Progenics Pharmaceuticals Annual Report 2004

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FY2004 Annual Report · Progenics Pharmaceuticals

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Safe Harbor Statement

This annual report contains forward-looking statements that involves

risks and uncertainties . Any statements contained herein that are not

statements of historical fact may be forward-looking statements. When

the Company uses the words ‘anticipates,’ ‘plans,’ ‘expects’ and similar

expressions they are identifying forward-looking statements. Such for-

ward-looking statements involve risks and uncertainties which may cause

the Company’s actual results, performance or achievements to be materi-

ally different from those expressed or implied by forward-looking state-

ments. Such factors include, among others, the uncertainties associated

with product development, the risk that clinical trials will not commence

when or proceed as planned, the risks and uncertainties associated with

dependence upon the actions of the Company’s corporate, academic and

other collaborators and of government regulatory agencies ,the risk that

our licenses to intellectual property may be terminated due to our failure

to have satisfied performance milestones, the risk that products that

appear promising in early clinical trials do not demonstrate efficacy in

larger-scale clinical trials ,the risk that we may not be able to manufacture

commercial quantities of our products, the uncertainty of future profitabil-

ity and other factors set forth more fully in the Company’s Form 10-K for

the fiscal year ended December 31, 2004 and other periodic filings with

the Securities and Exchange Commission to which investors are referred

for further information. In particular, the Company cannot assure you that

any of its programs will result in a commercial product. The Company does

not have a policy of updating or revising forward-looking statements,

and thus it should not be assumed that the Company’s silence over time

means that actual events are bearing out as expressed or implied in

such forward-looking statements.

777 Old Saw Mill Road

Tarrytown, New York 10591

Phone: 914-789-2800

Fax: 914-789-2817

E-mail: info@progenics.com

Website: www.progenics.com

to live better

2004 Annual Report

Product Development Pipeline

PRE-CLINICAL

PHASE 1

PHASE 2

PHASE 3

Evaluation of tolerability
and pharmacology

Evaluation of tolerability,
dosing and activity

Larger scale evaluation
of safety and efficacy

Symptom Management
& Supportive Care

MNTX – opioid-induced

side effects in patients with:

Advanced medical illness

Post-operative

bowel dysfunction

Chronic pain

HIV Infection

PRO 542

PRO 140

ProVax

Cancer

PSMA

(prostate and other cancers)

Vaccines

Recombinant protein

Viral vector

Monoclonal antibody

GMK (melanoma)

Progenics Pharmaceuticals, Inc. is a biopharmaceutical company focusing
on the development and commercialization of innovative therapeutic
products to treat the unmet medical needs of patients with debilitating
conditions and life-threatening diseases. Our principal programs are
directed toward symptom management and supportive care and the
treatment of HIV infection and cancer. We have five product candidates
in clinical development and several others in preclinical development.

A Message from the CEO

Dear Shareholders:

Paul J. Maddon, M.D., Ph.D., Founder, Chief Executive Officer

and Chief Science Officer

During the last 12 months, Progenics Pharmaceuticals
reached a major milestone – we realized positive
results in a pivotal phase 3 clinical trial of our lead
product candidate, methylnaltrexone (MNTX) for the
treatment of opioid-induced constipation. In addition,
we established phase 2 proof-of-concept for the use
of MNTX in managing post-operative bowel dysfunc-
tion and successfully advanced oral MNTX through
initial human studies. These achievements come only
three-and-a-half years after in-licensing this com-
pound from academic researchers.

In the area of HIV therapy, we leveraged our research
discoveries in the mechanisms of viral entry into a
promising product candidate. We advanced the inves-
tigational drug PRO 140 into human testing. We also
made significant progress in the laboratory in devel-
oping a vaccine that may prevent HIV infection.

Preliminary results from a clinical study of a therapeu-
tic prostate cancer vaccine have also shown promise.

Last year’s major accomplishments include:

MNTX

o We reported top-line results from a phase 3 clinical trial of
MNTX for the treatment of opioid-induced constipation in

patients with advanced medical illness (AMI). MNTX induced

laxation (bowel movement) within four hours at more than

four times the rate of placebo. On average, laxation occurred

within about one hour in the MNTX-treated patients. These

results were highly statistically significant, and the drug was

generally well tolerated in this study.

o We also announced positive top-line results from a

phase 2 clinical trial of MNTX for the management of post-

operative bowel dysfunction. Patients who received MNTX

following colectomy surgery, the removal of a portion of the

colon, exhibited an acceleration of gastrointestinal recovery

by approximately one day on average compared to placebo.

Significant improvements were seen in clinically important

measures of gastrointestinal recovery: time to first bowel

movement and discharge eligibility from the hospital. MNTX

was generally well tolerated in this study, with no reports of

serious adverse events related to the drug.

o We completed phase 1 clinical trials of oral formulations of
MNTX. Analysis of data from healthy volunteers, who

THE YEAR AHEAD

MNTX

received MNTX at three dose levels, indicated that the drug

was well tolerated and exhibited predictable

o We anticipate completing the enrollment and data analysis
of our second phase 3 pivotal clinical study of MNTX for the

pharmacokinetics.

HIV

o We initiated phase 1 clinical trials of a new HIV therapy – a
humanized monoclonal antibody to block infection by

treatment of opioid-induced constipation in patients with

AMI and expect to file a New Drug Application with the Food

and Drug Administration (FDA) for this indication.

o After meeting with the FDA, we intend to initiate a phase 3

inhibiting the ability of the virus to enter healthy cells. PRO

clinical program of MNTX in post-operative bowel

140 is a viral-entry inhibitor that is designed to prevent HIV

dysfunction.

from gaining access to cells of the immune system. Unlike

currently approved therapies, PRO 140 blocks the CCR5 co-

receptor, one of the principal portals HIV uses to enter cells.

o In animal testing, our HIV vaccine candidate, ProVax, stimu-
lated the production of specific anti-HIV antibodies. When

tested in the laboratory, these antibodies inactivated certain

strains of HIV isolated from HIV infected patients. The vac-

o We are also preparing to initiate a phase 2 trial of an oral
formulation of MNTX for opioid-induced constipation in

chronic pain patients.

o To maximize the commercial potential of MNTX, we are
working towards completing a collaboration with one or

more potential partners.

cine-elicited antibodies rendering the virus non-infectious, a

HIV

critical step in preventing the establishment of HIV infection

o PRO 542, which is designed to block HIV attachment to

after initial exposure.

PSMA

o We were awarded grants totaling $8.0 million over four years
from the National Institutes of Health to develop novel

immune system cells, is expected to complete a multi-dose

phase 2 clinical study. We plan to review these results from

this study with the intent of making a decision regarding the

ongoing feasibility of the program.

immunotherapies for prostate cancer based on prostate-spe-

o PRO 140, an inhibitor of HIV binding to the CCR5 receptor,

cific membrane antigen (PSMA), a promising cancer target.

is scheduled to complete phase 1 studies, and we plan to

One grant for $3.8 million was awarded to fund the develop-

initiate a first-in-HIV clinical study.

ment and clinical testing of a fully human monoclonal anti-

body directed to PSMA for the treatment of metastatic

prostate cancer. An additional grant for $3.6 million was

awarded to fund the continued development of a recombi-

nant soluble PSMA vaccine. The vaccine is designed to enable

a patient’s immune system to recognize prostate cancer cells

as foreign and to eliminate them. Finally, a third grant for

PSMA

o We will complete a phase 1 clinical trial of a novel recom-
binant soluble vaccine that targets PSMA. We have com-

pleted preclinical testing of a PSMA viral-vector vaccine

and monoclonal antibody and will start phase 1 studies of

these product candidates.

$0.6 million was awarded to fund continued development of

We at Progenics Pharmaceuticals are grateful to our loyal share-

PSMA-targeted immunotoxins.

o Our joint-venture, PSMA Development Company LLC,

announced that its recombinant soluble PSMA vaccine gener-

ated potent immune responses that recognized human

prostate cancer cells in preclinical animal testing. The phase 1

clinical trial of this therapeutic vaccine is designed to evaluate

its tolerability and immune-stimulating properties. Preliminary

findings showed that certain prostate cancer patients pro-

duced anti-PSMA antibodies in response to the vaccine.

holders who share our vision of building a biopharmaceutical com-

pany that develops innovative therapies for major unmet medical

needs. We also thank the thousands of patients, physicians and

healthcare workers who participated in our clinical trials. In the

coming year, we pledge to continue to work diligently toward our

goal of commercializing our first product and to advance promis-

ing new product candidates through the development process.

Paul J. Maddon

Paul J. Maddon, M.D., Ph.D., Founder, CEO, and CSO

April 2005

Page 2

Page 3

Advanced
Medical Illness

Why do opioid pain relievers
cause side effects?

Narcotic medications such as morphine,

codeine and others are the mainstay in

controlling severe pain. We estimate that

180 million prescriptions for opioids are

written annually in the U.S. Opioids relieve

pain by interacting with receptors that are

located in the central nervous system.

However, opioids also activate receptors

outside the central nervous system, result-

Symptom management and supportive care

Our lead product candidate is methylnaltrexone (MNTX), an investigational drug

in pivotal phase 3 clinical testing. MNTX is designed to reverse the debilitating side

effects of opioid pain medications while maintaining pain relief, an important need

not currently met by any approved drugs. We are conducting clinical development

programs in three different settings: advanced medical illness, post-operative bowel

dysfunction, and chronic pain.

Advanced medical illness We are developing MNTX for the treatment of opi-
oid-induced constipation in patients with advanced medical illness (AMI), including

cancer, AIDS and heart disease. Approximately 1.0 million deaths occur each year in

the U.S. from AMI. Most of these patients receive opioids for pain at the end of life

and suffer debilitating constipation.

We have completed the first of two multi-center, double blind, randomized,

placebo-controlled phase 3 clinical studies of MNTX for the treatment of opioid-

induced constipation in patients with AMI. The results from this study were highly

statistically significant and support our efforts to develop MNTX as a drug to restore

bowel function in these patients. We are grateful to the patients and families who

allowed us to conduct this important study in their homes, the location where most

hospice patients are treated.

For this clinical trial, we enrolled 154 patients with a life expectancy of less than

six months and a history of opioid-induced constipation despite the use of laxative

and stool softeners. The primary efficacy endpoint of the study was whether a single

subcutaneous dose of MNTX induced laxation within four hours. On average, approx-

ing, in many cases, in undesirable side

imately 60% of patients receiving either of the two blinded doses of MNTX were

effects, including constipation, delayed

able to laxate within four hours, whereas only 13% of the placebo group responded

For terminally ill patients, debilitating

constipation is often a consequence
of their pain medications.

gastric emptying, nausea and vomiting,

itching and urinary retention. Current

treatment options for opioid-induced con-

stipation include laxatives and stool sof-

teners, which are only minimally effective.

As a result, many patients may have to stop

opioid therapy and endure pain in order to

obtain relief from opioid-induced constipa-

tion and other side effects.

during this time period. Median time to laxation varied between 45 minutes to 70

minutes, depending on the dose level of MNTX. Median time for the placebo group

was greater than 24 hours. Preliminary safety information from this study showed

that MNTX was generally well tolerated. The most frequent adverse events reported

included transient abdominal cramping and flatulence, both of which are necessary

physiological prerequisites to a bowel movement in patients with severe constipation.

We are conducting a second pivotal phase 3 clinical trial of MNTX in AMI that is

designed to measure the ability of MNTX to induce laxation within four hours and to

evaluate its ability to restore patients to a normal bowel schedule of three or more

laxations per week. Approximately 130 patients will receive study medication every

other day for two weeks at hospice centers in the U.S. and Canada. We expect to

complete enrollment of this second pivotal phase 3 trial in mid-2005, and announce

results in the second half of 2005.

If the results of our phase 3 clinical trial program of MNTX are sufficiently com-

pelling, we could submit to the FDA an New Drug Application for MNTX as early as

the end of 2005. We expect that the FDA would take between six and ten months to

act on our application, and that we could, therefore, receive marketing approval as

early as 2006.

Page 5

MNTX is being studied in hospice patients

with opioid-induced constipation.

“Opioid-induced constipation

“Patients on opioid pain thera-

“The ability to provide timely

causes severe suffering for

py often experience severe side-

treatment for opioid-induced

patients with advanced medical
illness who are receiving

effects, which can result in
invasive treatments, even hos-

constipation during periodic
home visits is an important

opioids for their pain.”

pitalization. Finding a solution

aspect of the supportive and

Jay R. Thomas, MD

Clinical Medical Director

San Diego Hospice

to this unmet medical need is

palliative care that hospice

important to the overall well-

nurses provide.”

being of hospice patients.”

Neal E. Slatkin, MD

Gail Austin Cooney, MD

Director

Medical Director

Department of Supportive Care,

Hospice of Palm Beach County

Pain and Palliative Medicine

City of Hope National Medical Center

Phase 3 primary efficacy endpoint: Laxation within 4 hrs

s
t
n
e
i
t
a
p
f
o
%

–––– Placebo ––––

–––– 0.15 mg/kg –––
MNTX
(p<0.0001)

–––– 0.30 mg/kg ––––
MNTX
(p<0.0001)

Post-operative bowel dysfunction

is a major factor of
prolonged hospital stay.

Post-operative
Bowel Dysfunction

Post-operative Bowel Dysfunction We are developing MNTX for the man-
agement of post-operative bowel dysfunction. Of the patients who undergo surgery

in the U.S. each year, approximately four million patients are at high risk for develop-

ing bowel dysfunction, a serious impairment of the gastrointestinal tract. Post-opera-

tive bowel dysfunction is caused by the release of endogenous opioids in response to

the trauma of surgery. The opioids patients receive for pain may also exacerbate the

problem. Bowel dysfunction is a major factor in increasing hospital stay, as patients

are typically not discharged until bowel function is restored.

We have completed a multi-center, double-blind, randomized, placebo-con-

trolled phase 2 clinical trial of MNTX in patients at risk for post-operative bowel dys-

function. The study was conducted in 65 patients who had undergone segmental

colectomies, which is the removal of a portion of the colon due to cancer or divertic-

ulitis. Patients who received MNTX exhibited an acceleration of gastrointestinal recov-

ery by approximately one day on average compared to placebo. Significant improve-

ments were seen in both time to first bowel movement and time to discharge eligibili-

ty from the hospital, both of which we believe are clinically important measures of

gastrointestinal recovery. MNTX was generally well tolerated in this study, with no

reports of serious adverse events related to MNTX. We plan to complete a more in-

depth analysis of the data and meet with the FDA in 2005 to discuss designing a

phase 3 clinical program.

Chronic Pain

How does MNTX work to
reverse side effects?

MNTX is designed to reverse certain side

effects associated with narcotic pain thera-

py by displacing opioids from binding sites

Chronic Pain We are developing MNTX for the treatment of constipation in
patients receiving opioids for chronic pain. More than 25 million patients in the U.S.

suffer from chronic pain, including those suffering from headaches, joint pain, lower-

back pain, sickle-cell disease, muscle pain and other disorders. Opioid pain relievers

are widely prescribed for these patients, many of whom suffer serious constipation as

a result despite the use of laxative and stool softeners. We have conducted two dou-

ble-blind, randomized phase 1 clinical studies of oral MNTX at three dose levels in a

total of 61 healthy volunteers. Analysis of data from these studies indicated that

on specific opioid receptors. As MNTX is

MNTX was well tolerated and exhibited predictable pharmacokinetics. In four clinical

not known to cross the blood-brain barrier

studies conducted previously by independent researchers, an oral form of MNTX

demonstrated activity against opioid side effects, including relief of opioid-induced

constipation. We plan to initiate phase 2 studies of oral MNTX in 2005 in chronic pain

patients who experience opioid-induced constipation.

in humans, it ‘‘turns off’’ the effects of opi-

oids outside the central nervous system,

including in the gastrointestinal tract,

while preserving opioid analgesic activity

within the central nervous system. To date,

patients treated with MNTX in addition to

opioid pain medications have reported no

impairment of pain relief and have experi-

enced a reversal of many of the side effects

related to opioids.

Page 9

MNTX is being evaluated for its ability to

improve patient recovery and accelerate
discharge after major abdominal surgery.

“Management of post-operative

bowel dysfunction is a major unmet

medical need. Clinical data from the

phase 2 trial supports the potential

of MNTX to shorten the period of

post-operative bowel dysfunction

following major bowel surgery and

reduce the length of hospital stay.

Ideally, post-operative patients

should not be discharged until they

have return of bowel function. In

my experience, there is no benefit

to allowing the gastrointestinal

tract to remain inactive after surgery
– the earlier the bowel becomes

active, recovery is accelerated and

the patient can be discharged from

the hospital sooner.”

Eugene R. Viscusi, M.D.

Director

Acute Pain Management Service

Thomas Jefferson University

Phase 2: MNTX accelerated each stage of
post-operative recovery by approximately one day

s
y
a
D

MTNX

Placebo

–––– Liquid Diet ––––

–––– Solid Food ––––

–––– Discharge ––––

Bowel Movement Eligible

HIV

What is the scope of the
AIDS crisis?

The Joint United Nations Program on HIV/AIDS

and the World Health Organization estimate that

39 million people worldwide were living with

HIV. In high-income countries, 1.6 million people

are infected, which includes an estimated

64,000 newly infected individuals. Of these 1.6

HIV entry inhibitors We are developing viral entry inhibitors that represent a potential
new class of drugs for HIV positive patients. HIV infection occurs when the virus binds to a host

cell, enters the cell, and by commandeering the cell’s own reproductive machinery, creates thou-

sands of copies of itself within the host cell.

Our scientists and their collaborators have made important discoveries in understanding

how HIV enters human cells and initiates viral replication. In the 1980s, our founders demon-

strated that the initial step of HIV infection involves the specific attachment of the virus to the

CD4 receptor on the surface of human immune system cells. In the 1990s, our scientists, in

collaboration with researchers at the Aaron Diamond AIDS Research Center, described the

discovery of a critical co-receptor for HIV on the surface of human immune system cells. This

co-receptor, CCR5, enables fusion of HIV with the cell membrane after binding of the virus to

the CD4 receptor. This fusion step results in entry of the viral genetic information into the cell

and subsequent viral replication.

Based on our pioneering research, we believe we are a leader in the discovery of viral-entry

million individuals, 1.0 million reside in North

inhibitors, a promising new class of HIV therapeutics. For the large number of patients who are

America. There were over three million deaths

failing conventional anti-retroviral or combination therapy, we believe viral-entry inhibitors

attributed to AIDS during 2004, of which 22,500

could become the next generation of therapy. We are pursuing several approaches in the

were from high-income countries.

research and development of products designed to block entry of HIV into human immune sys-

tem cells.

Why are new classes of therapy
needed for HIV?

Infection by the human immunodeficiency virus,

or HIV, causes a slowly progressing deterioration

of the immune system resulting in Acquired

Immune Deficiency Syndrome, or AIDS. HIV

specifically infects cells that have the CD4

receptor on their surface. Cells with the CD4

PRO 542 PRO 542 is our proprietary antibody-like product candidate that is designed to neu-
tralize HIV by preventing it from attaching to the CD4 receptor on the surface of immune sys-

tem cells. We are presently conducting a multi-dose, open-label phase 2 clinical study of PRO

542 in patients with advanced disease who are no longer responding to currently available anti-

retroviral medications. The goal of the study is to determine if repeat dosing can induce viral

load reductions in this setting. Viral load is the concentration of virus in the blood and is a widely

used indicator of infection levels. Reduction in viral load is a primary goal of HIV therapy. To

date, PRO 542 has been well tolerated. We expect to obtain results from our ongoing phase 2

clinical trial of PRO 542 in the second half of 2005.

receptor are critical components of the immune

system and include T lymphocytes, monocytes,

PRO 140 PRO 140 is a humanized monoclonal antibody designed to block the ability of HIV
to infect cells by inhibiting virus-cell binding. We have designed PRO 140 to target a distinct site

macrophages and dendritic cells. The devastat-

on CCR5 without interfering with the normal function of CCR5. We began phase 1 clinical trials

ing effects of HIV are largely due to the multipli-

in May 2004 to determine the tolerability, pharmacology and immunogenicity of PRO 140 in

cation of the virus in these cells, resulting in

healthy volunteers. We expect to complete these studies in mid-2005.

their dysfunction and destruction.

PRO 140 has shown promising activity in preclinical studies. In in vitro studies, PRO 140

At present, three classes of products have

demonstrated potent, broad-spectrum antiviral activity against more than 40 genetically diverse

received marketing approval from the FDA for

HIV viruses isolated directly from infected individuals. Single doses of a murine-based PRO 140

the treatment of HIV infection and AIDS: reverse

reduced viral burdens to undetectable levels in an animal model of HIV infection. In mice treated

transcriptase inhibitors, protease inhibitors and

with PRO 140, initially high HIV concentrations became undetectable for up to nine days after a

entry inhibitors. Reverse transcriptase and pro-

single dose. Additionally, multiple doses of PRO 140 reduced and then maintained viral loads at

tease inhibitors inhibit two of the viral enzymes

undetectable levels for the duration of therapy in an animal model of HIV infection. Sustaining

required for HIV to replicate once it has entered

undetectably low levels of virus in the blood is a key goal of HIV therapy.

the cell. Since the late 1990s, many HIV patients

have benefited from combination therapy of

protease and reverse transcriptase inhibitors.

While combination therapy slows the progres-

sion of disease, it is not a cure. HIV’s rapid muta-

tion rate results in the development of viral

strains that are resistant to reverse transcrip-

tase and protease inhibitors. Increasingly, after

years of combination therapy, patients begin to

develop resistance to these drugs. An additional

problem is that many currently approved drugs

produce toxic side effects in many patients.

ProVax ProVax is our vaccine product candidate for the prevention of HIV infection or as a
therapeutic treatment for HIV-positive individuals. We are currently performing government-

funded research and development of the ProVax vaccine in collaboration with the Weill Medical

College of Cornell University. ProVax contains critical viral surface proteins whose form closely

mimics the structures found on HIV. In animal testing, ProVax stimulated the production of spe-

cific anti-HIV antibodies. When tested in the laboratory, these antibodies inactivated certain

strains of HIV isolated from infected patients. The vaccine-elicited antibodies were observed to

bind to the surface of the virus, rendering it non-infectious.

Page 12

Viral-entry inhibitors represent

a potential new class of therapy
for HIV positive patients.

Prostate Cancer

What is the status of prostate
cancer in the U.S.?

PSMA immunotherapy Through PSMA Development Company LLC, our joint
venture with Cytogen Corporation, we are engaged in research and development

programs relating to vaccine and antibody immunotherapeutics based on PSMA.

The joint venture has recently completed a phase 1 clinical trial with its therapeutic

recombinant PSMA protein vaccine, which is designed to stimulate a patient’s

immune system to recognize and destroy prostate cancer cells. The vaccine combines

the PSMA cancer antigen with an immune stimulant to induce an immune response

against prostate cancer cells. This genetically engineered PSMA vaccine generated

potent immune responses that recognized human prostate cancer cells in preclinical

animal testing. The phase 1 clinical trial is designed to evaluate the tolerabilility and

immune-stimulating properties of the vaccine in patients with either newly diagnosed

Prostate cancer is the most common form

or recurrent prostate cancer. Enrollment in this clinical trial is complete, and prelimi-

of cancer affecting men in U.S. and is the

second leading cause of cancer deaths

among men each year. The American Cancer

Society estimated that 230,100 new cases

of prostate cancer would be diagnosed and

that 29,500 men would die from the dis-

ease in 2004 in the U.S. Conventional thera-

pies for prostate cancer include radical

prostatectomy, in which the prostate gland

is surgically removed, radiation and hor-

mone therapies and chemotherapy. Surgery

and radiation therapy may result in urinary

nary findings showed that certain prostate cancer patients produced anti-PSMA anti-

bodies in response to the vaccine. Additional research is required to optimize the pro-

duction, immune response and anti-tumor activity of the vaccine before this product

candidate will advance to phase 2.

The joint venture is also pursuing a vaccine program that utilizes viral vectors

designed to deliver the PSMA gene to immune system cells in order to generate

potent and specific immune responses against prostate cancer cells. In preclinical

studies, this vaccine generated a potent dual response against PSMA, yielding a

response by both antibodies and killer T-cells, the two principal mechanisms used by

the immune system to eliminate abnormal cells. The joint venture is completing pre-

clinical development activities on the PSMA viral-vector vaccine. We anticipate initiat-

ing phase 1 clinical trials in the second half of 2005.

The joint venture has also developed a fully human monoclonal antibody which

incontinence and impotence. Hormone

binds to PSMA. This antibody is designed to recognize the three-dimensional physical

therapy and chemotherapy are generally

not intended to be curative and are not

actively used to treat localized, early-stage

prostate cancer.

structure of the protein and possess a high affinity and specificity for PSMA. In an ani-

mal model of human prostate cancer, our PSMA monoclonal antibody substantially

reduced tumor growth by selectively delivering a radioisotope or toxin to human

prostate cancer cells. The joint venture expects to commence human clinical trials

with a PSMA monoclonal antibody-toxin conjugate in 2006.

What is PSMA?

PSMA, or prostate-specific membrane

antigen, is a protein that is abundantly

expressed on the surface of prostate can-

cer cells. PSMA is also found on cells in the

newly formed blood vessels of most other

solid tumors. We believe that PSMA has

applications in immunotherapeutics for

prostate cancer and potentially other

types of cancer.

Page 15

PSMA immunotherapy is designed

to target a key biological marker
found on prostate cancer cells.

Corporate Information

Stockholders’ Information

Senior Management

Board of Directors

Cancer Scientific
Advisory Board

Virology Scientific
Advisory Board

Securities and Related
Information