Progenics Pharmaceuticals
Annual Report 2004

Plain-text annual report

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 % 70 50 30 10 –––– 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 7 6 5 4 3 2 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 Company Information Annual Meeting of Stockholders Independent Accountants Paul J. Maddon, M.D., Ph.D. Founder, Chief Executive Officer and Chief Science Officer Robert A. McKinney, C.P.A. Chief Financial Officer Vice President, Finance and Operations and Treasurer Robert J. Israel, M.D. Senior Vice President, Medical Affairs Lynn M. Bodarky, M.B.A. Vice President, Business Development and Licensing Thomas A. Boyd, Ph.D. Vice President, Preclinical Development and Project Management Richard W. Krawiec, Ph.D. Vice President, Investor Relations and Corporate Communications Alton B. Kremer, M.D., Ph.D. Vice President, Clinical Research William C. Olson, Ph.D. Vice President, Research and Development Nitya G. Ray, Ph.D. Vice President, Manufacturing Kurt W. Briner Co-Chairman President and Chief Executive Officer (retired) Sanofi Pharma, SA Alan N. Houghton, M.D. (Chairman) Chairman, Immunology Program, Sloan-Kettering and Professor, Weill/Cornell Medical College Paul F. Jacobson Co-Chairman Private Investor Paul J. Maddon, M.D., Ph.D. Founder, Chief Executive Officer and Chief Science Officer Charles A. Baker Chairman, President and Chief Executive Officer (Retired) The Liposome Company, Inc. Mark F. Dalton President Tudor Investment Corporation Stephen P. Goff, Ph.D. Higgins Professor of Biochemistry, Department of Biochemistry and Molecular Biophysics, and Investigator, Howard Hughes Medical Institute, Columbia University David A. Scheinberg, M.D., Ph.D. Vincent Astor Chair and Chairman, Molecular Pharmacology and Chemistry Program, Sloan-Kettering and Professor, Weill/Cornell Medical College David B. Agus, M.D. Research Director, Prostate Cancer Institute, Cedars-Sinai Medical Center Angus G. Dagleish, M.D., Ph.D. Chairman and Professor of Medical Oncology, St. George’s Hospital, London Samuel J. Danishefsky, Ph.D. Kettering Professor and Head, Bioorganic Chemistry, Sloan-Kettering Institute and Professor of Chemistry, Columbia University Warren D.W. Heston, Ph.D. Director, Research Program in Prostate Cancer; Staff. Dept. of Cancer Biology, Lerner Research Institute; Staff, Urological Institute, Cleveland Clinic Hospital, Cleveland Clinic Foundation Philip O. Livingston, M.D. Member, Sloan-Kettering and Professor, Weill/Cornell Medical College John Mendelsohn, M.D. President,The University of Texas M. D. Anderson Cancer Center David A. Scheinberg, M.D., Ph.D. Vincent Astor Chair and Chairman, Molecular Pharmacology and Chemistry Program, Sloan-Kettering and Professor, Weill/Cornell Medical College Stephen P. Goff, Ph.D. (Chairman) Higgins Professor of Biochemistry, Department of Biochemistry and Molecular Biophysics, and Investigator, Howard Hughes Medical Institute, Columbia University Dennis R. Burton, Ph.D. Professor of Immunology, The Scripps Research Institute Lawrence A. Chasin, Ph.D. Professor of Biological Sciences, Columbia University Leonard Chess, M.D. Professor of Medicine, Columbia University Wayne A. Hendrickson, Ph.D. Professor of Biochemistry, Columbia University Sherie L. Morrison, Ph.D. Professor of Microbiology, University of California, Los Angeles Robin A. Weiss, Ph.D. Professor of Viral Oncology, Department of Immunology and Molecular Pathology, University College, London Other Scientific Consultants Scott M. Hammer, M.D. Chief, Division of Infectious Diseases, Professor of Medicine, Columbia University Jonathan Moss, M.D., Ph.D. Professor, Department of Anesthesia and Critical Care, and Vice Chairman for Research, University of Chicago Medical Center Page 16 For general and financial information about the Company, please contact: The annual meeting will be held at 10:00 am on Tuesday, May 10, 2005. Progenics Pharmaceuticals, Inc. 777 Old Saw Mill River Road Tarrytown, New York 10591 Phone: 914.789.2800 Fax: 914.789.2817 E-mail: info@progenics.com Website: www.progenics.com Landmark at Eastview Westchester Room 777 Old Saw Mill River Road, Tarrytown, New York, 10591. A formal notice of the meeting with a proxy statement will be mailed to each stockholder. PricewaterhouseCoopers LLP 300 Madison Avenue New York, New York 10017 Legal Counsel Dewey Ballantine LLP 1301 Avenue of the Americas New York, New York 10019 Transfer Agent American Stock Transfer and Trust Company 40 Wall Street New York, New York 10005 The Company’s Common Stock is traded on The Nasdaq National Market under the symbol PGNX. As of March 30, 2005 the Company had approximately 140 stockholders of record. The following table sets forth the reported high and low sales prices for the Company’s Common Stock as reported by Nasdaq for the periods indicated: 2004 First Quarter Second Quarter Third Quarter Fourth Quarter High Low 23.45 20.79 16.92 18.08 17.60 14.85 8.50 12.25 2005 First Quarter 24.40 14.09 Disclaimer:The photographs of individuals in this annual report, who are not identified by name, are not those of actual patients, but those of unrelated third parties. Design: Bloch Graulich Whelan Inc / NY 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 

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