Overview
Rigel Pharmaceuticals, Inc. was incorporated in Delaware in June 1996, and is based in South San Francisco. Rigel is a clinical-stage drug development company that discovers and develops novel, small molecule drugs for the treatment of inflammatory diseases, cancer and viral diseases. Our goal is to file one new investigative new drug (IND) application in a significant indication each year. We have achieved this goal each year beginning in 2002. Our pioneering research focuses on intracellular signaling pathways and related targets that are critical to disease mechanisms. Rigel’s productivity has resulted in strategic collaborations with large pharmaceutical partners to develop and market our product candidates. We have product development programs in inflammatory/autoimmune diseases such as rheumatoid arthritis, thrombocytopenia, asthma and allergy as well as in cancer .
During 2006 and the start of 2007, we:
· Initiated a Phase 2 clinical trial in rheumatoid arthritis, or RA, with R788 (Third Quarter 2006);
· Initiated a Phase 2 clinical trial in Immune Thrombocytopenia Purpura, or ITP, with R788 (2007);
· Filed an Investigational New Drug Application to test R788 as a treatment for patients with Lymphoma (Fourth Quarter 2006);
· Selected R348, an orally-available selective inhibitor of Janus Kinase 3 (JAK3) to enter preclinical studies (Fourth Quarter 2006)
· Announced that Merck Serono, S.A., or Merck Serono, initiated two Phase 1 studies with R763, the first for the treatment of patients with refractory solid tumors (Third Quarter 2006) and the second for the treatment of patients with hematologic tumors (2007); and
· Announced Pfizer’s selection of R343 for advanced preclinical development in allergic asthma triggering a $5.0 million milestone payment to us (Second Quarter of 2006).
Strategy
Rigel’s research team is focused on creating a portfolio of product candidates that can be developed into small molecule therapeutics for our own proprietary programs as well as with potential collaborative partners. We recognize that the product development process is subject to both high costs and a high risk of failure. We believe that identifying a variety of product candidates and working in conjunction with other pharmaceutical companies may minimize the risk of failure, fill the product pipeline gap at major pharmaceutical companies and ultimately, may increase the likelihood of advancing clinical development and commercial success.
The key elements to our scientific and business strategy are to:
· utilize our robust discovery engine to rapidly discover and validate new product candidates in a broad range of therapeutic indications;
· develop a diverse portfolio of drug candidates that address a large range of therapeutic indications or that represent significant market opportunities;
· advance at least one new product candidate into the clinic each year; and
· establish strategic collaborations with pharmaceutical and biotechnology companies, preferably after Phase 2 trials, to develop and market our product candidates.
Clinical and Preclinical Product Development Programs
Rigel’s product development portfolio features multiple novel small molecule drug candidates whose specialized mechanisms of action are intended to provide therapeutic benefit for a range of immune/autoimmune disease areas as well as cancers and infection diseases.
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Product Pipeline |
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Current Stage |
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Outlook |
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R788 - |
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Oral SYK Inhibitor |
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RA |
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Phase 2 |
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Top-line data in 2H 2007 |
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ITP |
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Phase 2 |
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Top-line data in middle 2007 |
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B-Cell Lymphoma |
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IND filed, Phase 1 |
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Expect to initiate a clinical trial in 1H 2007 |
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R763 - |
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Oral Aurora Kinase Inhibitor |
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Solid Tumors |
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Phase 1 - Merck Serono |
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Hematological malignancies |
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Phase 1 - Merck Serono |
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R343 - |
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Inhaled SYK Inhibitor |
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Asthma |
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Preclinical - Pfizer |
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Phase 1 in 2007 |
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R348 - |
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Oral JAK3 Inhibitor |
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RA/Psoriasis |
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Preclinical |
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Transplant rejection |
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Preclinical |
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Key: “Phase 1” refers to clinical testing in humans to determine safety; “Phase 2” refers to clinical testing in humans to determine efficacy.
Clinical Stage Programs
Rheumatoid Arthritis
Disease background. Rheumatoid arthritis, or RA, is a chronic inflammatory disease that affects multiple tissues, but typically produces its most pronounced symptoms in the joints. RA is often progressive and debilitating, preventing people from living a symptom-free life. Ultimately the chronic inflammation of the joints affects nearly 2.1 million people in the United States.
The current treatment options for RA have significant potential side effects and other shortfalls, including gastrointestinal complications and kidney damage. RA patients receive multiple drugs depending on the extent and aggressiveness of the disease. Most RA patients eventually require some form of disease modifying anti-rheumatic drug or DMARD. DMARDs include methotrexate, an anti-cancer agent, and/or a variety of immunomodulatory agents (TNF inhibitors, co-stimulation inhibitors), of which, the latter must be delivered via injection.
Orally-available Syk Inhibitor Program. We intend to focus our RA program on the development of a safe oral DMARD that can be used early in the course of the disease, preventing its progression prior to major bone and cartilage destruction.
R788 is our lead product candidate. It has a novel mechanism of action blocking IgG receptor signaling in macrophages and B-cells. We completed R788 studies to evaluate its safety and pharmacokinetics in combination with methotrexate, a commonly prescribed treatment for RA. Results of this trial suggest no adverse interaction. In September 2006, we commenced a Phase 2, multicenter, ascending dose, randomized, double-blind, placebo-controlled, dose ranging study to evaluate up to three doses of R788 in RA patients failing to respond to methotrexate. We expect to receive results from the study in the second half of 2007.
Orally-available JAK3 inhibitor Program. Another approach to the treatment of RA may be through the inhibition of JAK3, a cytoplasmic tyrosine kinase which plays an important role in lymphocyte differentiation and proliferation in a variety of autoimmune diseases. Rigel is conducting a preclinical development program with R348, an oral, selective JAK3 inhibitor which is aimed at evaluating the drug candidates’ potential in RA and other diseases (see Preclinical Research Programs section on page 5).
Immune Thrombocytopenia Purpura
Disease background. Immune thrombocytopenia purpura, also referred to as thrombocytopenia or ITP, is a blood disorder whereby the immune system attacks and destroys platelets in the blood resulting in an abnormally low platelet count, which can result in easy bruising, bleeding gums, and internal bleeding. Approximately 200,000 people in the U.S. suffer from ITP. The majority of cases are in women, with 50% of the new cases being found in children.
First line medical therapy for ITP consists primarily of steroids, which help prevent bleeding by decreasing the rate of platelet destruction. The current treatment options for chronic ITP have potentially significant side effects and lack long-term effectiveness. When steroid therapy fails, the patient’s spleen may need to be removed (splenectomy), which poses the risk of other significant complications. There is no consensus on the appropriate management for chronic ITP, but due to the fact that sustained remission is infrequent—new therapies are needed. Rigel is focusing its ITP program on the chronic form of the disorder, targeting the underlying autoimmune cause of the disease.
Orally-available Syk Inhibitor Program. Platelet destruction from ITP is mediated by IgG signaling. R788 is a potent inhibitor of IgG signaling. In preclinical studies, R788 was shown to improve thrombocytopenia in an ITP mouse model. We commenced Phase 2 clinical trials of R788 to evaluate its safety and efficacy in refractory ITP patients in the January 2007 and expect to receive results from the study in the middle of 2007.
B-Cell Lymphoma
Disease background. Lymphoma is a large class of blood cancers that affect the lymphatic system, which is part of the immune system. In 2006, lymphoma affected an estimated 500,000 Americans, with 332,000 of them suffering from non-Hodgkins varieties of the disease. Diffuse large B-cell lymphoma is the most common type of non-Hodgkin’s lymphoma and is generally categorized as aggressive, marked by rapidly growing tumors in the lymph nodes, spleen, liver, bone marrow and other organs.
A variety of treatment options exist, including chemotherapy and radiation, but the five year survival rates for non-Hodgkins lymphoma patients are only about 50%. For those who do survive, recurrences of the disease are common, warranting additional and novel approaches to treatment of the lymphoma as well.
Orally-available Syk Inhibitor Program. Research has shown that Syk kinase appears to amplify B-cell antigen receptor signaling, a mechanism which causes proliferation of B-cell lymphoma cell lines. Inhibition of Syk kinase, via Rigel’s R788, resulted in the inhibited proliferation of and was shown to be cytotoxic in multiple diffuse large B-cell lymphoma cell lines, suggesting that R788 may be useful in the treatment of certain B-cell lymphomas.
Rigel has filed an IND for this indication and expects to begin a clinical trial in the first half of 2007.
Lupus
Disease background. Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease that can affect multiple parts of the body, including the skin, joints, lungs, blood vessels, hearts, kidneys, liver, brain and the nervous system. An autoimmune disease, Lupus occurs when the body’s immune system loses its ability to distinguish between foreign substances (antigens) and its own cells and tissues. The patient’s immune system produces auto-antibodies which target the body’s cells and form immune complexes. As these immune complexes build up in the tissues, inflammation, pain and other disease symptoms “flare” up. The disease leads to inflammation-mediated end organ damage and may, in severe cases, be life-threatening.
More than 16,000 Americans develop lupus each year and estimates are that nearly 1.5 million Americans have been diagnosed with Lupus. Current treatments involve a range of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids to stem inflammation as needed.
Orally-available Syk Inhibitor Program. R788 has been shown to block immune complex mediated inflammation in preclinical studies and may also provide protection against organ failure in patients with the disease. Rigel is evaluating the feasibility of entering R788 in clinical tests in patients with SLE in the future.
Oncology
Disease background. Cancer is the second leading cause of death in the United States. More than one million Americans are diagnosed with cancer each year, and nearly half of all men and over one-third of all women in the United States will develop cancer during their lifetimes. Anyone can get cancer at any age, however, approximately 77% of all cancers are diagnosed in people age 55 and older. Although cancer occurs in all racial and ethnic groups, the rate of incidence varies from group to group.
Aurora Kinase Inhibitor Program. Aurora kinase plays a central role in the cell division process and the overexpression of Aurora kinase can cause cells to quickly form an abnormal number of chromosomes. As such, Aurora kinase is frequently associated with various solid tumor human cancers such as cancers of the breast, bladder, colon, ovary, head and neck, and pancreas. Increased knowledge of Aurora kinase and its potential to regulate cell growth may be the basis for treating and even preventing some cancers.
Rigel has identified R763 as a lead compound in our Aurora kinase inhibition program, targeting cancer cell proliferation. R763 is a potent, highly-selective, small-molecule inhibitor of Aurora kinase. In October 2005, we signed a licensing agreement with Merck Serono, that gave Merck Serono the exclusive rights to develop and commercialize R763, in addition to other product candidates arising from our Aurora kinase inhibitor program. Under the agreement, we were responsible for filing an IND for R763, while Merck Serono will be responsible for the further development and commercialization of R763. We filed an IND for R763 with the Food and Drug Administration, or FDA, in December 2005 and obtained FDA approval to proceed under the IND in January 2006. Merck Serono initiated clinical trials for R763 in solid tumors in September 2006 and leukemia is 2007.
Asthma
Disease background. Allergic asthma is a chronic inflammatory disorders of the airways. Asthma affects the lower respiratory tract and is marked by episodic flare-ups, or attacks, that can be life threatening. In some patients, allergens, such as pollen, trigger the production of immunoglobulin E antibodies, or IgE antibodies, which then bind to mast cells and cause an intracellular signal that results in the release of various chemical mediators. When this process occurs repeatedly over time, it creates persistent inflammation of the airway passages, resulting in the chronic congestion and airway obstruction associated with allergic rhinitis and asthma, respectively.
Inhaled Syk Inhibitor Program. In the first quarter of 2005, we announced a collaborative research and license agreement with Pfizer, Inc. for the development of inhaled products for the treatment of allergic asthma and other respiratory diseases, such as chronic obstructive pulmonary disease (COPD). The collaboration is focused on our preclinical small molecule compounds, which inhibit IgE receptor signaling in respiratory tract mast cells by blocking the signaling enzyme Syk, or spleen tyrosine kinase, a novel drug target for respiratory diseases. Mast cells play important roles in both early and late phase allergic reactions, and Syk inhibitors could prevent both phases.
In May 2006, Rigel announced that Pfizer had selected R343 for advanced preclinical development in allergic asthma via intrapulmonary delivery. As a result, Rigel received a $5 million milestone payment from Pfizer. We expect Pfizer will enter the clinic with R343 by the end of 2007.
Preclinical Research Programs
Rigel is conducting proprietary research in three broad disease areas: immunology/inflammation, virology and oncology. With each disease area, we are investigating mechanisms of action of pathogens as well as screening compounds against potential novel intracellular targets and optimizing those leads that appear to have the greatest potential.
Immunology/Inflammation. Currently, we are researching autoimmune mediated inflammation disorders such as RA, transplant rejection, Graft vs. Host Disease (GVHD), psoriasis, multiple sclerosis and inflammation of the bowel. We have identified more than one kinase that may be inhibited in order to treat inflammation related disorders, and we are in the process of screening other compounds against various kinases in order to find additional lead compounds to potentially treat inflammation-related disorders.
Rigel’s JAK3 Program is focused on RA, organ transplant and other immune disorders. JAK3 is an attractive target based on its selectivity. It plays a critical role in lymphocyte development and function. In October 2006, Rigel selected R348, an orally-available potent, selective JAK3 inhibitor to enter preclinical studies. During 2007, we hope to move it into the clinic in one or more of the indications noted above.
Virology. In the area of virology, Rigel is investigating various targets to inhibit the replication of hepatitis C virus (HCV) and Human Immune Deficiency Virus (HIV). Recent Rigel data elucidates the signaling pathway of HIV replication and suggests the potential for an entirely new class of antiretroviral therapies. Rigel will continue to explore innovative and selective means of arresting these and other viral pathogens and expects to advance this area of preclinical research in 2007.
Oncology. In addition to our programs focused on inhibiting kinases, as with the clinical candidate R763 which is under development by our partner, Merck Serono, Rigel is exploring ligases, a class of enzymes that also may yield possible drug targets in immunology and virology. Aside from R763, our oncology research programs are focused in two areas: ubiquitin ligases and inhibition of the tyrosine kinase receptor known as Axl.
Ubiquitin ligase program. Ubiquitin ligases are enzymes that regulate protein degradation within the cell. The breakdown of proteins, in turn, affects many important cellular functions, including cell division. Targeting ligases represents a novel approach to treating diseases where normal cellular processes are out of balance. Because unchecked cell division is the hallmark of cancer, researchers believe that this part of the cell machinery represents a particularly compelling target for cancer therapies. Ubiquitin ligase targets are numerous and modular. This provides the potential for intervening in a highly specific fashion with respect to a disease, potentially improving efficacy and minimizing side-effects.
We believe we are a leader in investigating and characterizing the ubiquitin ligase system for the discovery and development of potential new therapeutics in the oncology as well as immunology and virology areas. We have initiated one of the industry’s broadest efforts with respect to ubiquitin ligases, working on the development of numerous ligase targets, and were one of the first companies to discover potent and highly selective small molecule inhibitors of ubiquitin ligases. Some of these inhibitors have shown positive activity in animal models of disease.
In November 2004, we entered into a broad collaboration agreement with Merck and Co., Inc., or Merck, to investigate ubiquitin ligases to find treatments for cancer and potentially other diseases. The collaboration is based on a number of new targets designated by Merck. However, we may nominate our own targets for potential inclusion in the collaboration. We also have an ongoing program with Daiichi to pursue compounds against a specific ubiquitin ligase target.
Axl Inhibition. Our scientists identified and characterized a role for the receptor tyrosine kinase Axl in angiogenesis and tumor growth. These findings were published in Cancer Research, the journal of the American Association for Cancer Research in October 2005. We found that Axl signaling controls diverse processes in endothelial cells, including growth, survival, migration, and morphologic differentiation—mechanisms that are central to tumor growth and formation. As part of an effort to develop novel therapeutic strategies for cancer treatment, we developed a unique genetic screening protocol to discover genes that regulate cell migration in primary human endothelial cells. Our findings indicate that Axl regulates processes vital for both neovascularization and tumorigenesis. Axl inhibition could potentially target tumor growth and angiogenesis.
Corporate Collaborations
Rigel currently has collaborations with six major pharmaceutical/biotech companies to leverage our product development efforts. These collaborations are: one with Janssen Pharmaceutica N.V., a division of Johnson & Johnson, relating to oncology therapeutics and diagnostics, two with Pfizer Inc.; one initiated
in 1999 and the other in January 2005, relating to intrapulmonary asthma and allergy therapeutics; one with Novartis Pharma AG with four different programs relating to immunology, oncology and chronic bronchitis; one with Daiichi Pharmaceuticals Co., Ltd. in the area of oncology; one with Merck, also in the area of oncology, and one with Merck Serono, relating to our Aurora kinase inhibitor program.
Merck Serono
In October 2005, we entered into a collaborative research and license agreement with Merck Serono under which we granted to Merck Serono an exclusive license to develop and commercialize product candidates from our Aurora kinase inhibitor program. Our Aurora kinase inhibitor program includes R763 which is a highly potent, orally-available multi-Aurora kinase inhibitor that has been shown in vitro and in in-vivo tumor xenograft models to inhibit proliferation and trigger apoptosis in several tumor cell lines including the cancer of the cervix, colon, lung, pancreas and prostate.
We were responsible for all costs associated with the preparation and filing of an IND for R763, while Merck Serono is responsible for all development of R763 following regulatory acceptance of the IND and costs thereafter. In February 2006, we received a milestone payment of $5 million upon the regulatory acceptance of the R763 IND in January 2006. In September 2006, we received a $3.0 million payment from Merck Serono in connection with the initiation of the Phase 1 study of R763. In February 2007, we announced that Merck Serono has also initiated a Phase 1 study in hematologic tumors. We will be eligible to receive additional milestones, under certain conditions, upon commencement of a Phase 2 clinical trial of R763, other clinical events and marketing approval and royalties on any future product sales.
Pfizer
Effective January 1999, we entered into a research collaboration with Pfizer to identify and validate intracellular drug targets that control and inhibit the production of IgE in B-cells in the area of asthma/allergy. The research phase of the collaboration was initially scheduled to end in January 2001, but Pfizer elected to exercise its option to extend the collaboration to January 2002. During the research phase, the collaboration was successful in identifying several intracellular drug targets that control the production of IgE, a key mediator in allergic reactions and asthma in B-cells. Through the conclusion of the research phase
