma has increased
about 4% per year from 5.7 per 100,000 to 12.5 per 100,000 in 1994.
Other important skin cancers include Karposi’s sarcoma and cutaneous
Each year approximately one T-cell lymphoma. An estimated 9,200 deaths occurred in 1998, 7,300
million new cases of highly from melanoma and 1,900 from other skin cancers. Mortality rates for
curable basel cell or squamous melanoma have been relatively constant since the late 1970s at about 2
cell cancers are reported.
per 100,000.
Existing therapies are
dynamically invasive – surgery, While early detection is critical, there are five methods of treatment for
radiation, electrodessication and basal cell cancer and squamous cell cancer: surgery (currently used in
cryosurgery. 90% of cases), radiation therapy, electrodessication (tissue destruction
by heat), cryosurgery (tissue destruction by freezing) and laser therapy
PDT is the only noninvasive non
destruction treatment for early skin cancer. For malignant melanoma, the primary growth cells
alternative possibility currently must be adequately excised, and it may be necessary to remove nearby
on the horizon. lymph nodes. PDT can reduce the invasive nature of existing therapies
and increase survival rates, by very direct local application of the
therapy.
With basal cell or squamous cell cancers, a cure is highly likely if
detected and treated early. Malignant melanoma can spread to other
parts of the body quickly. However when detected in its earliest stages,
and with proper treatment, it is also highly curable. The overall five-year
survival rate for patients with malignant melanoma is 88%. For localized
malignant melanoma the five-year relative survival rate is 95%, and
rates for regional and distant diseases are 61% and 16%, respectively.
About 82% of melanomas are diagnosed at a localized stage, which is
the state at which PhotoDynamic Therapy is most effective.

Urinary Bladder Cancer


Estimated Annual Market @US$5 Million

Bladder cancer rates are relatively stable at about 17 per 100,000 in the
The potential PhotoDynamic United States with an estimated 54,400 new cases diagnosed in
Diagnosis and Therapy treatment 1998. Overall bladder cancer incidence is nearly four times higher in
market is in excess of US$7.25 men than women, and two times higher in whites than in African-
Billion annually. Americans; it is twice as prevalent in smokers as in non-smokers.
Since the 1970s mortality rates for bladder cancer have decreased for all
populations in the United States. There were an estimated 12,500
deaths due to bladder cancer in the U.S. for 1998. As with other forms
of cancer early detection is key to survival.
Treatment consists of surgery either alone or in conjunction with other
treatments. This is the method of choice in more than 90% of cases.
Preoperative chemotherapy or with radiation before cystectomy (bladder
removal) has improved treatment results. PhotoDynamic therapy clinical
trials are under way with prospective positive results. When diagnosed
at a localized stage the five-year relative survival rate is 94% and 74%
of cancers are detected this early. For regional and distant stages the
five-year relative survival rates fall to 49% and 6% respectively.

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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

Cervical Cancer and Dysplasia


The Japanese market of 180 Estimated Annual Market @ US$50 Million
million people is one of great
potential acceptance of PDT is an ideal non-invasive, non-destructive treatment for patients with
medical protocols such as cervical disease. In Japan where PDT (QLT’s Photofrin™) has been
PDT. This may causal to the approved for the treatment of such conditions, the benefits of PDT is
socio-cultural bias of Japanese well recognized – in part due to a cultural bias against mutilation or
people against physical other invasions of the physical being/body. Approximately 21,000
invasion of the body, as with Japanese women are diagnosed with either cervical cancer or cervical
the employment of invasive
dysplasia (a pre-cancerous condition) every year. Unlike surgery,
surgical procedures in the
treatment of medical
treatment with PDT does not eliminate the ability to conceive or carry a
conditions of any type. baby to full-term.

Ophthalmology: (AMD)
(Age-related Macular Degeneration)
Currently the most closely watched
area within PDT is the treatment of Estimated Annual Market @US$1.75 Billion
Age-related Macular Degeneration –
Diseases of the eye caused by abnormal blood vessels and rapidly
the leading cause of blindness
amongst people aged 50 years or growing cells constitute a major health problem. AMD, diabetic
greater. retinopathy, glaucoma, secondary cataracts, neovascularization of the
cornea and iris, as well as intraocular tumors all have potentially serious
health consequences, with implications for a person’s ability to remain in
the workforce or in an independent living environment. AMD alone is
The only alternative treatment the leading cause of blindness in the elderly and may affect more than
currently available is hot laser 1.5% of the population over the age of 50 years. Some 200,000 new
photocoagulation. Collateral
cases are diagnosed annually in North America alone with
damage associated with this
additional 300,000 cases occurring worldwide. Although wet AMD
procedure in that not only is the
blood vessel sealed but the cells (degeneration due to leaking blood vessels) represents an estimated
immediately in the region are also 15% of all AMD cases, it accounts for 90% of severe vision loss
destroyed. This net result leaves associated with the disease. These estimates are expected to increase
the patient permanently blind at the dramatically as the baby boom generation ages.
location where the bleeding was
stemmed. Clinical trials just completed found that patients who underwent QLT’s
verteporfin therapy were more likely to have stable or improved vision
after 12 months than were people who received placebo injections
containing no medicine. These findings are based on results from 609
patients at 22 different medical centers. Overall, patients who received
PDT is the leading competing the therapy were 34% more likely to have stable or improved vision than
technology to redress this the placebo-treated patients, and the treatment appears to cause few
debilitating condition.
side effects. QLT’s second generation photosensitizer has the additional
advantage in that the post-treatment sensitivity to light is quite limited;
the patient is asked to avoid direct exposure to sunlight for a 24-hour
period. This contrasts sharply with historic therapies that left patients
sensitive to sunlight for as long as six weeks. Existing therapies are very
limited in their effectiveness and can lead to further vision loss insofar as
some form of collateral cellular destruction accompanies cauterization of
the leaking vessels.
Among those patients with AMD receiving QLT’s therapy, 16%
experienced improvement in vision of one or more lines on a standard
eye chart compared to 7% for patients receiving placebo. Statistically
significant results on the combined data favoring Visudyne™ therapy
were also obtained for all secondary test endpoints, including contrast
sensitivity and lesion growth. Results also showed that Visudyne
therapy was well tolerated, with less than 2% of patients withdrawing
from the study due to adverse effects.

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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

Phase III studies demonstrated that, with re-treatment, the effects of


Visudyne therapy can be sustained for at least one year. Patients in the
study received an average of 3.4 treatments during the 12-month
period. A comprehensive analysis of the 12-month results of the TAP
study is currently under way and is expected to be submitted to a peer-
reviewed medical journal.
PDT therapy can be administered in doctors’ offices and takes only
minutes for delivery. There were 1.8 million office visits due to AMD in
the 1997-98 reporting year, creating a large pool of AMD patients
already in the care of ophthalmologists. Ophthalmologists frequently
utilize laser-based therapies in their medical practice and therefore are
pre-adapted to learning PhotoDynamic therapy.

Lung Cancer
Estimated Annual Market @US$80 Million

PhotoDynamic therapy can be used to treat cancer at various stages of


progression. As a palliative treatment for inpatients with advanced
disease PDT offers symptomatic relief and an improved quality of life by
The FDA approved PDT in debulking large advanced tumors which, in the case of lung cancer,
September 1998 for the
might obstruct an airway. In addition, PDT may be used as a curative
treatment of early stage lung
cancer. This is the first
treatment in early-stage localized lung cancer by destroying the entire
approval for the use of PDT as a tumor. Approximately 180,000 Americans are diagnosed annually
‘curative’ treatment. with lung cancer and that comprises nearly 15% of all new
cancer cases. While 41% of patients survive the first year, failure to
detect lung cancer early in its course contributes to a five-year survival
rate of only 14%. Based on data demonstrating a 75% complete
response rate and other ongoing studies, the FDA approved and
delivered marketing clearance to porfimer sodium for injection to include
palliative treatment for late-stage obstructive lung cancer patients this
past December 23, 1998. Nineteen ninety eight brought FDA approval of
PDT curative treatment of early stage lung cancer – a hallmark in the
evolution of this technology in that this was the first ever approval of
PDT as a “curative” protocol and not merely a symptomatic treatment
procedure.

Autoimmune Disease:
(Psoriasis, Rheumatoid Arthritis, Organ Transplant Rejection)
Estimated Annual Market @US$715 Million

To ensure that all Approximately 5% of adults suffer from autoimmune disorders in


manifestations of cancer which the body’s immune system attacks its own cells. Symptoms range
have been redressed, PDT from moderate irritation and associated pain to life threatening and fatal
investigators are seeking conditions. To date there are no cures for these diseases and existing
answers in the direction of therapies are limited to alleviating symptoms. Several competitors are
selective autoimmune exploring the innovative approach to treating autoimmune conditions
PhotoDynamic therapy. with PDT (verteporfin and 3rd generation photosynthesizers) which
involves injecting the patient with a photosynthesizer and then
subjecting the entire body to illumination (similar to a sun tanning bed)
with the drug’s complementary light and wavelength. In this application
PDT treatment selectively inactivates the Langerhans cells of the affected
patient's immune system, eliminating general immunosuppression
caused by many of the current treatments. Because immune system
cells travel throughout the entire body, the treatment produces a

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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

systemic effect. Other prospective skin tissue applications for this


Autoimmune disorders may be treatment protocol includes skin grafting. Recent work, in vitro with
treated by a modulation of PDT as mice, demonstrates that skin grafts treated with verteporfin survive
it is possible to use the
three times longer than those grafts that are not exposed to light.
photosensitizer to selectively
downgrade or impair part of the Currently extensive pre-clinical research is being conducted in a number
immune system called of venues on prospective target conditions, including lupus, multiple
Langerhans cells. That, in turn, sclerosis, transplantation, psoriasis and arthritis.
dampens down the inflammation
that leads to the development of Safety and proof of concept are being assessed in Phase I clinical trials
psoriasis. using verteporfin to treat psoriatic and rheumatoid arthritis with new
results forthcoming. In the case of psoriatic plaque, treatment with
verteporfin has demonstrated substantial retrenchment of the plaque.

Breast Cancer
Estimated Annual Market @US$50 Million

There were an estimated 180,000 new invasive cases of breast cancer


among women in the United States during 1998. Among men, 1600 new
cases were diagnosed in the same period. After an accelerating rate
U.S. annual health care
expenditures will increase from increase of 4% during the 1980’s, breast cancer incidence rates in
US$1.0 Trillion in 1996 to US$2.1 women have leveled off to approximately 110 cases per
Trillion in 2007. 100,000. About 44,000 deaths correlated with breast cancer during
1998 (43,500 women, 400 men); in women breast cancer is the second
ranked cause of cancer death. In the United States about one woman
in eight is at risk of developing breast cancer, and 1 out of 28
women are at risk of dying of breast cancer. Earlier detection and
improved treatment seem to be effecting a noticeable decrease in
mortality rates (in the 1940s only 72% of women diagnosed with breast
cancer survived for five years. Currently the five year survival rate for
localized breast cancer has increased to 97%).

PDT treatment of breast PDT investigations currently underway and in clinicals are focused on
cancer in women is metastasized breast cancer treatment modality that is immunotherapy in
complicated by the nature of concept. Cancer immunotherapy treatment is intended to produce
the cancer in that it typically tumor tissue destruction in the primary area of treatment. An important
evolves in small hard to detect distinction of cancer immunotherapy (echoed in the autoimmune disease
nodes, and possibly in more treatment protocols discussed above) is that this therapy is also intended
than one location. If detected to trigger an autoimmune reaction in the patient to complete the
early, the procedure is
destruction of the primary tumor and to concomitantly destroy any
relatively straightforward.
metastases. This approach is predicated on the appreciation that long-
term control or elimination of cancer of necessity requires the utilization
of the patient’s own immune surveillance and defense systems. An
optimal cancer treatment would be one that fully restores and stimulates
the body’s own immunobiological response to the growth of malignant
cells. PhotoDynamic therapy as in the treatment of both a metastasized
tumor and the collateral stimulation of the autoimmune system describes
some of the current efforts underway under the rubric of PDT
investigative work and associated clinicals. Pre-clinical work engaging a
photothermal response at the infrared end of the spectrum has gained
support from the FDA for the development of clinical plans to determine
an optimal approach to test the efficacy of the procedure.
Current aggressive treatments to mitigate metastic breast cancer include
the controversial bone marrow transplant procedure. This procedure
costs US$60,000 today, down from US$140,000 in 1990. PhotoDynamic
Therapy expenditures are likely to come in at less than an order of
magnitude lower; less than US$6,000.
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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

Cardiovascular Disease
Estimated Annual Market @US$3.5Billion
The coronary arteries supply a constant flow of oxygen-rich blood to the
heart, which pumps some 2000 gallons of blood throughout the body
each day. Arteriosclerosis results from the accumulation of cholesterol,
macrophages, and smooth muscle cells in the walls of blood vessels.
This often results in the narrowing of the lumen and reduction of blood
flow. In coronary arteries (vessels that supply the heart with blood),
arteriosclerosis can result in angina or heart attack. In the
Restenosis, or the
rehardening of arteries
cerebrovascular circulation (arteries supplying blood to the brain) such
post angioplasty, is an blockage can result in stroke. In the peripheral circulation (arteries
ideal condition to be supplying blood to the legs) atherosclerosis can result in ischemia
treated with PDT. leading to decreased function and ultimately loss of limbs. Currently,
atherosclerosis is treated with medical therapy, surgery or endovascular
Current advanced work procedures such as balloon angioplasty. In the U.S. some 600,000
demonstrates the ability of patients annually undergo coronary angioplasty to open or
the cells lining the interior remedy closed arteries due to accumulation of plaque on the inside walls
of the vascular wall to
of their arteries. Additionally another 150,000 such procedures are
recover their plasticity
consequently permitting
performed in the lower extremities. Typically 50% of all patients suffer
the conduit to function restenosis within six months of angioplasty treatments. Restenosis is the
normally. reclosing of blood vessels so treated. Clearly such reclosing or reversal
of the condition is a potentially life threatening condition for those so
afflicted. PhotoDynamic Therapy in the form of photoangioplasty holds
great promise due to the ability to deliver both photosensitizing drug and
light source to the typically local trouble focal point. In addition
photoangioplasty is a procedure which permits the flow of blood to
continue during the application, unlike the more traditional forms of
angioplasty. Drawing on the experience with the successful treatment of
psoriatic plaque on skin surfaces, current efforts are underway to further
develop therapeutic applications for reduction of atherosclerosis or
arterial restenosis utilizing the localized delivery of PhotoDynamic
therapy.

Cosmetic Applications
Estimated Annual Market@US$1.5 Billion
Hair removal and acne treatment have emerged as two secondary order
PDT is proving to find
applications from the research currently underway in a variety of sites
direct commercial and under a broad range of investigative protocols; all under the
cosmetology in treating: umbrella of PhotoDynamic technology application.
• Acne
PDT application for the removal of unwanted hair employing a
• Unwanted hair
• Surface psoriasis
photosensitive 5-ALA agent activated by laser generated light has
produced results to the extent that about 30% of the targeted hair was
prevented from regrowing after a one treatment application.
Similarly, small localized fluorescence employing 5-ALA, based on historic
knowledge of ALA activity in sebaceous (oil) glands, activated by a non-
laser red light achieved success in destroying the bacteria responsible for
acne lesions.
By extension, it is reasonable to intuit that PDT may find purchase as in
the treatment of a variety of indications that are medical in nature and of
serious cosmetic concern. The general utility of the treatment, its
viability as an outpatient protocol and the very fact of its non-toxic
repeatability and potential cost effectiveness may very well create a

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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

market for PhotoDynamic treatment of such fundamental cosmetic


applications as hair removal and acne.

PDT Effects on Dye-Fed Insects


Estimated Annual Market@US$3 Billion
Light activated dyes as insecticides or pesticides that target insects could
prove to be an untapped market and undeveloped application.
Radical and early research
investigations claim the Preliminary studies conducted during the 1970s demonstrated PDT’s
prospect of adding potential as an insecticide technology. The experimental procedure
insecticide/pesticide treatment entailed feeding flies (musca domestica) on a solution of milk sugar with
application market. various concentrations of 7 distinct dyes. After a dark period some flies
were exposed to natural light, some to artificial light and the balance
The primary hurdle centers on remained in the dark. The results showed very little mortality in those
the problem of ensuring that insects fed dyes but not exposed to light. There was 100% mortality
the procedure affects ONLY
observed with three of these dyes after an exposure of 1-3 hours in
the target organism class and
natural or artificial light. While this avenue is clearly in its infancy and
not affects any other life
forms. there remain many hurdles to overcome, not the least of which includes
species selectivity issues, this result set indicates a potentially vibrant
market for PhotoDynamic application technology. The target level for
PDT of the insecticide market may be upwards of 5-10% share of the
total insecticide market, yielding a potential US$3 billion dollar market at
the user end. Additional target treatment arenas could include diseases
such Lyme and Rocky Mountain Spotted Fever where the treatment
could preclude the necessity to find the exact location where the insect
has attached to the human host.

Clinical Competitive Landscape

The table below describes the PDT clinical investigative landscape


correlating drug, technicals, applications and companies.
Photosensitizers in clinical proving programs include:
 Hematoporphyrin derivative (HpD), investigated in the “ear, nose and
throat” (ENT), the esophagus, and the tracheo-bronchial tree.
 Photofrin II, investigating the ENT tract, the esophagus and the tracheo-
bronchial tree.
 Meso-tetra (hydroxyphenyl)-chlorin (mTHPC); the ENT tract, the
esophagus and the tracheo-bronchial tree.
 Aminolevulinic acid (ALA)-mediated porphyrins (PPIX), - the urinary tract
and bladder, stomach, and skin.
 Monoclonal antibody (Mab)-dye conjugates, - colon and rectum.
 Zinc Phthalocyabnine (ZnPC) in liposomes – oral cavity.
 Benzoporphyrine derivative (BPD-MA) (Verteporfin) – ophthalmology.

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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

Photophysical data on 1st and 2nd generation PDT photosensitizers


currently under investigation
Drug Light
Lambda Treatment
Compound /mg Dose Diseases Treated Company
/nm /timez/s
kg-1 J cm-2
Haemotoporphoryn 628 1.5-5 75-250 750-2500 Early stage treatment of QLT/Sanofi-Winthrop
(HpD-Photofrin™ – (3.0X103) esophagus, bladder, lung, (Photofrin),
Photosan™) cervix, stomach and mouth Seehof (Photosan)
cancers. Palliative in later FDA Approved
stages
ALA (converted to 635 60 50-150 500-1500 Skin, stomach, colon, DUSA
Protoporfhytin IX) (5.0X103) bladder, mouth cancers. In clinical trials
Also various non-malignant
skin conditions
Benzoporphyrin 690 4 50 1500 Age-related Macular QLT – Phase III
derivative – (BpD – (3.5X104) Degeneration (AMD) Submission 1999
Verteporfin™)
Tin etiopurpurin 665 1.2 150-200 1500-2000 Breast and Skin cancers, Miravant
(SnET2– Purlytin™) (3.0X104) AMD Phase II/III trials
Monoaspartyl 660 1.0 25-200 1500 Skin Cancers Meija Seika
Chlorine (MACE) (4.0X104)
Lutetium 732 1.0 150 1500 Metastic brain tumors, Pharmacyclics Phase I/II
texaphyrin (Lu-Tex) (4.2X104) breast cancers,
atherosclerotic plaques
Aluminum 675 1.0 50-200 1500 Brain, colon, bladder and AIPcS2 used by Russian
disulphonate (2.0X105) pancreatic cancers. Head Labs
phthalocyanin and neck cancers in animal
(Photosene™) studies only.
Metatelrahydroxych 652 0.15 5-20 50-200 Head, neck, prostrate, Scotia Quantanova
olin(mTHPC (3.5X104) pancreas, lung, brain, biliary Phase III trials
– temoporfin – tract, and mouth cancers;
Foscan™) superior to HpD and ALA in
mouth cancers.
Chemistry in Britain November 3, 1998
All values are solvent dependant and apply only to monomeric forms.
z
At 100 mW cm-2, it takes 1000s to deliver 100 Jcm-2 light dose.

Investment Landscape
Non-pure play – Large pharmaceutical distribution and
marketing partners
Non-pure play: Established pharmaceutical giants have paired up with small research
Large biopharmaceuticals
and development biotechnology companies to keep pace with developing
engaged in marketing and
distribution
technologies in the unfolding noninvasive photosensitizer marketplace.
These include Novartis – CIBA Vision, Pharmacia – UpJohn, Sanofi
– Winthrop, Glaxo-Wellcome, American Home Products –
Cyanamid - Lerdele, Ligand, Hoechst-Celanese, and Beaufour
Ipsen. While it can be taken as a given that there may be some original
R&D taking place within these companies, only and Nippon
Petrochemicals seem to be actively engaged in original drug candidate
research. Mostly these multi-national pharmaceutical giants are taking
the deal making approach where they provide financing and/or
marketing distribution expertise and services on a royalty arrangement
with the biotechnology company. As for vehicles for equity investment,
none of the of the world’s leading pharmaceutical companies offers a

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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

“pure play” in the PDT market. PhotoDynamic Therapy applications


represent a small but non-trivial component in a much larger integrated
and diversified organization.
Niche Contenders
Research and Development
A number of companies developing various PDT technologies have
Pure-play: targeted applications in the market arenas identified above. Of these,
Biotechnology companies several are contenders along similar drug candidate lines employing the
engaged in original research and same basic singlet photon excitation technology. Of these QLT
development PhotoTherapeutics, Inc. (QLTI) has the clear lead with the 1995 FDA
approval for its first generation drug in 1995 and currently has a two-to-
three year lead in the treatment of wet-AMD employing its second
generation photosynthesizer - verteporfin, with FDA approvals expected
by early 2000. Miravant Medical Technologies (MRVT) has
refocused its efforts at the AMD market with a refinancing deal with its
partner Pharmacia – UpJohn that has provided the required up-front
financial and clinical studies support. Miravant has also extended
financial and intellectual cooperation to Ramus Medical Technologies,
a private company which may further Miravant’s efforts in the area of
cardiovascular applications, and Xillix Technologies Corporation
(XLX CN), a Canadian company specializing in fluorescence endoscopy
imaging devices. DUSA Pharmaceuticals Inc. (DUSA) is a
pharmaceutical company developing PhotoDynamic therapy and
photodetection by way of employing 5-aminolevulinic acid (5-ALA) with
regard to certain diseases such as actinic keratoses (pre-cancerous skin
lesions), acne and psoriasis. DUSA has cooperative agreements with
Richard Wolf Medical Instruments Corporation a worldwide private
firm based in Germany, specializing in endoscopy and National
Biological Corporation, a U.S. based corporation which manufactures
light therapy equipment for professional and home use. Bausch &
Lomb (BOL) has dedicated its research and development team to attend
to the AMD market and is currently in Phase I trials for a drug delivery
system entitled Vitraset™, to treat all forms of age-related macular
degeneration. The Company has indicated that they expect the AMD
market to equal that of glaucoma treatments which currently is
estimated at about 25% of the overall eye disease treatment
marketplace of about $3.5 billion annually. Bausch & Lomb expects that
by 2004, the diseases of then eye market will exceed $4.5 billion, with
AMD treatment market exceeding $1.2 billion. Pharmacyclics Inc.
(PCYC) is focused on the development of energy-potentiating drugs to
enable/improve PhotoDynamic therapy for use in oncology and
cardiovascular disease applications. PCYC has an agreements with
HOECHST Celanese Corporation, Nycomed Pharma SA, E-Z-EM
Inc., and Alcon Laboratories (a subsidiary of NESTLE
Corporation) for process optimization, manufacture, and supply of the
company’s products including its proprietary texaphyrin-based products.
Procept Inc. (PRCT) is a biopharmaceutical company (its investigation
of PhotoDynamic therapeutics was greatly enhanced by its merger in
March 1999 with Pacific Pharmaceuticals and BG Development
Corp.). Together this group has three candidates for cancer therapy on
a FDA fast-track regulatory approval, of which one is boronated
protoporphyrin compound for use in PhotoDynamic therapy.
Theratechnologies Inc. (TH-CN) is a biotechnology company which
core research includes PDT treatments of cancers affecting bone marrow
(PDT) and Growth Hormone-releasing Factor (GRF) analogues for tissue
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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

regeneration and other indications. AzurTec Inc., a private U.S.


company, is exploring PDT applications employing the dye, toluidine blue
O, which is currently employed primarily in the detection of squamous
cell carcinoma. Currently, the only pharmaceutical grade producer for
toluidine blue O is Zila Inc. (ZILA), which is in the final stages of
gaining FDA approval for its oral cancer diagnostic ORATEST™, a
PhotoDynamic diagnostic tool relying on the dye’s photochemical
properties. Scotia QuantaNova, a division of Scotia
Pharmaceuticals (Canada) Ltd., a wholly owned subsidiary of Scotia
Holdings (SQ –FTSE) of the United Kingdom, is focused on the
development of PDT with its lead proprietary drug FOSCAN™, rooted in
the company’s historic concentrated development of lipids technology.
Photogen Technologies, Inc. (PHGN) is another niche contender
that is exploring a technology that differs from the rest; one based on a
two-photon excitation approach. It also differs from rest of the pack by
virtue of its interest in detection, as well as therapy, applications.
Drug Contract
PhotoDynamic Therapy and Detection as a drug-device combination
Ancillary play: protocol require the production facilities of pharmaceutical drug
Chemical compound manufacturing manufacturers capable of delivering a FDA quality grade pharmaceutical
companies serving the PDT sector drug or dye with which to carry out the intended procedures. Currently
there are a number of drug manufacturers engaged in contractual
arrangements with companies developing PDT drug candidates.
American Home Products of Puerto Rico, a division of American
Home Products Corporation, is manufacturing Porphyrin for QLT
PhotoTherapeutics, Inc. King Pharmaceuticals Inc. (KING) of
Tennessee has just negotiated a contract between its subsidiary,
Parkedale Pharmaceuticals of Michigan, and QLT PhotoTherapeutics, Inc.
to manufacture the finished lyophilized product in the production of
Visudyne for use in the treatment of AMD. Both Nippon Fine
Chemicals of Japan and Laporte Fine Chemicals of Germany are
supplying intermediate ingredients in the manufacture of Visudyne from
their North American subsidiaries. Pharmacia-Upjohn is the
manufacturer for Miravant’s SnET2 photosynthesizer.

Light Device
Therapy takes advantage of dye/drug phototoxicity and selectivity by
irradiating the suspect area with excitation light that induces the dye
Secondary partner play:
fluorescence. This technique depends on matching up wavelength with
Light delivery device manufacturers drug/dye and designing and developing the delivery mechanism. Both
“light amplification by stimulated emission of radiation” (laser) and non-
laser light excitation generators are employed. Determining the
potentiality of this device aspect of the PDT technology is the province
on the niche device developers and manufacturers. Of these Coherent,
Inc. (COHR) designs, manufactures and sells lasers, laser systems and
related accessories directly for the medical invasive, remedial and
cosmetic markets. Laserscope (LSCP), another specialty designer
and manufacturer is directly involved in developing and building
procedure and treatment lights and conveyance equipment, especially
for the PDT market. LSCP and COHR both received FDA approval in
1998 for their PDT LASER Systems for use with QLT’s Photofrin for
treatment in early-stage lung cancer and for late stage esophageal
cancer. LumaCare, a private company based in the U.K. has patented
technologies on non-coherent light sources for use at part of a PDT
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Light-activated Medicine - PhotoDynamic Therapy (PDT) February 2005

protocol. Rare Earth Medical, Inc., another private concern, has


patented a fiber optic light diffuser (Lightstic) and has partnered with
Laserscope (LSCP) to supply this growing PDT market. DIOMED
LTD., (headquartered in Cambridge, UK) specializes in diode laser
technology and has developed a lightweight, portable, and user-friendly
device that generates a non-thermal laser light for use in PDT. Diomed
was the first to demonstrate, against much resistance, and gain approval
for a device that could excite Photofrin at 630 Lambda. Light Sciences
LP, a private company headquartered in the U.S., is developing a novel
light delivery system for multitreatment extended-duration
PhotoDynamic therapy. Light Sciences innovative approach seeks to
extend both the reach of conventional PDT and the extent of the tumor
size that PDT currently undertakes to treat. MedLight SA, a Swiss-
based optics, light and endoscopic manufacturer specializes in delivering
the appropriate wavelength to the required local and depth. ESC
Medical Systems LTD. (ESCMF), develops, manufactures and markets
medical devices utilizing their proprietary intense pulsed light source
technology for use in non-invasive treatment protocols, including the
treatment of vascular lesions and other clinical applications. Medac
GmbH, Rüsch GmbH, and Zeiss GmbH all have light delivery devices,
laser applications for use in PhotoDynamic Therapy. Rüsch is currently
undergoing clinical testing for two approaches; one with a
homogeneous, cylindrical laser beam for use in cylindrical hollow organs
such as the bronchi, and another for the illumination of a spherical
hollow organ such as the bladder, where a double-balloon system is
deployed.

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