Sales of Zevalin History of Rituxan in addition to Zevalin Sales of Zevalin Future of Rituxan Rheumatoid arthritis
Schuler, Quinn, General Assignment Reporter has reference to this Academic Journal, PHwiki organized this Journal IDEC Pharmaceuticals Corporation (IDPH) Incorporated in 1985; currently 995 employees; located in San Diego, CA Primarily engaged in the research, development, manufacture, in addition to commercialization of targeted therapies as long as the treatment of cancer, autoimmume, in addition to inflammatory diseases. 2 commercial products: Rituxan (in partnership with Genentech) in addition to Zevalin (IDEC) Both Rituxan in addition to Zevalin are monoclonal antibodies directed against CD20 which target CD20-expressing B cells including Non-Hodgkins Lymphoma B cells 3-5 pipeline products: IDEC-114, IDEC-131, IDEC-151, IDEC-152, IDEC-160, IDEC-201 Total revenue (12 months): $441 mil R & D expenses as long as 2002: $93.6 mil Income (12 months): $159 mil = 36% profit margin Current price: ~ $ 33 Earnings per share: ~ $ 0.85 P/E: ~34 PEG: 1.3x 1.5x Outst in addition to ing shares: 155 mil Market capitalization: $ 5.0 bil PROPRIETARY TECHNOLOGIES by IDEC PRIMATIZED Antibody Technology PRIMATIZED antibodies are chimeric antibody molecules consisting of the variable antigen-binding region from a mouse antibody fused to the constant region of a primate antibody (macaque). Primatized antibodies are structurally identical to human antibodies in addition to reduce potential human-anti-mouse reactivity. IDEC was issued a US patent in 1998 as long as the development of PRIMATIZED antibodies. Macaque monkeys can also be immunized with human antigens to develop genetically engineered primatized antibodies which are produced in host cell lines. 3 product c in addition to idates currently under development utilize this technology. Proprietary Vector Technology IDEC has developed methods of engineering mammalian cell cultures using proprietary gene expression technologies or vector technologies that rapidly in addition to reproducibly select as long as stable cells to produce high levels of desired proteins. This allows as long as efficient production of proteins at yields that are competitive with current commercial cell culture manufacturing methods, in addition to has been used in the production of Rituxan. Fc Fa IgH m,d,g,e,a IgL k,l Ag Ag Fb Hybridoma Technology A hybridoma is a cell line in which an antibody-producing B cell (human) is fused to an immortalized or long-lived mouse cell to produce a hybrid cell. The hybrid cell is cloned in addition to exp in addition to ed in culture to yield continuous production of an antibody of pre-determined specificity. Fab
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Industry-wide sales projections of monoclonal antibody therapeutics Credit Suisse First Boston EXECUTIVE OFFICERS William H. Tastetter, Ph.D. Chairman, Chief Executive Officer (1986) William R. Rohn President, Chief Operating Officer (1993) Paul C. Grint, M.D. Senior Vice President, Chief Medical Officer (2001) Nabil Hanna, Ph.D. Senior Vice President, Chief Scientific Officer (1990) Wolfgang Berthold, Ph.D. Senior Vice President, Biopharmaceutical Sciences (2000) John M. Dunn Senior Vice President, Legal in addition to Compliance, General Counsel in addition to Corporate Secretary (2002) Connie L. Matsui Senior Vice President, Planning in addition to Resource Devt (1992) Edward M. Rodiriguez Vice President, Finance in addition to Controller (1991) Michael E. Wiebe, Ph.D. Vice President, Quality (2001) Mark C. Wiggins Vice President, Marketing in addition to Business Devt (1998) Cash in addition to Cash Equivalents = $1,447,865,000 Operating Expenses Revenues
RITUXAN Humanized anti-CD20 monoclonal antibody approved as long as NHL in November 1997; also being used off-label to treat CLL; first monoclonal Ab approved as long as treatment of cancer Co-marketed by Genentechsales reached $779 mil by 2001 in addition to has steadily grown as long as the past four years ($152, $262, $424, $779 mil); IDEC retains approx. 40% of total sales; Estimate $1.38 bil in total sales as long as 2003; Expect 4-8% growth each quarter; $2500 per 500 mg dose Estimated that 300,000 people in the US are afflicted with NHL (140,000 treatable with Rituxan) Efficiency: Overall response rate of 48% with 6% complete response rate with a median time of 11.6 months Achieved new approval in 2001 to exp in addition to its use in patients with relapsed or refractory, low-grade or follicular CD20+ B cell NHL, up to eight rather than four weekly infusions, in addition to use of Rituxan in the treatment of bulky disease (tumors greater than 10 cm in diameter) Approved in Japan as long as NHL co-promoted by Nippon-Roche in addition to Zenayaku Kogyo 60 percent of patients undergoing treatment with Rituxan plus cyclophosphamide, doxorubicin, vincristine, in addition to prednisone (CHOP) are still in remission after more than 4 to 7 years Data from a phase III trial in Europe (GELA) indicate that patients with aggressive NHL treated with Rituxan plus CHOP show a 23 percent improvement in survival over patients treated with CHOP alone Preclinical evidence that Rituxan may be useful as long as the treatment of autoimmune in addition to inflammatory diseases, either alone or in combination with other drugs, including immune thromocytopenic purpura (ITP), systemic lupus erythematosus (SLE), in addition to rheumatoid arthritis (RA) Sales of Zevalin Projections from S&P: $68 million in 2003, $118 million in 2004, $200 million in 2007 Sales to Date: $13.7million since April 2002 $5.7million in Q1 2003 Price per Dose = $17,000 ZEVALIN Anti-CD20 (retuximab) non-humanized antibody coupled to yttrium-90 (beta-emitter) was approved as long as NHL in February 2002. IDEC has exclusive rights to this product in the US. Outside, Schering AG has exclusive marketing rights with IDEC receiving milestone payments in addition to royalties. Provides a new treatment option as long as patients when Rituxan or chemotherapy is not sufficient; concentrates the effect of radioimmunotherapy to the site of the tumor Each treatment is complete in 8 days, but patient must make several hospital visits as long as treatment in addition to imaging, in addition to requires an integrated ef as long as t among the hospital community in addition to physicians/oncologists using Zevalin to treat NHL disease. Efficiency: 74% overall rate in addition to 15% complete response (80% with Rituxan combined versus 56% Rituxan alone n=143) CMS reimbursement rule (wage index adjustment) as long as Zevalin became effective in March 2003 has led roughly 24% of the hospitals to lose money with the Zevalin regimen. Expect no sales from these hospitals, thereby reducing the Zevalin sales estimates from $36 mil down to $27 mil. Competes with Bexxar (Corixa/Glaxo-Smith-Kline) 131I-coupled anti-CD20 mAb (beta/gamma emitter); Bexxar produced a 70% overall response rate in low-grade NHL (35% complete response lasting a median of 3+ years n=251); 40% complete response rate in patients who are resistant to Retuximab treatment
Charlotte Wolter, NHL patient, in addition to Dr. Thomas Witzig, M.D., Hematologist, on Zevalin IDEC-114 (primatized anti-CD80 or anti-B7.1) This Ab selectively targets co-stimulatory B7-1 lig in addition to on APCs. The neutralized molecule cannot bind to the CD28 in addition to CTLA-4 receptors on T cells, thus blocking the second signal as long as inflammatory T-cell activation. Two Phase II clinical trials as long as treatment of PSORIASIS (inflammation of skin affecting 1.5 Mil people in US) DISCONTINUED due to lack of efficacy XOMA humanized anti-CD11a (Raptiva/Xanelim/Efalizumab) blocks T cell binding Developed in addition to marketed by Genentech Psoriasis (BLA/MAA); Rheumatoid Arthritis, Psoriatic Arthritis (Phase II) RECENTLY HALTED CORIXA PVAC proprietary immunomodulator based on heat-killed Mycobacterium vaccae (Phase II) Phase I/II clinical trial initiated in January 2002 as long as treatment of relapsed or refractory NON-HODGKINS LYMPHOMA in addition to also in combination with Rituxan (estimated 300,000 patients in US have some as long as m of NHL, 140,000 of which are low-grade NHL or trans as long as med low-grade NHL) NEW PRODUCTS IN THE PIPELINE . NEW PRODUCTS continued . IDEC-131 (anti-CD40L or anti-CD154) CD40L is a member of the TNFR family; expressed on activated T cells; provides co-stimulatory help to CD40-expressing B cells, macrophages, in addition to dendritic cells. Ultimately reduce Ab production in addition to restore normal immune response. 1 Phase II clinical trial in PSORIASIS XOMA Raptiva CORIXA PVAC MEDAREX HuMax-CD4 (out-licensed to GENMAB) 1 Phase II clinical trial in IMMUNE THROMBOCYTOPENIC PURPURA (anti-platelet disease) 1 Phase II clinical trial in CROHNS DISEASE (Inflammatory bowel disease) JOHNSON & JOHNSON/CENTOCOR Remicade (anti-TNF; approved) XOMA Neuprex rBPI21(Phase II) 1 physician-sponsored IND in MULTIPLE SCLEROSIS (demyelinating disease affecting 2.5 mil worldwide, 350,000 in US) CORIXA Anergix.MS (MHC class II complexed with MS peptide; Phase I/II done) Clinical trials as long as IDEC-131 were suspended in 2002 due to safety concerns (thromboembolism), in addition to are expected to resume in 2003
NEW PRODUCTS continued . IDEC-151 (primatized anti-CD4) CD4 is expressed on thymocyte subsets in addition to mature T cells; Helper T cells use CD4 to bind MHC class II. IDEC-151 is thought to prevent the helper T cell from becoming activated, without seriously affecting other immune system functions. Completed a Phase II clinical trial n =32 in combination with methotrexate as long as RHEUMATOID ARTHRITIS (RA) (2 million people affected in the US in addition to 1-2 percent worldwide); results promising JOHNSON & JOHNSON/CENTOCOR Remicade (anti-TNF) CORIXA Anergix.RA (MHC class II – collagen peptide complex; completed Phase I/II) Anervax.RA (peptide vaccine; completed Phase II) MEDAREX HuMax-CD4 in addition to HuMax-IL-15 (outlicensed to GENMAB) AMGEN/WYETH Enbrel soluble TNFR (neutralizes TNF) ABBOTT rTNFR IDEC-152 (primatized anti-CD23) CD23 or FcReRII is a C-type lectin; low affinity receptor as long as IgE; expressed on mature B cells, activated macrophages, eosinophils, follicular DCs, in addition to platelets 1 Phase I/II clinical trial initiated Feb 2002 n=30 as long as ALLERGIC ASTHMA in addition to ALLERGIC RHINITIS (17 million people affected in the US); reduction in IgE levels but no observable reduction in clinical symptom scores 1 Phase I study initiated in Sep 2002 as long as CHRONIC LYMPHOCYTIC LEUKEMIA (30% of all leukemias, 7% NHLs, 8,100 new cases each year in US) NEW PRODUCTS continued . IDEC-160 (HMN-214) This is a licensed, orally-administered small molecule developed by Nippon Shinyaku of Japan 1 Phase I clinical trial initiated Sep 2002 (in US only) as long as treatment of solid tumor cancers Shinyaku has a Phase I/II trial in in addition to marketing rights Japan/Asia IDEC-201 (beta-interferon gene therapy) IDEC-201 is a beta-interferon gene therapy based on a replication-defective adenoviral vector. Licensing agreement signed in January 2003 to co-develop this drug with BIOGEN as long as treatment of GLIOMA (brain cancer affecting 36,000 people in the US); Biogen in addition to IDEC share worldwide development in addition to marketing rights on this product Phase I/II clinical trial as long as treatment of GLIOMA ongoing OTHER TECHNOLOGIES AND TREATMENTS IN THE WORKS DOMAIN-DELETED ANTIBODIES Domain-deleted antibodies have fragments of the constant region in the immunoglobulin heavy chain removed Coupled to yttrium-90, domain-deleted antibodies could potentially provide successful delivery of radioisotope to solid tumors such as prostate, ovarian, colon, in addition to lung cancers Anticipate launching a pilot study with yttrium-90 labeled domain-deleted antibodies in 2003 CANCER VACCINES / THERAPY Currently collaborating with NCI to combine the prostate specific antigen PAGE-4 with IDECs patented PROVAX adjuvant technology in therapeutic vaccines as long as human clinical trials on prostate cancer (189,000 men in US affected with prostate cancer) MEDAREX MDX-010 (Anti-CTLA4) Phase I/II as long as prostate in addition to melanoma Preclinical studies of IDEC-152 (anti-CD23) in the treatment of chronic lymphocytic leukemia (CLL). All CLL cells express CD23. Anticipate launching a Phase I/II trial with IDEC-152 on CLL this year
PATENT/LEGAL ISSUES RITUXAN in addition to ZEVALIN Lawsuits filed by GSK in May 1999 in addition to Sept 2000 regarding patent infringement of Rituxan sales in US in addition to Europesettled by Genentech in addition to GSK Lawsuits filed by GSK in addition to Corixa in Sept 2001 in US in addition to Europe regarding patent infringement of manufacture in addition to sales of Zevalinunder appeals in Europe, settled in US through a lump-sum licensing agreement ANTI-CD40L Lawsuits filed by Dartmouth in addition to Columbia as long as anti-CD40Lresolved Lawsuits filed by IDEC against Immunex as long as anti-CD40L patent infringement IMMUNOTHERAPY INDUSTRY: COMPARABLE COMPANIES POTENTIAL RISKS OF INVESTMENT Slowing Rituxan sales growth: 95% of IDECs sales are dependent on Rituxan Zevalins failure to gain NHL market share in addition to failure to obtain approval in Europe Competition if Corixa/GSKs Bexxar is approved Adverse ruling in patent litigation regarding Zevalin in addition to Rituxan Competitive drug pricing Reliance on third-party vendors in addition to contract manufacturers (e.g. Yttrium-90) Limited sales in addition to marketing experience Uncertainties in new drug approvals in addition to clinical trials Healthcare reimbursement in addition to re as long as m (e.g. CMS categorized Zevalin as a procedure rather than a drug) Product liability
RHEUMATOID ARTHRITIS Rheumatoid Arthritis (RA) is a chronic, systemic, inflammatory disease that chiefly affects the synovial membranes of multiple joints in the body. RA is considered an autoimmune disease that is acquired in addition to in which genetic factors appear to play a role. The presence of HLA-DR4 antibody in 70 percent of patients with RA lends support to the genetic predisposition to the disease. Rheumatoid Factor(s) (RF) are antibodies to IgG, in addition to are present in 60-80 percent of adults with the disease. High titers of RF are usually associated with more severe in addition to active joint disease, greater systemic involvement, in addition to a poorer prognosis as long as remission. RA, as well as other autoimmune diseases, includes widespread immunologic in addition to inflammatory alterations of connective tissue. The prevalence of the disease is 1-2 percent of the general population world-wide with 2 million people affected in the US. Females with RA outnumber males by a 3:1 margin. Onset of the disease in adults is usually between the ages of 40 to 60 years, although it can occur at any age. The etiology of RA is unknown. Viral or bacterial infections are suspected. Indolent NHL Follicular lymphoma comprises 20% of all non-Hodgkin’s lymphomas in addition to up to 70% of the indolent lymphomas. Most patients with follicular lymphoma are over age 50. Nodal involvement is most common, often accompanied by splenic in addition to bone marrow disease. The median survival ranges from 8 to 12 yrs, thus designated “indolent.” The vast majority of patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. Rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment. Therapeutic options include purine nucleoside analogs, oral alkylating agents, combination chemotherapy, interferon, in addition to monoclonal antibodies. Radiolabeled monoclonal antibodies, vaccines, in addition to autologous or allogeneic bone marrow or peripheral stem cell transplantation are under clinical evaluation. Rearrangement of the bcl-2 gene is present in over 90% of patients with follicular lymphoma; over-expression of the bcl-2 protein is associated with the inability to eradicate the lymphoma by inhibiting apoptosis. Aggressive NHL Diffuse large B-cell lymphoma is the most common of the non-Hodgkin’s lymphomas, comprising 30% of newly-diagnosed cases. Most patients present with rapidly enlarging masses, often with symptoms both locally in addition to systemically. The vast majority of patients with localized disease are curable with combined modality therapy. For patients with advanced stage disease, 40% of presenting patients are cured with doxorubicin-based combination chemotherapy. An international index as long as aggressive NHL (diffuse large cell lymphoma) identifies 5 significant risk factors prognostic of overall survival: age (<60 years of age), serum lactate dehydrogenase, stage (I or II versus III or IV), in addition to extranodal site involvement (0 or 1 versus 2-4). Patients with 2 or more risk factors have less than a 50% chance of relapse-free in addition to overall survival at 5 years. This study also identifies patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system (CNS), liver, lung, in addition to spleen. A retrospective analysis of 605 patients with diffuse large cell lymphoma who did not receive Some cases of large B-cell lymphoma have a prominent background of reactive T cells in addition to often of histiocytes, so-called T-cell/histocyte-rich large B-cell lymphoma. This subtype of large cell lymphoma has a very aggressive clinical course with frequent liver, spleen, in addition to bone marrow involvement. Non-Hodgkins Lymphoma Classifications Low-grade A Small lymphocytic, CLL (SL) B Follicular, small cleaved cell (FSC) C Follicular, mixed small cleaved in addition to large cell (FM) Intermediate-grade D Follicular, large cell (FL) E Diffuse, small cleaved cell (DSC) F Diffuse mixed, small in addition to large cell (SM) G Diffuse, large cell cleaved or noncleaved (DM) High-grade H Immunoblastic, large cell (IBL) I Lymphoblastic, convoluted or non-convoluted (LL) J Small noncleaved cell, Burkitts or non-Burkitts (SNC) History of Rituxan in addition to Zevalin Rituxan (Rituximab): a primatized MCA directed against CD20 approved as long as use in refractory low-grade or follicular, CD20+, B-cell non-Hodgkins lymphoma in 1997-44,000 cases/year first monoclonal antibody approved as long as cancer therapy largest selling oncology product in the world- in addition to it may grow as variations as long as its use are studied in addition to adopted (e.g., it is being used in addition to tested as a Maintenance therapy) good preliminary data supports its use in rheumatoid arthritis in addition to systemic lupus in addition to phase 3 trials are in progress Zevalin (Ibritumomab tiuxetan): the same MCA conjugated to chelating agent that binds either a beta or gamma emitter ( as long as therapy or imaging) approved as long as treatment of relapsed or refractory low grade (to chemo in addition to Rituxan), follicular, or trans as long as med B-cell non-Hodgkin's lymphoma (NHL) in February 2002 first radioimmunotherpay approved as long as cancer therapy Sales of Rituxan Two-tier copromotion arrangement with Genentech + royalties from non-US sales (from Roche) Sales of Zevalin IDEC holds 100% marketing rights within the US in addition to signed an agreement with Schering AG as long as outside US which pays milestones in addition to royalties IDEC only recently started getting reimbursed so revenues are just beginning to be seen 2002 since April (13.7 million), 2003 Q1(5.7 million)
Future of Rituxan Rituxan sales decreased during the past quarter – is the market saturated or does this reflect the price increase Many clinical trials exploring Rituxan as treatment in other diseases – would IDEC retain marketing rights as long as this label Competition Projections – S&P $1.29billion in 2003; $1.44billion in 2004 But this ignores use as long as other indications Rheumatoid arthritis a chronic condition 1 percent of the population (2/3 women) overactive immune system attacks joints in addition to causes crippling pain Current therapy are: anti-T cells or anti inflammatory drugs Rituxan is the only B cells directed therapy, but there is a controversy about the importance of B cells in the disease Only minor side effects in preliminary studies in addition to it is already in addition to FDA approved Drug So Efficacy in addition to Safety of Rituximab,a B-Cell Targeted Chimeric Monoclonal Antibody: A R in addition to omized, Placebo-Controlled Trial in Patients with Rheumatoid Arthritis (Edwards et al: Arthritis Rheum. 2002 Sep;46(9):S197. Abstract 446.
Other Autoimmune Diseases effectiveness in one patient with refractory type II essential mixed cryoglobulinemia (MC) in addition to one with refractory Goodpasture’s syndrome Treatment of Systemic Lupus (SLE) is promising complete remission in a patient with refractory Wegener’s granulomatosis dramatic in addition to sustained improvement” in five patients with refractory adult or pediatric dermatomyositis Future of Zevalin Direct Competition: Feb 23, 2003 infringement suit filed against Corixa in addition to GSK as long as Bexxar, a CD20 specific radio-ligated antibody Projections: $68 million in 2003, $118 million in 2004, $200 million in 2007 Additional studies may create new uses (other disorders or primary treatment) Existing products: Conclusions Use of existing products as long as slight variations in the cancer area should continue to increase sales as long as several years Sales are already being driven by some off label use Preliminary data suggests approval as long as RA in addition to related uses will occur This could double (optimistically) the top line as long as existing products, lowering P/E to below 20 or increasing the price of the stock
IDEC Patents Combination therapies as long as B-cell lymphomas comprising administration of anti-CD20 antibody Granted US in addition to European patent protection PRIMATIZED Antibody Technology Chimeric antibody molecules consisting of the variable antigen-binding region from mouse antibodies fused to the constant region of primate antibodies (macaque). Primatized antibodies are structurally identical to human antibodies in addition to reduce potential human-anti-mouse reactivity. Granted worldwide patent protection: covers antibody technology as well as specific antigen targets of PRIMATIZED antibodies Method as long as integrating genes at specific sites in mammalian cells via homologous recombination in addition to vectors as long as accomplishing the same Methods of engineering mammalian cell cultures using proprietary gene expression technologies or vector technologies that rapidly in addition to reproducibly select as long as stable cells to produce high levels of desired proteins. This allows as long as efficient production of proteins at yields that are competitive with current commercial cell culture manufacturing methods, in addition to has been used in the production of Rituxan. IDEC literature Zevalin in addition to Rituxan: Clinical Trials Additional Radiation Absorbed Dose Estimates as long as Zevalin trade mark Radioimmunotherapy. Cancer Biother Radiopharm. 2003 Apr;18(2):253-8. Wiseman GA, Leigh BR, Dunn WL, Stabin MG, White CA. Mayo Clinic, Rochester, MN. Radiation Dosimetry Results From a Phase II Trial of Ibritumomab Tiuxetan (Zevalin trade mark ) Radioimmunotherapy as long as Patients With Non-Hodgkin’s Lymphoma in addition to Mild Thrombocytopenia. Cancer Biother Radiopharm. 2003 Apr;18(2):165-78. Wiseman GA, Leigh BR, Erwin WD, Sparks RB, Podoloff DA, Schilder RJ, Bartlett NL, Spies SM, Grillo-Lopez AJ, Witzig TE, White CA. Mayo Clinic, Rochester, MN. Other: Notch-regulated ankyrin-repeat protein inhibits notch1 signaling: multiple notch1 signaling pathways involved in T cell development. J Immunol. 2003 Jun 15;170(12):5834-41. Yun TJ, Bevan MJ. IDEC Pharmaceuticals, San Diego, CA 92121. Department of Immunology in addition to Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195. CD154 Regulates Primate Humoral Immunity to Influenza. Am J Transplant. 2003 Jun;3(6):680-688. Crowe JE, Sannella EC, Pfeiffer S, Zorn GL, Azimzadeh A, Newman R, Miller GG, Pierson RN. Departments of Pediatrics, Microbiology in addition to Immunology, Cardiothoracic Surgery, in addition to Medicine, V in addition to erbilt University Medical Center, Nashville, TN, USA IDEC Pharmaceuticals, San Diego, CA, USA Nashville Veterans Affairs Medical Center, Nashville, TN, 37232, USA.
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